Franco M Muggia, M.D.

CA-125 surveillance for women with ovarian, fallopian tube or primary peritoneal cancers: What do survivors think?
Boyd, L.; Bedell, S.; Curtin, J.; Wallach, R.; Pothuri, B.; Muggia, F.; Tiersten, A.; Blank, S.
2011 MAR ;121(1):S64-S64, Gynecologic oncology
— id: 132764, year: 2011, vol: 121, page: S64, stat: Journal Article,

Postoperative Intraperitoneal 5-Fluoro-2'-Deoxyuridine Added to Chemoradiation in Patients Curatively Resected (R0) for Locally Advanced Gastric and Gastroesophageal Junction Adenocarcinoma
Cohen DJ; Newman E; Iqbal S; Chang RY; Potmesil M; Ryan T; Donahue B; Chandra A; Liu M; Utate M; Hiotis S; Pachter LH; Hochster H; Muggia F
2011 Feb;19(2):478-485, Annals of surgical oncology
PURPOSE: Chemoradiation after surgery for locally advanced gastric cancer improves overall and relapse-free survival compared with observation. However, locoregional recurrences remain high. Accordingly, we instituted this pilot/feasibility study, including intraperitoneal 5-fluoro-2'-deoxyuridine (IP FUDR) as part of the treatment. METHODS: Gastric/gastroesophageal junction adenocarcinoma stage Ib-IV (M0) patients who underwent R(0) resection were eligible and had IP catheters inserted at time of surgery. IP FUDR (3 g/dose/day) was given during study days 1-3 and 15-17 before combined 5-fluorouracil, leucovorin, and external beam radiation (45 Gy). Endpoints included toxicity, completion rate, locoregional recurrence, and survival. RESULTS: Twenty-eight patients (22 men) were enrolled from 2002-2006 at two institutions; their median age was 59.5 years. After R(0) resection, a median 22 (range, 8-102) lymph nodes were examined, and 22 patients had positive nodes. AJCC stages were IB (n = 8), II (n = 10), IIIA (n = 5), IIIB (n = 1), and IV (n = 4). Full-dose IP FUDR and chemoradiation treatment was completed in 20 and 25 patients, respectively. At nearly 4-year median follow-up, 11 patients were disease-free, 5 were alive with disease, 7 were dead of disease, and 1 was dead from other cause; 4 have been lost to follow-up. Recurrences were local in one, intra-abdominal in six, distant in two, multiple sites in two, and unknown in one. The median relapse-free survival is 65.3 months, and the median overall survival has not yet been reached. CONCLUSIONS: IP FUDR before chemoradiation after R(0) gastric cancer resection is well tolerated without compromising completion of postoperative adjuvant treatment. Larger randomized trials studying IP FUDR as part of gastric cancer multidisciplinary treatment are needed to prove efficacy in reducing regional recurrence and improving survival
— id: 135531, year: 2011, vol: 19, page: 478, stat: Journal Article,

Pegylated liposomal doxorubicin with bevacizumab in the treatment of platinum-resistant ovarian cancer: Toxicity profile results
Czok, S.; Jewell, A.; Shawki, S.; Boyd, L.; Smith, H.; Blank, S.; Muller, C.; Verschraegen, C.; Muggia, F.
2011 MAR ;121(1):S83-S83, Gynecologic oncology
— id: 132765, year: 2011, vol: 121, page: S83, stat: Journal Article,

Intraperitoneal Drug Delivery for Ovarian Cancer: Why, How, Who, What, and When?
Echarri Gonzalez, Maria Jose; Green, Robin; Muggia, Franco M.
2011 FEB ;25(2):156-170, Oncology
In 1996, intraperitoneal (IP) administration of cisplatin plus intravenous (IV) cyclophosphamide proved superior to both drugs given intravenously at the same doses-which, at the time, was the standard treatment in the United States. The IP 'option' was not adopted, however, because the standard treatment had shifted to IV cisplatin plus paclitaxel. Two additional phase III trials by the Gynecologic Oncology Group (GOG) comparing IP versus IV cisplatin, but including other variables, have shown similar superior effects of the IP route on outcome, but with toxicities-particularly local tolerance and neuropathy-increased. An ongoing trial by the GOG is again looking into an IP versus IV comparison, and introducing in one of the IP arms the substitution of IP carboplatin for IP cisplatin. All three arms of this trial contain bevacizumab (Avastin). Two other trials comparing IV versus IP administration of platinums or platinums and paclitaxel have just been launched, led by Japanese and Canadian investigators, respectively. While awaiting additional data on the ongoing debate over IP versus IV therapy, it is important that we consider issues concerning why the IP route may be relevant, how can one increase the safety of this route, and who should be treated and with what drugs, particularly when faced with a patient outside the clinical trials setting. The underlying hypothesis for use of IP therapy is based on the existence of a dose-effect relationship for platinum drugs in ovarian cancer. We review the known data on this relationship, and explore why interest in platinum drugs has become the central focus of ovarian cancer treatment
— id: 136662, year: 2011, vol: 25, page: 156, stat: Journal Article,

Loss of p27KIP1 Expression in Fully-staged Node-negative Breast Cancer: Association with Lack of Hormone Receptors in T1a/b, but not T1c Infiltrative Ductal Carcinoma
Mirchandani, Deepu; Roses, Daniel F; Inghirami, Giorgio; Zeleniuch-Jacquotte, Anne; Cangiarella, Joan; Guth, Amber; Safyan, Rachael Ann; Formenti, Silvia C; Pagano, Michele; Muggia, Franco
2011 Dec;31(12):4401-4405, Anticancer research
Nuclear expression of the cell cycle inhibitor p27(KIP1) is reduced in a variety of human malignancies, including breast cancer. Loss of nuclear p27(KIP1) during tumor progression, documented by immunohistochemistry (IHC), has been studied for its potential prognostic implication. We examined by IHC the association between nuclear p27(KIP1) expression and hormone receptor status in T1N0M0 breast cancer. PATIENTS AND METHODS: The correlation between nuclear p27(KIP1) expression and estrogen (ER) and progesterone (PR) hormone receptor status was analyzed in 122 human T1N0M0 (68 T1a/b, 54 T1c) breast cancer specimens. All patients were staged as N0 by axillary node dissection. RESULTS: A statistically significant reduction in p27(KIP1) expression was observed as tumor size increased from T1a/b (7%) to T1c (22%). The proportion of tumors with low nuclear p27(KIP1) expression was higher in the ER-negative/PR-negative group compared to the ER-positive/PR-positive group, but this difference was only statistically significant in the T1a/b subgroup (p=0.0007). CONCLUSION: Further investigations into causes of p27(KIP1) deregulation and their relationship to hormone receptor expression in T1N0M0 breast ductal carcinomas are warranted. Such studies may help identify prognostic, as well as predictive, markers of therapy resistance
— id: 149934, year: 2011, vol: 31, page: 4401, stat: Journal Article,

Delayed Neoplastic and Renal Complications in Women Receiving Long-term Chemotherapy for Recurrent Ovarian Cancer
Muggia, Franco; Cannon, Timothy; Safra, Tamar; Curtin, John
2011 Jan 19;103(2):160-161, Journal of the National Cancer Institute
— id: 120643, year: 2011, vol: 103, page: 160, stat: Journal Article,

Bortezomib: understanding the mechanism of action
Piperdi, Bilal; Ling, Yi-He; Liebes, Leonard; Muggia, Franco; Perez-Soler, Roman
2011 Nov;10(11):2029-2030, Molecular cancer therapeutics
— id: 146229, year: 2011, vol: 10, page: 2029, stat: Journal Article,

BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin
Safra T; Lucia B; Nicoletto MO; Rolnitzky L; Pelles-Avraham S; Geva R; Donach ME; Curtin J; Novetsky A; Grenader T; Lai WC; Gabizon AA; Boyd L; Muggia FM
2011 Oct;10(10):2000-2007, Molecular cancer therapeutics
Epithelial ovarian cancer (EOC) patients with BRCA mutations (BRCA+) benefit from platinum-based treatment more than non-carriers. Impaired ability to repair DNA by homologous recombination increases their chemosensitivity. We investigated whether BRCA+ predicts for improved outcome following pegylated liposomal doxorubicin (PLD) for recurrence. Recurrent EOC patients receiving second- or third-line PLD from 1998 to 2009 in 4 institutions (Israel, Italy, NY) were subjected to retrospective comparisons between 40(25.8%) patients who were BRCA+, and 115(74.2%) deemed non-hereditary (NH). Median age was 59 years (range 31-83); 111(72%) had a platinum-free interval >6 months (PLD alone [n=65] and PLD plus platinum[n=90]); 104 received PLD in second-line and 51 in third-line. BRCA+ versus NH comparisons: median time to treatment failure (TTF) 15.8 months (95% CI 11.4-21.6) versus 8.1 months (95% CI 6.1-10.3;p=0.009); overall survival (OS) 56.8 months (95% CI 32.5-indeterminate) versus 22.6 months (95% CI 17.0-34.1;p=0.002). In multivariate Cox models BRCA status was significantly associated with TTF (HR=1.66; 95% CI 1.08-2.55;p=0.02) and OS (adjusted HR 2.07; 95% CI 1.18-3.60;p=0.01). Adjusted HR relating platinum sensitivity to OS was 1.58 (95% CI 0.93-2.68; p=0.09); no significant association found with age at diagnosis, line of PLD or combinations, or institution. In this retrospective analysis, recurrent EOC BRCA mutation carriers treated with PLD had an improved outcome, and this result appeared to be independent of platinum sensitivity. Tumors arising in a background of defective BRCA function are more sensitive than other epithelial ovarian cancers to DNA damaging agents such as PLD, even after acquiring platinum resistance
— id: 136569, year: 2011, vol: 10, page: 2000, stat: Journal Article,

Vaccination With Patient-Specific Tumor-Derived Antigen in First Remission Improves Disease-Free Survival in Follicular Lymphoma
Schuster, Stephen J.; Neelapu, Sattva S.; Gause, Barry L.; Janik, John E.; Muggia, Franco M.; Gockerman, Jon P.; Winter, Jane N.; Flowers, Christopher R.; Nikcevich, Daniel A.; Sotomayor, Eduardo M.; McGaughey, Dean S.; Jaffe, Elaine S.; Chong, Elise A.; Reynolds, Craig W.; Berry, Donald A.; Santos, Carlos F.; Popa, Mihaela A.; McCord, Amy M.; Kwak, Larry W.
2011 JUL 10 ;29(20):2787-2793, Journal of clinical oncology
Purpose Vaccination with hybridoma-derived autologous tumor immunoglobulin (Ig) idiotype (Id) conjugated to keyhole limpet hemocyanin (KLH) and administered with granulocyte-monocyte colony-stimulating factor (GM-CSF) induces follicular lymphoma (FL) -specific immune responses. To determine the clinical benefit of this vaccine, we conducted a double-blind multicenter controlled phase III trial. Patients and Methods Treatment-naive patients with advanced stage FL achieving complete response (CR) or CR unconfirmed (CRu) after chemotherapy were randomly assigned two to one to receive either Id vaccine (Id-KLH + GM-CSF) or control (KLH + GM-CSF). Primary efficacy end points were disease-free survival (DFS) for all randomly assigned patients and DFS for randomly assigned patients receiving at least one dose of Id vaccine or control. Results Of 234 patients enrolled, 177 (81%) achieved CR/CRu after chemotherapy and were randomly assigned. For 177 randomly assigned patients, including 60 patients not vaccinated because of relapse (n = 55) or other reasons (n = 5), median DFS between Id-vaccine and control arms was 23.0 versus 20.6 months, respectively (hazard ratio [HR], 0.81; 95% CI, 0.56 to 1.16; P = .256). For 117 patients who received Id vaccine (n = 76) or control (n = 41), median DFS after randomization was 44.2 months for Id-vaccine arm versus 30.6 months for control arm (HR, 0.62; 95% CI, 0.39 to 0.99; P = .047) at median follow-up of 56.6 months (range, 12.6 to 89.3 months). In an unplanned subgroup analysis, median DFS was significantly prolonged for patients receiving IgM-Id (52.9 v 28.7 months; P = .001) but not IgG-Id vaccine (35.1 v 32.4 months; P = .807) compared with isotype-matched control-treated patients. Conclusion Vaccination with patient-specific hybridoma-derived Id vaccine after chemotherapy-induced CR/CRu may prolong DFS in patients with FL. Vaccine isotype may affect clinical outcome and explain differing results between this and other controlled Id-vaccine trials
— id: 135629, year: 2011, vol: 29, page: 2787, stat: Journal Article,

The regulation of MASPIN expression in epithelial ovarian cancer: Association with p53 status, and MASPIN promoter methylation: A Gynecologic Oncology Group study
Secord, Angeles Alvarez; Darcy, Kathleen M.; Hutson, Alan; Huang, Zhiqing; Lee, Paula S.; Jewell, Elizabeth L.; Havrilesky, Laura J.; Markman, Maurie; Muggia, Franco; Murphy, Susan K.
2011 NOV ;123(2):314-319, Gynecologic oncology
Objectives. To elucidate the regulation of MASPIN expression in epithelial ovarian cancer (EOC) and associations with p53 status and MASPIN promoter methylation. Methods. Seven EOC cell lines and 110 advanced stage EOC specimens were analyzed for MASPIN promoter methylation. The cell lines were treated with 5-azacytidine (5-azaC) and evaluated for MASPIN promoter methylation, protein, and mRNA expression. Wild-type (wt) p53 was transiently transfected into the mutant p53 (m p53) SKOV3 cells which were treated with 5-azaC. Phosphor imager analysis quantified the percent methylation of the MASPIN promoter. Results. Of the 3 MASPIN-low m p53 cell lines 2 had greater than 5% MASPIN methylation whereas only 1 of 4 MASPIN-high wtp53 cell lines had greater than 5% MASPIN methylation. Despite the presence of aberrant MASPIN promoter methylation in SKOV3 cells, wt p53-transfection alone resulted in a 3.3-fold increase in MASPIN mRNA. The combination of 5-azaC and wt p53-transfection produced a 36% reduction in MASPIN promoter methylation and 4.5-fold increase in MASPIN transcription. Among the 110 ovarian cancer specimens analyzed for methylation of the MASPIN promoter, 81.8% were weakly methylated, 14.5% were heavily methylated and 3.6% were fully methylated. There was no relationship between promoter methylation and p53 status or MASPIN protein expression. However, MASPIN protein was 6 times more likely to be detected in cancer specimens that harbor a p53 mutation relative to cancer specimens with a wt p53 gene. Conclusion. The regulation of MASPIN is a complex multifactorial process that may be controlled by both p53-dependent and -independent epigenetic mechanisms. (C) 2011 Elsevier Inc. All rights reserved
— id: 141784, year: 2011, vol: 123, page: 314, stat: Journal Article,

Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: Prediction and prevention
Szebeni, Janos; Muggia, Franco; Gabizon, Alberto; Barenholz, Yechezkel
2011 SEP 16 ;63(12):1020-1030, Advanced drug delivery reviews
Some therapeutic liposomes and lipid excipient-based anticancer drugs are recognized by the immune system as foreign, leading to a variety of adverse immune phenomena. One of them is complement (C) activation, the cause, or major contributing factor to a hypersensitivity syndrome called C activation-related pseudoallergy (CARPA). CARPA represents a novel subcategory of acute (type I) hypersensitivity reactions (HSR), which is mostly mild, transient, and preventable by appropriate precautions. However, in an occasional patient, it can be severe or even lethal. Because a main manifestation of C activation is cardiopulmonary distress, CARPA may be a safety issue primarily in cardiac patients. Along with an overview of the various types of liposome-immune system interactions, this review updates the experimental and clinical information on CARPA to different therapeutic liposomes and lipid excipient-based (micellar) anticancer drugs, including PEGylated liposomal doxorubicin sulfate (PLD, Doxil (R)) and paclitaxel (Taxol (R)). The substantial individual variation of in vitro and in vivo findings reflects an extremely complex immune phenomenon involving multiple, redundant pathways of C activation, signal transduction in allergy-mediating cells and vasoactive mediator actions at the effector cell level. The latest advances in this field include the proposal of doxorubicin-induced shape changes and aggregation of liposomes in Doxil as possible contributing factors to CARPA caused by PLD, and the finding that Doxil-induced immune suppression prevents HSR to co-administered carboplatin, a significant benefit of Doxil in combination chemotherapy with carboplatin. The review evaluates the use of in vitro C assays and the porcine liposome-induced cardiopulmonary distress model for predicting CARPA. It is concluded that CARPA may become a frequent safety issue in the upcoming era of nanomedicines, necessitating its prevention at an early stage of nanomedicine R&D.
— id: 140056, year: 2011, vol: 63, page: 1020, stat: Journal Article,

Endocrine-responsive breast cancer: a 28-year Odyssey
West, A; Friedman, Kp; Muggia, F
2011 ;5:237-237, ecancermedicalscience
Details on the 28-year treatment history of a patient with an endocrine-responsive breast cancer are provided. She was originally diagnosed as having a T1N0M0 cancer after a modified radical mastectomy at age 41. Fifteen years later, in 1998, she presented with hemoptysis and pleuritic chest pain: a 10 cm right atrial tumor and estrogen receptor (ER) positive endobronchial and adjacent lung parenchyma adenocarcinoma were documented. Epithelial markers normalized as she manifested a partial response (PR) lasting 3 years with tamoxifen treatment. From 2001 to 2007 she benefitted from exemestane treatment. Upon progression in the previous lung area and left adrenal, exemestane withdrawal led to transient decrease in markers. Six months later (in July 2008), with growth in her adrenal tumor, laparoscopic adrenalectomy was performed: in addition to ER positivity, the tumor showed Her2 overexpression and amplification. She has subsequently had some control of disease with fulvestrant, letrozole + trastuzumab, and subsequently letrozole + lapatinib. In addition to the chronicity of disease, this history illustrates the expanding range of treatments available for endocrine-responsive breast cancer commensurate to our greater understanding of tumor biology
— id: 150577, year: 2011, vol: 5, page: 237, stat: Journal Article,

Preoperative concurrent paclitaxel-radiation in locally advanced breast cancer: pathologic response correlates with five-year overall survival
Adams, Sylvia; Chakravarthy, A Bapsi; Donach, Martin; Spicer, Darcy; Lymberis, Stella; Singh, Baljit; Bauer, Joshua A; Hochman, Tsivia; Goldberg, Judith D; Muggia, Franco; Schneider, Robert J; Pietenpol, Jennifer A; Formenti, Silvia C
2010 Dec;124(3):723-732, Breast cancer research & treatment
We have previously demonstrated high pathologic response rates after neoadjuvant concurrent chemoradiation in patients with locally advanced breast cancer (LABC). We now report disease-free survival (DFS) and overall survival (OS) in the context of pathologic response. 105 LABC patients (White 46%, Non-White 54%) were treated with paclitaxel (30 mg/m(2) intravenously twice a week) for 10-12 weeks. Daily radiotherapy was delivered to breast, axillary, and supraclavicular lymph nodes during weeks 2-7 of paclitaxel treatment, at 1.8 Gy per fraction to a total dose of 45 Gy with a tumor boost of 14 Gy at 2 Gy/fraction. Pathological complete response (pCR) was defined as the absence of invasive cancer in breast and lymph nodes and pathological partial response (pPR) as the persistence of <10 microscopic foci of invasive carcinoma in breast or lymph nodes. Pathologic response (pCR and pPR) after neoadjuvant chemoradiation was achieved in 36/105 patients (34%) and was associated with significantly better DFS and OS. Pathological responders had a lower risk of recurrence or death (HR = 0.35, P = 0.01) and a longer OS (HR = 4.27, P = 0.01) compared with non-responders. Median DFS and OS were 57 and 84 months for non-responders, respectively, and have not yet been reached for responders. Importantly, pathologic response was achieved in 54% of patients with HR negative tumors (26/48). In conclusion, pathologic response to concurrent paclitaxel-radiation translated into superior DFS and OS. Half of the patients with HR negative tumors achieved a pathologic response
— id: 114178, year: 2010, vol: 124, page: 723, stat: Journal Article,

Erlotinib added to carboplatin and paclitaxel as first-line treatment of ovarian cancer: A phase II study based on surgical reassessment
Blank, Stephanie V; Christos, Paul; Curtin, John P; Goldman, Noah; Runowicz, Carolyn D; Sparano, Joseph A; Liebes, Leonard; Chen, Helen X; Muggia, Franco M
2010 Dec;119(3):451-456, Gynecologic oncology
BACKGROUND: The purpose of this study was to determine whether adding the anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to carboplatin/paclitaxel improved pathologic complete response (pCR) at reassessment surgery in epithelial ovarian, fallopian tube, or primary peritoneal cancers (OFPC). METHODS: Patients with stage III-IV OFPC initiated treatment within 12weeks of initial cytoreductive surgery or, after histologic confirmation of diagnosis, neoadjuvantly. Treatment included paclitaxel (175mg/m(2)) and carboplatin (AUC 6) every 3weeks for up to 6 cycles, plus oral erlotinib 150mg daily. The primary objective was to determine whether the pCR rate at reassessment surgery was at least 60% after optimal cytoreduction at initial surgery (< 1cm residual disease), or at least 40% after suboptimal cytoreduction (at least 1cm residual disease) using a two-stage design (alpha=0.10, beta=0.10). RESULTS: The study population included 56 patients with stage III-IV OFPC. EGFR gene amplification was present in 15% of the 20 tumors evaluated. Twenty-eight patients had protocol therapy after optimal cytoreduction (stratum I), 23 had protocol therapy either after suboptimal cytoreduction (stratum II), and 5 received neoadjuvant therapy prior to cytoreduction (stratum III). Pathologic CR was confirmed in 8 patients (29%; 95% confidence intervals 13%, 49%) in stratum I and 3 patients (11%, 95% C.I. 2%, 28%) in stratum II, which did not meet the prespecified efficacy endpoint in either stratum. CONCLUSIONS: Among unselected patients, erlotinib plus carboplatin-paclitaxel did not improve pCR rates compared with historical experience with carboplatin-paclitaxel alone in patients with stage III-IV OFPC
— id: 114176, year: 2010, vol: 119, page: 451, stat: Journal Article,

Novel therapies delay the progression of smoldering multiple myeloma: Case report and discussion
Jhaveri A.; Muggia F.
2010 ;:182-182, ecancermedicalscience
This clinical vignette illustrates how our therapeutic approaches to early stages of multiple myeloma have changed over the past decade with novel therapies reducing disease and preventing disease progression. Recent paradigms of multiple myeloma describe the disease as a spectrum of clinical stages, including asymptomatic 'smoldering' states that progress to symptomatic states. The average 5-year survival rate of patients with multiple myeloma diagnosed between 1996 and 2004 according to surveillance epidemiology and end results (SEER) data is 35.9%. Here, we describe the use of novel therapeutic agents including bortezomib, lenalidomide, bisphosphonates, Doxil/Caelyx, and dexamethasone, and their success in affecting the course of disease. Multiple trials have shown an increased benefit of these newer agents over prior multiple myeloma treatment regimens. At 13 years and 8 months from diagnosis, our patient is doing well, and thus is a model of how long-term control of multiple myeloma prolongs survival. the authors; licensee ecancermedicalscience
— id: 140544, year: 2010, vol: , page: 182, stat: Journal Article,

Paclitaxel plus oxaliplatin for recurrent or metastatic cervical cancer: a New York Cancer Consortium Study
Kuo, Dennis Yi-Shin; Blank, Stephanie V; Christos, Paul J; Kim, Mimi; Caputo, Thomas A; Pothuri, Bhavana; Hershman, Dawn; Goldman, Noah; Ivy, Percy S; Runowicz, Carolyn D; Muggia, Franco; Goldberg, Gary L; Einstein, Mark H
2010 Mar;116(3):442-446, Gynecologic oncology
OBJECTIVE: Survival in women with recurrent or metastatic cervical cancer remains poor. More effective and less toxic regimens are needed. Cisplatin is an effective radiosensitizer, but its single agent activity in recurrent cervical cancer, especially after prior cisplatin exposure, is disappointing, with a response rate of only 13%. Oxaliplatin has preclinical activity in cisplatin-resistant tumors and may have synergic activity when combined with paclitaxel. Our objective is to determine the efficacy and toxicity of paclitaxel and oxaliplatin in patients with recurrent or metastatic cervical cancer. METHODS: Patients with histologic confirmation of primary metastatic or recurrent cervical cancer not amenable to surgical management were eligible. Treatment consisted of paclitaxel 175 mg/m(2) IV and oxaliplatin 130 mg/m(2) IV every 21 days. The primary endpoints were toxicity, recorded every cycle, and response, determined by RECIST criteria and were assessed every 9 weeks, with subsequent confirmation as required. Sample size determinations were made using a Simon's two-stage design with a projected overall response proportion of 13% with cisplatin alone. Survival rates were calculated with Kaplan-Meier methods. RESULTS: Of the 35 patients enrolled, 32 were evaluable. The median age was 56 (27-78); 30 had had prior radiation (23 concomitant with cisplatin). Patients completed a mean of 4.2 cycles (1-11). There were 2 complete and 5 partial responses for a total response rate of 7/32 (22%; 95% CI: 9.3%-40.0%). Eight patients had stable disease for an overall clinical benefit rate of 15/32 (47%; 95% CI: 29.1%-65.3%). The mean time to best response was 13.5 weeks (95% CI: 10.6, 16.4). The mean progression-free survival was 21 weeks (95% CI: 14.7, 27.2) and mean overall survival was 52 weeks (95% CI: 39.4, 64.8). A total of 135 cycles were administered. There were 28 (20.1%) grade 3/4 hematologic toxicities and 46 (34.1%) grade 3/4 non-hematologic toxicities, which were predominantly sensory neuropathy. There were 13 treatment delays, 4 dose reductions, and no treatment-related deaths. CONCLUSIONS: The combination of paclitaxel and oxaliplatin is an effective regimen in patients with recurrent or persistent cervical cancer including a majority previously exposed to cisplatin. Further study and comparison with other platinum-based regimens is warranted
— id: 133469, year: 2010, vol: 116, page: 442, stat: Journal Article,

Tolerability of long-term use of trabectedin in combination with pegylated liposomal doxorubicin (PLD) in patients (pts) with relapsed ovarian cancer (ROC)
Meerpohl H.-G.; Romero I.; Colombo N.; Arranz J.A.; Zintl P.; Muggia F.; Tanovic A.; Santabarbara P.
2010 ;282:S204-S205, Archives of gynecology & obstetrics
Objective: OVA-301 was an open-label, multicenter, randomized Phase III study comparing Tr+ PLD to PLD alone in 672 pts with ROC. The combination significantly improved PFS and RR, with a trend toward longer OS and manageable noncumulative toxicity (Monk, Ann Oncol 2008, Abs. N8LBA4). Protracted tolerability of trabectedin 1.1 mg/m² and PLD 30 mg/m², 3 h-q3 weeks vs. PLD 50 mg/m2 q4 weeks in pts receiving over 6 cycles was analyzed. Materials and methods: Safety evaluated in 320 (of 663 treated) pts receiving >6 cycles by adverse events (AEs), laboratory data and physical findings (NCI CTC Version 3.0). Results: Balanced baseline characteristics: median age 56 years; ECOG 0: 68%; median platinum-free interval: 9.2 months; prior taxanes: 78%; papillary/serous histology: 72%. (See Table 1) Conclusions: This novel non-platinum, non-taxane combination is an efficacious regimen in pts with ROC with reasonable long-term tolerability in pts that received C6 cycles. Hematological toxicity and transaminase elevations were more common in the combination arm, yet transient, and not cumulative; and less frequent than at <6 cycles. HFS, mucosal inflammation and stomatitis were more common with PLD. Discontinuation rates due to AEs were low. Updated data will be presented
— id: 114212, year: 2010, vol: 282, page: S204, stat: Journal Article,

Trabectedin Plus Pegylated Liposomal Doxorubicin in Recurrent Ovarian Cancer
Monk, BJ; Herzog, TJ; Kaye, SB; Krasner, CN; Vermorken, JB; Muggia, FM; Pujade-Lauraine, E; Lisyanskaya, AS; Makhson, AN; Rolski, J; Gorbounova, VA; Ghatage, P; Bidzinski, M; Shen, K; Ngan, HYS; Vergote, IB; Nam, JH; Park, YC; Lebedinsky, CA; Poveda, AM
2010 JUL 1 ;28(19):3107-3114, Journal of clinical oncology
Purpose The objective of this study was to compare the efficacy and safety of trabectedin plus pegylated liposomal doxorubicin (PLD) with that of PLD alone in women with recurrent ovarian cancer after failure of first-line, platinum-based chemotherapy. Patients and Methods Women >= 18 years, stratified by performance status (0 to 1 v 2) and platinum sensitivity, were randomly assigned to receive an intravenous infusion of PLD 30 mg/m(2) followed by a 3-hour infusion of trabectedin 1.1 mg/m(2) every 3 weeks or PLD 50 mg/m(2) every 4 weeks. The primary end point was progression-free survival (PFS) by independent radiology assessment. Results Patients (N = 672) were randomly assigned to trabectedin/PLD (n = 337) or PLD (n = 335). Median PFS was 7.3 months with trabectedin/PLD v 5.8 months with PLD (hazard ratio, 0.79; 95% CI, 0.65 to 0.96; P = .0190). For platinum-sensitive patients, median PFS was 9.2 months v 7.5 months, respectively (hazard ratio, 0.73; 95% CI, 0.56 to 0.95; P = .0170). Overall response rate (ORR) was 27.6% for trabectedin/PLD v 18.8% for PLD (P = .0080); for platinum-sensitive patients, it was 35.3% v 22.6% (P = .0042), respectively. ORR, PFS, and overall survival among platinum-resistant patients were not statistically different. Neutropenia was more common with trabectedin/PLD. Grade 3 to 4 transaminase elevations were also more common with the combination but were transient and noncumulative. Hand-foot syndrome and mucositis were less frequent with trabectedin/PLD than with PLD alone. Conclusion When combined with PLD, trabectedin improves PFS and ORR over PLD alone with acceptable tolerance in the second-line treatment of recurrent ovarian cancer
— id: 110855, year: 2010, vol: 28, page: 3107, stat: Journal Article,

A phase II trial of the epothilone B analog ixabepilone (BMS-247550) in patients with metastatic melanoma
Ott, Patrick A; Hamilton, Anne; Jones, Amanda; Haas, Naomi; Shore, Tsiporah; Liddell, Sandra; Christos, Paul J; Doyle, L Austin; Millward, Michael; Muggia, Franco M; Pavlick, Anna C
2010 ;5(1):e8714-e8714, PLoS ONE
BACKGROUND: Ixabepilone (BMS-247550), an epothilone B analog, is a microtubule stabilizing agent which has shown activity in several different tumor types and preclinical models in melanoma. In an open label, one-arm, multi-center phase II trial the efficacy and toxicity of this epothilone was investigated in two different cohorts: chemotherapy-naive (previously untreated) and previously treated patients with metastatic melanoma. METHODOLOGY/PRINCIPAL FINDINGS: Eligible patients had histologically-confirmed stage IV melanoma, with an ECOG performance status of 0 to 2. Ixabepilone was administered at a dose of 20 mg/m(2) on days 1, 8, and 15 during each 28-day cycle. The primary endpoint was response rate (RR); secondary endpoints were time to progression (TTP) and toxicity. Twenty-four patients were enrolled and 23 were evaluable for response. Initial serum lactate dehydrogenase (LDH) levels were elevated in 6/11 (55%) of the previously treated and in 5/13 (38%) of the previously untreated patients. No complete or partial responses were seen in either cohort. One patient in the previously treated group developed neutropenia and fatal septic shock. Seventeen patients (8 in the previously untreated group and 9 in the previously treated group) progressed after 2 cycles, whereas six patients (3 in each group) had stable disease after 2-6 cycles. Median TTP was 1.74 months in the previously untreated group (95% CI = 1.51 months, upper limit not estimated) and 1.54 months in the previously treated group (95% CI = 1.15 months, 2.72 months). Grade 3 and/or 4 toxicities occurred in 5/11 (45%) of previously untreated and in 5/13 (38%) of previously treated patients and included neutropenia, peripheral neuropathy, fatigue, diarrhea, and dyspnea. CONCLUSIONS/SIGNIFICANCE: Ixabepilone has no meaningful activity in either chemotherapy-naive (previously untreated) or previously treated patients with metastatic melanoma. Further investigation with ixabepilone as single agent in the treatment of melanoma is not warranted. TRIAL REGISTRATION: Clinical Trials.gov NCT00036764
— id: 106468, year: 2010, vol: 5, page: e8714, stat: Journal Article,

Weekly Paclitaxel with intermittent imatinib mesylate (gleevec(r)>): tolerance and activity in recurrent epithelial ovarian cancer
Safra, Tamar; Andreopoulou, Eleni; Levinson, Benjamin; Borgato, Lucia; Pothuri, Bhavana; Blank, Stephanie; Tiersten, Amy; Boyd, Leslie; Curtin, John; Muggia, Franco
2010 Sep;30(9):3243-3247, Anticancer research
OBJECTIVE: Imatinib mesylate (IM, Gleevec), a potent PDGF/PDGFR tyrosine kinase inhibitor, affects stroma and vascular endothelial cells. Our study sought to determine the safety and activity of paclitaxel with an intermittent schedule of IM. MATERIALS AND METHODS: rEOC patients previously treated with platinum/paclitaxel and </=2 regimens for recurrence were enrolled. Paclitaxel 80 mg/m(2) was given on days 3, 10, 17 every 28 days and oral IM 300 mg bid on days 1-4, 8-11, and 13-18. RESULTS: Between 2007-2009, 14 patients enrolled, 12 were evaluable. Nine patients were on study at 12 weeks. Objective responses (by RECIST and/or CA125) occurred in 4 patients. There were no grade 4, and only four grade 3 toxic events: diarrhea, edema and 2 cases of neutropenia. Early study closure was due to sufficient safety information with preliminary encouraging efficacy results. CONCLUSION: This weekly paclitaxel regimen with intermittent IM is tolerable with anti-tumor activity, making it suitable as part of future studies
— id: 113816, year: 2010, vol: 30, page: 3243, stat: Journal Article,

Phase II Study of Liposomal Cisplatin (SPI-77) in Platinum-sensitive Recurrences of Ovarian Cancer
Seetharamu, N; Kim, E; Hochster, H; Martin, F; Muggia, F
2010 Feb;30(2):541-545, Anticancer research
BACKGROUND: Cisplatin is a highly effective chemotherapeutic agent against epithelial ovarian cancer but is associated with significant toxicities. SPI-77 is a liposomal pegylated formulation of cisplatin that was developed to reduce systemic toxicity and to better deliver cisplatin to tumors. We assessed the response rates and safety of SPI-77, in patients with recurrent epithelial ovarian cancer. PATIENTS AND METHODS: Patients were selected for having previously achieved a platinum treatment free interval of greater than 6 months (e.g. platinum-sensitive) and high potential of achieving responses when rechallenged with a platinum drug. SPI-77 was administered at a dose of 260 mg/m(2) every 21 days until disease progression. RESULTS: Enrollment was terminated after 5 patients were treated because of concern with the adequacy of the formulation. Four out of the five patients had stable disease as best response. While no serious, unexpected adverse events occurred in spite of large cumulative doses of SPI-77, there were concerns related to the large lipid load and prolonged persistence of residual platinum in body stores. CONCLUSION: The results of this study, although inconclusive regarding its primary endpoints, provide some important lessons for the development of similar liposomal platinum agents
— id: 108804, year: 2010, vol: 30, page: 541, stat: Journal Article,

A phase I trial of dose-dense (biweekly) carboplatin combined with paclitaxel and pegfilgrastim: a feasibility study in patients with untreated Stage III and IV ovarian, tubal or primary peritoneal cancer: a Gynecologic Oncology Group study
Tiersten, Amy D; Sill, Michael W; Knight, Danielle; Muggia, Franco; Garcia, Agustin A; Swensen, Ron; Warshal, David P; Mannel, Robert S; Fracasso, Paula M
2010 Sep;118(3):303-307, Gynecologic oncology
PURPOSE: Dose-dense regimens have been shown to improve outcome when given as adjuvant therapy to patients with breast cancer compared with their three weekly counterparts. We investigated the feasibility of a dose-dense regimen with carboplatin/paclitaxel followed by pegfilgrastim in patients with advanced ovarian cancer. We also investigated the toxicities including the percentage of patients with grade 2 or greater peripheral neurotoxicity and the clinical response of this regimen. PATIENTS AND METHODS: Women with untreated Stage III or IV epithelial ovarian, (fallopian) tubal, or primary peritoneal cancer were treated with carboplatin area under the curve (AUC) 5 and paclitaxel 175 mg/m(2) day one, and pegfilgrastim 6 mg day two every 2 weeks for six cycles. RESULTS: Between 9/06 and 9/08, 43 patients enrolled. Thirty-one patients completed six or more cycles of therapy. The dose limiting toxicities resulting in treatment discontinuation included: grade 3 and 4 neuropathy, grade 4 thrombocytopenia, grade 4 thrombocytopenia/grade 3 febrile neutropenia, and grade 4 supraventricular tachycardia. Twelve patients (30%) had >or=grade 2 neuropathy from this regimen. The overall response rate in patients with measurable disease was 58% (11 out of 19). CONCLUSION: Dose-dense carboplatin/paclitaxel appears to be effective. However, based on dose limiting toxicities occurring when administering 6 cycles of treatment, it is not feasible. Given the neuropathy and thrombocytopenia, we do not recommend 6 cycles of this regimen without modification
— id: 111685, year: 2010, vol: 118, page: 303, stat: Journal Article,

Phase II study of darinaparsin in patients with advanced hepatocellular carcinoma
Wu, Jennifer; Henderson, Charles; Feun, Lynn; Van Veldhuizen, Peter; Gold, Philip; Zheng, Hui; Ryan, Theresa; Blaszkowsky, Lawrence S; Chen, Haobin; Costa, Max; Rosenzweig, Barry; Nierodzik, MaryLynn; Hochster, Howard; Muggia, Franco; Abbadessa, Giovanni; Lewis, Jonathan; Zhu, Andrew X
2010 Oct;28(5):670-676, Investigational new drugs
BACKGROUND: Darinaparsin is a novel organic arsenic that reaches higher intracellular concentration with decreased toxicity compared to inorganic arsenic. We conducted a multi-center phase II study with darinaparsin in patients with advanced HCC. METHODS: Eligibility criteria included unresectable or metastatic measurable HCC, up to two prior systemic treatments, ECOG performance status < or = 2, Child Pugh Class A or B and adequate organ functions. Darinaparsin was administered at 420 mg/m(2) intravenously, twice weekly at least 72 h apart for 3 weeks in a 4-week cycle. The primary end point was response rate. A Simon two-stage design was used. RESULTS: Among 15 patients in the first stage, no objective responses were observed. Two patients had stable disease. The median number of cycles on study per patient was 2 (1-6). The median progression free survival and overall survival were 55 days (95% confidence interval: 50-59) and 190 days (95% confidence interval: 93-227), respectively. No treatment related hospitalizations or deaths occurred. Treatment related grade 1-2 toxicities included nausea, vomiting (26.7% each), fatigue (20%), anorexia and diarrhea (13.3% each). Grade 3 anorexia, wheezing, agitation, abdominal pain and SGPT were observed in 1 patient each (6.7%). One patient experienced grade 4 hypoglycemia (6.7%). CONCLUSIONS: Darinaparsin could be safely administered with tolerable toxicity profiles, and no QTc prolongation in patients with advanced HCC. However, at this dose and schedule, it has shown no objective responses in HCC and this trial was terminated as planned after the first stage of efficacy analysis
— id: 138148, year: 2010, vol: 28, page: 670, stat: Journal Article,

Platinum compounds and radiation
Baer L; Muggia F; Formenti S
Platinum and other heavy metal compounds in cancer chemotherapy : molecular mechanisms and clinical applications New York : Humana Press, 2009,
— id: 5323, year: 2009, vol: , page: 211, stat: Chapter,

Breast cancer arising in a BRCA-mutated background: therapeutic implications from an animal model and drug development
Fasano, J; Muggia, F
2009 APR ;20(4):609-614, Annals of oncology
To date, the presence of a hereditary background has not influenced the selection of drug treatment in breast cancer. However, increasingly, negative hormone receptors and Her2 (often referred to as 'triple negative') or a medullary carcinoma histology has been reported in BRCA mutation carriers. Accordingly, such patients are often considered for adjuvant protocols based on chemotherapy (and not based on endocrine manipulations or trastuzumab). Mouse models introducing a conditional BRCA-null expression in the breast have recently provided powerful support for cisplatin-based treatment and have implications for the design of adjuvant studies in these patients
— id: 98098, year: 2009, vol: 20, page: 609, stat: Journal Article,

Paclitaxel plus oxaliplatin for recurrent or metastatic cervical cancer: A New York Cancer Consortium study
Kuo, DY; Blank, SV; Kim, M; Caputo, TA; Pothuri, B; Hershman, D; Goldman, NA; Ivy, P; Runowicz, CD; Muggia, F; Goldberg, GL; Einstein, MH
2009 FEB ;112(2):S15-S15, Gynecologic oncology
— id: 97668, year: 2009, vol: 112, page: S15, stat: Journal Article,

The utility of TRC093; A humanized monoclonal antibody directed against cleaved collagen in the detection of patients at risk of ovarian and breast cancer
Liebes L.; Lu J.; Pennell R.; Blank S.; Pua T.; Muggia F.; Fishman D.; Theuer C.; Roth J.; Brooks P.
2009 ;8(12 SUPPL 1):?-?, Molecular cancer therapeutics
Background: TRC093 is a humanized monoclonal antibody that specificallybinds cleaved collagen and has been shown to inhibit angiogenesisand tumor growth in preclinical studies. TRC093 is currentlybeing evaluated in a phase I clinical study for the treatment of metastatic human tumors (Gordon et al. EJC Supp 6, abs #414, pp130, 2008). Interestingly, one of the patients in this studywith granulosa cell carcinoma of the ovary with progressivedisease had a mixed response in the liver after 2 months of treatment. Given these encouraging results, we began to examinethe biological relevance of the cryptic epitope recognized byTRC093 in ovarian carcinoma and whether a soluble form of thiscryptic collagen epitope may represent a clinically useful markerfor patients at risk for ovarian and breast cancer. To thisend, we have adapted an ELISA assay for the detection of theshed collagen cryptic epitope that is defined by this antibodyto examine a patient population at risk for ovarian and breastcancer. Methods: To begin to assess the relevance of the cryptic collagenepitope recognized by TRC093 in ovarian tumor growth, humanSKOV3 ovarian carcinoma cells were injected subcutaneously intonude mice. Six days later when detectable tumors were observed,mice were treated (i.p.) 3x per week with TRC093 over a doserange up to 250 mug/injection for a period of 28 days.To assess the relevance of a shed soluble form of the crypticcollagen epitope in a patient population at risk for ovarianand breast cancer, serum samples from a group of high-risk womenvolunteers prospectively enrolled at the NYU School of Medicinewere analyzed for TRC093 epitope concentration by ELISA as previouslydescribed (Ng et al., Clin Can Res, 14:6253). Results: TRC093 significantly (p< 0.05) inhibited SKOV3 tumorgrowth at 100 mug and 250 mug/injection as comparedto control. These findings suggest that theTRC093 cryptic collagenepitope may represent a relevant therapeutic target for ovariancarcinoma. In a group of 23 high-risk women identified withrespect to their clinical status, a mean mu SEM of 42.9mu 9.8 mug/ml was determined for the patients withovarian/ breast cancer history compared with a mean of 15.3mu 2.9 mug/ml for normal women in this study population(p = 0.0254). Conclusions: The TRC093 shed serum epitope can distinguish betweena high-risk population of women with breast or ovarian cancerand normal clinical status. We are expanding the sample sizewith more ovarian surgical patients. The xenograft studies providefurther support for the potential use of the SKOV3 human ovariancarcinoma model to examine the effect of TRC093 in combinationwith cisplatin and or bevacizumab. The TRC093 epitope may representa key therapeutic target in ovarian cancer
— id: 112583, year: 2009, vol: 8, page: ?, stat: Journal Article,

Platinum compounds 30 years after the introduction of cisplatin: implications for the treatment of ovarian cancer
Muggia, Franco
2009 Jan;112(1):275-281, Gynecologic oncology
Cisplatin and carboplatin have dominated the drug therapy of ovarian cancer and other gynecologic malignancies during the past three decades. This review, based on a recent international conference on metal coordination compounds, highlights advances in our understanding of their mechanisms of action and resistance. Two emerging areas are of special importance: 1) the role of transporters and exporters (first identified in the regulation of copper) in imparting the special selectivity of platinum drugs (also including oxaliplatin) for specific tumors; and 2) the relevance of inactivated DNA repair pathways, and in particular those related to BRCA genes in determining sensitivity of tumors to platinum drugs. The status of DNA repair pathways may become relevant to response to platinums and to the treatment of ovarian cancer in general: repair inhibitors are under testing alone or in combination with cytotoxic drugs for cancer
— id: 111649, year: 2009, vol: 112, page: 275, stat: Journal Article,

Heidelberger symposium on the 50th anniversary of fluoropyrimidines
Muggia, Franco M
2009 May;8(5):991-991, Molecular cancer therapeutics
— id: 121317, year: 2009, vol: 8, page: 991, stat: Journal Article,

XIII International Charles Heidelberger Symposium and 50 Years of Fluoropyrimidines in Cancer Therapy Held on September 6 to 8, 2007 at New York University Cancer Institute, Smilow Conference Center
Muggia, Franco M; Peters, Godefridus J; Landolph, Joseph R Jr
2009 May;8(5):992-999, Molecular cancer therapeutics
This conference opened with Franco Muggia, host and principal organizer, thanking Joseph Landolph, co-Chair of the International Scientific Organizing Committee and its members (Franco Muggia, co-Chair, Max Costa, Steven Burakoff, Howard Hochster, Eliezer Huberman, John Bertram, Peter Danenberg, and Richard Moran); the members of the Local Organizing Committee (Drs. Costa, Guttenplan, Geacintov, and Hochster); and the Charles and Patricia Heidelberger Foundation for Cancer Research for developing the scientific program and for working to help him create this special symposium honoring the late Charles Heidelberger, former president of the American Association for Cancer Research, member of the National Academy of Sciences, and extraordinary scientist in the fields of carcinogenesis and cancer chemotherapy. It was most appropriate to commemorate the 50th anniversary of the patent obtained by him for 5-fluorouracil (5FU), a drug that came to symbolize the promise chemotherapy of nonhematologic malignancies. After this compound was shown to be helpful in the treatment of colorectal and breast cancers, Dr. Heidelberger proceeded to develop other fluoropyrimidines and to inspire Ph.D. students and postdoctoral fellows to investigate their mechanisms of action and to develop assays applicable to clinical specimens (what we now refer to as translational science). Steven Burakoff, director of the NYU Cancer Institute (2000 to 2008), followed with welcoming remarks. Dr. Burakoff pointed to his personal fortuitous connection to the Symposium: The famous immunologist, Michael Heidelberger, Charles' father, who was known as the Father of Immunochemistry, trained Elvin Kabat while at Columbia, who trained Baruch Benacerraf, who moved from NYU to Harvard and subsequently became Burakoff's mentor. The renowned NYU Division of Immunology carries the name Michael Heidelberger because he spent more than 30 years in the Department of Pathology at the NYU School of Medicine after retiring from Columbia University. [Mol Cancer Ther 2009;8(5):992-9]
— id: 121318, year: 2009, vol: 8, page: 992, stat: Journal Article,

Phase II trial of dacarbazine and thalidomide for the treatment of metastatic melanoma
Ott, Patrick A; Chang, Jason L; Oratz, Ruth; Jones, Amanda; Farrell, Kathleen; Muggia, Franco; Pavlick, Anna C
2009 ;55(4):221-227, Chemotherapy
OBJECTIVE: This phase II study evaluated the efficacy and tolerability of dacarbazine in combination with thalidomide in metastatic melanoma patients. METHODS: Chemotherapy-naive patients with histologically confirmed, measurable metastatic melanoma with no evidence of brain metastases and adequate hematologic and organ function received dacarbazine (1,000 mg/m(2) i.v. every 3 weeks) and thalidomide (starting dose of 200 mg/day orally at night, escalated every 3 weeks) as tolerated. The primary endpoint was objective tumor response, evaluated after every 3 cycles of treatment. Fifteen patients, age range 29-77 years, were accrued for this study. All had stage IV disease (1 M1a, 5 M1b, 9 M1c). Nine patients had had no prior adjuvant therapy, 6 had received prior immunotherapy. The median number of cycles was 5 (range 1-18), with 8 patients receiving >or=3 cycles. The median thalidomide dose administered was 200 mg/day with a maximum tolerated dose of 400 mg/day. RESULTS: Of the 13 patients evaluable for response, 1 patient had a partial response, 3 patients had stable disease and 9 patients had progressive disease. No complete responses were seen. Two patients were not evaluable for response: 1 withdrew due to toxicity and 1 died of unrelated causes. Grade III neutropenia, thrombocytopenia and nausea were attributed to dacarbazine. Grade III/IV constipation, peripheral neuropathy, fatigue, edema and rash were attributed to thalidomide. CONCLUSION: The addition of thalidomide to dacarbazine in metastatic melanoma yielded activity insufficient to proceed with additional trials of this combination. Thalidomide dose escalation beyond 200 mg/day was limited by unacceptable toxicity. Therefore, this combination does not warrant further investigation
— id: 100608, year: 2009, vol: 55, page: 221, stat: Journal Article,

Phase I study of bryostatin 1, a protein kinase C modulator, preceding cisplatin in patients with refractory non-hematologic tumors
Pavlick, Anna C; Wu, Jennifer; Roberts, John; Rosenthal, Mark A; Hamilton, Anne; Wadler, Scott; Farrell, Kathleen; Carr, Michelle; Fry, David; Murgo, Anthony J; Oratz, Ruth; Hochster, Howard; Liebes, Leonard; Muggia, Franco
2009 Sep;64(4):803-810, Cancer chemotherapy & pharmacology
PURPOSE: Preclinical data suggested that bryostatin-1 (bryo) could potentiate the cytotoxicity of cisplatin when given prior to this drug. We designed a phase I study to achieve tolerable doses and schedules of bryo and cisplatin in combination and in this sequence. METHODS: Patients with non-hematologic malignancies received bryo followed by cisplatin in several schedules. Bryo was given as an 1 and a 24 h continuous infusion, while cisplatin was always given over 1 h at 50 and 75 mg/m(2); the combined regimen was repeated on an every 3-week and later on an every 2-week schedule. Bryo doses were escalated until recommended phase II doses were defined for each schedule. Patients were evaluated with computerized tomography every 2 cycles. RESULTS: Fifty-three patients were entered. In an every 2-week schedule, the 1-h infusion of bryo became limited by myalgia that was clearly cumulative. With cisplatin 50 mg/m(2) its recommended phase II dose was 30 mug/m(2). In the 3-week schedule, dose-limiting toxicities were mostly related to cisplatin effects while myalgias were tolerable. Pharmacokinetics unfortunately proved to be unreliable due to bryo's erratic extraction. Consistent inhibition of PKC isoform eta (eta) in peripheral blood mononuclear cells was observed following bryo. CONCLUSIONS: Bryo can be safely administered with cisplatin with minimal toxicity; however, only four patients achieved an objective response. Modulation of cisplatin cytotoxicity by bryo awaits further insight into the molecular pathways involved
— id: 97002, year: 2009, vol: 64, page: 803, stat: Journal Article,

Idiotype vaccine therapy (BiovaxID) in follicular lymphoma in first complete remission: Phase III clinical trial results
Schuster, SJ; Neelapu, SS; Gause, BL; Muggia, FM; Gockerman, JP; Sotomayor, EM; Winter, JN; Flowers, CR; Stergiou, AM; Kwak, LW
2009 JUN 20 ;27(18):-, Journal of clinical oncology
— id: 109136, year: 2009, vol: 27, page: , stat: Journal Article,

CA-125 change after chemotherapy in prediction of treatment outcome among advanced mucinous and clear cell epithelial ovarian cancers: a Gynecologic Oncology Group study
Tian, Chunqiao; Markman, Maurie; Zaino, Richard; Ozols, Robert F; McGuire, William P; Muggia, Franco M; Rose, Peter G; Spriggs, David; Armstrong, Deborah K
2009 Feb 4;115(7):1395-1403, Cancer
BACKGROUND:: There are limited data regarding unique clinical or laboratory features associated with advanced clear cell (CC) and mucinous (MU) epithelial ovarian cancers (EOC), particularly the relationship between CA-125 antigen levels and prognosis. METHODS:: A retrospective review of 7 previously reported Gynecologic Oncology Group phase 3 trials in patients with stage III/IV EOC was conducted. A variety of clinical parameters were examined, including the impact of baseline and changes in the CA-125 level after treatment of CC and MU EOC on progression-free (PFS) and overall survival (OS). RESULTS:: Clinical outcomes among patients with advanced CC and MU EOC were significantly worse when compared with other cell types (median PFS, 9.7 vs 7.0 vs 16.7 months, respectively, P < .001; median OS, 19.4 vs 11.3 vs 40.5 months, respectively, P < .001). Suboptimal debulking was associated with significantly decreased PFS and OS among both. Although baseline CA-125 values were lower in CC (median, 154 mu/mL) and MU (100 mu/mL), compared with other cell types (275 mu/mL), this level did not appear to influence outcome among these 2 specific subtypes of EOC. However, an elevated level of CA-125 at the end of chemotherapy was significantly associated with decreased PFS and OS (P < .01 for all). CONCLUSIONS:: Surgical debulking status is the most important variable at prechemotherapy predictive of prognosis among advanced CC and MU EOC patients. Changes in the CA-125 levels at the end treatment as compared with baseline can serve as valid indicators of PFS and OS, and likely the degree of inherent chemosensitivity. Cancer 2009. (c) 2009 American Cancer Society
— id: 95534, year: 2009, vol: 115, page: 1395, stat: Journal Article,

The prognostic value of pretreatment CA 125 in patients with advanced ovarian carcinoma : a Gynecologic Oncology Group study
Zorn, Kristin K; Tian, Chunqiao; McGuire, William P; Hoskins, William J; Markman, Maurie; Muggia, Franco M; Rose, Peter G; Ozols, Robert F; Spriggs, David; Armstrong, Deborah K
2009 Mar 1;115(5):1028-1035, Cancer
BACKGROUND:: The objective of the current study was to determine the prognostic significance of a pretreatment serum CA 125 level in patients with advanced epithelial ovarian carcinoma (EOC) who received treatment with a standard chemotherapy regimen. METHODS:: Patients with International Federation of Gynecology and Obstetrics stage III/IV ovarian carcinoma who were on 1 of 7 Gynecologic Oncology Group (GOG) phase 3 trials and received treatment with a standard regimen of intravenous cisplatin and paclitaxel were included. A Cox regression model was used to assess the impact of CA 125 levels drawn before the initiation of chemotherapy on progression-free survival (PFS) both overall and by subgroup, including surgical debulking status, disease stage, and histologic subtype. RESULTS:: In total, 1299 patients who were on the cisplatin/paclitaxel arms of the GOG trials were eligible. The median CA 125 level was 246 U/mL. Only 7.6% of patients had a normal CA 125 level (</=35 U/mL). The lowest median CA 125 level was observed in the group with mucinous tumors; however, 69% of women who had mucinous tumors had abnormal CA 125 levels. Shorter PFS was observed with increasing CA 125 and persisted in multivariate analysis. Overall and in the serous subgroup, a 1-fold increase in CA 125 level was associated with a 7% increase in the hazard of disease progression (P < .001). This association was even more pronounced in patients who had stage III disease that was debulked to microscopic disease (15%; P = .003) and in patients who had endometrioid tumors (17%; P = .001). CONCLUSIONS:: A normal CA 125 level in the setting of advanced EOC was rare even after surgical debulking. The pretreatment CA 125 level was an independent predictor of PFS in patients with advanced EOC who received a standard chemotherapy regimen, particularly in the setting of disease that was debulked to a microscopic residual and in the serous or endometrioid subtypes. Cancer 2009. (c) 2009 American Cancer Society
— id: 95535, year: 2009, vol: 115, page: 1028, stat: Journal Article,

Concurrent radiotherapy, paclitaxel and dose escalating carboplatin in the treatment of cervical cancer--a phase I study
Addeo, Daniela; Blank, Stephanie; Muggia, Franco; Formenti, Silvia
2008 Sep-Oct;28(5B):3143-3146, Anticancer research
BACKGROUND: Concurrent radiation therapy (RT) and chemotherapy represents the standard treatment of locally advanced cervical cancer. This study was designed to determine the feasibility and toxicity of concomitant administration of RT with twice per week paclitaxel and carboplatin. MATERIALS AND METHODS: Nine women with cervical cancer stage IB2-IVA were treated with standard RT and twice per week paclitaxel at a dose of 30 mg/m2 with carboplatin in escalating doses starting at an AUC of 5. RESULTS: One out of the four patients who received carboplatin at AUC 5 developed grade III toxicity according to the National Cancer Institute (NCI) grading system. Two out of the five patients who received carboplatin at AUC 6 developed grade III toxicity. A clinical response was achieved in 8 patients (89%), with a complete response (CR) in 5 patients (56%). CONCLUSION: Combining RT with twice weekly paclitaxel (30 mg/m2) and carboplatin (AUC of 6) is a tolerated regimen, active in controlling locally advanced cervical cancer
— id: 93551, year: 2008, vol: 28, page: 3143, stat: Journal Article,

Pharmacodynamics of tubulin and tubulin-binding agents: extending their potential beyond taxanes
Andreopoulou, Eleni; Muggia, Franco
2008 Mar;8 Suppl 2:S54-S60, Clinical breast cancer
Chemotherapeutic agents that disrupt the assembly or disassembly of microtubules, including paclitaxel and docetaxel, are among the most commonly prescribed anticancer therapies. However, the utility of taxane-based therapy is limited principally by problems with formulation, slow administration, cumulative neurotoxicity, and resistance in part through induction of P-glycoprotein. The broad-spectrum anticancer activity of taxane therapy has encouraged investigators to identify a class of structurally novel microtubulin-stabilizing agents that could produce comparable outcomes with fewer problems. Preclinical studies indicate that epothilones have a broad spectrum activity in paclitaxel-resistant breast cancer models. Several epothilone analogues have displayed promising antitumor activity in initial clinical trials. Ixabepilone, an epothilone derivative in the later stages of clinical development, has exhibited antitumor activity in breast cancers, with or without previous taxane therapy. The most common adverse events associated with ixabepilone are reversible sensory neuropathy and neutropenia. This review briefly outlines the basic science behind microtubule-targeting agents and examines the preclinical studies of several of these agents in breast cancer models. Also discussed are results from clinical trials of epothilones alone and in combination in patients with breast cancer
— id: 133615, year: 2008, vol: 8 Suppl 2, page: S54, stat: Journal Article,

Brain metastases from choriocarcinoma: Two patients illustrating key management issues
Chen, T; Ginosar, D; Fink, M; Chen, A; Cieplinski, W; Curtin, J; Muggia, FM
2008 JUN ;20(3):405-407, Journal of chemotherapy
— id: 86847, year: 2008, vol: 20, page: 405, stat: Journal Article,

Co-existence of breast and ovarian cancers in BRCA germ-line mutation carriers
Dilawari, A; Cangiarella, J; Smith, J; Huang, A; Downey, A; Muggia, F
2008 ;2:109-109, ecancermedicalscience
The co-existence of breast and ovarian cancers in the same individual should raise suspicion of a hereditary process. Patients with either BRCA1 or BRCA2 germ-line mutations have an average risk of 39% and 11% respectively of developing ovarian cancer by the age of 70; they have a risk of 35-85% of developing breast cancer in their lifetime. We report here unusual pathologic features in a BRCA2 germ-line mutation carrier recently diagnosed with synchronous breast and ovarian cancers, and summarize the findings in six other women who were diagnosed with ovarian cancer either simultaneously with the diagnosis of breast cancer or at varying times after the diagnosis. While in most instances this may be a coincidental occurrence in highly susceptible individuals, the patient we highlight raises the provocative hypothesis that at times breast cancer metastasizes to the ovaries of mutation carriers and stimulates the development of an ovarian cancer as well as other cancers. In addition, these ovarian cancers may have different mechanisms of metastases predisposing them to travel to unusual sites
— id: 150575, year: 2008, vol: 2, page: 109, stat: Journal Article,

Novel neurosensory testing in cancer patients treated with the epothilone B analog, ixabepilone
Goel, S; Goldberg, GL; Kuo, DYS; Muggia, F; Arezzo, J; Mani, S
2008 DEC ;19(12):2048-2052, Annals of oncology
Background: We have previously established the recommended phase II dose (RPTD) of ixabepilone as 40 mg/m(2) administered over 1 h repeated every 3 weeks with neuropathy as a cumulative dose-limiting toxicity. We expanded the cohort at the RPTD to include detailed assessment of nerve damage in these patients. We report our findings on vibration perception threshold (VPT) and neuropathy. Patients and methods: Forty-four patients were treated with a median (range) of three (1-14) cycles of ixabepilone. The V
— id: 98117, year: 2008, vol: 19, page: 2048, stat: Journal Article,

Tolerance and activity of oxaliplatin with protracted topotecan infusion in patients with previously treated ovarian cancer. A phase I study
Hochster, Howard; Chen, Thomas T; Lu, Janice M; Hills, Day; Sorich, Joan; Escalon, Juliet; Ivy, Percy; Liebes, Leonard; Muggia, Franco
2008 Mar;108(3):500-504, Gynecologic oncology
BACKGROUND: Topotecan 14-day infusion combined with cisplatin was highly active in ovarian cancer, but too myelosuppressive. We therefore sought to evaluate the feasibility of substituting oxaliplatin for cisplatin to improve safety. METHODS: Ovarian and primary peritoneal cancer patients, pretreated with at least one prior platinum-containing regimen, performance status (PS) 0-1, without prior pelvic radiation were eligible. Topotecan was continuously infused days 1-15; oxaliplatin was given days 1 and 15; cycles were repeated every 28 days. Five dose levels were explored: topotecan (mg/m2/day)/oxaliplatin (mg/m2) doses: (1) 0.2/65; (2) 0.2/75; (3) 0.2/85; (4) 0.3/85; (5) 0.4/85. RESULTS: Twenty-three patients (20 ovarian, 1 tubal, and 2 peritoneal) were entered: median age 56 years (range, 37-77); PS: 0=12 and 1=11; histology: papillary serous 7, serous 4, adenocarcinoma 8, poorly differentiated 2. Median of 4 cycles were delivered. Grade 3 neutropenia occurred in 3 of 7 patients at level 5 (with fever at levels 4 and 5), without grade 4 neutropenia or thrombocytopenia. Other toxicities were mild and reversible (mainly gastrointestinal), except one grade 3 neuropathy and one oxaliplatin-related grade 3 hypersensitivity reaction. Six objective responses (five of them complete) were documented among 22 patients spanning several dose levels. CONCLUSION: Topotecan continuous infusion, combined with oxaliplatin, was associated with no grade 4 hematologic toxicity and evidence of activity. The recommended phase II dose is topotecan 0.4 mg/m2/day continuous infusion d1-15 with oxaliplatin 85 mg/m2 on days 1 and 15. A phase II evaluation as second-line treatment for both platinum-sensitive and -resistant ovarian cancer recurrences is ongoing
— id: 76389, year: 2008, vol: 108, page: 500, stat: Journal Article,

A RANDOMIZED PHASE III STUDY OF TRABECTEDIN WITH PEGYLATED LIPOSOMAL DOXORUBICIN (PLD) VERSUS PLD IN RELAPSED, RECURRENT OVARIAN CANCER (OC)
Monk, BJ; Herzog, T; Kaye, S; Krasner, CN; Vermorken, J; Muggia, F; Pujade-Lourraine, E; Renshaw, FG; Lebedinsky, C; Poveda, A
2008 SEP ;19(1):2-2, Annals of oncology
— id: 98115, year: 2008, vol: 19, page: 2, stat: Journal Article,

Tumor residual after surgical cytoreduction in prediction of clinical outcome in stage IV epithelial ovarian cancer: a Gynecologic Oncology Group Study
Winter, William E 3rd; Maxwell, G Larry; Tian, Chunqiao; Sundborg, Michael J; Rose, G Scott; Rose, Peter G; Rubin, Stephen C; Muggia, Franco; McGuire, William P
2008 Jan 1;26(1):83-89, Journal of clinical oncology
PURPOSE: To identify factors predictive of poor prognosis in a similarly treated population of women with stage IV epithelial ovarian cancer (EOC). PATIENTS AND METHODS: A retrospective review of 360 patients with International Federation of Gynecology and Obstetrics stage IV EOC who underwent primary surgery followed by six cycles of intravenous platinum/paclitaxel was performed. A proportional hazards model was used to assess the association of potential prognostic factors with progression-free survival (PFS) and overall survival (OS). RESULTS: The median PFS and OS for this group of stage IV ovarian cancer patients was 12 and 29 months, respectively. Multivariate regression analysis revealed that histology, malignant pleural effusion, intraparenchymal liver metastasis, and residual tumor size were significant prognostic variables. Whereas patients with microscopic residual disease had the best outcome, patients with 0.1 to 1.0 cm residual disease and patients with 1.1 to 5.0 cm residual disease had similar PFS and OS. Patients with a residual size more than 5 cm had a diminished PFS and OS when compared with all other groups. Median OS for microscopic, 0.1 to 5.0 cm, and more than 5.0 cm residual disease was 64, 30, and 19 months, respectively. CONCLUSION: Patients with more than 5 cm residual disease have the shortest PFS and OS, whereas patients with 0.1 to 1.0 and 1.1 to 5.0 cm have similar outcome. These findings suggest that ultraradical cytoreductive procedures might be targeted for selected patients in whom microscopic residual disease is achievable. Patients with less than 5.0 cm of disease initially and significant disease and/or comorbidities precluding microscopic cytoreduction may be considered for alternative therapeutic options other than primary cytoreduction
— id: 135338, year: 2008, vol: 26, page: 83, stat: Journal Article,

Pegylated liposomal doxorubicin (PLD): enhanced skin toxicity in areas of vitiligo
Yuan, Y; Orlow, Sj; Curtin, J; Downey, A; Muggia, F
2008 ;2:111-111, ecancermedicalscience
Pegylated liposomal doxorubicin (PLD, Doxil, Caelyx) is widely used for the treatment of ovarian cancer. It is a stable formulation encapsulating doxorubicin in a 'Stealth' (i.e., pegylated) liposome with a half-life of about 72 hours. This drastically altered pharmacology confers on it a considerably lower risk of cardiotoxicity, no acute emesis, and near absence of alopecia or problems with extravasation necrosis. On the other hand, PLD's dose-limiting toxicity is cutaneous. Since the original phase I report, cutaneous toxicities reported with PLD fall into four common categories: the well known hand-foot syndrome (also called palmoplantar erythrodysesthesia, or PPE), a diffuse follicular rash, intertrigo-like eruption, and hyperpigmentation including melanotic macules
— id: 150576, year: 2008, vol: 2, page: 111, stat: Journal Article,

Pegylated liposomal doxorubicin HCL (PLD; Caelyx/Doxil): experience with long-term maintenance in responding patients with recurrent epithelial ovarian cancer
Andreopoulou, E; Gaiotti, D; Kim, E; Downey, A; Mirchandani, D; Hamilton, A; Jacobs, Allan; Curtin, John; Muggia, F
2007 Apr;18(4):716-721, Annals of oncology
BACKGROUND: We hypothesized that a response to pegylated liposomal doxorubicin (PLD, Caelyx/Doxil) followed by maintenance is beneficial and safe in recurrent ovarian cancer. PATIENTS AND METHODS: Sixteen patients have received PLD for more than 1 year for recurrent ovarian (14) or fallopian tube (2) cancer. All had stable disease or better responses to PLD + carboplatin (5) or topotecan (9) doublets or to PLD alone (2). PLD maintenance therapy 30-40 mg/m(2) was given every 4-8 weeks. This analysis focuses on cardiac status, overall tolerance, and time to recurrence. RESULTS: Termination of PLD was due to progression in all patients. Noteworthy was the lack of cumulative myelosuppression and, with one exception, clinical cardiac toxicity. This patient was hospitalized with cardiogenic shock and fever complicating grade 4 pancytopenia from topotecan ten months after discontinuation of PLD. Seven patients continue to receive PLD after a median of 1680 mg/m(2) (1180-2460 mg/m(2)). Four of these had documented relapses after 3-6 years on maintenance occurring in the setting of lengthening of the treatment interval. Maintenance PLD was reinstituted after 'reinduction' with a platinum. CONCLUSIONS: PLD appears to be safe as long-term maintenance in ovarian cancer and may be important for a continued response.
— id: 72988, year: 2007, vol: 18, page: 716, stat: Journal Article,

Mucinous cancer of the appendix: challenges in diagnosis and treatment
Andreopoulou, E; Yee, H; Warycha, M A; Macari, M; Berman, R; Lowy, A; Muggia, F
2007 Aug;19(4):451-454, Journal of chemotherapy
The authors report and discuss a case of a mucinous carcinoma of the appendix, a rare entity with a distinct natural history that poses diagnostic and therapeutic challenges. Mucinous peritoneal carcinomatosis is most commonly associated with primary tumors of the appendix and colon. Typically, spread remains confined to the abdominal cavity. Imaging assessment of these mucinous lesions is difficult, while tumor markers (CEA and CA19.9) may be surrogates for extent of disease. Treatment consists of surgical debulking, sometimes coupled with intraperitoneal drug delivery, but recurrence is universal. New treatment approaches are needed. Mucin genes are regulated in part by epidermal growth factor receptor signaling. Therefore, we initiated a phase II study of cetuximab for mucinous peritoneal carcinomatosis, that was part of this patient's treatment
— id: 73927, year: 2007, vol: 19, page: 451, stat: Journal Article,

Feasibility and cardiac safety of pegylated liposomal doxorubicin plus trastuzumab in heavily pretreated patients with recurrent HER2-overexpressing metastatic breast cancer
Andreopoulou, Eleni; Gaiotti, Darci; Kim, Eugene; Volm, Matthew; Oratz, Ruth; Freedberg, Robin; Downey, Andrea; Vogel, Charles L; Chia, Stephen; Muggia, Franco
2007 Aug;7(9):690-696, Clinical breast cancer
BACKGROUND: Few studies have evaluated concomitant pegylated liposomal doxorubicin (PLD) plus trastuzumab as therapy for HER2-overexpressing metastatic breast cancer (MBC). This open-label, prospective, phase II trial assessed the safety and efficacy of this regimen, with cardiac tolerance as the principal focus. PATIENTS AND METHODS: Women with HER2-overexpressing recurrent MBC, baseline left ventricular ejection fraction >or= 55%, and no history of serious cardiac illness were eligible; preexisting cardiac risk factors, including previous anthracyclines and previous trastuzumab for MBC, were allowed. Patients received weekly trastuzumab and every-3-week PLD until progression, prohibitive toxicity, or patient refusal. Left ventricular ejection fraction was assessed during and after therapy. Grade 3/4 congestive heart failure (CHF) was monitored for premature closure. RESULTS: The trial closed after 2.5 years for slow accrual. Twelve patients were enrolled: 7 had received adjuvant anthracyclines; 9 had received previous MBC treatment, of whom 7 had received trastuzumab in combination with chemotherapy. Patients received a mean of 4.8 cycles of PLD; 8 patients experienced stable disease; 4 patients experienced progression. Mean left ventricular ejection fraction levels did not change substantially: 60.4%, 57%, 60.3%, and 56.8% at baseline, after cycle 2, after cycle 4, and after completion of treatment, respectively. No patients experienced grade 4 CHF. One patient discontinued treatment after grade 3 CHF. Three patients experienced grade 2 left ventricular dysfunction, of whom 2 discontinued treatment. Cardiac function improved in all 4 patients after going off study. Other adverse events were generally mild (grade 1/2) and infrequent. CONCLUSION: Pegylated liposomal doxorubicin plus trastuzumab might be an option for heavily pretreated patients with recurrent HER2-overexpressing MBC
— id: 75388, year: 2007, vol: 7, page: 690, stat: Journal Article,

Intraperitoneal(IP) 5'-fluoro-2'deoxyuridine(FUDR): Safety and outcome when administered prior to adjuvant chemoradiotherapy(chemoRT) following R0 resection for gastric adenocarcinoma
Cohen DJ; Ryan T; Newman E; Iqbal S; Liu M; Utate M; Moore S; Potmesil M; Hochster H; Muggia FM
2007 ;25(18S Suppl):4627-4627, Journal of clinical oncology
Background: ChemoRT after surgery for locally advanced gastric cancer improves overall and relapse-free survival (OS and RFS) compared to observation (NEJM 2000,345:72530). However, loco-regional recurrences (>50%) remain high and we hypothesized that adding IP FUDR would further improve outcome. Methods: Patients (pts) ECOG performance status (PS) 02, gastric/gastroesphogeal(GEJ) adenocarcinoma stage Ib-IV (M0) undergoing R0 resection were eligible, and had insertion of IP catheters at surgery. IP FUDR(3gm/dose/day) was given on protocol days 1, 2, 3 and 15, 16, 17 prior to 5-FU/LV and external beam RT (45Gy) as in cited study. Simon 2-stage optimum design was used to demonstrate safety. Endpoints also included were loco-regional recurrence and survival. Results: 28 pts with gastric/GEJ adenocarcinoma (25/3) were enrolled from 2002 to 2006 at 2 institutions: median age 59.5 years (range 3981), M /F (21/7). R0 gastric resection was performed with dissection of median 22 (range 8102) lymph nodes(LN's). 22/28 pts were lymph node positive. Full dose IP FUDR was completed in 20/28 pts. 4 pts required dose reduction (1 for grade(gr) 2 hepatic enzyme elevation, 2 gr 2 neutropenia, 1 gr 4 neutropenia), 3 discontinued therapy (1 gr 3 abdominal pain, 1 GI abscess, and 1 bleeding arterial pseudoaneurysm). One pt received no IP treatment due to catheter failure. 24/28 pts completed chemoRT and had toxicity comparable to that previously reported in the Intergroup 0116 trial. At 26 month median follow up (range 2.843.4), of the 26 pts evaluable for response, 16 pts are NED, 6 alive with disease, 3 dead of disease, and 1 dead from other cause. 5 recurrences were intra-abdominal, 1 local, 2 distant, and 1 at multiple sites. At present analysis, the median RFS is 32.5 months. Conclusions: IP FUDR prior to chemoRT after R0 gastric cancer resection is well tolerated. A randomized study to test its role in reducing regional recurrence and improving outcome is warranted. (FDA Orphan Products grant# FD-R-215004)
— id: 75186, year: 2007, vol: 25, page: 4627, stat: Journal Article,

Peripheral blood mononuclear and tumor cell pharmacodynamics of the novel epothilone B analogue, ixabepilone
Mani, S; McDaid, HM; Grossman, A; Muggia, F; Goel, S; Griffin, T; Colevas, D; Horwitz, SB; Egorin, MJ
2007 JAN ;18(1):190-195, Annals of oncology
Background: We previously demonstrated that peak microtubule bundle formation (MBF) in peripheral blood mononuclear cells (PBMCs) occurs at the end of drug infusion and correlates with drug pharmacokinetics (PK). In the current study, a new expanded evaluation of drug target effect was undertaken. Patients and methods: Patients with advanced solid malignancies were treated with ixabepilone 40 mg/m(2) administered as a 1-h i.v. infusion every 3 weeks. Blood, plasma, and tumor tissue sampling was carried out to characterize pharmacodynamics and PK. Results: Forty-seven patients were treated with 141 cycles of ixabepilone. In both PBMCs (n = 27) and tumor cells (n = 9), peak MBF occurred at the end of infusion; however, at 24-72 h after drug infusion, the number of cells with MBF was significantly greater in tumor cells, relative to PBMCs. A Hill model (EC50 = 109.65 ng/ml; r(2) = 0.94) was fitted, which demonstrated a relationship between percentage of PBMCs with MBF and plasma ixabepilone concentration. The percentage of PBMCs with MBF at the end of infusion also correlated with severity of neutropenia (P = 0.050). Conclusions: Plasma ixabepilone concentration and severity of neutropenia correlate with the level of MBF in PBMCs. Therefore, this technically straightforward assay should be considered as a complement to the clinical development of novel microtubule-binding agents
— id: 70138, year: 2007, vol: 18, page: 190, stat: Journal Article,

Prognostic factors for stage III epithelial ovarian cancer: A Gynecologic Oncology Group Study
Winter, WE; Maxwell, GL; Tian, CQ; Carlson, JW; Ozols, RF; Rose, PG; Markman, M; Armstrong, DK; Muggia, F; McGuire, WP
2007 AUG 20 ;25(24):3621-3627, Journal of clinical oncology
Purpose Conflicting results on prognostic factors for advanced epithelial ovarian cancer ( EOC) have been reported because of small sample size and heterogeneity of study population. The purpose of this study was to identify factors predictive of poor prognosis in a similarly treated population of women with advanced EOC. Patients and Methods A retrospective review of demographic, pathologic, treatment, and outcome data from 1,895 patients with International Federation of Gynecology and Obstetrics stage III EOC who had undergone primary surgery followed by six cycles of intravenous platinum/paclitaxel was conducted. A proportional hazards model was used to assess the association of prognostic factors with progression-free survival ( PFS) and overall survival ( OS). Results Increasing age was associated with increased risks for disease progression ( HR = 1.06; 95% CI, 1.02 to 1.11 for an increase every 10 years) and death ( HR = 1.12; 95% CI, 1.06 to 1.18). Mucinous or clear-cell histology was associated with a worse PFS and OS compared with serous carcinomas. Patients with performance status ( PS) 1 or 2 were at an increased risk for recurrence compared with PS 0 ( HR = 1.12; 95% CI, 1.01 to 1.24). Compared with patients with microscopic residual disease, patients with 0.1 to 1.0 cm and > 1.0 cm residual disease had an increased risk of recurrence ( HR = 1.96; 95% CI, 1.70 to 2.26; and HR = 2.36; 95% CI, 2.04 to 2.73, respectively) and death ( HR = 2.11; 95% CI, 1.78 to 2.49; P < .001; and HR = 2.47; 95% CI, 2.09 to 2.92, respectively). Conclusion Age, PS, tumor histology, and residual tumor volume were independent predictors of prognosis in patients with stage III EOC. These data can be used to identify patients with poor prognosis and to design future tailored randomized clinical trials
— id: 74149, year: 2007, vol: 25, page: 3621, stat: Journal Article,

Proceedings of a GOG workshop on intraperitoneal therapy for ovarian cancer
Alberts, DS; Markman, M; Muggia, F; Ozols, RF; Eldermire, E; Bookman, MA; Chen, T; Curtin, J; Hess, LM; Liebes, L; Young, RC; Trimble, E
2006 DEC ;103(3):783-792, Gynecologic oncology
Ovarian cancer is the leading cause of gynecologic cancer deaths in the U.S. The concept of intraperitoneal ding delivery for therapy of intraperitoneal cancers, such as ovarian cancer, arose in the 1960s. The field of intraperitoneal cisplatin therapy for ovarian cancer was initiated in the late 1970s and early 1980s. The markedly improved survival data resulting from a phase III trial of intraperitoneal cisplatin for ovarian cancer in early 2006 led to an NCl Clinical Announcement and a Gynecologic Oncology Group-sponsored workshop on intraperitoneal therapy in January, 2006, in San Diego, California. The proceedings of this workshop summarize both research trial results and practical implementation issues associated with intraperitoneal therapy discussed at this workshop. (c) 2006 Elsevier Inc. All rights reserved
— id: 69631, year: 2006, vol: 103, page: 783, stat: Journal Article,

Report of first-stage accrual for NCI 5886, a phase II study of erlotinib, carboplatin and paclitaxel as first-line treatment of ovarian cancer
Blank, SV; Curtin, JP; Goldman, NA; Runowicz, CD; Speyer, JL; Tiersten, AD; Dancey, J; Wadler, S; Muggia, FM
2006 JUN 20 ;24(18):274S-274S, Journal of clinical oncology
— id: 69299, year: 2006, vol: 24, page: 274S, stat: Journal Article,

Phase I dose-escalating study of bi-weekly pemetrexed (MTA) with fixed dose rate gemcitabine (gem) in patients with advanced cancer
Chen, AL; Ryan, T; Muggia, F; Chachoua, A; Escalon, J; Moore, S; Haniff, F; Levinson, B; Nicol, S; Hochster, H
2006 JUN 20 ;24(18):91S-91S, Journal of clinical oncology
— id: 69296, year: 2006, vol: 24, page: 91S, stat: Journal Article,

Completion rates of adjuvant chemotherapy for colon cancer: a historical perspective
Grann, Victor R; Muggia, Franco M
2006 May 3;98(9):570-571, Journal of the National Cancer Institute
— id: 95536, year: 2006, vol: 98, page: 570, stat: Journal Article,

A risky business: Implementing a platinum-based desensitization protocol in the outpatient setting
Green, R; Downey, A; McCaffrey, K; Fusco, E; Muggia, F
2006 MAR ;33(2):437-438, Oncology nursing forum
— id: 63780, year: 2006, vol: 33, page: 437, stat: Journal Article,

Preventing intraperitoneal port (abdominal mediport) related complications: Efficacy of evidence-based treatment guidelines
Green, R; Downey, A; McCaffrey, K; Fusco, E; Muggia, F
2006 MAR ;33(2):434-435, Oncology nursing forum
— id: 63779, year: 2006, vol: 33, page: 434, stat: Journal Article,

Prolonged topotecan infusion with cisplatin in the first-line treatment of ovarian cancer: an NYGOG and ECOG study
Hochster, Howard S; Plimack, Elizabeth R; Mandeli, John; Wadler, Scott; Runowicz, Carolyn; Goldberg, Gary; Speyer, James; Wallach, Robert; Muggia, Franco
2006 Feb;100(2):324-329, Gynecologic oncology
OBJECTIVE: To determine the toxicity and efficacy of combined therapy with cisplatin and prolonged infusion topotecan as front line therapy in women with epithelial ovarian cancer. PATIENTS AND METHODS: Women with previously untreated, measurable and non-measurable epithelial ovarian cancer, stages Ic-IV were eligible. Patients were treated with cisplatin 75 mg/m(2) on day 1, followed by topotecan 0.3 to 0.4 mg/m(2)/day given as a continuous infusion over 14-21 days, every 28 days. Dose levels and duration of infusion were adjusted for toxicity as appropriate. Patients were evaluated for response to treatment and treatment toxicity by standard NYGOG criteria. RESULTS: Sixty patients were enrolled. Among the 20 patients with post-surgical residual disease >2 cm, 80% [95% CI (56.3%, 94.3%)] demonstrated an objective response to therapy. The median progression-free survival for all 60 patients enrolled was 19.3 months with a median overall survival of 45.6 months given the median follow-up of 55 months (range 6-81 months). Five year survival is estimated to be 41%. Toxicity was observed in the first four patients treated with topotecan (0.4 mg/m(2)/day x 21 days) and dosing was continued at 0.3 mg/m(2)/day x 14 days thereafter. Of the 56 patients treated at the amended dose level, marrow suppression continued to be dose-limiting, with 86% of patients experiencing grade 3 or 4 neutropenia, 55% experiencing grade 3 or 4 thrombocytopenia and 50% of patients experiencing grade 3 or 4 anemia. Nonetheless, only 11/245 cycles administered were associated with febrile neutropenia and/or infection (8 port-related). Other non-hematologic toxicity was as expected. There were no treatment-related deaths. CONCLUSION: This large, multicenter phase II study of prolonged infusion topotecan in combination with cisplatin demonstrated similar response, time to progression and survival compared with reported results of taxane and platinum combinations. Hematologic toxicity was greater but tolerated. Further studies investigating topotecan in combination with platinum therapy as a first line agent are warranted
— id: 62741, year: 2006, vol: 100, page: 324, stat: Journal Article,

New and emerging intraperitoneal (IP) drugs for ovarian cancer treatment
Muggia, Franco M
2006 Dec;33(6 Suppl 12):S18-S24, Seminars in oncology
Chemotherapy after surgical debulking represents an essential component of treatment for patients with advanced ovarian cancer. Three quarters of patients respond very well to initial treatment with platinum-containing drugs used either alone or in combination with a taxane, usually paclitaxel. With relapse rates exceeding 50% and median survival time of 2 years for patients after relapse, efforts are focused on treatment approaches to achieve and extend clinical complete remissions. These approaches include consolidation and maintenance therapy, intraperitoneal (IP) administration of cytotoxic agents, new combination chemotherapy regimens, development of new cytotoxic agents, and molecular-targeted therapies (beyond tumor DNA, the classical target of cytotoxic drugs). IP chemotherapy, which involves direct instillation of chemotherapy into the tumor site in the peritoneal cavity, is the focus of this review article. This article discusses studies involving new and emerging IP drugs for both first-line chemotherapy treatment of advanced ovarian cancer and recurrent platinum-sensitive ovarian cancer
— id: 71924, year: 2006, vol: 33, page: S18, stat: Journal Article,

Topotecan continuous infusion: CA-125 responses including patients pretreated with other schedules of topotecan
Muggia, Franco; Kosloff, Rebecca; Liebes, Leonard; Hochster, Howard
2006 May;11(5):529-531, Oncologist
— id: 69425, year: 2006, vol: 11, page: 529, stat: Journal Article,

Association of low P27 with loss of hormone receptors in small (T1a/b) breast cancers
Wu, J; Mirchandani, D; Smith, JA; Inghirami, G; Roses, D; Zeleniuch-Jacquotte, A; Muggia, F
2006 JUN 20 ;24(18):33S-33S, Journal of clinical oncology
— id: 69294, year: 2006, vol: 24, page: 33S, stat: Journal Article,

Epidermal growth factor receptor inhibitors for the treatment of epithelial ovarian cancer
Blank, Stephanie V; Chang, Richard; Muggia, Franco
2005 Apr;19(4):553-559, Oncology
The majority of patients with ovarian cancer, especially those who present with stages IIIC and IV, will relapse soon after completion of platinum-based induction treatment. It is imperative to find ways to improve and/or enhance the efficacy of induction and to prolong the duration of the first remission. The epidermal growth factor receptor (EGFR) family has been exploited, and currently, three agents that directly target this group of receptors are in use in the treatment of colorectal, non-small-cell lung and breast cancers. EGFR and HER2/neu are overexpressed in a significant percentage of epithelial ovarian cancers. Thus, it would be reasonable to explore directly targeted therapy in ovarian cancer. Numerous investigational trials involving a variety of EGFR inhibitors in ovarian cancer are ongoing. Our institution has an active phase II clinical study that seeks to define the role of erlotinib (Tarceva) in potentiating first-line chemotherapy, and to determine whether the drug offers a significant contribution as maintenance therapy. It is hoped that data from these and other studies will help investigators to understand more clearly the biology of ovarian cancer and to delineate the role of EGFR inhibitors in the management of ovarian cancer
— id: 55979, year: 2005, vol: 19, page: 553, stat: Journal Article,

Tolerability of carboplatin, paclitaxel and erlotinib as first-line treatment of ovarian cancer
Blank, SV; Curtin, JP; Goldman, NA; Fusco, E; Lesko, Z; Hochster, H; Runowicz, CD; Wadler, S; Muggia, FM
2005 JUN 1 ;23(16):467S-467S, Journal of clinical oncology
— id: 57798, year: 2005, vol: 23, page: 467S, stat: Journal Article,

A phase I study of continuous intravenous infusion (CIV) low-dose topotecan (T) combined with thoracic radiotherapy (RT)
Chandra, A; Chang, R; Steinfeld, A; Chachoua, A; Muggia, F; Formenti, S; Hochster, H
2005 ;63(2):2314-2314, International journal of radiation oncology biology physics
— id: 109248, year: 2005, vol: 63, page: 2314, stat: Journal Article,

A phase I study of oxaliplatin (OX) in combination with bortezomib (B) in patients with advanced malignancy
Chang, R; Beric, A; Liebes, LF; Wright, J; Ivy, P; Norwood, B; Escalon, J; Muggia, FM; Hochster, HS
2005 JUN 1 ;23(16):880S-880S, Journal of clinical oncology
— id: 57806, year: 2005, vol: 23, page: 880S, stat: Journal Article,

Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle
Hamilton, A L; Eder, J P; Pavlick, A C; Clark, J W; Liebes, L; Garcia-Carbonero, R; Chachoua, A; Ryan, D P; Soma, V; Farrell, K; Kinchla, N; Boyden, J; Yee, H; Zeleniuch-Jacquotte, A; Wright, J; Elliott, P; Adams, J; Muggia, F M
2005 Sep 1;23(25):6107-6116, Journal of clinical oncology
PURPOSE: We performed a phase I study of a day (D) 1 and D4 bortezomib administration once every 2 weeks to determine the recommended phase II dose and toxicity profile, and the extent of 20S proteasome inhibition obtained. PATIENTS AND METHODS: Patients with solid tumors or lymphomas were treated with bortezomib at 0.25 to 1.9 mg/m2 on D1 and D4, every 2 weeks. 20S proteasome levels in blood were assayed at baseline and at 1, 4, and 24 hours postdose in cycle 1. RESULTS: On this D1 and D4 every 2 weeks' schedule, dose-limiting toxicity (DLT) was evident at the 1.75 and 1.9 mg/m2 dose levels, most commonly in patients receiving individual total doses > or = 3.0 mg. The main DLT was peripheral neuropathy evident at the higher doses and in patients previously exposed to neurotoxic agents. Other DLTs included diarrhea and fatigue; grade 3 thrombocytopenia was also noted. Reversible inhibition of 20S proteasome activity was dose dependent and best fit a total dose (mg) per fraction rather than mg/m2; 70% of baseline activity was inhibited by a dose of 3.0 to 3.5 mg given on D1 and on D4 every other week. Antitumor effects short of confirmed partial responses were observed in patients with melanoma, non-small-cell lung cancer, and renal cell carcinoma. CONCLUSION: Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. DLTs include neuropathy, fatigue, and diarrhea
— id: 57888, year: 2005, vol: 23, page: 6107, stat: Journal Article,

Phase I study of combined pegylated liposomal doxorubicin with protracted daily topotecan for ovarian cancer
Mirchandani, Deepu; Hochster, Howard; Hamilton, Anne; Liebes, Leonard; Yee, Herman; Curtin, John P; Lee, Sang; Sorich, Joan; Dellenbaugh, Cornelia; Muggia, Franco M
2005 Aug 15;11(16):5912-5919, Clinical cancer research
PURPOSE: To determine the maximum tolerated dose and dose-limiting toxicity of Doxil with low-dose continuous infusion topotecan and subsequently with low-dose oral topotecan. Other specific aims were preliminary assessment of activity in advanced ovarian and tubal malignancies, pharmacokinetics of oral topotecan, and correlation of response with topoisomerase I and II expression in tumors. METHODS: Eligible patients had histopathologically documented advanced cancers beyond standard therapy, performance status <2, and adequate organ functions. Doxil (30-40 mg/m2 i.v.) was given on day 1, with topotecan either oral topotecan 0.4 mg/m2 bid for 14 days or continuous infusion topotecan (0.3-0.4 mg/m2/d) for 14 to 21 days, in 28-day cycles. Fifty-seven patients, 23 with epithelial ovarian or tubal cancers were enrolled. Plasma levels of lactone form of topotecan were determined on patients receiving oral topotecan. RESULTS: Grade 4 neutropenia and thrombocytopenia and grade 3 diarrhea were dose-limiting toxicities at the highest dose levels explored. Doxil (40 mg/m2/day 1) and continuous infusion topotecan at 0.4 mg/m2/days 1 to 14 could be safely given and is the recommended phase II dose. Oral topotecan was limited by low and erratic plasma topotecan levels and frequent gastrointestinal toxicity. Particularly long partial responses and stable disease were observed in patients with epithelial ovarian or tubal cancers. Clinical benefit (objective responses and stable diseases) correlated with elevated expression of both topoisomerases by immunohistochemistry in four of six epithelial ovarian or tubal cancer tumor samples. CONCLUSION: Doxil with 14-day topotecan infusion is a well-tolerated regimen and suitable for study in platinum-resistant or refractory ovarian or tubal cancers. Frequent gastrointestinal toxicity and/or erratic absorption complicate treatment with a longer topotecan infusion or with oral topotecan, respectively, and these combinations are not recommended
— id: 61253, year: 2005, vol: 11, page: 5912, stat: Journal Article,

Dialogues in oncology. Section editor's note
Muggia F
2005 ;10(5):323-4 May, Oncologist
— id: 64773, year: 2005, vol: 10, page: 323, stat: Journal Article,

Ezra Greenspan,
Muggia, F
2005 FEB ;10(2):170-171, Oncologist
— id: 48735, year: 2005, vol: 10, page: 170, stat: Journal Article,

Modern management of recurrent ovarian carcinoma - A systematic approach to a chronic disease - The Michener/Belinson article reviewed
Muggia, FM; Blank, SV
2005 SEP ;19(10):1288-+, Oncology
— id: 64628, year: 2005, vol: 19, page: 1288, stat: Journal Article,

Phase 1 clinical trials in oncology
Muggia, Franco M
2005 Jun 9;352(23):2451-2453, New England journal of medicine
— id: 95537, year: 2005, vol: 352, page: 2451, stat: Journal Article,

Evaluation of vinorelbine in persistent or recurrent nonsquamous carcinoma of the cervix: a Gynecologic Oncology Group Study
Muggia, Franco M; Blessing, John A; Waggoner, Steven; Berek, Jonathan S; Monk, Bradley J; Sorosky, Joel; Pearl, Michael L
2005 Jan;96(1):108-111, Gynecologic oncology
OBJECTIVE: The Gynecologic Oncology Group (GOG) has studied a number of drugs to determine their activity in patients with previously treated squamous and nonsquamous cancer arising in the uterine cervix. A Phase II study with intravenous vinorelbine was initiated for this purpose in patients with Stage IVB, recurrent, or persistent nonsquamous carcinomas who had received one prior chemotherapy or were not eligible for other studies. METHODS: Eligible patients had to have measurable disease, GOG performance status of 0-2 and adequate bone marrow, liver, and renal function. The treatment consisted of vinorelbine 30 mg/m(2) on days 1 and 8, repeated every 21 days. Tumor measurements and toxicities were recorded every treatment cycle. RESULTS: Thirty patients were enrolled with 28 patients deemed eligible and evaluable. Only two confirmed partial responses (7.1%) were noted. Neutropenia was the most common toxicity with 9 of 28 (32%) experiencing either grade 3 or 4 changes. Anemia was severe in seven. Neuropathy was more than mild in three patients. Severe events, such as fatigue, hypertension, or pulmonary changes attributed to drug administration, occurred only in one or two instances. CONCLUSION: With the dose schedule and assessment criteria employed, vinorelbine had only minimal activity in nonsquamous cancer of the cervix
— id: 48109, year: 2005, vol: 96, page: 108, stat: Journal Article,

Investigational agents for epithelial ovarian cancer
Muggia, Franco; Kosloff, Rebecca
2005 Oct;5(5):855-868, Expert review of anticancer therapy
Ovarian cancer is the leading cause of gynecologic cancer deaths and accounts for 4% of women's cancer diagnoses and 5% of all cancer mortalities. Despite the ability of current chemotherapy and cytoreductive surgery to put patients in remission, most patients with advanced cancer will eventually relapse. Many advances in the treatment of ovarian cancer have been reported in the past several years and a historical background is provided. Attention will then turn to analogs of current chemotherapeutic agents, new cytotoxic drugs, targeted molecular therapy, intraperitoneal therapy and immunotherapy. This review will give a perspective on current drugs, potential agents and upcoming clinical trials
— id: 111739, year: 2005, vol: 5, page: 855, stat: Journal Article,

Postoperative intraperitoneal (IP) 5'-fluoro-2'-deoxyuridine (FUDR) added to chemoradiation in patients curatively resected (RO) for locally advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma
Newman, E; Chang, RY; Potmesil, M; Donahue, B; Marcus, SG; Hiotis, SP; Iqbal, S; Ryan, T; Hochster, HS; Muggia, FM
2005 JUN 1 ;23(16):348S-348S, Journal of clinical oncology
— id: 57796, year: 2005, vol: 23, page: 348S, stat: Journal Article,

Neoadjuvant chemotherapy, surgery, and adjuvant intraperitoneal chemotherapy in patients with locally advanced gastric or gastroesophageal junction carcinoma: a phase II study
Newman, Elliot; Potmesil, Milan; Ryan, Theresa; Marcus, Stuart; Hiotis, Spiros; Yee, Herman; Norwood, Brendan; Wendell, Marc; Muggia, Franco; Hochster, Howard
2005 Dec;32(6 Suppl 9):S97-100, Seminars in oncology
A phase II trial, using neoadjuvant chemotherapy and intraperitoneal (IP) consolidation, was conducted in patients with locally advanced, potentially resectable gastric cancer or cancer of the gastroesophageal junction, both staged as T3N0, T4N0, or any TN1 or TN2 disease. Preoperative chemotherapy consisted of two cycles of irinotecan 75 mg/m(2) with cisplatin 25 mg/m(2)/week for 4 weeks followed by a 2-week break. Unless disease progression was encountered, surgery was performed and followed by two courses of adjuvant therapy with IP floxuridine 3 g x 3 days plus IP cisplatin 60 mg/m(2) on day 3. Of 32 evaluable patients, 29 (90.6%) underwent surgery, and 25 (86.2%) had R0 on resection. Evidence of primary-tumor downstaging was documented in at least one half of the patients. Toxicity of induction therapy was primarily grade 3/4 neutropenia (38.2%/8.8%), grade 3 diarrhea (20.6%), and grade 3 nausea/vomiting (14.7%). Except for three catheter complications, toxicities with IP therapy were infrequent. After a median follow-up of 28.0 months in 32 patients, 10 patients (31.3%) had no evidence of disease, 4 (12.5%) were alive with disease, 13 (40.6%) had died from disease, and 5 (15.6%) died from unrelated causes. Among 25 patients who underwent R0 resection, there were no local recurrences. Sites of first recurrences were outside the abdominal cavity in seven patients, in the liver in two, and in the abdominal cavity in four patients. Median overall survival for all 32 patients was 36.5 months from the start of treatment after median follow-up of 28 months, whereas median disease-specific survival had not been reached at the time of this analysis. For patients with R0 resection, median overall survival was 48 months after median follow-up of 35 months. The data suggest that an approach consisting of systemic induction therapy, curative surgery with high R0 resection rates, and IP adjuvant therapy has acceptable toxicity and encouraging survival outcomes
— id: 62748, year: 2005, vol: 32, page: S97, stat: Journal Article,

Sequential phase II studies for endometrial cancer (EC): Pegylated liposomal doxorubicin (LD) with either paclitaxel (P) or docetaxel (D)
Szmulewitz, RZ; Chang, RY; Blank, SV; Curtin, JP; Hochster, HS; Hamilton, AL; Hornreich, G; Muggia, FM
2005 JUN 1 ;23(16):487S-487S, Journal of clinical oncology
— id: 57799, year: 2005, vol: 23, page: 487S, stat: Journal Article,

Efficacy and safety of liposomal anthracyclines in phase I/II clinical trials
Alberts, David S; Muggia, Franco M; Carmichael, James; Winer, Eric P; Jahanzeb, Mohammad; Venook, Alan P; Skubitz, Keith M; Rivera, Edgardo; Sparano, Joseph A; DiBella, Nicholas J; Stewart, Simon J; Kavanagh, John J; Gabizon, Alberto A
2004 Dec;31(6 Suppl 13):53-90, Seminars in oncology
Preclinical studies have established the pharmacologic advantages of liposomal anthracyclines, including pharmacokinetic profiles after bolus dosing that resemble continuous infusion of conventional anthracyclines, increased drug concentrations in tumor cells compared with the surrounding tissues, and reduced toxicity relative to conventional anthracycline treatment. Based on these studies, many phase I and phase II clinical trials were conducted to assess the safety and potential activity of liposomal anthracyclines in the management of both solid and hematologic tumors. These studies provided valuable insight into the safety of pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]), nonpegylated liposomal doxorubicin (Myocet [NPLD]), and liposomal daunorubicin (DaunoXome [DNX]) over a range of doses, either as single-agent therapy or in combination with other cytotoxic agents. Other liposomal anthracyclines in development may be well tolerated but their activity remains to be elucidated by clinical trials. The available data also suggest that liposomal anthracyclines have activity not only against tumor types with known sensitivity to conventional anthracyclines, but also potentially for tumors that are typically anthracycline-resistant. Despite the availability of clinical data from a wide variety of tumor types and patient populations, further studies of liposomal anthracycline therapy are needed to fully establish their safety, efficacy, and dosing in the treatment of these patients
— id: 95539, year: 2004, vol: 31, page: 53, stat: Journal Article,

Risk assessment in non-Ashkenazi women attending a cancer risk assessment clinic
Blank, SV; Smith, JA; Carapetyan, KJ; Utate, MA; Muggia, FM; Curtin, JP
2004 JUL 15 ;22(14):550S-550S, Journal of clinical oncology
— id: 48685, year: 2004, vol: 22, page: 550S, stat: Journal Article,

Epothilone B analog (BMS-247550) at the recommended phase II dose (R
Chen, T; Molina, A; Moore, S; Goel, S; Desai, K; Hamilton, A; Griffin, T; Colevas, AD; Mani, S; Muggia, F
2004 JUL 15 ;22(14):155S-155S, Journal of clinical oncology
— id: 48676, year: 2004, vol: 22, page: 155S, stat: Journal Article,

Thalidomide (Thal) tolerance in patients treated with transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC)
Goldenberg, A; Volm, M; Hochster, H; Muggia, F; Rosen, R; Teperman, L; Morgan, G; Schwartz, J; Sung, M; Wadler, S
2004 JUL 15 ;22(14):376S-376S, Journal of clinical oncology
— id: 48682, year: 2004, vol: 22, page: 376S, stat: Journal Article,

Biweekly 72-hour 9-aminocamptothecin infusion as second-line therapy for ovarian carcinoma: phase II study of the New York Gynecologic Oncology Group and the Eastern Cooperative Oncology Group
Hochster, Howard; Plimack, Elizabeth R; Runowicz, Carolyn D; Speyer, James; Wallach, Robert C; Sorich, Joan; Mandeli, John; Wadler, Scott; Wright, John; Muggia, Franco M
2004 Jan 1;22(1):120-126, Journal of clinical oncology
PURPOSE: To determine the antitumor activity of the novel topoisomerase I inhibitor 9-aminocamptothecin (9-AC) given over 72 hours every 2 weeks in patients with ovarian carcinoma previously treated with one platinum-containing regimen. PATIENTS AND METHODS: Patients with ovarian carcinoma who received one prior platinum-containing regimen were eligible. Patients were stratified based on whether their disease was measurable, or nonmeasurable but assessable. 9-AC 35 microg/m(2)/h was administered by continuous infusion for 72 hours every 2 weeks via ambulatory pump. RESULTS: Sixty patients were entered, 32 with measurable and 28 with nonmeasurable but assessable disease. Ten (16.7%) of 60 patients responded (95% CI, 7.2% to 26.1%), with four complete responses and six partial remissions. The response rate for patients with measurable and nonmeasurable but assessable disease was 22% (95% CI, 7.6% to 36.2%) and 10.7% (95% CI, 2.3% to 28.2%), respectively. None of the responders were platinum-resistant. Nineteen patients (32%) had stable disease. The major toxicities were hematologic, with 25% of patients having grade 3 and 35% having grade 4 neutropenia, including five episodes of febrile neutropenia, 17% having grade 3 to 4 thrombocytopenia, and 27% having grade 3 to 4 anemia. Nonhematologic toxicity included grade 3 to 4 nausea (27%) and grade 3 to 4 vomiting (12%). CONCLUSION: This phase II multicenter trial of biweekly 72 hour 9-AC infusion as second-line therapy for ovarian cancer demonstrates comparable activity to standard approved agents in patients with both measurable and nonmeasurable but assessable disease. Toxicity consists mainly of moderate but controllable myelosuppression. Further studies combining 9-AC with other agents active in ovarian cancer for use as second-line therapy are warranted
— id: 42292, year: 2004, vol: 22, page: 120, stat: Journal Article,

A phase I study of carboplatin plus oral topotecan in advanced malignancies
Kim, E; Hochster, H; Novik, Y; Chachoua, A; Speyer, J; Muggia, F
2004 JUL 15 ;22(14):161S-161S, Journal of clinical oncology
— id: 48677, year: 2004, vol: 22, page: 161S, stat: Journal Article,

Phase I clinical and pharmacokinetic study of BMS-247550, a novel derivative of epothilone B, in solid tumors
Mani, Sridhar; McDaid, Hayley; Hamilton, Anne; Hochster, Howard; Cohen, Marvin B; Khabelle, Dineo; Griffin, Tom; Lebwohl, David E; Liebes, Leonard; Muggia, Franco; Horwitz, Susan Band
2004 Feb 15;10(4):1289-1298, Clinical cancer research
PURPOSE: The purpose of this study was to determine the maximum tolerated dose, toxicity, and pharmacokinetics of BMS-247550 administered as a 1-h i.v. infusion every 3 weeks. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were premedicated and treated with escalating doses of BMS-247550. Blood sampling was performed to characterize the pharmacodynamics and pharmacokinetics of BMS-247550. RESULTS: Twenty-five patients were treated at six dose levels ranging from 7.4 to 59.2 mg/m(2). At 50 mg/m(2), 4 of 9 patients (44.4%) had dose-limiting toxicity (neutropenia, abdominal pain/nausea). At 40 mg/m(2) (the recommended Phase II dose), 2 of 12 patients (16.7%) had dose-limiting neutropenia. Overall, the most common nonhematological toxicity was fatigue/generalized weakness (grade 3-4 seen in 9.0% of patients), followed by neurosensory deficits manifested as peripheral neuropathy and by gastrointestinal discomfort. At 40 mg/m(2), the incidence of grade 3 fatigue, abdominal pain, diarrhea, and neuropathy was 7.7%. Grade 1-2 neuropathy was observed in all patients enrolled and treated at 40 mg/m(2). Two patients with paclitaxel-refractory ovarian cancer, one patient with taxane-naive breast cancer, and another patient with docetaxel-refractory breast cancer had objective partial responses (lasting 6.0, 5.3, 3.0, and 4.5 months, respectively). The mean pharmacokinetic parameter values during course 1 for clearance, volume of distribution, and apparent terminal elimination half-life at the 40 mg/m(2) (recommended Phase II dose) dose level were 21 liters/h/m(2), 826 liters/m(2), and 35 h (excluding one outlier of 516 h), respectively. Values during course 1 and course 2 were similar. CONCLUSIONS: The recommended dose for Phase II evaluation of BMS-247550 is 40 mg/m(2), although more long-term observations are needed. BMS-247550 has advantages over taxanes in relation to drug resistance and warrants further study
— id: 44739, year: 2004, vol: 10, page: 1289, stat: Journal Article,

Liposomal anthracycline treatment for ovarian cancer
Markman, Maurie; Gordon, Alan N; McGuire, William P; Muggia, Franco M
2004 Dec;31(6 Suppl 13):91-105, Seminars in oncology
Platinum/taxane regimens induce high response rates and prolong survival in women with ovarian cancer. After recurrence, however, response to second-line chemotherapy is limited. Pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]), is the only liposomal anthracycline indicated for second-line treatment of platinum- and paclitaxel-refractory ovarian cancer. Response rates ranged from 14% to 20% in nonrandomized trials of this patient population. In a large phase 3 randomized trial, single-agent PLD and topotecan had similar efficacy overall in response rates, but PLD-treated patients had significantly improved overall survival compared with topotecan with a pronounced advantage in platinum-sensitive patients. Another randomized trial reported that PLD and paclitaxel were comparable with regards to response rate, progression-free survival, and overall survival, regardless of the degree of platinum sensitivity. Additional nonrandomized trials of PLD in combination with other active agents resulted in response rates ranging from 20% to 76%. PLD is generally well tolerated and its side-effect profile compares favorably with other commonly used chemotherapeutic agents in this clinical setting. Proper dosing and monitoring may further enhance tolerability while preserving the efficacy of this versatile agent for ovarian cancer
— id: 95538, year: 2004, vol: 31, page: 91, stat: Journal Article,

Phase II trial of carboplatin and infusional cyclosporine in platinum-resistant recurrent ovarian cancer
Morgan, Robert J Jr; Synold, Timothy W; Gandara, David; Muggia, Franco; Scudder, Sidney; Reed, Eddie; Margolin, Kim; Raschko, James; Leong, Lucille; Shibata, Stephen; Tetef, Merry; Vasilev, Steven; McGonigle, Kathryn; Longmate, Jeff; Yen, Yun; Chow, Warren; Somlo, George; Carroll, Mary; Doroshow, James H
2004 Oct;54(4):283-289, Cancer chemotherapy & pharmacology
PURPOSE. To determine the response rate to 26-h continuous infusion cyclosporine A (CSA) combined with a fixed dose level of carboplatin (CBDCA) in patients with recurrent ovarian cancer, and to determine the effect of CSA on the pharmacokinetics of CBDCA. EXPERIMENTAL DESIGN. To examine the effect of duration of CSA exposure on reversal of CBDCA resistance, clonogenic assays were performed in vitro in platinum-resistant A2780 cells. CBDCA (AUC 4) with CSA repeated every 3 weeks was then administered to patients on this phase II study. Pharmacokinetics of CSA and CBDCA were determined in a subset of patients. RESULTS. Preincubation of platinum-resistant A2780 cells with CSA reversed CBDCA resistance in a concentration-dependent and time-dependent manner. A group of 23 patients received 58 courses of CBDCA/CSA therapy. One partial response was observed. Eight patients achieved disease stabilization. Toxicity was similar to that observed in our previous phase I study and consisted of myelosuppression, nausea, vomiting, and headache. The mean+/-SD end-of-infusion CSA level (HPLC assay) was 1253+/-400 microg/ml. The pharmacokinetic studies suggest that CSA does not increase CBDCA AUC. CONCLUSIONS. Steady-state levels of >1 microg/ml CSA (HPLC assay) are achievable in vivo. Modest partial reversal of platinum resistance (in one patient with an objective response and in eight patients with stable disease noted) is achievable in vivo in patients pretreated with CSA. This phenomenon is not explained by alterations in CBDCA pharmacokinetics
— id: 44817, year: 2004, vol: 54, page: 283, stat: Journal Article,

Platinums: extending their therapeutic spectrum
Muggia, F M; Fojo, T
2004 Nov;16 Suppl 4:77-82, Journal of chemotherapy
Three decades since the introduction of cisplatin into clinical cancer treatment, this drug and its second generation analogues, carboplatin and oxaliplatin, form an integral part of recent evolving achievements in the treatment of solid tumors. For example, landmark studies have established a role for cisplatin after resection in lung cancer, and improved survival from platinum-based chemoradiation in cancer of the uterine cervix and combination chemotherapy in mesothelioma, small cell lung, ovarian, and endometrial cancers. Colon cancer survival has improved with the addition of oxaliplatin to its treatment. Here we summarize how insights into the mechanism of action of platinum compounds and studies of their structure-activity relationships may identify platinums with unusual selectivity towards tumors such as melanoma, renal cell, and breast cancer and other cancers not usually treated with existing platinums. Both new drug development and mechanistic studies with established drugs should lead to the next generation of clinical studies with platinum compounds, and their integration with emerging 'targeted therapies'
— id: 50633, year: 2004, vol: 16 Suppl 4, page: 77, stat: Journal Article,

Safety of prolonged Doxil administration in recurrent gynecologic cancers
Muggia, F; Kim, E; Downey, A; McCaffrey, K; Green, R; Ho, MF; Mirchandani, D; Sorich, J; Hochster, H; Hamilton, A
2004 JUL 15 ;22(14):462S-462S, Journal of clinical oncology
— id: 48684, year: 2004, vol: 22, page: 462S, stat: Journal Article,

'Retarded pharmaceuticals' assuming a clinical role
Muggia, FM
2004 NOV ;27(5):437-438, Onkologie
— id: 46473, year: 2004, vol: 27, page: 437, stat: Journal Article,

Re: 'Radiation recall dermatitis induced by pegylated liposomal doxorubicin'
Muggia, Franco M
2004 Jan;15(1):35-35, Anti-cancer drugs
— id: 44818, year: 2004, vol: 15, page: 35, stat: Journal Article,

Recent updates in the clinical use of platinum compounds for the treatment of gynecologic cancers
Muggia, Franco M
2004 Dec;31(6 Suppl 14):17-24, Seminars in oncology
Platinum compounds have long played a role in the treatment of gynecologic cancers. Single-agent cisplatin and carboplatin have shown activity in endometrial cancer, and more recent studies have begun to investigate a variety of new platinum-based combinations. In cervical cancer, chemotherapy is used primarily to treat advanced or recurrent disease. Agents with proven single-agent activity in this setting include cisplatin, ifosfamide, and doxorubicin, and a number of cisplatin-based combination therapies are under clinical investigation. A variety of cisplatin-based combinations have also been used in ovarian cancer chemotherapy, with more recent studies investigating the substitution of carboplatin or oxaliplatin for cisplatin and the addition of paclitaxel. This review will examine recent clinical data on the use of platinum-based chemotherapies for the treatment of these gynecologic cancers
— id: 48889, year: 2004, vol: 31, page: 17, stat: Journal Article,

Relevance of chemotherapy dose and schedule to outcomes in ovarian cancer
Muggia, Franco M
2004 Dec;31(6 Suppl 15):19-24, Seminars in oncology
The current standard of care in ovarian cancer is complete surgical cytoreduction followed by adjuvant (postoperative) platinum-based chemotherapy. Taxanes are frequently combined with platinum compounds in the adjuvant chemotherapy setting and, whether they are given in combination or sequentially, they produce greater progression-free and overall survival than historical combination regimens. Because the treatment of ovarian cancer relies on chemotherapy, this article reviews the evidence for a correlation between chemotherapy delivered at full dose on schedule (FDOS) and patient outcomes. Meta-analyses have suggested that the dose intensities of cisplatin and carboplatin correlate with survival. However, the findings in these hypothesis-generating analyses have not been confirmed in prospective trials. In addition, increasing the dose of cisplatin above a certain threshold is not recommended in ovarian cancer because of the greater toxicity with higher doses of platinum compounds. The delivered dose intensities of taxanes used as single agents have not been shown to correlate with patient outcomes, but adding a taxane to platinum compounds appears both to attenuate the toxicity of the platinum compounds and to facilitate the delivery of FDOS chemotherapy. In the literature on ovarian cancer there is no clear consensus on the benefit of maintaining FDOS chemotherapy. Clinical studies, especially a proposed trial of a dose-dense carboplatin and paclitaxel combination, may provide stronger evidence for the effect of FDOS chemotherapy in ovarian cancer
— id: 48890, year: 2004, vol: 31, page: 19, stat: Journal Article,

The emerging roles of screening and prevention in women's cancer
Muggia, Franco M
2004 ;9(2):228-231, Oncologist
— id: 44819, year: 2004, vol: 9, page: 228, stat: Journal Article,

Cisplatin and irinotecan in squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group
Muggia, Franco M; Blessing, John A; McGehee, Ramon; Monk, Bradley J
2004 Aug;94(2):483-487, Gynecologic oncology
OBJECTIVE: To evaluate the combination of cisplatin and irinotecan as first-line treatment of patients with advanced, persistent, or recurrent squamous cell carcinoma of the cervix. METHODS: Patients with no prior treatment for metastatic disease, presence of measurable tumors, performance status of 0 or 1, and adequate bone marrow, renal, and hepatic functions were potentially eligible for this trial. Cisplatin and irinotecan were given weekly at starting doses of 25 and 65 mg/m(2), respectively, for three consecutive weeks. Cycles were to be repeated every 28 days with dose adjustments as required. Patient accrual was based on a two-stage design with at least seven responses out of 28 patients in the first stage required to proceed to a second stage of accrual seeking a response rate of 40% or better. RESULTS: Of 34 patients entered onto the study, 31 were eligible and 27 were evaluable for response. Ten had received prior chemoradiation containing cisplatin. Among the five (two complete and three partial) observed responses, two were in the subset of patients who had received prior chemoradiation. This level of activity was deemed insufficient to warrant a second stage of accrual. Predominant toxicities were myelosuppression and gastrointestinal symptoms, although six patients experienced none of these adverse effects. CONCLUSION: At these doses, weekly cisplatin and irinotecan failed to demonstrate sufficient activity to undertake a phase III study. Although not apparent in this study, prior chemoradiation may affect response to platinum-based combinations and its impact should be considered in the design of future trials
— id: 44815, year: 2004, vol: 94, page: 483, stat: Journal Article,

Evaluation of vinorelbine in persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study
Muggia, Franco M; Blessing, John A; Method, Michael; Miller, David Scott; Johnson, Gary A; Lee, Roger B; Menzin, Andrew
2004 Feb;92(2):639-643, Gynecologic oncology
PURPOSE: Vinorelbine is being explored by the Gynecologic Oncology Group (GOG) for its possible use in advanced or recurrent squamous cell carcinoma of the uterine cervix. The objective of this Phase II trial was to evaluate a days 1 and 8 every-21-days schedule and determine its activity in patients who had failed standard chemotherapy. PATIENTS AND METHODS: Eligible patients with measurable disease and satisfactory baseline bone marrow, liver, and kidney functions were treated with vinorelbine 30 mg/m(2) given on days 1 and 8 every 21 days. A two-stage sampling design was used, proceeding to a second stage accrual if sufficient activity was documented in the first 25 patients. RESULTS: The study did proceed to the second stage and accrued 44 patients. There were six objective responses (one complete, five partial) for a response rate of 13.7% (95% confidence interval: 5.2-27.4%). There were three patients with response in extra-pelvic sites (including the complete response) and three with response in the pelvis. The overall frequency of grades 3 and 4 neutropenia was 41%, whereas neuropathy was reported in 27% and was severe in three. Treatment-related pain, very severe in two instances, was also reported in 27%. CONCLUSION: Vinorelbine has moderate activity in a pretreated population with squamous cell carcinoma of the cervix. Accordingly, vinorelbine in this days 1 and 8 schedule is being studied further in combination with cisplatin by the GOG
— id: 42595, year: 2004, vol: 92, page: 639, stat: Journal Article,

Phase II trial of the combination of bryostatin-1 and cisplatin in advanced or recurrent carcinoma of the cervix: a New York Gynecologic Oncology Group study
Nezhat, Farr; Wadler, Scott; Muggia, Franco; Mandeli, John; Goldberg, Gary; Rahaman, Jamal; Runowicz, Carolyn; Murgo, Anthony J; Gardner, Ginger J
2004 Apr;93(1):144-148, Gynecologic oncology
OBJECTIVES: Bryostatin-1 is a macrocyclic lactone that has been shown to regulate protein kinase C (PKC) activity and thereby potentially inhibit tumor invasion, angiogenesis, cell adhesion, and multidrug resistance. In preclinical experiments, bryostatin-1 induces tumor growth inhibition and enhances cytotoxicity when combined with other agents including cisplatin in cervical cancer cells. It was therefore anticipated that combination bryostatin-1-cisplatin therapy would be effective in patients with cervical cancer. The current study was conducted to evaluate this therapeutic approach in patients with recurrent or advanced-stage cervical carcinoma. METHODS: An IRB-approved New York Gynecologic Oncology Group (NYGOG) trial was activated for patients with a histological diagnosis of metastatic cervical cancer or in patients with recurrent disease not eligible for surgery or radiation. Enrolled patients received bryostatin-1 (50-65 microg/m(2)) as a 1-h infusion followed by cisplatin (50 mg/m(2)). The combined treatment was administered every 21 days. RESULTS: Fourteen patients were enrolled. The majority of patients had squamous cell carcinoma. Ten out of fourteen patients had recurrent disease. Fifty percent of the patients received bryostatin at 50 microg/m(2) and 50% received bryostatin at 65 microg/m(2). Seventy-one percent completed two cycles of treatment. The most common grade II-III toxicities were myalgia, anemia, and nausea or vomiting. One patient developed a hypersensitivity reaction and one developed grade III nephrotoxicity. Seventy-one percent (10/14) of patients were evaluated for tumor response. Eight out of ten (80%) of patients had progressive disease and 2/10 (20%) had stable disease. There were no treatment responses. CONCLUSIONS: Despite promising preclinical data, this clinical trial indicates that the combination of cisplatin and bryostatin-1 at the doses and schedule used is not effective in patients with advanced-stage or recurrent cervical cancer. There is even the possibility of therapeutic antagonism. The development of a serum assay for bryostatin-1 and additional mechanistic studies would be useful for future bryostatin clinical trials
— id: 44821, year: 2004, vol: 93, page: 144, stat: Journal Article,

Familial breast cancer screening: ethical and social implications
Paradiso, A; Muggia, F
2004 ;15 Suppl 1(2):I5-I6, Annals of oncology
— id: 44816, year: 2004, vol: 15 Suppl 1, page: I5, stat: Journal Article,

A phase I and pharmacokinetic study of docetaxel combined with Doxil (pegylated liposomal doxorubicin) without and with granulocyte colony stimulating factor
Pavlick, Anna C; Chodkiewicz, Catherine; Liebes, Leonard; Hamilton, Anne; Wasserheit, Carolyn; Hochster, Howard; Speyer, James; Phillips, Zoe; Downey, Andrea; Sorich, Joan; Muggia, Franco
2004 Feb;15(2):119-125, Anti-cancer drugs
The purpose of this study was (i) to determine the maximum tolerated dose (MTD) of docetaxel that can be administered in combination with Doxil, given without and with granulocyte colony stimulating factor (G-CSF), (ii) to define the pharmacokinetics (PK) of docetaxel when used in combination with Doxil, and (iii) to make preliminary observations on the anti-tumor activity of this combination in patients with metastatic solid tumors. Thirty-seven patients with metastatic cancer were enrolled. Courses were repeated every 3 weeks. Patients received a fixed dose of Doxil 30 mg/m(2) in combination with escalating doses of docetaxel ranging from 40 to 100 mg/m(2). After encountering dose-limiting febrile neutropenia, subsequent escalation was accomplished with G-CSF support. Selected patients at the recommended phase II dose underwent PK evaluation. The most common toxicity observed was neutropenia. Dose-limiting toxicity (30 mg/m(2) Doxil + 80 mg/m(2) docetaxel) was febrile neutropenia in three of six patients treated without G-CSF. Major non-hematological toxicities included alopecia, mucositis and hand-foot syndrome, and were observed after cumulative doses of chemotherapy. Objective responses (complete/partial) were documented in eight of 37 patients (four with breast cancer) and stable disease was seen in 17 patients. PK studies showed an increased tissue retention (decreased clearance) of docetaxel when given with Doxil. The recommended phase II dose of Doxil/docetaxel is 30/60 mg/m(2), q3 weeks, without G-CSF. Further dose escalation to 30/80 mg/m(2) is safe with G-CSF support. Anti-tumor activity, particularly against breast cancer, was observed at various dose levels. Our observations should provide evidence for phase II studies of this combination in patients with breast cancer and other anthracycline/taxane-sensitive cancers
— id: 44738, year: 2004, vol: 15, page: 119, stat: Journal Article,

A phase II study of liposomal lurtotecan (OSI-211) in patients with topotecan resistant ovarian cancer
Seiden, Michael V; Muggia, Franco; Astrow, Allan; Matulonis, Ursula; Campos, Susanna; Roche, Maria; Sivret, Julia; Rusk, Jason; Barrett, Emma
2004 Apr;93(1):229-232, Gynecologic oncology
OBJECTIVES: To determine the safety and efficacy of a novel topoisomerase I inhibitor, liposomal lurtotecan, in patients with topotecan resistant ovarian cancer. METHODS: The trial was an open-label phase II study for patients stratified by resistance to either single agent topotecan or to a prior topotecan-containing regimen. Liposomal lurtotecan was delivered at a dose of 2.4 mg/m(2) on Days 1 and 8 of a 21-day cycle. Dose escalations and reductions were allowed based on hematologic toxicity. Patients were evaluated every two cycles for response to liposomal lurtotecan. RESULTS: Twenty-two women were accrued, with 16 women resistant to single agent topotecan and 6 women resistant to topotecan given in combination with a second chemotherapy agent. Hematologic toxicity consisted of mild to moderate thrombocytopenia, anemia, and neutropenia with mild to moderate gastrointestinal toxicity and fatigue. There were no responses, although eight patients had stable disease. CONCLUSIONS: Liposomal lurtotecan at this schedule demonstrates moderate hematologic toxicity and no evidence of clinical activity in a group of heavily pretreated women previously exposed to the topoisomerase I inhibitor topotecan. The study of this agent in alternative patient populations or with alternative schedules is ongoing
— id: 44820, year: 2004, vol: 93, page: 229, stat: Journal Article,

Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil): possible role in hypersensitivity reactions
Chanan-Khan, A; Szebeni, J; Savay, S; Liebes, L; Rafique, N M; Alving, C R; Muggia, F M
2003 Sep;14(9):1430-1437, Annals of oncology
BACKGROUND: Pegylated liposomal doxorubicin (Doxil) has been reported to cause immediate hypersensitivity reactions (HSRs) that cannot be explained as IgE-mediated (type I) allergy. Previous in vitro and animal studies indicated that activation of the complement (C) system might play a causal role in the process, a proposal that has not been tested in humans to date. PATIENTS AND METHODS: Patients with solid tumors (n = 29) treated for the first time with Doxil were evaluated for HSRs and concurrent C activation. HSRs were classified from mild to severe, while C activation was estimated by serial measurement of plasma C terminal complex (SC5b-9) levels. Increases in SC5b-9 were compared in patients with or without reactions, and were correlated with Doxil dose rate. RESULTS: Moderate to severe HSRs occurred in 45% of patients. Plasma SC5b-9 at 10 min after infusion was significantly elevated in 92% of reactor patients versus 56% in the non-reactor group, and the rise was greater in reactors than in non-reactors. We found significant association between C activation and HSRs, both showing direct correlation with the initial Doxil dose rate. CONCLUSIONS: C activation may play a key role in HSRs to Doxil. However, low-level C activation does not necessarily entail clinical symptoms, highlighting the probable involvement of further, as yet unidentified, amplification factors
— id: 44752, year: 2003, vol: 14, page: 1430, stat: Journal Article,

Preoperative twice-weekly paclitaxel with concurrent radiation therapy followed by surgery and postoperative doxorubicin-based chemotherapy in locally advanced breast cancer: a phase I/II trial
Formenti, Silvia C; Volm, Matthew; Skinner, Kristin A; Spicer, Darcy; Cohen, Deidre; Perez, Edith; Bettini, Anna C; Groshen, Susan; Gee, Conway; Florentine, Barbara; Press, Michael; Danenberg, Peter; Muggia, Franco
2003 Mar 1;21(5):864-870, Journal of clinical oncology
PURPOSE: Preoperative chemotherapy is the conventional primary treatment in locally advanced breast cancer (LABC). We investigated the safety and efficacy of primary twice-weekly paclitaxel and concurrent radiation (RT) before modified radical mastectomy followed by adjuvant doxorubicin-based chemotherapy. PATIENTS AND METHODS: Stage IIB (T3N0) to III LABC patients were eligible. Primary chemoradiation consisted of paclitaxel, 30 mg/m(2) delivered intravenously for 1 hour twice weekly for a total of 8 to 10 weeks, and concurrent RT (45 Gy at 1.8 Gy/fraction). Modified radical mastectomy was performed at least 2 weeks after completion of chemoradiation or on recovery of skin toxicity. Postoperatively, patients who responded to paclitaxel and RT received four cycles of doxorubicin/paclitaxel, whereas patients who did not respond received doxorubicin/cytoxan. RESULTS: Forty-four patients were accrued. Toxicity from paclitaxel/RT included grade 3 skin desquamation (7%), hypersensitivity (2%), and stomatitis (2%). Postsurgery complications occurred in six patients (14%). The only grade 4 toxicity of postmastectomy chemotherapy was hematologic (10%). Grade 3 toxicities were leukopenia (24%), infection (22%), peripheral neuropathy (17%), arthralgia and pain (17%), stomatitis (12%), fatigue (10%), esophagitis (5%), and nausea (2%). Overall clinical response rate to preoperative paclitaxel and RT was 91%. Thirty-four percent of patients achieved a pathologic response in the mastectomy specimen: 16% pathologic complete responses (clearance of invasive cancer in the breast and axillary contents) and 18% pathologic partial responses (< 10 residual microscopic foci of invasive breast cancer). CONCLUSION: Twice-weekly paclitaxel with concurrent RT is a feasible and effective primary treatment for LABC. Future studies should compare primary chemoradiation to chemotherapy in LABC
— id: 34943, year: 2003, vol: 21, page: 864, stat: Journal Article,

Phase I clinical study of infusional 5-fluorouracil with oxaliplatin and gemcitabine (FOG regimen) in patients with solid tumors
Goel, S; Bulgaru, A; Hochster, H; Wadler, S; Zamboni, W; Egorin, M; Ivy, P; Leibes, L; Muggia, F; Lockwood, G; Harvey, E; Renshaw, G; Mani, S
2003 Nov;14(11):1682-1687, Annals of oncology
BACKGROUND: The aim of this study was to determine the maximum tolerated dose, recommended phase II dose (RPTD) and toxicities of the FOG regimen (infusional 5-fluorouracil, oxaliplatin, gemcitabine). PATIENTS AND METHODS: Patients with advanced solid tumors were treated in an accelerated titration scheme. 5-Fluorouracil was administered intravenously at 200 mg/m(2)/day for 14 days and repeated every 21 days (one cycle). Gemcitabine was administered on days 1 and 8 over 30 min at 450-650 mg/m(2). Oxaliplatin was administered on day 1 over 2 h at 85-130 mg/m(2). For cycles 1, 3 and beyond, gemcitabine followed oxaliplatin; for cycle 2, gemcitabine preceded oxaliplatin. RESULTS: Forty-five and 39 patients were assessable for toxicity and response, respectively. Cycle 1 dose-limiting toxicities (DLT) included neutropenia, thrombocytopenia and diarrhea. No DLT was observed in cycle 1 at the first four dose levels (DL). At DL-5, two of four (50%) patients experienced DLT in cycle 1. Expanding DL-4, nine of 26 (35%) patients experienced DLT in cycle 1. Because recurrent grade 3 toxicities were observed in three of six (50%) patients at DL-3, DL-2 was considered the RPTD. At the RPTD, three patients had a partial response (response rate 23%). CONCLUSIONS: The RPTD for the 5-fluorouracil-oxaliplatin-gemcitabine combination is 200/100/450 mg/m(2). This novel regimen has demonstrated activity in advanced solid tumors and merits further investigation
— id: 44740, year: 2003, vol: 14, page: 1682, stat: Journal Article,

Phase I study of amifostine as a cytoprotector of the gemcitabine/cisplatin combination in patients with advanced solid malignancies
Haigentz, Missak Jr; Kim, Mimi; Sorich, Joan; Lee, Janet; Hochster, Howard; Macapinlac, Manuel; Mirchandani, Deepu; Sewak, Sanjeev; Pavlick, Anna; Volm, Matthew; Hamilton, Anne; Muggia, Franco M
2003 Apr;14(4):321-326, Anti-cancer drugs
Our objective was to evaluate the role of amifostine as a cytoprotector in patients with solid tumors receiving the myelosuppressive regimen of gemcitabine/cisplatin combination. Patients with advanced solid tumors were randomized to gemcitabine-amifostine-cisplatin (GAP) or gemcitabine-cisplatin (GP) in Cycle 1 (C1) and then were crossed over to the other treatment in Cycle 2 (C2). Amifostine at 740 mg/m2, followed by gemcitabine and cisplatin, were given for 2 consecutive weeks, every 4 weeks. Two GP combinations were studied: G 1000 mg/m2 and P 40 mg/m2 days 1, 8 (high dose), and G 800 mg/m2 and P 30 mg/m2 days 1, 8 (low dose). Forty patients were enrolled. Of the 19 patients treated with high-dose GP, 11 (nine patients GP in C1 and GAP in C2, two patients GAP in C1 and GP in C2) completed 2 cycles of therapy. Of the eight non-evaluable patients, five patients dropped out due to toxicity or refusal after treatment with amifostine in C1. Of the 21 patients treated with low-dose GP, 15 (eight patients GP in C1 and GAP in C2, seven patients GAP in C1 and GP in C2) were likewise evaluable. The incidence of grade 3 or 4 hematologic toxicities was similar for GP and GAP during the first 2 cycles of treatment, and there were no statistically significant differences in mean absolute neutrophil count, hemoglobin level and platelet levels between the cycles in each arm. We conclude that amifostine, at 740 mg/m2, does not lead to less myelosuppression when combined with gemcitabine/cisplatin chemotherapy regimens and may possibly contribute to subjective intolerance
— id: 44744, year: 2003, vol: 14, page: 321, stat: Journal Article,

Pegylated liposomal doxorubicin (PLD) and carboplatin (C): A phase I study of combination therapy with maintenance PLD
Hamilton AL; Pavlick A; Volm M; Adams S; Hochster H; Moore S; Mozina J; Cordner M; Utate M; Muggia F
2003 ;22:2003-2003 #1986, Proceedings (American Society of Clinical Oncology)
Anthracyclines and platinums have activity in GYN, lung, breast and upper GI tumors, lymphomas and sarcomas. C and PLD (Doxil, Caelyx) have non-overlapping toxicity profiles: C produces myelosuppression, nausea and peripheral neuropathy while PLD causes schedule-dependent mucocutaneous toxicity. This study aimed to define the RPTD of the two agents in combination. Design: Patients (pt) received C and PLD on D1 of a 21 day schedule. 5 dose levels (DL) were studied (C AUC / PLD mg/m2): DL1: 4/20; DL2: 4/25; DL3: 4/30; DL4: 5/30; DL5: 6/30. DLT were febrile neutropenia, G4 heme or G3 non-heme toxicity other than hypersensitivity (HSR). Pt with heme toxicity could omit C in later cycles and continue PLD until disease progression. Pt with mucocutaneous toxicity extended the PLD dosing interval to 28 days. Results: 20 pt were treated: 7M/13F. Age: med 58.5, range 36-85. Tumors: ovarian (EOC)(7), MMT (2), endometrial (1), cervix (2), H&N (3), NPC (2), leiomyosarc (1), breast (1), islet cell (1). Prior chemo: 13. Pt received a median of 4 cycles of C/PLD (range 1-8) and 8 pt received maintenance PLD after cessation of C. No DLT occurred at any DL. At DL5 (n=6 eval), C1 toxicities were G1-2 ANC/Hb (4), G2 vaginal mucositis (1), G2 HSR (1), G1-2 nausea/vom (2), G2 fatigue (1), G2 hand-foot syndrome (1), G1 diarrhea (1). No cardiac events were observed. RECIST responses were observed in 4 pts (MMT 2, NPC 1, EOC 1). In pt with EOC, Ca125 responses were seen in 4/4 evaluable pt. Conclusions: C and PLD can be safely administered together at full dose, and maintenance PLD is feasible. This combination warrants phase III evaluation in ovarian cancer and may be a useful regimen in other solid tumors. Supported by M01 RR00096 and the Lynne Cohen Foundation for Ovarian Cancer Research
— id: 79467, year: 2003, vol: 22, page: 2003, stat: Journal Article,

Oxaliplatin with weekly bolus fluorouracil and low-dose leucovorin as first-line therapy for patients with colorectal cancer
Hochster, Howard; Chachoua, Abraham; Speyer, James; Escalon, Juliette; Zeleniuch-Jacquotte, Anne; Muggia, Franco
2003 Jul 15;21(14):2703-2707, Journal of clinical oncology
PURPOSE: To determine the activity of biweekly oxaliplatin, combined with weekly bolus fluorouracil (FU) and low-dose leucovorin (LV) chemotherapy (bFOL), as first-line therapy for patients with metastatic colorectal cancer. PATIENTS AND METHODS: Patients with measurable metastatic colorectal cancer; no previous therapy for advanced disease (adjuvant therapy allowed if >6 months since completion); and performance status 0, 1, or 2 were eligible and were treated with oxaliplatin 85 mg/m2 days 1 and 15 plus LV 20 mg/m2 over 10 to 20 minutes, followed by a 500 mg/m2 bolus dose of FU on days 1, 8, and 15 every 28 days. Patients underwent response evaluation by computed tomographic scan every 2 months. RESULTS: Forty-two patients were entered, and 41 patients were treated, including 20 men and 22 women, nine with previous adjuvant chemotherapy and four with radiation therapy. Three patients achieved complete response, and 23 patients achieved partial response, for a response rate of 63% (95% CI, 49% to 78%). Major toxicities included cumulative neuropathy grade 2 (24%) and grade 3 (12%; requiring discontinuation of oxaliplatin), diarrhea grade 3 to 4 (29%) and grade 3 to 4 hematologic toxicity (10%). Median time to progression was 9.0 months (95% confidence interval, 7.1 to 10.8 months) with median survival of 15.9 months (95% confidence interval, 11.4 to 19.7 months). CONCLUSION: The bFOL regimen seems to have activity comparable to be infusional programs of FU combined with oxaliplatin. Prospective trials are warranted to determine the relative merits of this schedule compared with the currently indicated schedules
— id: 44743, year: 2003, vol: 21, page: 2703, stat: Journal Article,

Mechanisms of proteasome inhibitor PS-341-induced G(2)-M-phase arrest and apoptosis in human non-small cell lung cancer cell lines
Ling, Yi-He; Liebes, Leonard; Jiang, Jian-Dong; Holland, James F; Elliott, Peter J; Adams, Julian; Muggia, Franco M; Perez-Soler, Roman
2003 Mar;9(3):1145-1154, Clinical cancer research
PURPOSE: PS-341 is a novel dipeptide boronic acid proteasome inhibitor with in vitro and in vivo antitumor activity that induces mechanisms of apoptosis by unknown mechanisms. EXPERIMENTAL DESIGN: Human non-small cell lung cancer cell lines were used to investigate effects PS-341 on cell proliferation, cell cycle progression, and the induction of apoptosis. RESULTS: PS-341 was 38-360-fold more cytotoxic against H460 cells when compared with the proteasome inhibitors MG-132 and PSI. Differential PS-341 cytotoxic effects were found with respect to P53 function: H322 cells (p53 mutant) were 6-fold less sensitive as compared with H460 cells (p53 wild type); and H358 cells (p53 null) were 1.6-fold more sensitive as compared with H460 cells (p53 wild type). A concentration- and time-dependent cell cycle blockade at G(2)-M phase was seen for H460 cells without any direct effects on microtubule polymerization or depolymerization. PS-341 exposure in H460 cells led to stabilization of p53, induction of p21(cip/waf-1) and MDM2 expression, an increase in cyclin B and cyclin A, and the activation of cyclin B and cyclin A kinases. MDM2 induction was found only in H460 cells, whereas in H322 and H358 cells, G(2)-M-phase arrest, p21(cip/waf-1) induction, and an increase in cyclin B1 were found. The commitment of G(2)-M-phase cells to apoptosis was verified by the activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase in drug-free medium. CONCLUSIONS: Our data suggest that the PS-341-induced G(2)-M-phase arrest may be associated with the inhibition of degradation of cell cycle regulators and that the up-regulation of p21(cip/waf-1) expression may be via p53-dependent and/or -independent pathways. The resulting disturbance of cell cycle progression leads either to growth inhibition or to the initiation of apoptotic pathways
— id: 44754, year: 2003, vol: 9, page: 1145, stat: Journal Article,

Intraperitoneal therapy as consolidation for patients with ovarian cancer and negative reassessment after platinum-based chemotherapy
Lu, M Janice; Sorich, Joan; Hazarika, Maitreyee; Kim, Mimi; Del Priore, Giuseppe; Jacobs, Allan J; Chiang, Chang; Liu, Paul C; Fusco, Eileen; Curtin, John P; Muggia, Franco M
2003 Aug;17(4):969-975, Hematology-oncology clinics of North America
Although three large phase III trials have documented the benefit of IP chemotherapy, this therapy as consolidation has been studied in only a few pilot studies. These small studies have included patients with a variety of baseline prognostic characteristics, and only one series had a comparator group of surgically documented pathologic complete response to uniform systemic chemotherapy. No randomized trials have been done to assess the impact of IP consolidation on progression-free survival or survival in either positively or negatively reassessed patients. It is hoped that the current experience will trigger further consideration of future phase III trials to assess the value of IP consolidation after initial induction with chemotherapy (ie, chemical debulking)
— id: 39088, year: 2003, vol: 17, page: 969, stat: Journal Article,

Sequential single agents as first-line chemotherapy for ovarian cancer: a strategy derived from the results of GOG-132
Muggia, F M
2003 Nov-Dec;13 Suppl 2(1):156-162, International journal of gynecological cancer
First-line chemotherapy for ovarian cancer during the past decade has evolved toward the use of carboplatin and paclitaxel combinations. This has been based on randomized trials showing that combinations of these two drugs lead to a outcome similar to that obtained using cisplatin and paclitaxel (that had, in turn, proven superior in progression-free survival and overall survival to cisplatin and cyclophosphamide) but with less toxicity. Surprisingly, taxane-platinum combinations were not superior to control arms in two studies (ICON3 and GOG-132) utilizing carboplatin or cisplatin as the comparators. This has renewed interest in the role of single agents in first-line chemotherapy - a concept also supported by a number of prior clinical trials with single-agent platinum compounds yielding results not inferior to combinations. Early 'pre-emptive' crossover (prior to the stipulated clinical progression) to paclitaxel or a paclitaxel-containing regimen, however, occurred in 24% of patients initially treated with cisplatin on GOG-132. This has led to the interpretation of this trial as a combination versus sequential design. Although not subscribing to this interpretation, the results of GOG-132 and ICON3 not only raise doubts over a clear superiority of combinations over single agents but also lead to a consideration of sequential treatment designs for first line. Advantages of such designs are: (a) ability to provide 'dose-dense' platinums followed by 'dose-dense' paclitaxel and, perhaps, other drugs; and (b) the potential of acquiring biological data linked to the antitumor effects of a specific drug. Mathematical modeling and recent positive results in breast cancer adjuvant therapy support the use of 'dose-dense' strategies, and these should be considered in the design of future trials in ovarian cancer
— id: 44823, year: 2003, vol: 13 Suppl 2, page: 156, stat: Journal Article,

Boosting bioavailability to topotecan: What do we gain?
Muggia, FM
2003 JAN 1 ;21(1):177-177, Journal of clinical oncology
— id: 37139, year: 2003, vol: 21, page: 177, stat: Journal Article,

Doxorubicin for metastatic breast cancer: time for a change?
Muggia, Franco
2003 ;21(6):967-968, Cancer investigation
— id: 44822, year: 2003, vol: 21, page: 967, stat: Journal Article,

Treatment of sarcomas: thinking out-of-the-box
Muggia, Franco M; Pavlick, Anna
2003 Apr;21(2):321-322, Cancer investigation
— id: 44824, year: 2003, vol: 21, page: 321, stat: Journal Article,

Emerging treatments for ovarian cancer
Muggia, Franco; Lu, M Janice
2003 May;8(1):203-216, Expert opinion on emerging drugs
The survival at 5 years, of patients with ovarian cancer, has steadily improved since 1960, when surgery and alkylating agents were the only initial modalities employed to cope with the usual late presentation of the disease. In the 1980s, cisplatin and then carboplatin became established as the most active drugs, alone or in combination with other drugs. In the last decade, the antimicrotubulin drug paclitaxel, and the topoisomerase I inhibitor topotecan were noted to be active after failure of platinum drugs. These drugs, as well as others with known activity in the second-line setting, such as the pegylated liposomal doxorubicin, gemcitabine and oral etoposide, all play a role in the treatment of these patients and likely prolong survival without eradicating the disease. The plight of these patients has stimulated new areas of drug development. Here, the evolution of the current therapeutic strategy, the scientific rationale for cytotoxic and non-cytotoxic agents and their status at present are reviewed. 'Targeted' drug trials, in contrast to trials studying cytotoxic drug analogues, currently represent only a minor portion of clinical trials in ovarian cancer
— id: 38999, year: 2003, vol: 8, page: 203, stat: Journal Article,

Vaccine therapy of follicular lymphoma in first remission: Long-term follow-up of phase II results and high rate of chemotherapy-induced complete remissions in a controlled, randomized phase III trial
Neelapu, SS; Gause, BL; Nikcevich, DA; Schuster, SJ; Winter, J; Gockerman, JP; Sotomayor, E; Inghirami, G; Muggia, F; Watson, T; Snow, S; Kubovic, P; Ferraro, M; Jaffe, ES; Reynolds, CW; Kwak, LW
2003 NOV 16 ;102(11):307B-308B, Blood
— id: 42519, year: 2003, vol: 102, page: 307B, stat: Journal Article,

A phase I study of paclitaxel, estramustine phosphate and vinorelbine (Pacl-E-Vin) in advanced malignancies: triple tubulin targeting
Sewak, Sanjeev; Chachoua, Abraham; Hamilton, Anne; Taneja, Samir; Lee, Janet; Utate, Minerva; Sorich, Joan; Muggia, Franco M
2003 Jan;14(1):67-72, Anti-cancer drugs
Anti-tubulin couplets have activity in hormone-resistant prostate cancer. This study was designed to define the dose-limiting toxicity (DLT) and recommended phase II dose (RPTD) of the unique triplet combination of paclitaxel, estramustine phosphate (EMP) and vinorelbine (Pacl-E-Vin). Patients with advanced malignancies who had failed standard therapy, ECOG performance status (PS 0-2) and adequate organ function were included. Dose of EMP was fixed at 300 mg/m /dose p.o. t.i.d. on days 1-3 and 8-10. Vinorelbine dose was 20 mg/m /day i.v. on days 3 and 10. Paclitaxel was dose escalated from 40 to 50 mg/m /day i.v. on days 3 and 10. Cycles were repeated every 3 weeks. Twelve adults (median age 72) were entered on this study. Primary tumors included prostate ( =7), cervix ( =2), melanoma ( =1), colon (1) and lung with synchronous prostate cancer ( =1). Nine patients had received no prior chemotherapy, one had received a prior regimen and two had received two or more prior regimens. Of four evaluable patients at dose level 1, one patient had grade 3 neutropenia leading to the day 10 dose being withheld. Of five evaluable patients at dose level 2, there was one DLT (febrile neutropenia) and two grade 3 neutropenias leading to the day 10 dose being withheld. One patient had a lower extremity deep vein thrombosis. Other side effects were mild and reversible. Nine patients were evaluable for efficacy: three with prostate cancer had a greater than 50% prostate-specific antigen (PSA) response, and a patient with synchronous prostate and lung cancer had a greater than 50% PSA response. We conclude that the DLT of Pacl-E-Vin is neutropenia. RPTD is vinorelbine 20 mg/m, paclitaxel 40 mg/m, both administered on days 3 and 10, and EMP 900 mg/m /day on days 1-3 and 8-10, q3w. Dose omission at day 10 followed by 20% dose reduction of paclitaxel and vinorelbine is recommended in the event of grade 3 neutropenia. Activity in hormone-refractory prostate cancer is promising and warrants phase II evaluation
— id: 34609, year: 2003, vol: 14, page: 67, stat: Journal Article,

Liposome-induced hypersensitivity reactions: The role of complement activation
Szebeni, J; Baranyi, L; Savay, S; Milosevits, J; Bunger, R; Laverman, P; Metselaar, JM; Storm, G; Chanan-Khan, A; Liebes, L; Muggia, FM; Cohen, R; Barenholz, Y; Alving, CR
2003 AUG 7 ;13(1):47-48, Journal of liposome research
— id: 37173, year: 2003, vol: 13, page: 47, stat: Journal Article,

Complement activation underlying pseudoallergic drug reactions
Szebeni, J; Baranyi, L; Savay, S; Milosevits, J; Chanan-Khan, AA; Liebes, L; Muggia, FM; Barenholz, Y; Bunger, R; Alving, CR
2003 SEP ;40(2-4):180-180, Molecular immunology
— id: 55475, year: 2003, vol: 40, page: 180, stat: Journal Article,

Intraperitoneal therapy for stage III ovarian cancer: A therapy whose time has come!
Alberts, DS; Markman, M; Armstrong, D; Rothenberg, ML; Muggia, F; Howell, SB
2002 OCT 1 ;20(19):3944-3946, Journal of clinical oncology
— id: 32549, year: 2002, vol: 20, page: 3944, stat: Journal Article,

Pre-clinical studies of concomitant PS-341 and ionizing radiation therapy: local and systemic anti-tumor effects
Formenti, S; Demaria, S; Liebes, L; Ng, B; Devitt, M; Babbs, J; Muggia, F
2002 NOV ;38(4):34-A256, European journal of cancer
— id: 98237, year: 2002, vol: 38, page: 34, stat: Journal Article,

Correlation of p53 immunostaining in primary and residual ovarian cancer at the time of positive second-look laparotomy and its prognostic role: A Southwest Oncology Group ancillary study
Hawes, D; Liu, PY; Muggia, FM; Wilczynski, S; Cote, R; Felix, J; Terada, K; Belt, RJ; Alberts, DS
2002 OCT ;87(1):17-23, Gynecologic oncology
Objective. The objective of this study was to verify the correlation between p53 immunostaining at initial diagnosis and at positive reassessment after completing platinum-based chemotherapy and to assess prognostic differences between patients whose tumors display positive immunostaining versus those that have negative immunostaining at such reassessment. Methods. This study made use of samples from patients entered into a prospective randomized study of the Southwest Oncology Group (SWOG 8835) that treated patients with minimal residual disease at second-look laparotomy with either intraperitoneal (ip) mitoxantrone or fluorodeoxyuridine (FUDR). Unstained slides from tumor obtained at the initial diagnosis and at reassessment were retrospectively requested from individual institutions. The degree of nuclear staining was determined using the anti-p53 mouse monoclonal antibody Pab1801 and previously published techniques, with a cutoff of 10% or more staining of tumor cell nuclei for a positive result. Cox model regression analysis was performed for overall survival and progression-free survival, with p53 status, ip treatment, and baseline CA125 as independent variables. Results. p53 determination was feasible in 22 patients both at diagnosis and at the second-look samples; 9 additional patients had only either sample available. Since concordance between the 10 negative and 12 positive immunostained samples was 100%, all 31 patients were considered in the Cox model. The death hazard ratio of p53-positive versus p53-negative patients was 4.18 (two-sided P value of 0.006). Conclusion. p53 immunostaining at second-look laparotomy correlates with the immunostaining at diagnosis. In this series confined to patients with minimal residual disease after initial therapy subjected to second-line intraperitoneal treatment, it appears to identify a poor prognostic (positive) subset for survival. (C) 2002 Elsevier Science (USA)
— id: 32544, year: 2002, vol: 87, page: 17, stat: Journal Article,

Use of medroxyprogesterone acetate in the treatment of Mullerian adenosarcoma: a case report
Hines, Brian J; Porges, Robert F; Mittal, Kush; Muggia, Franco M; Curtin, John P
2002 Apr;85(1):192-195, Gynecologic oncology
BACKGROUND: Mullerianadenosarcoma is a rare pelvic malignancy that most commonly arises from the endometrium. These tumors are relatively insensitive to chemotherapy and radiation and are primarily treated by surgical resection. We report a case of mullerian adenosarcoma arising outside of the uterus from a background of endometriosis treated with a combination of surgical resection and medroxyprogesterone acetate. CASE: A 43-year-old woman with a history of endometriosis was diagnosed with advanced extrauterine mullerian adenosarcoma. After suboptimal tumor dubulking surgery she was treated with medroxyprogesterone acetate. Ten months postoperatively she remains without evidence of disease. CONCLUSION: Medroxyprogesterone acetate may be a useful drug in the treatment of advanced mullerian adenosarcoma
— id: 36624, year: 2002, vol: 85, page: 192, stat: Journal Article,

PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis
Ling, Yi-He; Liebes, Leonard; Ng, Bruce; Buckley, Michael; Elliott, Peter J; Adams, Julian; Jiang, Jian-Dong; Muggia, Franco M; Perez-Soler, Roman
2002 Aug;1(10):841-849, Molecular cancer therapeutics
Treatment with the proteasome inhibitor, PS-341 resulted in concentration- and time-dependent effects on Bcl-2 phosphorylation and cleavage in H460 cells that coincided with the PS-341-induced G2-M phase arrest. The observed Bcl-2 cleavage paralleled the degree of PS-341-induced apoptosis but was detected to a similar extent with comparable concentrations of two other proteasome inhibitors (MG-132 and PSI). Calpain inhibitors, ALLM and ALLN, and the caspase inhibitors, Z-VAD and AC-YVAD did not induce BcI-2 phosphorylation and cleavage. Exposure to PS-341 resulted in an additional Mr 25,000 cleavage fragment of Bcl-2, whereas only a Mr 23,000 fragment was observed with other anticancer agents. The formation of the Mr 25,000 fragment was not prevented by caspase inhibitors unlike the Mr 23,000 fragment, which suggests mediation by a caspase-independent pathway. Cell fractionation studies revealed that the Bcl-2 cleaved fragments localize within membrane structures and was an early event (at approximately 12 h, posttreatment), and before the observed cleavage of poly(ADP-ribose) polymerase (PARP), beta-catenin, and DNA fragmentation (at approximately 36 h posttreatment). The Mr 23,000 Bcl-2 cleavage product was inhibited by the pan-caspase inhibitor and the inhibitors of capase-3, -8, -9; but the PARP cleavage was prevented only by the pan-caspase and caspase-3 inhibitors, which suggests that the Mr 23,000 Bcl-2 cleavage occurred at both the initiation and execution stages of apoptosis. The inhibition of the ubiquitin/proteasome pathway by PS-341 leads, at an early stage of apoptosis, to Bcl-2 phosphorylation and a unique proteolytic cleavage product, which are associated with G2-M phase arrest and the induction of apoptosis
— id: 44756, year: 2002, vol: 1, page: 841, stat: Journal Article,

Validation of the pharmacodynamics of BMS-247550, an analogue of epothilone B, during a phase I clinical study
McDaid, HM; Mani, S; Shen, HJ; Muggia, F; Sonnichsen, D; Horwitz, SB
2002 Jul;8(7):2035-2043, Clinical cancer research
The primary aims of this study were to evaluate the time course and dose response of microtubule bundle formation in peripheral blood mononuclear cells (PBMCs) and to correlate these data with BMS-247550 pharmacokinetics. The data presented here were obtained from 17 patients enrolled in a Phase I trial who received five dose levels of BMS-247550 (7.4-59.2 mg/m(2)), given as a 1-h infusion once every 3 weeks. Plasma drug exposure or area under the curve (AUC), and tubulin bundle formation in PBMCs were assessed in cycles 1 and 2. Similar analyses were also performed on tumor biopsies from one eligible patient. PBMCs exhibited dramatic microtubule bundle formation 1 h after infusion that declined by 24 h, showing a positive correlation with AUC((0-24)) for cycles 1 and 2. A similar pattern of tubulin bundle formation also was observed in a smaller proportion of breast tumor cells from one patient who exhibited a partial response to BMS-247550. This patient's tumor expressed multidrug resistance (MDR1) and MDR-associated protein (MRP1), and in addition poly(ADPribose) polymerase cleavage, a marker of cell death, was observed within 23 h after drug infusion. This patient was also heterozygous for a novel polymorphism at the extreme COOH terminus of beta-tubulin (Gly 437 Gly/Ser), although the relevance of the polymorphism to the response is unknown. In summary, microtubule bundle formation in PBMCs occurs within 1 h of treatment with BMS- 247550 and is related to plasma AUC. Similar bundle formation was seen in one tumor sample, despite expression of MDR1 and MRP1. Cell death occurred 23 h after peak microtubule bundle formation in these tumor cells. These findings validate in vitro pharmacodynamic observations
— id: 32372, year: 2002, vol: 8, page: 2035, stat: Journal Article,

Current data with liposomal anthracyclines in metatastic breast cancer
Muggia F; Formenti SC; Volm M
2002 Aug;1(1):11-14, Current trends in anthracyclines
— id: 109306, year: 2002, vol: 1, page: 11, stat: Journal Article,

Stable disease in mesothelioma: A therapeutic achievement?
Muggia, F
2002 Aug 9;20(5-6):859-860, Cancer investigation
— id: 32376, year: 2002, vol: 20, page: 859, stat: Journal Article,

Phase II trial of the pegylated liposomal doxorubicin in previously treated metastatic endometrial cancer: a Gynecologic Oncology Group study
Muggia, Franco M; Blessing, John A; Sorosky, Joel; Reid, Gary C
2002 May 1;20(9):2360-2364, Journal of clinical oncology
PURPOSE: To determine whether pegylated liposomal doxorubicin (PLD) has antitumor activity in pretreated patients with persistent or recurrent endometrial carcinoma and to define the nature and degree of toxicity of PLD. PATIENTS AND METHODS: Women with histologically documented recurrent or persistent measurable endometrial carcinoma and with failure of one prior treatment regardless of prior anthracycline therapy were enrolled. PLD was administered intravenously over a 1-hour period at a dose of 50 mg/m(2) every 4 weeks; the dosage was modified in accordance with observed toxicity. RESULTS: Of 46 patients entered, 42 were assessable for response, as three were declared ineligible on central pathology review and one was not assessable for response. Forty had received prior chemotherapy, 11 hormonal therapy, and 29 radiation therapy. Doxorubicin had been given to 32 patients, carboplatin with paclitaxel to six, carboplatin to one, and fluorouracil to one. Four patients had partial responses lasting 1.1, 2.1, 3.3, and 5.4 months; the overall response rate was 9.5% (95% confidence interval, 2.7% to 22.6%). Three of these responses (in liver and in lymph node) occurred in patients who had progressed after doxorubicin with either paclitaxel or cisplatin. The median number of courses was 2.5 (range, one to 14). Toxicity was generally mild: only 25 patients experienced leukopenia, with a median WBC count of 2,900 (range, 800 to 3,900) at nadir. The only grade 4 toxicities were one episode each of esophagitis, hematuria, and vomiting. The median overall survival was 8.2 months. CONCLUSION: PLD has only limited activity in pretreated advanced, recurrent endometrial cancer, but further trials in anthracycline-naive patients and in previously untreated patients are ongoing. Its toxicity profile should permit its use in combination with myelosuppressive drugs
— id: 27563, year: 2002, vol: 20, page: 2360, stat: Journal Article,

Phase I and pharmacologic study of i.p. 9-aminocamptothecin given as six fractions over 14 days
Muggia, Franco M; Liebes, Leonard; Hazarika, Maitreyee; Wadler, Scott; Hamilton, Anne; Hornreich, Gila; Sorich, Joan; Chiang, Chung; Newman, Elliot; Potmesil, Milan; Hochster, Howard
2002 Sep;13(8):819-825, Anti-cancer drugs
We sought to define the tolerance of 9-amino-20(S)-camptothecin (9-AC) when given by the i.p. route to patients with cancer in the peritoneal cavity consisting of nodules that did not exceed 1 cm in maximum diameter. 9-AC was given in six fractions over 12 days, at doses ranging from 1.25 to 13.5 mg/m(2) in cycles repeated every 28 days. Dose escalations after the first two dose levels took place in cohorts of three patients, with expansion of the dose level once a dose-limiting toxicity (DLT) was encountered. All patients had blood and i.p. pharmacokinetic (PK) analysis during cycle 1 of each dose level. Topoisomerase (Topo) I signal was serially measured in peripheral blood mononuclear cells (PBMCs) in blood and cells collected in i.p. cytologic washings. Twelve patients received 31 cycles of 9-AC. Tolerance to repeated i.p. drug administration was generally excellent. The DLT was neutropenia encountered at the highest dose level in two patients, whereas the dose of 9 mg/m(2) was well tolerated. The DLTs were associated with peak plasma levels ranging from 47 to 81 ng/ml and also depletion of Topo I in PBMCs. The i.p.:plasma AUC ratio (+/-SD) was 11.5 (+/-3.8). Two patients had objective evidence of clinical benefit and only one of seven patients deemed evaluable for response had progressive disease. We conclude that i.p. 9-AC demonstrates excellent local tolerance at a dose and schedule associated with evidence of systemic effects. A dose of 9 mg/m(2)/cycle administered in a schedule of six divided fractions is suitable for further evaluation against tumors involving primarily the peritoneal cavity
— id: 39386, year: 2002, vol: 13, page: 819, stat: Journal Article,

Neoadjuvant chemotherapy with CPT-11 and cisplatin downstages locally advanced gastric cancer
Newman, Elliot; Marcus, Stuart G; Potmesil, Milan; Sewak, Sanjeev; Yee, Herman; Sorich, Joan; Hayek, Mary; Muggia, Franco; Hochster, Howard
2002 Mar-Apr;6(2):212-223, Journal of gastrointestinal surgery
We examined the role of neoadjuvant therapy in downstaging locally advanced gastric cancer. Preoperative staging was performed with a combination of CT scans, endoscopic ultrasonography and/or laparoscopy, and laparoscopic ultrasonography. Patients with T > or =3 tumors and/or node-positive disease by preoperative clinical staging were eligible for entry. Neoadjuvant therapy consisted of two cycles of CPT-11 (75 mg/m(2)) with cisplatin (25 mg/m(2)) weekly four times every 6 weeks. This was followed by resection with D2 lymph node dissection and two cycles of intraperitoneal chemotherapy with floxuridine and cisplatin. Twenty-two patients were entered into the study (4 with T3N0 disease and 18 with T3N1 disease). Induction chemotherapy was well tolerated with major toxicities being neutropenia and diarrhea. A median of 78%/75% of the planned dosage of CPT-11/cisplatin was delivered. Two patients withdrew consent during the first cycle and were lost to follow-up. One patient progressed to stage IV disease during induction chemotherapy and did not undergo surgery. Nineteen patients underwent surgery. One patient had undetected stage IV disease (liver) and underwent a palliative R2 resection. Of the 18 remaining patients, 17 had curative R0 resections and one had a palliative R1 resection. A median of 21 lymph nodes (range 1 to 121) were examined histologically. There was one postoperative death. Surgical morbidity did not appear to increase after the neoadjuvant regimen. The median postoperative length of hospital stay was 9 days (range 3 to 75 days). Postoperative pathologic staging yielded 16% T3 lesions compared to 85% before treatment based on clinical staging; postoperative American Joint Committee on Cancer staging yielded 37% stage IIIA disease compared to 70% stage IIIA before treatment. With a median follow-up of 15 months, median survival has not yet been reached. We conclude that CPT-11-based neoadjuvant therapy downstages locally advanced gastric cancer. Further follow-up is necessary to determine the ultimate impact of this combination therapy on recurrence and survival
— id: 39653, year: 2002, vol: 6, page: 212, stat: Journal Article,

Thalidomide in hepatocellular cancer (HCC) with optional interferon-alpha upon progression
Schwartz JD; Sung MW; Lehrer D; Goldenberg A; Muggia F; Volm M
2002 ;21:- #1847, Proceedings (American Society of Clinical Oncology)
— id: 92760, year: 2002, vol: 21, page: , stat: Journal Article,

Endometrial carcinoma with cerebellar metastasis: a case report and review of the literature
Sewak, Sanjeev; Muggia, Franco M; Zagzag, David
2002 Jun;58(2):137-140, Journal of neuro-oncology
BACKGROUND: Endometrial cancer is the most common malignancy involving the female genital tract in the United States. There is a paucity of reports of brain metastases in this disease, and most of these reports emphasize that this pattern of dissemination is rare. CASE: We present a case of a 63-year-old woman who had high-grade endometrial carcinoma treated with surgery and radiotherapy. She had three separate episodes of relapse in the lungs, the first two relapses being treated surgically. Chemotherapy was also administered following surgery for the first relapse. The third pulmonary recurrence was treated with chemotherapy and then consolidated with thoracic radiation. Four years from the date of diagnosis, and a few weeks after completion of thoracic radiotherapy, she had evidence of a solitary cerebellar metastasis. This was treated surgically and followed by whole brain irradiation. She died 6 months after this central nervous system diagnosis with systemic dissemination of her cancer. CONCLUSION: The existing literature on brain metastases from endometrial cancer is reviewed together with the patterns of spread of endometrial cancer. We call attention to the unusually long course of this patient. Partially successful treatment for metastatic disease may have predisposed eventual development of brain metastases. This occurrence reinforces reports emphasizing their increasing incidence in association with endometrial cancer
— id: 34739, year: 2002, vol: 58, page: 137, stat: Journal Article,

Role of complement activation in hypersensitivity reactions to doxil and hynic PEG liposomes: experimental and clinical studies
Szebeni, J; Baranyi, L; Savay, S; Milosevits, J; Bunger, R; Laverman, P; Metselaar, J M; Storm, G; Chanan-Khan, A; Liebes, L; Muggia, F M; Cohen, R; Barenholz, Y; Alving, C R
2002 Feb-May;12(1-2):165-172, Journal of liposome research
Pegylated liposomal doxorubicin (Doxil) and 99mTc-HYNIC PEG liposomes (HPL) were reported earlier to cause hypersensitivity reactions (HSRs) in a substantial percentage of patients treated i.v. with these formulations. Here we report that (1) Doxil, HPL, pegylated phosphatidylethanolamine (PEG-PE)-containing empty liposomes matched with Doxil and HPL in size and lipid composition, and phosphatidylglycerol (PG)-containing negatively charged vesicles were potent C activators in human serum in vitro, whereas small neutral liposomes caused no C activation. (2) Doxil and other size-matched PEG-PE and/or PG-containing liposomes also caused massive cardiopulmonary distress with anaphylactoid shock in pigs via C activation, whereas equivalent neutral liposomes caused no hemodynamic changes. (3) A clinical study showed more frequent and greater C activation in patients displaying HSR than in non-reactive patients. These data suggest that liposome-induced HSRs in susceptible individuals may be due to C activation, which, in turn, is due to the presence of negatively charged PEG-PE in these vesicles
— id: 44755, year: 2002, vol: 12, page: 165, stat: Journal Article,

Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy
Demaria S; Volm MD; Shapiro RL; Yee HT; Oratz R; Formenti SC; Muggia F; Symmans WF
2001 Oct;7(10):3025-3030, Clinical cancer research
PURPOSE: Neoadjuvant chemotherapy for breast cancer creates new possibilities for the analysis of biological factors in the tumor and/or host, which may play a role in the response to treatment. In this study we analyzed whether changes in local antitumor immunity take place after neoadjuvant paclitaxel therapy and if they correlate with response to treatment. Experimental Design: Neoadjuvant chemotherapy (paclitaxel, 200 mg/m2 q2w, 4 treatments) was followed by definitive surgical management. Histological sections from the pre- and post-treatment surgical specimens of 25 patients were analyzed for the extent of lymphocytic infiltration and presence of tumor infiltrating lymphocytes (TILs). The cumulative apoptotic response in the tumor after the first dose of paclitaxel was also studied in 10 of 25 patients. RESULTS: Pretreatment lymphocytic infiltrate in the tumor was minimal in the majority of patients and showed no relationship with clinical response. In the patients without TILs before treatment, development of TILs after treatment was noted in 0/3 (0%) patients with stable disease, 3/12 (25%) patients with clinical partial response, and 4/6 (67%) patients with clinical complete response and pathological residual disease. These correlated with the tumor cell apoptotic response to the first dose of paclitaxel. CONCLUSIONS: These results suggest that development of TILs after treatment correlates with clinical response to neoadjuvant paclitaxel therapy. The possible mechanism(s) whereby neoadjuvant chemotherapy may lead to induction of antitumor T cells is discussed. Immunological processes may influence the response of breast cancer patients to neoadjuvant treatment
— id: 24141, year: 2001, vol: 7, page: 3025, stat: Journal Article,

A Phase I/II study of weekly paclitaxel and 3 days of high dose oral estramustine in patients with hormone-refractory prostate carcinoma
Ferrari AC; Chachoua A; Singh H; Rosenthal M; Taneja S; Bednar M; Mandeli J; Muggia F
2001 Jun 1;91(11):2039-2045, Cancer
BACKGROUND: The maximum tolerated dose (MTD) and efficacy of weekly 1-hour paclitaxel with 3 days of high dose oral estramustine were evaluated in patients with hormone-refractory prostate carcinoma. METHODS: Patients enrolled in cohorts of three received two cycles of six weekly treatments with 1 week of rest: Cohort I received paclitaxel 40 mg/m2 and estramustine 600 mg/m2, and Cohorts II-IV received paclitaxel 60 mg/m2, 75 mg/m2, or 90 mg/m2, respectively, and estramustine 900 mg/m2. Toxicity was assessed weekly, and response was measured by serum prostate specific antigen (PSA), abdominal computed tomography scans, and bone scans at Week 13. RESULTS: Eighteen patients were enrolled, with 12 in Cohorts III and IV. Four patients did not complete treatment. Grade 3 toxicity included one patient with nausea and diarrhea in Cohort III and one patient each with neutropenia and edema followed by Grade 4 thromboembolism in Cohort IV. Grade 1-2 anemia or myelotoxicity were not observed; 3 patients had neuropathy, 5 patients had hair loss, and 8 patients had gastrointestinal symptoms. A decline in the serum PSA level > or = 50% occurred in none of three patients, one of three patients, four of six patients, and four of six patients in Cohorts I-IV, respectively. An intent-to-treat analysis showed responses in 9 of 18 patients (50%) in Cohorts I-IV, with 9 of 15 responders (60%) in Cohorts II-IV. Seven patients achieved declines in serum PSA levels > 75%. The median duration of PSA response was 16.7 weeks. Response was observed in one of three patients with measurable disease. CONCLUSIONS: The MTD for 1-hour weekly paclitaxel was 90 mg/m2 with 3 days of 900 mg/m2 estramustine. Hematologic and neurotoxicity were reduced markedly, and gastrointestinal symptoms were ameliorated, but thromboembolic events were unaffected. PSA response rates were within the expected 60% range for these agents
— id: 34610, year: 2001, vol: 91, page: 2039, stat: Journal Article,

Clinical course of locally advanced breast cancer (LABC) patients with pathological response to primary concurrent 5-fluorouracil and radiation (FU/RT)
Formenti, S. C.; Cohen, D.; Tsao-Wei, D. D.; Muggia, F. M.
2001 ;51(3 Supplement 1):195-196, International journal of radiation oncology biology physics
— id: 109249, year: 2001, vol: 51, page: 195, stat: Journal Article,

Phase I and pharmacologic study of i.v. hydroxyurea infusion given with i.p. 5-fluoro-2 '-deoxyuridine and leucovorin
Garcia, AA; Muggia, FM; Spears, CP; Jeffers, S; Silberman, H; Pujari, M; Koda, RT
2001 JUL ;12(6):505-511, Anti-cancer drugs
Preclinical data suggests that the action of fluoropyrimidines may be enhanced by the addition of hydroxyurea. We developed a phase I trial to determine the maximum tolerated dose and pharmacokinetics of i.v, hydroxyurea (HU) in combination with i.p. 5-fluoro-2'-deoxyuridine (FUdR) and leucovorin (LV). Eligible patients had metastatic carcinoma confined mostly to the peritoneal cavity, and adequate hepatic, renal and bone marrow function. Patients were treated with a fixed dose of FUdR (3 g) and LV (640 mg) administered on days 1-3. HU was administered as a 72-h infusion starting simultaneously with i.p. therapy on day 1, The following dose levels were studied: 2.0, 2.5, 3.0 and 3.6 g/m(2)/day. Pharmacokinetics were studied in blood and peritoneal fluid, Twenty-eight patients were accrued. Steady-state plasma and peritoneal fluid HU levels increased with increasing dose, and steady state was achieved within 12 h of continuous dosing, The steady-state HU plasma:peritoneal fluid concentration ratio ranged from 1.06 x 10(3) to 1.2 5x 10(3) and the plasma HU clearance ranged from 4.63 to 5.81 l/h/m(2). Peritoneal fluid AUC = 137 639+/-43 914 mug/ ml min, t(1/2) = 100.9+/-56.4 min and CI = 25.29+/-10.88 ml/min. Neutropenia represented the dose-limiting toxicity. We conclude that i.p. FUdR and LV in combination with i.v. HU is well tolerated, The addition of systemic HU increased the incidence of myelosuppression. [(C) 2001 Lippincott Williams & Wilkins.]
— id: 55010, year: 2001, vol: 12, page: 505, stat: Journal Article,

Estramustine potentiates taxane in prostate and refractory breast cancers
Hamilton A; Muggia F
2001 May;15(5 Suppl 7):40-43, Oncology
Estramustine is nornitrogen mustard linked to estradiol. It binds to tubulin and to microtubule-associated proteins, depolymerizes cytoplasmic microtubules, and disrupts the nuclear matrix. It has limited clinical activity as a single agent, but preclinical studies suggest that it is an effective modulator of antitubulins. This paper reviews the rationale for the combination of estramustine with antitubulins and the clinical toxicity profile of estramustine. Also discussed are data from phase II studies in hormone-resistant prostate cancer and in taxane-resistant breast cancer that suggest that the modulation of antitubulins by estramustine that has been demonstrated in vitro is indeed clinically relevant. Finally, current approaches to improving the tolerability of estramustine are described
— id: 20620, year: 2001, vol: 15, page: 40, stat: Journal Article,

Inhibition of H-ras membrane binding and topoisomerase-1 in a phase I trial of topotecan combined with the farnesyl transferase inhibitor, R115777 (Zarnestra)
Hochster, H; Liebes, L; Buckley, M; Sorich, J; Fry, D; Hamilton, A; Wright, J; Muggia, F
2001 NOV ;7(11):3710S-3710S, Clinical cancer research
— id: 54797, year: 2001, vol: 7, page: 3710S, stat: Journal Article,

A unique combination effect on cytotoxic activity is observed with H460 cells following sequential administration of the proteasome inhibitor, PS-341 and the chemopreventative agent, 2-phenethyl isothiocyanate (PEITC)
Mendoza, S; Ng, B; Hamilton, A; Elliott, PJ; Muggia, F; Liebes, L
2001 NOV ;7(11):3750S-3750S, Clinical cancer research
— id: 54798, year: 2001, vol: 7, page: 3750S, stat: Journal Article,

Re: Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes
Mirchandani, D; Muggia, F
2001 SEP 19 ;93(18):1420-1421, Journal of the National Cancer Institute
— id: 54890, year: 2001, vol: 93, page: 1420, stat: Journal Article,

Low p27 in T1N0M0 breast cancers - association with other unfavorable molecular markers of prognosis
Mirchandani, D; Tang, T; Inghirami, G; Roses, D; Shapiro, R; Harris, M; Muggia, F
2001 WIN ;69(3):337-119, Breast cancer research & treatment
— id: 98269, year: 2001, vol: 69, page: 337, stat: Journal Article,

Chemoradiation for patients with cervical cancer
Muggia F; Formenti SC; Curtin J
Progress in oncology 2001 Boston MA : Jones & Bartlett, 2001,
— id: 5316, year: 2001, vol: , page: 168, stat: Chapter,

Liposomal encapsulated anthracyclines: new therapeutic horizons
Muggia FM
2001 Mar;3(2):156-162, Current oncology reports
After two decades of work in liposomal formulations for clinical use, two preparations containing doxorubicin (Doxil, ALZA, Pablo Alto, CA; and Evacet, The Liposome Company, Princeton, NJ), and one containing daunorubicin (DaunoXome; Gilead Sciences, Foster City, CA) have been undergoing widespread clinical study. Results have lived up to the promise that liposomal encapsulation may lead to toxicity attenuation, while retaining or even enhancing the efficacy of the parent anthracyclines. The eventual role of these agents in clinical practice is being defined in a number of studies that are reviewed herein. Already, approved indications have been achieved for doxorubicin against Kaposi's sarcoma and ovarian cancers, and for daunorubicin against Kaposi's sarcoma. The three compounds vary widely in their pharmacology, and these differences may contribute to their preferential localization into certain tumors. Additional indications for these liposomal encapsulated anthracyclines are likely to be established in the ensuing years
— id: 26786, year: 2001, vol: 3, page: 156, stat: Journal Article,

Phase III data on Caelyx in ovarian cancer
Muggia, F; Hamilton, A
2001 Dec;37 Suppl 9:S15-S18, European journal of cancer
Impressive responses to pegylated liposomal doxorubicin (Doxil/Caelyx) in pretreated ovarian cancer patients during phase I studies led to a phase II study in platinum and taxane failures. A 26% objective response rate was obtained in this trial and this was confirmed by further phase II studies. The stage was set for a phase III trial in comparison with topotecan, the drug that had become standard in the salvage treatment of patients who were platinum-refractory or -resistant. The completed trial indicates equivalence of results in terms of response rates, time to treatment failure and survival. Differences exist in the toxicity spectrum and in subset analysis according to platinum resistance. On this basis, Caelyx is being positioned as part of chemotherapeutic regimens in first-line phase III trials
— id: 111710, year: 2001, vol: 37 Suppl 9, page: S15, stat: Journal Article,

CPT-11/cisplatin neoadjuvant therapy downstages locally advanced gastric cancer
Newman, E; Marcus, SG; Potmesil, M; Hochster, H; Yee, H; Sewak, S; Hayek, M; Muggia, FM
2001 APR ;120(5):A129-A129, Gastroenterology
— id: 55029, year: 2001, vol: 120, page: A129, stat: Journal Article,

Increased breast cancer tumor localization and enhanced cytotoxicity of radioimmunotherapy and chemotherapy combinations
Ng, B; Kramer, E; Ceriani, R; Volm, M; Hamilton, A; Muggia, F; Formenti, S; Furmanski, P; Liebes, L
2001 ;69(3):303-303 #527, Breast cancer research & treatment
— id: 109250, year: 2001, vol: 69, page: 303, stat: Journal Article,

Treatment of patients with ovarian carcinoma with pegylated liposomal doxorubicin - Analysis of toxicities and predictors of outcome
Safra, T; Groshen, S; Jeffers, S; Tsao-Wei, DD; Zhou, LY; Muderspach, L; Roman, L; Morrow, CP; Burnett, A; Muggia, FM
2001 JAN 1 ;91(1):90-100, Cancer
BACKGROUND. Pegylated liposomal doxorubicin is a new formulation with activity against epithelial ovarian carcinoma (EOC). The authors sought to determine patient characteristics that may predict for response to this treatment and favorable time to failure as well as survival. METHODS. Eight patients in a Phase I study and 44 patients ill two consecutive Phase II studies who were treated with pegylated liposomal doxorubicin (40-60 mg/m(2) every 3 weeks for the first two cycles and 40 mg/m(2) every 4 weeks thereafter) after failing initial platinum-based chemotherapies for ovarian carcinoma were analyzed. Associations were sought for response, time to failure (TTF), and survival after the treatment and various pretreatment characteristics. RESULTS. Treatment with pegylated liposomal doxorubicin yielded 23% objective responses in measurable disease and 31% overall responses, including serum CA 125-defined responses. The median TTF was 5.2 months (95% confidence interval, 4.1-6.9 months) in all patients, and the median response duration in all responders was 13.2 months (95% confidence interval, 11.9-18.5 months). The overall median survival was 15 months (95% confidence interval, 11-40 months). The main predictive factors were tumor size and baseline hemoglobin level for TTF, and these plus Karnofsky performance status were the main predictive factors for survival. CONCLUSIONS. Pegylated liposomal doxorubicin is an effective drug when it is given as secondary therapy to patients with EOC. Lack of bulky disease is the major predictor for a favorable response, TTF, and survival. The role of this treatment in combination with other effective drugs should be explored in both previously treated and untreated patients with ovarian carcinoma. Cancer 2001;91:90-100. (C) 2001 American Cancer Society
— id: 55251, year: 2001, vol: 91, page: 90, stat: Journal Article,

Serial fine needle aspirations during neoadjuvant chemotherapy: Assessment of apoptotic responses in breast cancer
Symmans, W. F.; Volm, M.; Shapiro, R. L.; Demaria, S.; Yee, H.; Formenti, S. C.; Muggia, F.
2001 ;8(Supplement 1):S46-S46, International journal of molecular medicine
— id: 109251, year: 2001, vol: 8, page: S46, stat: Journal Article,

Increase in the lymphocytic infiltrate in breast cancer after neoadjuvant paclitaxel chemotherapy
Demaria, Sandra; Volm, M. D.; Shapiro, R. L.; Yee, H. T.; Oratz, R.; Formenti, S.; Muggia, F.; Symmans, W. F.
2000 ;43(41):334-334, Proceedings (American Association for Cancer Research)
— id: 109238, year: 2000, vol: 43, page: 334, stat: Journal Article,

Phase I trial of paclitaxel and etoposide for recurrent ovarian carcinoma - A gynecologic oncology group study
Fleming, GF; Roth, BJ; Baker, SD; Sutton, GP; Look, KY; Muggia, FM; Fracasso, PM; McGuire, WP
2000 DEC ;23(6):609-613, American journal of clinical oncology
A phase I study was performed to determine the maximum tolerated doses of intravenous etoposide and paclitaxel for women with previously treated persistent or recurrent ovarian cancer. Starting doses were paclitaxel 135 mg/m(2) during 24 hours and etoposide 50 mg/m(2)/day for 3 consecutive days. The study was designed to escalate first the dose of etoposide, and then the dose of paclitaxel, in successive cohorts of patients. In an attempt to determine whether toxicity was affected by sequence of the drugs, the order of administration of the two drugs was reversed on alternate cycles. The starting doses of paclitaxel (135 mg/m(2)/24 hours) and etoposide (50 mg/m(2)/day x 3) caused severe neutropenia even with the addition of granulocyte colony-stimulating factor, and the trial was amended to administer the paclitaxel during 3 hours. However, this also proved too myelosuppressive without growth factor support. Twenty-one women were treated. A complete response was observed in one of nine patients with measurable disease, and a major decrease in CA-125 was noted in two patients who did not have measurable disease. Because of the severe myelosuppression observed in most patients, dose reduction was often required after the first cycle. The power to detect sequence-dependent variation in toxicity was minimal; however, no large differences were observed. A combination of the usual doses of these drugs will be difficult to administer in patients who have received previous chemotherapy for ovarian cancer
— id: 55266, year: 2000, vol: 23, page: 609, stat: Journal Article,

Proteasome inhibition by PS-341: A phase I study
Hamilton, A; Eder, JP; Pavlick, A; Clark, JW; Chachoua, A; Ryan, DP; Farrell, K; Wasserstrom, H; Liebes, L; Wright, J; Elliott, P; Adams, J; Muggia, F
2000 NOV ;6(6):4549S-4549S, Clinical cancer research
— id: 54445, year: 2000, vol: 6, page: 4549S, stat: Journal Article,

BRCA1 germline mutation presenting as an adenocarcinoma of unknown primary
Klein, P; Prolla, G; Wallach, R; Melamed, J; Muggia, FM
2000 MAY-JUN ;6(3):188-190, Cancer journal
BACKGROUND The work-up of adenocarcinoma of unknown primary usually includes history, physical examination, radiographic imaging, tumor markers, and more recently molecular and genetic information. We report here on how the suggestion by family history of a BRCA1 mutation guided the diagnostic and therapeutic approach in a patient with metastatic carcinoma of unknown primary. METHODS BRCA1 mutation was screened for by polymerase chain reaction (PCR) and single-strand conformational polymorphism analysis. Primers for PCR amplification included selected BRCA1 exons 2, 110, 11L, 13, and 20. The PCR product was cloned into a PCRII vector and sequenced with a Sequenase Version 2.0 Sequencing Kit. RESULTS Single-strand conformational polymorphism analysis suggested a mutation in the region of exon 20 and sequencing confirmed the presence of a germline mutation 5382insC. CONCLUSIONS This case illustrates an unusual presentation of adenocarcinoma of unknown primary in a patient with a germline BRCA1 mutation, the use of a suspected germline mutation to guide the work-up and treatment, and finally the value of positive emission tomography scanning in the work-up of an unknown primary
— id: 54549, year: 2000, vol: 6, page: 188, stat: Journal Article,

Intraperitoneal topoisomerase-I inhibitors. Preliminary findings with 9-aminocamptothecin
Muggia F; Liebes L; Potmesil M; Hamilton A; Hochster H; Hornreich G; Sorich J; Downey A; Wasserstrom H
2000 ;922(1):178-187, Annals of the New York Academy of Sciences
The i.p. administration of topoisomerase I (Topo I) inhibitors has a pharmacologic advantage over intravenous application, including preservation of the biologically active lactone form. In our ongoing study, patients have received 9-amino-20(S)-camptothecin (9-AC) i.p. on days 1, 3, 5, 8, 10, and 12, repeated every 4 weeks. The daily dose has been escalated to level IV of 1.5 mg/m2 (9.0 mg/m2 per course), median of 3 cycles, range 1-4, with a reversible Grade 3 neutropenia in one patient. Responses included one CR (resolution of a pleural effusion), two patients without progressive disease (PD), two not evaluable, and two patients too early for evaluation. The area under the curve (AUC)i.p./AUCpl ratio (pharmacologic advantage) ranged from 7.6 to 16.5 on average, and, using nonlinear modeling, the pharmacologic decay data were fit to one- or two-compartmental models. Overall, a 9-AC i.p. application is well tolerated and anticipated to be an active regimen against i.p. malignancies, particularly those known to be sensitive to systemic Topo-I inhibitors
— id: 39489, year: 2000, vol: 922, page: 178, stat: Journal Article,

Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study [see comments]
Muggia FM; Braly PS; Brady MF; Sutton G; Niemann TH; Lentz SL; Alvarez RD; Kucera PR; Small JM
2000 Jan;18(1):106-115, Journal of clinical oncology
PURPOSE: To assess progression-free survival (PFS) and overall survival (OS) in patients with suboptimally debulked epithelial ovarian cancer receiving cisplatin (100 mg/m(2)) or 24-hour infusion paclitaxel (200 mg/m(2)) or the combination of paclitaxel (135 mg/m(2)) followed by cisplatin (75 mg/m(2)). PATIENTS AND METHODS: After stratification for disease measurability, patients were randomized to receive six cycles of one of the treatments every 3 weeks. If measurable, complete response (CR) or partial response (PR) was determined. RESULTS: Six hundred fourteen of 648 patients who entered onto the trial were eligible. Monotherapies were discontinued more frequently (cisplatin because of toxicity or patient refusal [17%], and paclitaxel because of progression [20%]) compared with the combination therapy (7% and 6%, respectively). Neutropenia, fever, and alopecia were more severe with paclitaxel-containing regimens; whereas anemia, thrombocytopenia, neurotoxicity, nephrotoxicity, and gastrointestinal toxicity were more severe with cisplatin-containing regimens. The CR/PR rates on paclitaxel monotherapy were significantly lower compared with the cisplatin regimens (42% v 67%, respectively; P <.001). The relative hazard (RH) of first progression or death was significantly greater among those randomized to paclitaxel (RH = 1.41; 95% confidence interval [CI], 1.15 to 1.73; P <.001) when compared with cisplatin; however, RH did not differ significantly between the two cisplatin regimens (RH = 1.06; 95% CI, 0.895 to 1.30). Relative to cisplatin, the death rate on paclitaxel was 15% greater (RH = 1.15; 95% CI, 0. 929 to 1.42), and the death rate on the combination treatment was 1% less (RH = 0.99; 95% CI, 0.795 to 1.23). These differences among treatment groups were not statistically significant (P =.31). CONCLUSION: Cisplatin alone or in combination yielded superior response rates and PFS relative to paclitaxel. However, OS was similar in all three arms, and the combination therapy had a better toxicity profile. Therefore, the combination of cisplatin and paclitaxel remains the preferred initial treatment option
— id: 11877, year: 2000, vol: 18, page: 106, stat: Journal Article,

Modulation of taxanes in breast cancer
Muggia, Franco M; Hamilton, Anne
2000 Nov 03-06;18(SUPPL. 1):64-66, Cancer investigation
— id: 15829, year: 2000, vol: 18, page: 64, stat: Journal Article,

Phase II study of combination taxol and estramustine phosphate in the treatment of recurrent glioblastoma multiforme
Rosenthal MA; Gruber ML; Glass J; Nirenberg A; Finlay J; Hochster H; Muggia FM
2000 Mar;47(1):59-63, Journal of neuro-oncology
Taxol has activity in the treatment of high grade gliomas but estramustine phosphate (EMP) has not been used in this setting. In vitro data demonstrates that EMP is cytotoxic to glioma cell lines and estramustine binding proteins are expressed by glioma cells. The combination of Taxol and EMP is reported to be active in the treatment of hormone-refractory prostate cancer and in taxane-resistant breast and ovarian cancer. We therefore performed a phase II study to assess the activity and toxicity of this combination in high grade gliomas. Taxol was given at a dose of 225 mg/m2 intravenously over three hours on day 1 and EMP was given at a dose of 900 mg/m2 orally on days 1 through 3. Cycles were repeated every three weeks. Twenty patients with recurrent glioblastoma multiforme (GBM) were enrolled: 11 male, median age 45 years. All patients received anti-epileptic medications and 17 (80%) had received prior chemotherapy. Of 18 evaluable patients, two had partial responses (11) and six had stable disease (33%) for a minimum of eight weeks. Treatment was well tolerated with grade 3 neutropenia occurring in only three patients. There were no other grade 3 or 4 toxicities. The median time to progression for the cohort was only six weeks (range 3-60+ weeks). The median overall survival was 12 weeks (range 3-60+ weeks). In conclusion, the combination of Taxol and EMP is well tolerated and has modest activity in the treatment of recurrent GBM
— id: 36034, year: 2000, vol: 47, page: 59, stat: Journal Article,

Pegylated liposomal doxorubicin (doxil): Reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m(2)
Safra, T; Muggia, F; Jeffers, S; Tsao-Wei, DD; Groshen, S; Lyass, O; Henderson, R; Berry, G; Gabizon, A
2000 AUG ;11(8):1029-1033, Annals of oncology
Background: The indications for pegylated liposomal doxorubicin (doxil) are expanding. We, therefore, wished to assess the safety of delivering doses exceeding 500 mg/m(2) of doxil to patients with solid tumors. Patients and methods: Subjects accrued to eight phase I and II protocol studies conducted at two institutions, were assessed for cardiac function at baseline and at specified intervals by MUGA scans. In this retrospective analysis, the findings of 42 patients, from the total of 237 entered, who had reached or exceeded cumulative doses of 500 mg/m(2) (range 500-1500 mg/m(2)) were reviewed. Changes in left ventricular ejection fraction (LVEF), and in clinical cardiac status were analyzed. Six patients, three who had received prior doxorubicin, also underwent endomyocardial biopsies after cumulative doses of 490-1320 mg/m(2). Results: None of the 42 patients had clinical congestive heart failure (CHF) secondary to cardiomyopathy. Post doxil MUGA scans were available for 41 of the 42 patients. Five had a drop of 10% or more in LVEF; three of these had received prior doxorubicin. Billingham endomyocardial biopsy scores ranged from 0-1 in five patients, while the sixth had a score of 1.5 after both 900 mg/m(2) and 1320 mg/m(2) doxil. Of a remaining 195 patients, 1 episode of CHF was recorded in a patient who had received 312 mg/m(2) doxil over 120 mg/m(2) of mitoxantrone and chest radiation. Conclusions: Cumulative doses in excess of 500 mg/m(2) of doxil appear to carry a considerably lesser risk of cardiomyopathy as judged by serial LVEF's and clinical follow-up, than is generally associated with free doxorubicin. Heart biopsies have provided reassuring data in a small number of patients, even if pretreated with doxorubicin. However, since three doxorubicin pretreated patients were among the five experiencing drops in LVEF, more data are warranted on such patients
— id: 54530, year: 2000, vol: 11, page: 1029, stat: Journal Article,

Paclitaxel-induced apoptosis and mitotic arrest assessed by serial fine-needle aspiration: implications for early prediction of breast cancer response to neoadjuvant treatment
Symmans WF; Volm MD; Shapiro RL; Perkins AB; Kim AY; Demaria S; Yee HT; McMullen H; Oratz R; Klein P; Formenti SC; Muggia F
2000 Dec;6(12):4610-4617, Clinical cancer research
The extent of tumor reduction from neoadjuvant chemotherapy for breast cancer correlates with outcome. We investigated whether the initial cellular responses to paclitaxel are related to the extent of tumor reduction. Eleven women with breast cancer received paclitaxel (every 2 weeks for 4 cycles) as neoadjuvant treatment. Serial fine-needle aspirations (FNA; 25-gauge, 1 pass) were obtained before treatment and at 24, 48, 72, and 96 h after the first paclitaxel dose. Microscopic counts of apoptotic and mitotic indices were performed. The change in cancer volume from treatment was determined using radiological measurements with allowance for change in the histopathological amount of cancer. Apoptotic and mitotic responses usually subsided within 4 days. The duration of the initial apoptotic response was different for women with different treatment results. Cumulative apoptotic response for the first 4 days inversely correlated with the proportion of residual cancer after neoadjuvant treatment. FNA is a versatile clinical method to obtain breast cancer cells for therapy response studies. Apoptotic response to the first dose of paclitaxel is almost complete within 4 days, implying that more frequent (weekly) paclitaxel dosing might be beneficial. The apoptotic response to the first dose of paclitaxel appeared to predict the amount of cancer reduction from this treatment. This is a promising start toward the development of an early chemopredictive assay for paclitaxel treatment of breast cancer
— id: 22642, year: 2000, vol: 6, page: 4610, stat: Journal Article,

Primary paclitaxel in breast cancer: Does beta-tubulin predict pathologic response?
Formenti, SC; Muggia, FM; Volm, M; Danenberg, K; Danenberg, PV
1999 FEB ;26(1):35-35, Seminars in oncology
— id: 98325, year: 1999, vol: 26, page: 35, stat: Journal Article,

Twice-weekly paclitaxel and radiation therapy in locally advanced breast cancer: Clinical and pathological response
Formenti, SC; Skinner, K; Spicer, D; Muggia, F; Danenberg, K; Danenberg, P
1999 ;26(6):6-6, Seminars in oncology
— id: 109224, year: 1999, vol: 26, page: 6, stat: Journal Article,

Paclitaxel and radiation therapy in locally advanced breast cancer: Preliminary clinical results
Formenti, SC; Symmans, F; Volm, M; Skinner, K; Perez, E; Muggia, F
1999 FEB ;26(1):29-29, Seminars in oncology
— id: 98324, year: 1999, vol: 26, page: 29, stat: Journal Article,

Clinical pharmacodynamics of topoisomerase-1 inhibitor therapy: lessons and issues for future studies
Hochster, H; Liebes, L; Wadler, S; Runowicz, C; Potmesil, M; Speyer, J; Muggia, F
1999 NOV ;5(4):3775S-3776S, Clinical cancer research
— id: 53799, year: 1999, vol: 5, page: 3775S, stat: Journal Article,

Cytoprotection: shelter from the storm
Klein P; Muggia FM
1999 ;4(2):112-121, Oncologist
— id: 56438, year: 1999, vol: 4, page: 112, stat: Journal Article,

Doxorubicin-polymer conjugates: further demonstration of the concept of enhanced permeability and retention
Muggia FM
1999 Jan;5(1):7-8, Clinical cancer research
— id: 57058, year: 1999, vol: 5, page: 7, stat: Journal Article,

Doxorubicin-induced cardiomyopathy
Muggia FM; Speyer JL
1999 Feb 25;340(8):654-655, New England journal of medicine
— id: 57059, year: 1999, vol: 340, page: 654, stat: Journal Article,

MDR1 gene expression in primary and advanced breast cancer
Yang, X; Uziely, B; Groshen, S; Lukas, J; Israel, V; Russell, C; Dunnington, G; Formenti, S; Muggia, F; Press, M F
1999 Mar;79(3):271-280, Laboratory investigation
P-glycoprotein (Pgp)-associated multidrug resistance (MDR) is related to intrinsic and acquired cross resistance to anthracyclines, vinca alkaloids, and other antineoplastic antibiotics. Expression of MDR1 is widely considered to play an important role in conferring resistance to adjuvant chemotherapy in women with breast tumor cells in women with disseminated disease, although data supporting this view is, at best, conflicting. The expression of MDR1 gene and its gene product, P-glycoprotein, was investigated in primary and advanced breast cancers (both previously untreated and previously treated on specific treatment protocols) to assess the role of P-glycoprotein in determining responsiveness to adjuvant chemotherapy. Expression was assessed by immunohistochemistry, reverse transcription-PCR (RT-PCR), Northern Blot and Western Blot. MDR1 mRNA was detected in 40% of the breast cancers tested by RT-PCR with 40 cycles of PCR amplification. When reducing the PCR amplification cycles to 28, the MDR1 gene expression signal disappeared from breast cancers of the highest expressers; however, known MDR1 positive control normal tissues, such as adrenal, kidney, and liver continued to show an expression product. Western and Northern blots failed to demonstrate the MDR1 gene product, P-glycoprotein, in these breast cancers. In contrast, physiologic levels of P-glycoprotein was clearly detected in normal adrenal, kidney, and liver by these techniques. Immunohistochemistry confirmed that breast carcinoma cells lacked P-glycoprotein expression; however, interstitial mononuclear cells, morphologically consistent with lymphocytes or macrophages did show immunostaining in some of these breast tumors. MDR1 gene expression identified by RT-PCR was not correlated either with response to paclitaxel therapy (29 patients able to be evaluated, p = 0.34, Fisher Exact Test) or overall survival (32 breast cancer patients with clinical follow-up information, p = 0.336, log rank). In conclusion, P-glycoprotein was not expressed in breast carcinoma cells at significant levels, although it was expressed in stomal lymphocytes or macrophages. These results suggest that P-glycoprotein does not play a significant role in multidrug resistance of breast cancer
— id: 109139, year: 1999, vol: 79, page: 271, stat: Journal Article,

Concurrent paclitaxel and radiation in locally advanced breast cancer
Formenti, C; Skinner, S; Spicer, K; Cohen, D; Kutsch, D; Symmans, K; Volm, F; Muggia, FM
1998 SEP ;34(11):S12-S12, European journal of cancer
— id: 53659, year: 1998, vol: 34, page: S12, stat: Journal Article,

Molecular determinants of response of locally advanced breast cancer to 5-FU and radiation
Formenti, Silvia; Park, Ji Min; Salonga, Dennis; Williams-Hill, Donna; Danenberg, Kathleen; Muggia, Franco; Danenberg, Peter V.
1998 ;39(41):187-187, Proceedings (American Association for Cancer Research)
— id: 109243, year: 1998, vol: 39, page: 187, stat: Journal Article,

Phase I and pharmacologic study of estramustine phosphate and short infusions of paclitaxel in women with solid tumors
Garcia AA; Keren-Rosenberg S; Parimoo D; Rogers M; Jeffers S; Koda R; Muggia FM
1998 Sep;16(9):2959-2963, Journal of clinical oncology
PURPOSE: We sought to determine the tolerance of estramustine phosphate (EMP) combined with a 3-hour paclitaxel infusion in women with solid paclitaxel-pretreated solid tumors. Paclitaxel pharmacology was to be studied at the recommended phase II dose. PATIENTS AND METHODS: Paclitaxel was administered to cohorts of at least three assessable patients at doses of 150, 180, 210, and 225 mg/m2, while EMP was given at 900 and 1,200 mg/m2/d in divided doses orally for 2 days preceding and on the day of paclitaxel. The pharmacologic study was performed at 225 mg/m2 paclitaxel given in the absence and 3 weeks later in the presence of EMP 900 mg/m2/d. RESULTS: Thirty-eight patients received a total of 178 courses. Grade 3 nausea, vomiting, and diarrhea were common at EMP 1,200 mg/m2 and paclitaxel 225 mg/ m2; this was considered the maximum-tolerated dose. Since these toxicities appeared related to EMP, the pharmacologic study used a dose of 900 mg/m2 of this agent with 225 mg/m2 paclitaxel. Antitumor activity was documented against breast and ovarian cancers at all levels. Paclitaxel pharmacokinetics without and with EMP did not differ. CONCLUSION: EMP 900 mg/m2 for 3 days and 225 mg/m2 paclitaxel by 3-hour infusion are well tolerated; antitumor activity was seen in women with paclitaxel-pretreated solid tumors. This apparent enhancement of antitumor effects is unlikely to be mediated by P-glycoprotein
— id: 7575, year: 1998, vol: 16, page: 2959, stat: Journal Article,

Tomudex (ZD1694, NSC 639186) in platinum-pretreated recurrent epithelial ovarian cancer: a phase II study by the Gynecologic Oncology Group
Muggia FM; Blessing JA; Homesley HD; Sorosky J
1998 ;42(1):68-70, Cancer chemotherapy & pharmacology
PURPOSE: Tomudex is a second-generation folate analogue that when polyglutamated is a potent inhibitor of thymidylate synthase (TS). METHODS: Based on indications of antitumor activity in phase I trials, the Gynecologic Oncology Group initiated a phase II study of Tomudex 3 mg/m2 intravenously every 3 weeks in patients with epithelial ovarian cancer, who had been pretreated with platinum drugs, and had subsequently recurred more than 6 months following such treatment. RESULTS: Of 30 patients entered into the trial, 2 were pathologically ineligible, leaving 28 fully evaluable. In this patient population, Tomudex was generally well tolerated, but only three objective (partial) responses were documented. CONCLUSIONS: With the level of activity seen, the drug was not considered for further clinical development in ovarian cancer by the Gynecologic Oncology Group. However, it may be worthwhile to explore whether quantitation of TS could lead to selection of patients more likely to respond to this TS inhibitor
— id: 57344, year: 1998, vol: 42, page: 68, stat: Journal Article,

Doxil in breast cancer
Muggia, FM
1998 FEB ;16(2):811-811, Journal of clinical oncology
— id: 53587, year: 1998, vol: 16, page: 811, stat: Journal Article,

Camptothecins: a review of their development and schedules of administration
O'Leary J; Muggia FM
1998 Sep;34(10):1500-1508, European journal of cancer
Used for centuries in traditional Chinese medicine, camptothecin was rediscovered in the 1950s during a search for compounds that could be used as a source for steroid synthesis. Due to its limited water solubility, a sodium salt was used in the early clinical trials. The severe toxicity and erratic absorption relegated this compound to the research laboratory until the 1980s when the topoisomerase enzyme was identified as the cellular target of camptothecin, the topoisomerase enzyme was found to be overexpressed in cancer cells and a structure-activity relationship was determined for camptothecin. These new developments brought the camptothecins back to the clinical setting for further testing. The various analogues that have been most studied to date include: irinotecan (CPT-11), and its derivative SN-38, topotecan, and 9-aminocamptothecin. Numerous trials have been conducted in an attempt to establish the efficacy in various tumour types, to determine the dose-limiting toxicity and to define the optimal schedule of administration. It seems that large doses of these drugs given on intermittent schedules are not effective. Our hypothesis is that the camptothecins require a prolonged schedule of administration given continuously at low doses or frequent intermittent dosing schedules to be most effective. With these schedules, normal haematopoietic cells and mucosal progenitor cells with low topoisomerase I levels may be spared, while efficacy is preserved
— id: 57221, year: 1998, vol: 34, page: 1500, stat: Journal Article,

Taxanes in adjuvant and neoadjuvant therapies for breast cancer
O'Leary J; Volm M; Wasserheit C; Muggia F
1998 Jan;12(1 Suppl 1):23-27, Oncology
Paclitaxel (Taxol) is a diterpene originally obtained from the bark of the Pacific Yew Tree, Taxus Brevifolia. Its mechanism of action is unique. It stabilizes microtubule polymerization, thus blocking cells in the G2/M phase of the cell cycle. In breast cancer, initial studies using paclitaxel demonstrated high activity. The first study was reported in 1991 by Holmes et al who gave paclitaxel as a 24-hour infusion at 250 mg/m2 to 25 patients with metastatic breast cancer following only one prior chemotherapy regimen--they achieved a 56% response rate. Since then, numerous studies have confirmed the effectiveness of paclitaxel in patients with metastatic disease. A second taxane, docetaxel (Taxotere), has also demonstrated excellent activity. Clinical research is now focused on integrating the taxanes into combination drug regimens and into neoadjuvant and adjuvant schedules for patients with early stage breast cancer, as well as looking at the biologic determinants of response and resistance to taxanes. This article will review developments in the use of taxanes in the adjuvant and neoadjuvant settings and it will review the information on possible molecular markers that may be useful in predicting tumor responsiveness to taxanes
— id: 7722, year: 1998, vol: 12, page: 23, stat: Journal Article,

Anti-angiogenic effects of 9-amino-20(S)-camptothecin (9AC), topotecan (TTN), and camptosar (C
O'Leary, JJ; Shapiro, RL; Ren, CJ; Chuang, N; Cohen, HW; Muggia, F; Potmesil, M
1998 AUG 25 ;9(4):78-78, Annals of oncology
— id: 53386, year: 1998, vol: 9, page: 78, stat: Journal Article,

Gemcitabine plus cisplatin combination given with amifostine (GAP) to heavily pretreated patients with gynecologic and peritoneal cancers: tolerance and activity in ovarian cancer
Safra T; Jeffers S; Sorich J; Muggia FM
1998 Jul;9(6):511-514, Anti-cancer drugs
Nine patients with cancers of gynecologic or peritoneal origin were treated with a combination of gemcitabine, amifostine and cisplatin (GAP). The rationale of including amifostine was primarily related to the amount of prior cisplatin the patients had received and the need to protect against additional neurotoxicity. After encouraging activity and tolerance had been noted, entry of three patients with severely compromised bone marrow was also allowed. These three patients required dose reductions and did not tolerate treatment more often than every other week, but nevertheless, one of them experienced a partial response lasting 9 months. Another two of the nine patients had CA125 decreases fulfilling Rustin's definition of response and one had elimination of ascites. Future studies of this combination are warranted
— id: 57243, year: 1998, vol: 9, page: 511, stat: Journal Article,

Original p53 status predicts for pathological response in locally advanced breast cancer patients treated preoperatively with continuous infusion 5-fluorouracil and radiation therapy
Formenti SC; Dunnington G; Uzieli B; Lenz H; Keren-Rosenberg S; Silberman H; Spicer D; Denk M; Leichman G; Groshen S; Watkins K; Muggia F; Florentine B; Press M; Danenberg K; Danenberg P
1997 Dec 1;39(5):1059-1068, International journal of radiation oncology biology physics
PURPOSE/OBJECTIVE: 1) To test feasibility of preoperative continuous infusion (c.i.) 5-Fluorouracil (5-FU) and radiation (RT) in locally advanced breast cancer. 2) To study clinical and pathological response rates of 5-FU and radiation. 3) To attempt preliminary correlations between biological probes and pathological response. METHODS AND MATERIALS: Previously untreated, locally advanced breast cancer patients were eligible: only patients who presented with T3/T4 tumors that could not be resected with primary wound closure were eligible, while inflammatory breast cancer patients were excluded. The protocol consisted of preoperative c.i. infusion 5-FU, 200 mg/m2/day with radiotherapy, 50 Gy at 2 Gy fractions to the breast and regional nodes. At mastectomy, pathological findings were classified based on persistence of invasive cancer: pathological complete response (pCR) = no residual invasive cells in the breast and axillary contents; pathological partial response (pPR) = presence of microscopic foci of invasive cells in either the breast or nodal specimens; no pathological response (pNR) = pathological persistence of tumor. For each patient pretreatment breast cancer biopsies were analyzed by immunohistochemistry for nuclear grade, ER/PR hormonal receptors, her2/neu and p53 overexpression. RESULTS: Thirty-five women have completed the protocol and are available for analysis. 5-FU was interrupted during radiation in 10 of 35 patients because of oral mucositis in 8 patients, cellulitis in 1, and patient choice in another. Objective clinical response rate before mastectomy was 71% (25 of 35 patients): 4 CR, 21 PR. However, in all 35 patients tumor response was sufficient to make them resectable with primary wound closure. Accordingly, all patients underwent modified radical mastectomy: primary wound closure was achieved in all patients. At mastectomy there were 7 pCR (20%), 5 pPR (14%) and the remaining 23 patients (66%) had pathological persistence of cancer (pNR). Variables analyzed as potential predictors for pathological response (pPR and pCR) were: initial TNM clinical stage, clinical response, nuclear grade, hormonal receptor status, p53 overexpression, and Her2/neu overexpression in the pretreatment tumor biopsy. Only initial p53 status (lack of overexpression at immunohistochemistry) significantly correlated with achievement of a pathological response to this regimen (p = 0.010). CONCLUSION: The combination of c.i. 5-FU and radiation was well tolerated and generated objective clinical responses in 71% of the patients. With the limitation of the small sample size, the complete pathological response achieved (20%) compares favorably with that reported in other series of neoadjuvant therapy for similar stage breast cancer. These preliminary data suggest that initial p53 status predicts for pathological response (pPR and pCR) to the combination of c.i. 5-FU and radiotherapy in locally advanced breast cancer
— id: 34954, year: 1997, vol: 39, page: 1059, stat: Journal Article,

Tolerance of paclitaxel 3-hour infusion with and without granulocyte colony-stimulating factor on a biweekly schedule
Garcia AA; Parimoo D; Dimery I; Rogers M; Jeffers S; Muggia FM
1997 Dec;24(6 Suppl 19):S19-S62, Seminars in oncology
The object of this study was to define the toxicity and maximum tolerated dose of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) administered on a biweekly schedule, without and with granulocyte colony-stimulating factor support. Eligible patients had a diagnosis of recurrent or metastatic carcinoma and had received no more than one prior chemotherapy regimen. Patients were treated with paclitaxel administered as a 3-hour infusion. Entry dose level was 150/mg/m2. Subsequent dose levels were 175, 200, and 225 mg/m2. Granulocyte colony-stimulating factor was added at the two highest dose levels beginning on day 4, until absolute neutrophil count was above 10 x 10(9)/L. Forty-six patients were entered. Up to 175 mg/m2 could be safely administered every 2 weeks. Previously treated patients experienced severe dose-limiting neutropenia at 200 mg/m2, and at 225 mg/m2 all patients experienced treatment delays due to grade 3/4 neutropenia. Dose intensity was maintained in all patients due to the addition of granulocyte colony-stimulating factor. Escalation to 250 mg/m2 does not appear desirable, due to neurotoxicity
— id: 7574, year: 1997, vol: 24, page: S19, stat: Journal Article,

Activity of anthracyclines in refractory ovarian cancer: recent experience and review
Garcia, A; Muggia, F M
1997 ;15(4):329-334, Cancer investigation
— id: 133226, year: 1997, vol: 15, page: 329, stat: Journal Article,

Carboplatin as a radiation sensitizer in locally advanced cervical cancer: a pilot study
Muderspach LI; Curtin JP; Roman LD; Gebhardt JA; Klement V; Qian D; Morrow CP; Felix JC; Formenti SC; Muggia FM
1997 May;65(2):336-342, Gynecologic oncology
Radiation therapy is the mainstay in treatment of locally advanced cervical carcinoma. Several chemotherapeutic agents have been used as radiation sensitizers in the treatment of cervical cancer in an effort to improve local response and survival. A prospective study was designed to evaluate carboplatin as a radiosensitizer in advanced cervical cancer. Standard radiotherapy techniques were used to treat patients with Stage IIA-IIIB cervical cancer. Intravenous carboplatin was administered twice weekly concurrent with external beam radiation. Of 22 evaluable patients, there were 19 complete responders of whom 15 remain alive: 11 patients were alive and disease free at last visit for a median duration of 15 months follow-up (range, 4-43 months) and 4 patients remain alive with disease for a median duration of 17 months (range, 3-55 months). Seven have died, one of whom was without evidence of disease. There were no treatment-related deaths and no grade 4 toxicity. The most significant adverse effect was hematologic resulting in four patients with grade 3 neutropenia or anemia. There were no fistulae or late gastrointestinal or genitourinary complications. This pilot study suggests that carboplatin administered with standard radiation is safe, well-tolerated, and thus may be useful as a radiation sensitizer in the treatment of locally advanced cervical cancer
— id: 34956, year: 1997, vol: 65, page: 336, stat: Journal Article,

Clinical efficacy and prospects for use of pegylated liposomal doxorubicin in the treatment of ovarian and breast cancers
Muggia FM
1997 ;54 Suppl 4:22-29, Drugs
There is an urgent need for more active and better tolerated chemotherapy regimens for the treatment of advanced breast and ovarian cancers. Current therapeutic strategies in these malignancies include the use of moderately effective initial regimens that are usually accepted by patients. Tolerability considerations are especially important in the development of palliative regimens: retreatment for persistent or hormone-resistant disease must include quality-of-life analyses. Pegylated liposomal doxorubicin (PLD) has demonstrated a better therapeutic index than free doxorubicin in murine solid tumours and human tumour xenografts in nude mice. In early clinical studies in patients with refractory ovarian cancer, PLD has produced high response rates (26%) and gratifyingly long response durations (8 to 21 + months after onset of therapy). Less mature data also suggest that PLD is active against breast cancer. Information from these same clinical studies confirms the marked reduction in several toxicities associated with free doxorubicin, including nausea and vomiting, myelosuppression and cardiotoxicity. Alopecia is also markedly diminished. On the other hand, mucosal and skin toxicities appear to be more common with PLD. PLD therefore offers the prospect of retaining activity, together with attenuated acute toxicity. In addition to facilitating the development of palliative regimens with better tolerability, the drug may lend itself to effective integration of chemotherapy with loco-regional therapies; utilisation in 'maintenance' regimens that are associated with an acceptable quality of life for the patient, and the avoidance of long term toxicities associated with treatment. Moreover, additional study of PLD in combination with other drugs and modalities may extend the use of the drug beyond palliation to the development of combination regimens with other drugs at conventional doses, and high doses with G-CSF support
— id: 56974, year: 1997, vol: 54 Suppl 4, page: 22, stat: Journal Article,

Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation
Muggia, F M; Hainsworth, J D; Jeffers, S; Miller, P; Groshen, S; Tan, M; Roman, L; Uziely, B; Muderspach, L; Garcia, A; Burnett, A; Greco, F A; Morrow, C P; Paradiso, L J; Liang, L J
1997 Mar;15(3):987-993, Journal of clinical oncology
PURPOSE: A phase II study of liposomal doxorubicin was conducted in patients with ovarian cancer who failed to respond to platinum- and paclitaxel-based regimens. Liposomal doxorubicin was selected as a result of its superior activity against ovarian cancer xenografts relative to free doxorubicin and activity in refractory ovarian cancer patients that was noted during the phase I study. PATIENTS AND METHODS: Thirty-five consecutive patients were accrued in two institutions (22 in one and 13 in the other). All had progressive disease after either cisplatin or carboplatin and paclitaxel, or at least one platinum-based and one paclitaxel-based regimen. Patients received intravenous (I.V.) liposomal doxorubicin 50 mg/m2 every 3 weeks with a dose reduction to 40 mg/m2 in the event of grade 3 or 4 toxicities, or a lengthening of the interval to 4 weeks (and occasionally to 5 weeks) with persistence of grade 1 or 2 toxicities beyond 3 weeks. RESULTS: Nine clinical responses (one complete response [CR], eight partial responses [PRs]) were observed in 35 patients (25.7%), with seven of these having been confirmed by two consecutive computed tomographic (CT) measurements. The median progression-free survival was 5.7 months with an overall survival of 1.5 to 24+ months (median, 11 months). Although 13 patients experienced grade 3 or 4 nonhematologic skin and mucosal toxicities (either hand-foot syndrome or stomatitis), with dose modifications, the treatment was very well tolerated. Nausea that was clearly attributable to the drug, hair loss, extravasation necrosis, or decreases in ejection fraction did not occur. CONCLUSION: Liposomal doxorubicin has substantial activity against ovarian cancer refractory to platinum and paclitaxel. The responses achieved with liposomal doxorubicin were durable and maintained with minimal toxicity. This liposomal formulation should be evaluated further in combination with other drugs in less refractory patients
— id: 111689, year: 1997, vol: 15, page: 987, stat: Journal Article,

Severe neurotoxicity in vinorelbine-paclitaxel combinations - Response
Muggia, FM
1997 JAN 1 ;89(1):88-88, Journal of the National Cancer Institute
— id: 53369, year: 1997, vol: 89, page: 88, stat: Journal Article,

MDR1 gene expression in primary and advanced breast cancer
Yang, X.; Uziely, B.; Groshen, S.; Lukas, J.; Israel, V.; Russell, C.; Dunnington, G.; Formenti, S.; Muggia, F.; Press, M. F.
1997 ;38(0):389-389, Proceedings (American Association for Cancer Research)
— id: 109244, year: 1997, vol: 38, page: 389, stat: Journal Article,

Abdomino-pelvic hyperthermia and intraperitoneal carboplatin in epithelial ovarian cancer: feasibility, tolerance and pharmacology
Formenti SC; Shrivastava PN; Sapozink M; Jozsef G; Chan KK; Jeffers S; Morrow PC; Muggia FM
1996 Jul 15;35(5):993-1001, International journal of radiation oncology biology physics
PURPOSE: To investigate the feasibility, toxicity, and pharmacokinetics of intraperitoneal (i.p.) carboplatin (CB) with concomitant abdomino-pelvic hyperthermia (HT) in advanced ovarian cancer patients. METHODS AND MATERIALS: Patients with residual disease mainly confined to the peritoneal cavity after platinum based chemotherapy received an initial course of i.p. CB for baseline pharmacokinetics followed by three cycles of i.p. CB with concomitant regional hyperthermia. The goal of HT was to achieve at least 45 min of intraperitoneal temperature > 42 degrees but < 50 degrees C while maintaining normal tissue temperatures < 43 degrees C and systemic body temperatures < 38 degrees C. No analgesic premedication was used. Thermometry was recorded by multisensor fiberoptic probes placed within the peritoneal cavity, bladder, vagina, and oral cavity. RESULTS: Thirteen patients received a total of 31 sessions. Our intraperitoneal temperature goal could not be achieved because of patient intolerance. At best, we could maintain intraperitoneal temperatures > 40 degrees C, for more than 40 min in 7 of 31 sessions. The average values of thermal variables were T90 = 40 degrees C, TAVE = 41 degrees C, TMIN = 38.2 degrees C, and TMAX = 42.9 degrees C. The mean maximum systemic temperature was 38 degrees C. Acute thermal toxicities requiring early interruption of hyperthermia were systemic temperature exceeding 38 degrees C (11 of 31), abdominal pain or generalized distress (20 of 31), and vomiting (2 of 31). Hematological toxicities were not increased by hyperthermia. Pharmacokinetics were consistent with enhanced clearance of CB by HT. Lower radio frequencies (< 75 MHz) achieved better heat deposition in the peritoneal cavity than higher frequencies (> 75 MHz). Two of the 13 patients (a Stage III and a Stage IV patient) are alive with no evidence of disease at 40 and 43 months from treatment. CONCLUSIONS: Intraperitoneal temperatures in the range of 40 degrees C maintained for approximately 40 min can be achieved within the described setting. The probability of successful induction of therapeutic intraperitoneal temperatures appears to be higher when frequencies below 75 MHz are used. Patients who are potentially platinum sensitive and have minimal residual disease could potentially benefit from the combined treatment under the conditions studied. However, this temperature-time range appears inadequate against platinum resistant disease, and/or bulky residual pelvic disease. Alternative approaches such as whole body hyperthermia and carboplatin are warranted to overcome some of the obstacles observed
— id: 34957, year: 1996, vol: 35, page: 993, stat: Journal Article,

Amifostine protects bone marrow from platinum compounds without altering platinum-DNA adducts in buccal cells
Formenti, S. C.; Flor-Weiss, E. Dela; Gill, I.; Jeffers, S.; Blommaert, F.; Michaels, C.; Muggia, F. M.; Den Engelse, L.
1994 ;1(6):287-291, Cellular Pharmacology
The potential cytoprotective effect of amifostine (WR2721) was studied by analysing toxicities and platinum-DNA adducts in patients with solid tumours entered into two consecutive clinical trials of carboplatin 300 mg/m-2 day 1 and cisplatin 100 mg/m-2 day 3 given without amifostine (seven patients) and with amifostine (nine patients). Haematological toxicity was reduced by amifostine: grades 2-4 granulocytopenia was observed in only 3/21 courses and thrombocytopenia was observed in only 2/21 courses compared to grades 2-4 granulocytopenia in 22128 and thrombocytopenia in 13/28 when amifostine was not added. No delay in chemotherapy administration due to haematological recovery was seen in the group treated with amifostine as opposed to the need for delay in 50% of the chemotherapy cycles (14/28) given without chemoprotectant: mean delay was 16.2 days (range 8-21 days). Within this small sample size, no differences in other toxicities or in response rates could be observed between the two treatment groups. The addition of amifostine did not decrease the extent of platinum-DNA adducts formation in buccal cells collected before and after carboplatin and cisplatin, respectively during the first cycle of therapy. Amifostine appears to diminish the myelosuppression induced by platinum compounds, although no obvious modification of platinum-DNA adduct formation in other normal tissue (buccal cells) was noted
— id: 109223, year: 1994, vol: 1, page: 287, stat: Journal Article,

PREFACE
MUGGIA, FM; SPEYER, JL
1994 APR ;8(2):R9-&, Hematology-oncology clinics of North America
— id: 52506, year: 1994, vol: 8, page: R9, stat: Journal Article,

Calvert's formula and high-dose carboplatin
Uziely B; Formenti SC; Watkins K; Mazumder A; Muggia FM
1994 Aug;12(8):1740-1741, Journal of clinical oncology
— id: 34962, year: 1994, vol: 12, page: 1740, stat: Journal Article,

EFFECT OF LOCAL HYPERTHERMIA ON THE PHARMACOKINETICS PKS OF INTRAPERITONEAL IP CARBOPLATIN CB CLINICAL AND PRECLINICAL STUDY
MUGGIA F; FORMENTI S C; SAPOZINK M; CHAN K K; LOS G
1992 ;33(0):501-501, Proceedings (American Association for Cancer Research)
— id: 109245, year: 1992, vol: 33, page: 501, stat: Journal Article,

RADIATION-THERAPY AND FLUOROURACIL WITH OR WITHOUT SEMUSTINE FOR THE TREATMENT OF PATIENTS WITH SURGICAL ADJUVANT ADENOCARCINOMA OF THE RECTUM
WOOLLEY, PV; NAUTA, R; SMITH, FP; LINDBLAD, AS; PETRELLI, N; HERRERA, L; DOUGLASS, HO; MAYER, RJ; BRUCKNER, HW; DALTON, J; BONADONNA, G; GENNARI, L; HALL, TC; WEAVER, DW; LEICHMAN, L; KALSER, MH; BENEDETTO, P; MUGGIA, FM; GREEN, M; GREENWALD, E; LEVIN, B; GAYNOR, E; HARRIS, J; MARSH, JC; BARWICK, K; KNOWLTON, AH; LIVSTONE, EM; BUKOWSKI, RM; LOUTFI, A; RAMIREZ, G; THOMAS, PRM
1992 APR ;10(4):549-557, Journal of clinical oncology
— id: 52037, year: 1992, vol: 10, page: 549, stat: Journal Article,

ICRF-187 (ADR-529) cardioprotection against anthracycline-induced cardiotoxicity: clinical and preclinical studies
Green MD; Alderton P; Sobol MM; Gross J; Muggia FM; Speyer JL
1991 ;58(4):101-117, Cancer treatment & research
— id: 35093, year: 1991, vol: 58, page: 101, stat: Journal Article,

Phase I and pharmacologic evaluation of intraperitoneal 5-fluoro-2'-deoxyuridine
Muggia FM; Chan KK; Russell C; Colombo N; Speyer JL; Sehgal K; Jeffers S; Sorich J; Leichman L; Beller U; et al
1991 ;28(4):241-250, Cancer chemotherapy & pharmacology
Intraperitoneal (i.p.) 5-fluoro-2'-deoxyuridine (Floxuridine, FUdR, FdUrd) was evaluated in a phase I study at a starting level of 500 mg given on 1 day in 2 I 1.5% dialysate. Escalations within patients were allowed every other cycle. A total of 23 patients (age, 32-78 years) received 108 treatment courses. Local tolerance at all dose levels was excellent, with no cases of drug-related peritonitis being observed. Nausea and vomiting increased in severity in relation to dose and was universal at greater than 3,000 mg x 3 days. One patient each developed grade 1 mucositis as well as diarrhea at a dose of 3,000 mg x 3 days and leukopenia and thrombocytopenia at 5,000 mg x 3 days. Peritoneal fluid (PF) and plasma (PL) FdUrd profiles were monitored by an HPLC method in 13 subjects, with 7 being studied serially at 2-4 increment doses for up to 6 h. Profiles that exhibited apparent linear pharmacokinetics gave PF drug levels 2-4 logs higher than the PL counterparts, with the latter essentially declining in parallel to the former, indicating that the disposition of FdUrd from the peritoneal compartment is rate-determining. The mean terminal half-life for PF FdUrd was found to be 115 min and mean peritoneal clearance was 25 ml/min. The vast differences in drug levels and AUC found between the PF and the PL profiles suggests a high systemic clearance of FdUrd, which was confirmed in two patients receiving 2 g FdUrd by short i.v. infusion. A disproportionate increase in the plasma FdUrd levels and the corresponding AUC values was found with increasing dose, suggesting a disproportionate increase in the systemic partitioning of FdUrd when doses were escalated within a patient. Substantial levels of peritoneal 5-fluorouracil (FUra) were also detected in most of the subjects. Thus, FdUrd was found to have several desirable properties for i.p. administration: (1) a 2- to 4-log pharmacologic advantage. (2) the absence of local toxicities, and (3) a favorable antitumor spectrum and some evidence of antitumor effects in this phase I and pharmacology study. A 3,000-mg dose given in 2 1 1.5% dialysate for 3 consecutive days exhibited antitumor activity and produced no systemic toxicity except nausea and vomiting, which was controlled by antiemetics. This dose schedule is therefore recommended for phase II trials directed against small-volume disease in the peritoneal cavity, such as may be found in some stages of ovarian and gastrointestinal cancers.(ABSTRACT TRUNCATED AT 400 WORDS)
— id: 14203, year: 1991, vol: 28, page: 241, stat: Journal Article,

Plasma carcinoembryonic antigen as an indicator of cerebral metastases
Eden EA; Muggia JM; Hiesiger EM; Muggia FM
1990 Jun;8(3):281-287, Journal of neuro-oncology
Four patients in whom the plasma CEA reflected the clinical course of intracranial disease are presented. We conclude that a search to explain an elevated CEA should include the central nervous system. In addition, in selected patients with brain metastases the plasma CEA is a helpful indicator of tumor control and of its response to radiation and chemotherapy
— id: 21718, year: 1990, vol: 8, page: 281, stat: Journal Article,

Evidence of the selective alteration of anthracycline activity due to modulation by ICRF-187 (ADR-529)
Green MD; Alderton P; Gross J; Muggia FM; Speyer JL
1990 ;48(1):61-69, Pharmacology & therapeutics
Anthracyclines are powerful anticancer drugs whose use is limited by the development of chronic cardiotoxicity. The bisdioxopiperazine compound ICRF-187 (ADR-529) specifically abrogates this toxicity both in preclinical animal models and in humans. It does this without effecting either the acute toxicities or the anticancer activity. Therefore, with a specific antagonist, the mechanism of activity of the anthracyclines can be explored. This review discusses recent clinical trials and animal models addressing this issue and concludes by hypothesizing a mechanism of action
— id: 35095, year: 1990, vol: 48, page: 61, stat: Journal Article,

Phase II study of esorubicin (4'deoxydoxorubicin) in anthracycline naive patients with ovarian cancer
Green MD; Speyer JL; Wernz JC; Colombo N; Beller U; Muggia FM; Beckman EM
1990 Aug;8(3):333-336, Investigational new drugs
Sixteen patients with metastatic ovarian cancer who had not previously been treated with anthracyclines were treated with 4'deoxydoxorubicin at a dose of 30 mg/m2 intravenously every 3 weeks. There were no clinical responses in this group of patients. Toxicities were infrequent with neutropenia and thrombocytopenia being dose limiting. Nausea and vomiting occurred in only 4 patients. We conclude that 4'deoxydoxorubicin is an inactive drug in this patient population and does not warrant further investigation in this disease
— id: 15690, year: 1990, vol: 8, page: 333, stat: Journal Article,

Good tolerance of weekly oral idarubicin: (4-demethoxydaunorubicin): a phase I study with pharmacology
Hochster H; Green M; Liebes L; Speyer JL; Wernz J; Blum R; Muggia F
1990 ;26(4):297-300, Cancer chemotherapy & pharmacology
Idarubicin (4-demethoxydaunorubicin) is an orally active anthracycline. We treated 26 patients with 37 courses of the drug on a schedule of oral administration weekly x 3 followed by a 3-week rest period. The maximum tolerated dose on this schedule was 22.5 mg/m2 weekly x 3 every 6 weeks, with consistent myelosuppression being the dose-limiting toxicity; other toxicity was minimal. Pharmacologic studies showed a mean alpha half-life of 1.6 +/- 0.3 h and a beta half-life of 39 +/- 8.4 h for idarubicin. This schedule was well tolerated, with consistent toxicity patterns seen. Pharmacologic studies confirmed prolonged exposure to the drug and its active metabolite. In comparison with other schedules, this one may offer advantages in terms of consistent hematologic toxicity and prolonged exposure to both the parent compound and its active metabolite. Dose intensity was comparable with that on other schedules
— id: 35094, year: 1990, vol: 26, page: 297, stat: Journal Article,

Intraperitoneal carboplatin: favorable results in women with minimal residual ovarian cancer after cisplatin therapy
Speyer JL; Beller U; Colombo N; Sorich J; Wernz JC; Hochster H; Green M; Porges R; Muggia FM; Canetta R; et al
1990 Aug;8(8):1335-1341, Journal of clinical oncology
From August 1985 to November 1989 we conducted a trial of intraperitoneal (IP) carboplatin including a dose-escalation design in 25 women with advanced gynecologic malignancies. All had extensive prior therapy with cisplatin (median cumulative dose, 525 mg/m2). Carboplatin was administered IP in 2 L of 1.5% dextrose with a 4-hour dwell time every 4 weeks for six cycles at a starting dose of 200 mg/m2. Patients with reduced creatinine clearance (30 to 60 cc/min) were escalated more slowly than those with high (greater than 60 cc/min) clearance. Thrombocytopenia was dose-limiting and often more severe in patients with compromised renal function; there was no local drug toxicity. The median time of follow-up is 25 months. Complete responses (CRs) were documented in six of 23 assessable patients (26%) by repeat laparotomy, and an additional 11 patients (48%) had no disease evident by noninvasive restaging. Five of the CRs and six of the patients with no clinically evident disease have relapsed from 3 to 40 months after therapy. Six patients (26%) are alive and free of disease 8 to 47 (median, 20) months after therapy. IP carboplatin is effective against relapsed ovarian cancer, even after prior cisplatin therapy
— id: 15691, year: 1990, vol: 8, page: 1335, stat: Journal Article,

Phase II trial of ICRF-187 in patients with acquired immune deficiency related Kaposi's sarcoma (AIDS-KS)
Chachoua A; Green M; Wernz J; Muggia F
1989 Nov;7(4):327-331, Investigational new drugs
Thirteen patients with AIDS related Kaposi's Sarcoma were entered on a phase II trial of ICRF-187, 1000 mg/m2 IV daily for 3 days every 3 weeks. Eight patients had received prior chemotherapy for AIDS-KS. Six patients had prior opportunistic infection. There were no complete responses; one partial response lasting six months was seen. Toxicity was significant, and of the first 5 patients treated, 3 out of 5 had grade III or IV neutropenia. Because of this, subsequent patients received 800 mg/m2 IV days 1-3 if previously untreated or 600 mg/m2 if previously treated. Overall 4 of 13 patients had Grade IV neutropenia and 5 of 13 had Grade III neutropenia. One patient had Grade IV thrombocytopenia. ICRF-187 at a daily x 3 schedule has some efficacy in the treatment of AIDS related KS, future trials should evaluate lower doses or alternate schedules of administration
— id: 10450, year: 1989, vol: 7, page: 327, stat: Journal Article,

Phase I/II trial of thymostimulin in opportunistic infections of the acquired immune deficiency syndrome
Chachoua A; Green MD; Valentine F; Muggia FM
1989 ;7(3):225-229, Cancer investigation
Fifteen patients with acquired immune deficiency syndrome (AIDS) and opportunistic infection, were randomized to receive treatment with either thymostimulin (TP-1) at 1 mg/kg for 14 days then weekly for 12 weeks or placebo. The objectives of this study were to evaluate the toxicity of TP-1 in this patient population and to make observations on clinical response as measured by time to second opportunistic infection (OI) and changes in laboratory parameters of immune function. The study demonstrates that TP-1 can be administered safely. There were no differences, however, in time to second OI or overall survival between patient groups. In addition, no change in the immune function could be detected in patients receiving thymostimulin
— id: 10760, year: 1989, vol: 7, page: 225, stat: Journal Article,

Cancer chemotherapy : concepts, clinical investigations, and therapeutic advances
Muggia, Franco M
Boston MA : Kluwer, 1989,
— id: 2134, year: 1989, vol: , page: , stat: ,

The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group
Petrelli, N; Douglass, H O Jr; Herrera, L; Russell, D; Stablein, D M; Bruckner, H W; Mayer, R J; Schinella, R; Green, M D; Muggia, F M
1989 Oct;7(10):1419-1426, Journal of clinical oncology
A total of 343 patients with previously untreated metastatic measurable colorectal carcinoma were studied to evaluate the impact on toxicity, response, and survival of leucovorin-modulated fluorouracil (5-FU). A maximally tolerated intravenous bolus loading course regimen of 5-FU alone (500 mg/m2 x 5 days every 4 weeks with 25 mg/m2 escalation) was compared with a high-dose leucovorin regimen (600 mg/m2 of 5-FU with 500 mg/m2 of leucovorin weekly for 6 weeks with a 2-week rest) and with a similar low-dose leucovorin regimen (600 mg/m2 of 5-FU with 25 mg/m2 of leucovorin weekly for 6 weeks with a 2-week rest). The dose-limiting toxicity for the two 5-FU and leucovorin regimens was gastrointestinal, specifically diarrhea; severe diarrhea was seen frequently, and treatment-related toxicity was implicated in the demise of 11 of the patients (5%). Significant improvements in response rates were observed with a response rate of 33 of 109 (30.3%) on the high-dose leucovorin regimen (P less than .01 v control); 13 of 107 (12.1%) on the 5-FU control; and 21 of 112 (18.8%) on the low-dose leucovorin regimen. A trend toward longer survival in the 5-FU plus high-dose leucovorin regimen was observed. In this study, leucovorin was shown to significantly enhance the therapeutic effect of 5-FU in metastatic colorectal carcinoma
— id: 132491, year: 1989, vol: 7, page: 1419, stat: Journal Article,

The disposition of carboplatin in ovarian cancer patients
Gaver RC; Colombo N; Green MD; George AM; Deeb G; Morris AD; Canetta RM; Speyer JL; Farmen RH; Muggia FM
1988 ;22(3):263-270, Cancer chemotherapy & pharmacology
Carboplatin was given as a 30-min infusion to 11 ovarian cancer patients at doses of 170-500 mg/m2. The ages, weights, and creatinine clearances (Clcr) ranged from 44 to 75 years, from 44 to 74 kg, and from 32 to 101 ml/min, respectively. Plasma, plasma ultrafiltrate (PU), and urine samples were obtained at appropriate times for 96 h and were analyzed for platinum. The PU and urine were also analyzed for the parent compound by HPLC. In patients with a Clcr of about 60 ml/min or greater, carboplatin decayed biexponentially with a mean t1/2 alpha of 1.6 h and a t1/2 beta of 3.0 h. The mean (+/- SD) residence time, total body clearance, and apparent volume of distribution were 3.5 +/- 0.4 h, 4.4 +/- 0.85 l/h, and 16 +/- 3 l, respectively. Cmax and AUCinf values increased linearly with dose, and the latter values correlated better with the dose in mg than in mg/m2. No significant quantities of free, ultrafilterable, platinum-containing species other than the parent compound were found in plasma, but platinum from carboplatin became protein-bound and was slowly eliminated with a minimal t1/2 of 5 days. The major route of elimination was excretion via the kidneys. Patients with a Clcr of 60 ml/min or greater excreted 70% of the dose as the parent compound in the urine, with most of this occurring within 12-16 h. All of the platinum in 24-h urine was carboplatin, and only 2%-3% of the dosed platinum was excreted from 48 to 96 h. Patients with a Clcr of less than about 60 ml/min exhibited dose-disproportional increases in AUCinf and MRT values. The latter were inversely related to Clcr (r = -0.98). Over a dose range of 300-500 mg/m2, carboplatin exhibited linear, dose-independent pharmacokinetics in patients with a Clcr of about 60 ml/min or greater, but dose reductions are necessary for patients with mild renal failure
— id: 35098, year: 1988, vol: 22, page: 263, stat: Journal Article,

Phase I trial of escalating dose doxorubicin administered concurrently with alpha 2-interferon
Green MD; Speyer JL; Hochster HS; Liebes LF; Dunleavy S; Widman T; Wernz JC; Blum RH; Spiegel RJ; Muggia FM
1988 May 1;48(9):2574-2578, Cancer research
The clinical use of alpha 2-interferon and doxorubicin is based on in vitro and preclinical in vivo observations of synergistic antitumor efficacy. To test this combination a Phase I clinical and pharmacokinetic study of the concurrent use of alpha 2-interferon and doxorubicin was initiated in patients with malignant solid tumors. Each 5-wk treatment cycle consisted of 3 wk of drug administration and 2 wk of rest. The alpha 2-interferon was administered s.c. at a constant dose of 10 million IU/m2 on Mondays, Wednesdays, and Fridays in all patients while the doxorubicin was administered weekly beginning with a dose of 5 mg/m2 and escalated to the maximum tolerated dose of 25 mg/m2. At least three evaluable patients were entered at each dose level, and no dose escalations were allowed within patients. The dose-limiting toxicities were granulocytopenia and thrombocytopenia. Hepatic enzyme elevations and systemic symptoms due to interferon occurred at all dose levels. None was severe or dose limiting, and all were reversible. These toxicity data suggest that the hepatotoxic effects of interferon do not enhance doxorubicin toxicity when given by this dose and schedule. Doxorubicin plasma levels were measured at each dose level. The recommended dose of doxorubicin is 25 mg/m2 per wk when administered with 10 million IU/m2 of interferon in this schedule. This schedule allows for the administration of a greater total dose of doxorubicin than has been achieved when given every 3 wk with the same dose and schedule of alpha 2-interferon in a parallel study
— id: 11108, year: 1988, vol: 48, page: 2574, stat: Journal Article,

Treatment of epidemic Kaposi's sarcoma with a combination of interferon-alpha 2b and etoposide
Krigel RL; Slywotzky CM; Lonberg M; Green MD; Andes WA; Kempf R; Gupta S; Grace W; Spiegel RJ; Muggia FM; et al.
1988 Aug;7(4):359-364, Journal of biological response modifiers
A prospective clinical trial of concomitant interferon-alpha 2b and etoposide was conducted in 24 previously untreated patients with epidemic Kaposi's sarcoma. Eight of 21 evaluable patients (38%) achieved either a complete response (1 patient) or a partial response (7 patients). None of the responders had a prior history of opportunistic infection. Hematologic toxicity was severe, and 8 patients developed an opportunistic infection. The combination of interferon-alpha 2b and etoposide has modest activity, but no additive or synergistic activity was evident in the dose and schedule utilized in this study. The exact role for interferon-alpha in epidemic Kaposi's sarcoma, both as a single agent and in combinations, remains to be determined
— id: 34859, year: 1988, vol: 7, page: 359, stat: Journal Article,

Surgical treatment for advanced epithelial carcinoma of the ovary
Beller, U; Beckman, E M; Muggia, F M; Douglas, G W
1987 Sep;165(3):279-283, Surgery, gynecology & obstetrics
The three surgical steps in the management of carcinoma of the ovary--staging laparotomy, cytoreductive operation and second-look laparotomy--must be critically re-evaluated. During the past decade much data has been assembled on platinum based combination chemotherapy. The results of this type of chemotherapy questions the importance of these procedures. Whereas staging laparotomy will continue to determine important issues in the management of early disease, the use of cytoreduction and second-look laparotomy must be questioned as a routine or important determinant of current treatment results
— id: 123506, year: 1987, vol: 165, page: 279, stat: Journal Article,

Phase II study of oral idarubicin in patients with AIDS-associated Kaposi's sarcoma
Chachoua A; Green M; Laubenstein L; Wernz J; Muggia FM
1987 Jul-Aug;71(7-8):775-776, Cancer treatment reports
— id: 14635, year: 1987, vol: 71, page: 775, stat: Journal Article,

THE DISPOSITION OF CARBOPLATIN IN OVARIAN-CANCER PATIENTS
Gaver, RC; Colombo, N; Green, MD; George, AM; Deeb, G; Morris, AD; Canetta, RM; Speyer, JL; Farmen, RH; Muggia, FM
1987 Mar;28(3):195-195, Proceedings (American Association for Cancer Research)
— id: 31224, year: 1987, vol: 28, page: 195, stat: Journal Article,

Carcinoid syndrome from a tumor of Meckel's diverticulum
Green, M; Oratz, R; Muggia, F M
1987 Jul;83(1):184-186, American journal of medicine
— id: 67940, year: 1987, vol: 83, page: 184, stat: Journal Article,

PHASE-I TRIAL AND PHARMACOKINETICS OF ORAL 4 DEMETHOXYDAUN- ORUBICIN (IDARUBICIN)
Green, MD; Hochster, H; Speyer, JL; Liebes, L; Wernz, JC; Blum, RH; Ward, C; London, C; Mendoza, S; Muggia, FM
1987 Mar;28(3):192-192, Proceedings (American Association for Cancer Research)
— id: 31223, year: 1987, vol: 28, page: 192, stat: Journal Article,

A RANDOMIZED TRIAL OF ICRF-187 TO REDUCE DOXORUBICIN (DOX) CARDIOMYOPATHY - COMPARATIVE ACUTE TOXICITIES
Green, MD; Speyer, JL; Stecy, P; Rey, M; Kramer, E; Sanger, J; Ward, C; London, C; Blum, R; Wernz, J; Rohde, J; Muggia, FM
1987 May;5(1):117-117, Investigational new drugs
— id: 31182, year: 1987, vol: 5, page: 117, stat: Journal Article,

TREATMENT OF ADVANCED REFRACTORY LYMPHOMA WITH TENIPOSIDE AND LOMUSTINE
Grossberg, H; Opfell, R; Glick, J; Bakemeier, R; Schnetzer, G; Muggia, F
1987 Feb;71(2):215-216, Cancer treatment reports
— id: 31253, year: 1987, vol: 71, page: 215, stat: Journal Article,

Weekly 5-fluorouracil combined with PALA: toxic and therapeutic effects in colorectal cancer
Muggia FM; Camacho FJ; Kaplan BH; Green MD; Greenwald ES; Wernz JC; Engstrom PF
1987 Mar;71(3):253-256, Cancer treatment reports
A total of 51 patients (eight previously treated) received PALA added to 5-fluorouracil (5FU) given weekly. After 32 patients, the PALA schedule was changed from every other week to weekly, 24 hours preceding 5FU in accordance with preclinical leads (see text). Both schedules were associated with moderately severe toxic effects related primarily to PALA (skin rash) or to the combined effects of both drugs (diarrhea, vomiting, conjunctivitis, and neurotoxicity). Overall nine partial responses were observed, including three in patients previously treated with 5FU. However, future studies with this combination utilizing the current or other previously published schedules are not warranted in colorectal cancer. Since toxicity is a prominent impediment, the possibility of therapeutic synergy may perhaps be explored at drastically reduced doses of PALA, combined with other modulating measures
— id: 15694, year: 1987, vol: 71, page: 253, stat: Journal Article,

ENHANCEMENT OF METHOTREXATE (MTX) EFFECTS BY DIPYRIDAMOLE (DP)
Muggia, FM; Slowiaczek, P; Subar, M; Tattersall, MHN
1987 May;5(1):135-135, Investigational new drugs
— id: 31183, year: 1987, vol: 5, page: 135, stat: Journal Article,

Clinical evaluation of anti-tumor therapy
Muggia, Franco M.; Rozencweig, Marcel
Boston : Nijhoff, 1987,
— id: 48, year: 1987, vol: , page: , stat: ,

Treatment of metastatic malignant melanoma with dacarbazine and cisplatin
Oratz R; Speyer JL; Green M; Blum R; Wernz JC; Muggia FM
1987 Sep;71(9):877-878, Cancer treatment reports
— id: 15693, year: 1987, vol: 71, page: 877, stat: Journal Article,

Advanced ovarian cancer: three-year results of a 6-8 month, 2-drug cisplatin-containing regimen
Piccart MJ; Speyer JL; Wernz JC; Noumoff J; Beller U; Beckman M; Dubin N; Demopoulos R; Muggia F
1987 Jun;23(6):631-641, European journal of cancer & clinical oncology
Fifty-two patients with advanced (stage III and IV) ovarian cancer were treated with a regimen of cisplatin (100 mg/m2 over 5 days) and cyclophosphamide (600 mg/m2/day 4). Treatment was repeated every 3-4 weeks for 6-8 months and followed by second look surgery. The median follow up for this single institution study (1980-1984) is 36 months. The median progression-free survival (projected) is 24 months and the median overall survival (projected) is 37 months in this group of patients with unfavorable pretreatment characteristics: median age: 61, median performance status (ECOG) 2, poorly-differentiated tumors: 60%, extensive residual tumors (greater than 2 cm): 65%. Pretreatment performance status was the only independent predictor for prolonged survival. Pathologically documented complete responses were observed in 23% of all patients and 43% of the patients who underwent second-look surgery (28 patients). Neurotoxicity from this regimen was substantial: it occurred in 65% of cases, was severe in 17% and was often not entirely reversible. The results with this intensive 2-drug cisplatin-containing regimen compare favorably to other more complex regimens in the literature. It is possible that the 'dose intensity' of cis-platinum may be the most important element of current therapeutic regimens in ovarian cancer
— id: 11393, year: 1987, vol: 23, page: 631, stat: Journal Article,

Cisplatin and vinblastine chemotherapy for metastatic non-small cell carcinoma followed by irradiation in patients with regional disease
Blum RH; Cooper J; Schmidt AM; Ashinoff R; Collins A; Wernz JC; Speyer JL; Boyd A; Muggia FM
1986 Mar;70(3):333-337, Cancer treatment reports
Forty-four patients with non-small cell carcinoma of the lung were treated every 3 weeks with vinblastine (4 mg/m2/day iv X 2) and cisplatin (20 mg/m2/day iv X 3). Of the 28 patients with metastatic disease, eight (29%; 90% confidence interval of true response, 17%-47%) achieved objective response, for a median duration of 27 weeks. Median survival in this group was 47 and 28 weeks for responders and nonresponders, respectively. Of the 16 patients with advanced regional disease, 11 (69%; 90% confidence interval of true response, 49%-86%) achieved objective response. Thirteen of these patients received consolidation radiotherapy (4500 cGy/25 fractions/5 weeks), with a boost of 1000 cGy/5 fractions/1 week in those patients who achieved response. In the three patients who did not receive radiotherapy, two died during the induction phase, one from grade 4 leukopenia and sepsis and the second from unrelated factors. The third patient had systemic progression of disease during induction chemotherapy. Six patients experienced overall improvement in their chemotherapy response from the radiotherapy. Two patients who did not respond to the chemotherapy achieved partial response with irradiation. Four patients who had partial response to the chemotherapy achieved complete response with irradiation, and seven patients had no further change in their degree of response to irradiation. The overall median survival of this group was 81 weeks. Maintenance chemotherapy was not given. After radiotherapy, the site of first failure was outside the radiation field in nine of 13 patients (69%). Hematologic toxicity was dose-limiting. Other toxic effects that were not dose-limiting included nephrotoxicity, neurotoxicity, and acute nausea and vomiting. In the patients with advanced regional disease, there was no increase in the radiation toxicity attributable to the chemotherapy. We conclude that: (a) this dose schedule of vinblastine and cisplatin has reproducible activity in non-small cell carcinoma of the lung; (b) the response and median survival of patients with advanced regional disease are superior to those of patients with metastatic disease; and (c) in patients with advanced regional disease, treatment with chemotherapy followed by radiotherapy yielded an overall response rate of 81% (90% confidence interval of true response, 60%-93%) and improved survival compared to a similar group of patients studied by others receiving radiotherapy alone. We recommend further testing of this concept
— id: 15695, year: 1986, vol: 70, page: 333, stat: Journal Article,

Immune modulating therapy in gastrointestinal cancer
Chachoua A; Green M; Muggia FM
1986 Aug;81(8):623-628, American journal of gastroenterology
— id: 14636, year: 1986, vol: 81, page: 623, stat: Journal Article,

Activity of epirubicin in pancreatic carcinoma
Hochster H; Green MD; Speyer JL; Wernz JC; Blum RH; Muggia FM
1986 Feb;70(2):299-300, Cancer treatment reports
— id: 15696, year: 1986, vol: 70, page: 299, stat: Journal Article,

Oral 4-demethoxydaunorubicin (idarubicin) in bronchogenic lung cancer; phase II trial
Hochster HS; Green MD; Blum RH; Wernz JC; Speyer JL; Muggia FM
1986 ;4(3):275-278, Investigational new drugs
Eighteen patients with non-small cell lung cancer were entered into a phase II protocol of oral 4-demethoxydaunorubicin. All were evaluable for toxicity and 17 for response. The major toxicity was hematologic with eight patients developing an ECOG grade 3 or 4 toxicity. There were no responses to the treatment
— id: 15697, year: 1986, vol: 4, page: 275, stat: Journal Article,

PHASE-II TRIAL OF BAKERS ANTIFOL IN PATIENTS WITH RECURRENT OR INOPERABLE HEAD AND NECK-CANCER
KRASNOW, S; GREEN, M; PERRY, DJ; EISENBERGER, MA; JOHNSTONEARLY, A; MUGGIA, F; COHEN, MH
1986 AUG ;70(8):1039-1040, Cancer treatment reports
— id: 41555, year: 1986, vol: 70, page: 1039, stat: Journal Article,

KAPOSIS-SARCOMA AND AIDS
MUGGIA, FM; LONBERG, M
1986 JAN ;70(1):139-154, Medical clinics of North America
— id: 41630, year: 1986, vol: 70, page: 139, stat: Journal Article,

CONCURRENT ADMINISTRATION OF INTERFERON-ALPHA-2 (IFN) AND DOXORUBICIN (DOX)
SPEYER, JL; GREEN, MD; WERNZ, JC; DUNLEAVY, S; BLUM, RH; WIDMAN, T; MUGGIA, FM
1986 MAR ;27(2):182-182, Proceedings (American Association for Cancer Research)
— id: 41428, year: 1986, vol: 27, page: 182, stat: Journal Article,

APPARENT MYOCARDIAL-ISCHEMIA ASSOCIATED WITH VINBLASTINE ADMINISTRATION
SUBAR, M; MUGGIA, FM
1986 MAY ;70(5):690-691, Cancer treatment reports
— id: 41430, year: 1986, vol: 70, page: 690, stat: Journal Article,

Sequential methotrexate and 5-fluorouracil with bleomycin and cisplatin in the chemotherapy of advanced squamous cancer of the head and neck
Vogl SE; Komisar A; Kaplan BH; Engstrom PF; Kasule OH; Stolbach L; Lerner H; Muggia F
1986 Feb 15;57(4):706-710, Cancer
A bolus intravenous dose of 5-fluorouracil of 600 mg/M2 was added exactly 1 hour after methotrexate administration in an established combination program including bleomycin and cisplatin for advanced squamous cell cancer of the head and neck. Results were no better than those observed previously with the three drugs, and hematologic and mucosal toxicities were slightly worse. The overall response rate was 41% in 34 patients with recurrent or metastatic disease, with only 6% complete remissions. Median time to disease progression for responding patients was 14 weeks, compared with 10 weeks for nonresponders. Partial response had little impact on survival. Among 12 patients with far-advanced disease confined above the clavicles without prior radiotherapy, 9 (75%) achieved partial remission, but the median survival, even with later surgery or irradiation, was only 34 weeks
— id: 27127, year: 1986, vol: 57, page: 706, stat: Journal Article,

CELL-CYCLE ANALYSIS TO EVALUATE THE INTERACTION BETWEEN DOXORUBICIN (DOX) AND THE CARDIOPROTECTIVE AGENT, ICRF-187
WADLER, S; GREEN, MD; BASCH, R; MUGGIA, FM
1986 MAR ;27(2):370-370, Proceedings (American Association for Cancer Research)
— id: 41429, year: 1986, vol: 27, page: 370, stat: Journal Article,

SYNERGISTIC ACTIVITY OF DOXORUBICIN AND THE BISDIOXOPIPERAZINE (+)-1,2-BIS(3,5-DIOXOPIPERAZINYL-1-YL)PROPANE (ICRF 187) AGAINST THE MURINE SARCOMA S180 CELL-LINE
WADLER, S; GREEN, MD; MUGGIA, FM
1986 MAR ;46(3):1176-1181, Cancer research
— id: 41306, year: 1986, vol: 46, page: 1176, stat: Journal Article,

A RANDOMIZED MULTICENTER TRIAL OF CYCLOPHOSPHAMIDE, NOVANTRONE AND 5-FLUOROURACIL (CNF) VERSUS CYCLOPHOSPHAMIDE, ADRIAMYCIN AND 5-FLUOROURACIL (CAF) IN PATIENTS WITH METASTATIC BREAST-CANCER
BENNETT, JM; BYRNE, P; DESAI, A; WHITE, C; DECONTI, R; VOGEL, C; KREMENTZ, E; MUGGIA, F; DOROSHOW, J; PLOTKIN, D; GOLOMB, H; MUSS, H; BRODOVSKY, H; GAMS, R; HORGAN, LR; BRYANT, S; WEISS, A; CARTWRIGHT, K; DUKART, G
1985 ;3(2):179-185, Investigational new drugs
— id: 41230, year: 1985, vol: 3, page: 179, stat: Journal Article,

Liver cancer
Bottino, Joseph C.; Opfell, Richard W.; Muggia, Franco M
Boston : Nijhoff, 1985,
— id: 37, year: 1985, vol: , page: , stat: ,

Down's syndrome and testicular cancer: a possible association
Braun DL; Green MD; Rausen AR; David R; Wolman SR; Alba Greco M; Muggia FM
1985 Summer;7(2):208-211, American journal of pediatric hematology-oncology
— id: 18128, year: 1985, vol: 7, page: 208, stat: Journal Article,

Phase II trial of PCNU in advanced malignant melanoma: an Eastern Cooperative Oncology Group pilot study
Earhart, R H; Muggia, F M; Golomb, F M
1985 ;3(3):297-301, Investigational new drugs
PCNU, a chloroethylnitrosourea with high alkylating activity, low carbamoylating activity, optimal octanol: water partition coefficient and broad activity in animal systems, was administered to 32 evaluable patients with measurable metastatic melanoma by brief intravenous infusions every six weeks. The initial dose was 75 or 100 mg/m2, with escalation or reduction for toxicity, and a total of 58 evaluable courses were given. Half of the patient population had received no prior chemotherapy. One objective complete response (duration 585 days) and four objective partial responses (durations 55, 169, 405 and 102 days) occurred, the last recorded in a patient previously treated with DTIC. These responses included visceral, nodal and subcutaneous disease. The response rate was 16% with a 95% confidence interval of 5.5 to 33.7%. Thrombocytopenia was dose-limiting and leukopenia was relatively mild. Gastrointestinal toxicity was less severe than expected for a nitrosourea. PCNU has comparable clinical activity to that of other nitrosoureas in patients with advanced melanoma
— id: 78069, year: 1985, vol: 3, page: 297, stat: Journal Article,

DOXORUBICIN AND INTERFERON - RATIONALE AND CLINICAL-EXPERIENCE
GREEN, MD; SPEYER, J; WERNZ, J; KISNER, D; KOELLER, J; BLUM, R; VONHOFF, D; MUGGIA, F
1985 DEC ;12(2):61-67, Cancer treatment reviews
— id: 41597, year: 1985, vol: 12, page: 61, stat: Journal Article,

A PHASE-I STUDY OF THE CONCURRENT ADMINISTRATION OF ALPHA-2- INTERFERON AND DOXORUBICIN
Green, MD; Speyer, JL; Wernz, JC; Blum, RH; Dunleavy, S; Widman, T; Muggia, FM
1985 ;33(3):A767-A767, Clinical research
— id: 30846, year: 1985, vol: 33, page: A767, stat: Journal Article,

Single-dose dacarbazine and dactinomycin in advanced malignant melanoma
Hochster H; Levin M; Speyer J; Dunleavy S; Harris M; Roses D; Golomb F; Muggia F
1985 Jan;69(1):39-42, Cancer treatment reports
Twenty-one patients with advanced malignant melanoma were treated with dacarbazine at a dose of 800 mg/m2 as a single infusion and dactinomycin at a dose of 1.2 mg/m2 every 3 weeks. Hematologic toxicity was mild and gastrointestinal toxicity was tolerable. The response rate for evaluable patients was 22%, which included both men and women with visceral disease. Three of the four responses were complete. Durations of response were 4, 6, 9, and 48+ months. We conclude that dacarbazine can be safely and effectively given as a single dose along with dactinomycin. The possibility that this combination may be more effective than single agents in obtaining complete responses in patients with visceral disease must be explored further
— id: 25132, year: 1985, vol: 69, page: 39, stat: Journal Article,

4'Epidoxorubicin (epirubicin): activity in hepatocellular carcinoma
Hochster HS; Green MD; Speyer J; Fazzini E; Blum R; Muggia FM
1985 Nov;3(11):1535-1540, Journal of clinical oncology
Doxorubicin provides the most consistent response rate in hepatocellular carcinoma. We therefore initiated a trial with its analog 4'epidoxorubicin. Eighteen patients, all without prior treatment, were given the drug as a single agent every 3 weeks with dose escalation whenever possible. Five patients were treated by six-hour infusion and 13 by intravenous (IV) bolus injection, with the median dose being 90 mg/m2. The patients were of diverse ethnic background and included some with underlying cirrhosis and hepatitis B surface antigenemia. Three patients had partial remissions (6, 12, 48 weeks) for a response rate of 17%. Four patients also had prolonged stable disease (14, 26, 27, 38 weeks). Toxicity was mild, although cardiac toxicity developed in three patients at 685, 825, and 1,460 mg/m2 cumulative dose. The response to 4'epidoxorubicin in this study appears to be equivalent to the reported response rates for doxorubicin, with decreased toxicity
— id: 34972, year: 1985, vol: 3, page: 1535, stat: Journal Article,

PHASE I-II STUDY OF TRIAZINATE (TZT) FOR ADVANCED HEAD AND NECK-CANCER (HNC)
Krasnow, S; Eisenberger, M; Green, M; Muggia, F; Johnstonearly, A; Hightower, E; Ortega, L; Cohen, M
1985 ;26(MAR):172-172, Proceedings (American Association for Cancer Research)
— id: 30896, year: 1985, vol: 26, page: 172, stat: Journal Article,

Pancreatic cancer: a new target for adjuvant therapy and chemotherapy
Muggia FM; Megibow A; Douglass HO Jr
1985 ;201(4):295-300, Progress in clinical & biological research
— id: 43708, year: 1985, vol: 201, page: 295, stat: Journal Article,

Ovarian cancer: new therapeutic concepts, renewed optimism
Muggia FM; Piccart MJ; Speyer JL
1985 Nov;103(5):795-797, Annals of internal medicine
— id: 35101, year: 1985, vol: 103, page: 795, stat: Journal Article,

COLORECTAL-CANCER - SPECULATIONS ON THE ROLE OF INTRAPERITONEAL THERAPY
MUGGIA, FM
1985 ;12(3):112-115, Seminars in oncology
— id: 41185, year: 1985, vol: 12, page: 112, stat: Journal Article,

TESTICULAR CANCER AND THE LEGACY OF CHEMOTHERAPY
Muggia, FM
1985 ;15(1):1-5, Cancer chemotherapy & pharmacology
— id: 30904, year: 1985, vol: 15, page: 1, stat: Journal Article,

POTENTIAL FOR PLATINUM ANALOGS IN THE TREATMENT OF CANCER OF THE UTERINE CERVIX
MUGGIA, FM; LIRAPUERTO, V; CARUGATI, A; PAVLOVSKY, S
1985 SEP ;12(2):93-99, Cancer treatment reviews
— id: 41622, year: 1985, vol: 12, page: 93, stat: Journal Article,

TREATMENT OF KAPOSIS SARCOMA - OVERVIEW AND ANALYSIS BY CLINICAL SETTING
Odajnyk, C; Muggia, FM
1985 ;3(9):1277-1285, Journal of clinical oncology
— id: 30847, year: 1985, vol: 3, page: 1277, stat: Journal Article,

A PHASE-II STUDY OF BISANTRENE IN ADVANCED REFRACTORY BREAST-CANCER - AN EASTERN-COOPERATIVE-ONCOLOGY-GROUP PILOT-STUDY
PANDYA, KJ; MUGGIA, FM; SKEEL, RT; FALKSON, G; KAPLAN, BM; ETTINGER, DS
1985 ;8(5):353-357, American journal of clinical oncology
— id: 41183, year: 1985, vol: 8, page: 353, stat: Journal Article,

Intraperitoneal chemotherapy: technical experience at five institutions
Piccart MJ; Speyer JL; Markman M; ten Bokkel Huinink WW; Alberts D; Jenkins J; Muggia F
1985 Sep;12(3 Suppl 4):90-96, Seminars in oncology
With the rapid expansion of research programs examining intraperitoneal chemotherapy for ovarian cancer and other intraabdominal malignancies, there is a need for a reliable and safe access to the peritoneal cavity. The technical experience accumulated with either the Tenckhoff catheter or the Port-A-Cath in 288 patients treated at five institutions showed a low incidence of catheter-related peritonitis (5% and 8%, respectively), skin infection (6.6% and 0%), and bowel perforation following surgical implantation (3.5% and 1.3%). Postoperative leakage of intraabdominal fluid, bleeding, or ileus were uncommon and easily controlled. Drainage failure was the major problem with both systems; occurring in 45% of patients. Although both systems are workable, improved catheters for the administration of intraperitoneal chemotherapy are warranted
— id: 35102, year: 1985, vol: 12, page: 90, stat: Journal Article,

A PROSPECTIVE-STUDY OF THE CORRELATION BETWEEN CA-125 SERUM LEVELS AND SURGICALLY VERIFIED TUMOR BURDEN IN OVARIAN-CANCER (OV-CA) PATIENTS (
Piccart, M; Goldhirsch, A; Davis, B; Roesler, H; Muggia, F; Speyer, J
1985 ;26(MAR):148-148, Proceedings (American Association for Cancer Research)
— id: 30894, year: 1985, vol: 26, page: 148, stat: Journal Article,

Prospective evaluation of cardiotoxicity during a six-hour doxorubicin infusion regimen in women with adenocarcinoma of the breast
Speyer JL; Green MD; Dubin N; Blum RH; Wernz JC; Roses D; Sanger J; Muggia FM
1985 Apr;78(4):555-563, American journal of medicine
In order to test the possible cardiac-sparing effect of doxorubicin administered by six-hour intravenous infusion and to prospectively evaluate the role of resting left ventricular ejection fraction in monitoring these patients, 33 women with advanced breast cancer were treated with combination chemotherapy containing 5-fluorouracil, cyclophosphamide, and doxorubicin. Doxorubicin was administered via a femoral catheter as a six-hour infusion. Cardiac function was monitored prior to therapy and at intervals during therapy by history and physical examination and by measurement of resting left ventricular ejection fraction with gated pool radionuclide angiography. Twenty-six responses were observed (complete response, seven [21 percent]; partial response, 19 [57 percent]). Systemic toxicity included alopecia, myelosuppression, and nausea and vomiting. There was a progressive fall in resting left ventricular ejection fraction during treatment from a median baseline value of 0.63. Mean fall from baseline left ventricular ejection fraction at a cumulative doxorubicin dose of 200 to 300 mg/m2 was 0.06 (p less than 0.005); at 301 to 449 mg/m2 it was 0.09 (p less than 0.0005); and at 450 mg/m2 or greater it was 0.15 (p less than 0.0005). Clinical congestive heart failure developed in three patients. Even though the decrease in left ventricular ejection fraction was often within the 'normal range' (left ventricular ejection fraction 0.50 or greater), these changes were progressive and appeared to be part of a continuum of doxorubicin-induced myocardial damage. Steady-state infusion levels of doxorubicin in plasma ranged from 90 to 120 nM. They confirm the hypothesis that lower concentrations can be achieved by continuous infusion rather than by bolus infusion. In this study, however, administration of doxorubicin by six-hour infusion did not appear to have a major cardiac-sparing effect. Studies of anthracycline cardiac toxicity should include determination of baseline left ventricular ejection fraction and serial observations during therapy. Failure to include deteriorations in function above an arbitrary cutoff point or to make observations only at higher cumulative doses may underestimate drug-induced myocardial damage
— id: 15698, year: 1985, vol: 78, page: 555, stat: Journal Article,

THE ROLE OF ANTHRACYCLINES IN THE TREATMENT OF GASTRIC-CANCER
Wadler, S; Green, M; Muggia, F
1985 ;12(2):105-132, Cancer treatment reviews
— id: 30838, year: 1985, vol: 12, page: 105, stat: Journal Article,

DOXORUBICIN (DOX) AND THE CARDIOPROTECTIVE AGENT, ICRF-187, HAVE ADDITIVE CYTOTOXICITIES FOR THE MURINE SARCOMA S180 CELL- LINE
Wadler, S; Green, M; Polsky, D; Muggia, F
1985 ;26(MAR):342-342, Proceedings (American Association for Cancer Research)
— id: 30898, year: 1985, vol: 26, page: 342, stat: Journal Article,

TRIAL BASED ON BIOCHEMICAL MODULATION OF 5 FLUOROURACIL (5FU) BY DAILY SEQUENTIAL HYDROXYUREA (HU) IN COLORECTAL-CANCER
Walsh, C; Speyer, JL; Wernz, JC; Blum, RH; Muggia, FM
1985 ;26(MAR):168-168, Proceedings (American Association for Cancer Research)
— id: 30895, year: 1985, vol: 26, page: 168, stat: Journal Article,

Mitomycin and methotrexate: negative experience in untreated colorectal carcinoma
Wernz JC; Kao AK; Muggia FM; Asbury RF
1985 Feb;69(2):223-224, Cancer treatment reports
— id: 15699, year: 1985, vol: 69, page: 223, stat: Journal Article,

MALIGNANT MESOTHELIOMA OF THE TUNICA VAGINALIS TESTIS
ANTMAN, K; COHEN, S; DIMITROV, NV; GREEN, M; MUGGIA, F
1984 ;2(5):447-451, Journal of clinical oncology
— id: 41088, year: 1984, vol: 2, page: 447, stat: Journal Article,

Cardiotoxicity of anthracyclines
Green MD; Speyer JL; Muggia FM
1984 Feb;20(2):293-296, European journal of cancer & clinical oncology
— id: 35107, year: 1984, vol: 20, page: 293, stat: Journal Article,

Phase I-II study of the continuous infusion of doxorubicin in the treatment of non-small cell lung cancer
Green MD; Speyer JS; Bottino JC; Blum RH; Wernz JC; Muggia FM
1984 Apr;68(4):681-682, Cancer treatment reports
— id: 15703, year: 1984, vol: 68, page: 681, stat: Journal Article,

Intra-abdominal carcinomatosis with histologically normal ovaries
Hochster H; Wernz JC; Muggia FM
1984 Jun;68(6):931-932, Cancer treatment reports
— id: 15702, year: 1984, vol: 68, page: 931, stat: Journal Article,

Evaluation of a sequential 5-FU and hydroxyurea combination in advanced bowel cancer
Kao AK; Muggia FM; Dubin N; Lerner WA; Stark R; Wernz JC; Speyer JL; Blum RH
1984 Nov;68(11):1383-1385, Cancer treatment reports
Twenty-nine patients (two with small bowel cancer and 27 with colorectal cancer) were treated with a sequential 5-FU-hydroxyurea combination following the suggestion of schedule-dependent synergism in experimental systems. No enhanced toxicity was observed, but the response rate was only 4%. Seven additional patients manifested greater than or equal to 50% declines in CEA, but caution must be used in interpreting such changes as antitumor activity
— id: 15700, year: 1984, vol: 68, page: 1383, stat: Journal Article,

Treatment of epidemic Kaposi's sarcoma with etoposide or a combination of doxorubicin, bleomycin, and vinblastine
Laubenstein LJ; Krigel RL; Odajnyk CM; Hymes KB; Friedman-Kien A; Wernz JC; Muggia FM
1984 Oct;2(10):1115-1120, Journal of clinical oncology
An epidemic of disseminated Kaposi's sarcoma in male homosexuals has recently been described. Forty-one evaluable patients with epidemic Kaposi's sarcoma were treated with etoposide. The majority of these patients had early stage disease, no prior opportunistic infections, and no prior therapy. Twelve patients (30%) achieved complete remission, 19 (46%) partial remission, and ten (24%) no response. With follow-up time to 31 months, the median response duration is nine months. The median survival of patients with complete and partial remissions has not been reached. A combination of doxorubicin (Adriamycin, Adria Laboratories, Columbus, Ohio), bleomycin, and vinblastine (ABV) was used in 31 evaluable patients with epidemic Kaposi's sarcoma. The majority of these patients had late stage disease, prior opportunistic infections, or had failed prior treatment. Seven patients (23%) achieved complete remission, 19 (61%) partial remission, and five (61%) no response. With follow-up time to 24 months, the median response duration is eight months. The projected median survival for all patients treated with ABV is nine months. Both regimens were well tolerated, with an overall response rate of 76% for etoposide and 84% for ABV. However, while successfully treating the Kaposi's sarcoma, the underlying immune deficiency in these patients has persisted. Future treatments of Kaposi's sarcoma will need to focus on reversing the underlying immune incompetence as well as controlling the malignant manifestations of Kaposi's sarcoma arising in relation to the acquired immune deficiency syndrome
— id: 15701, year: 1984, vol: 2, page: 1115, stat: Journal Article,

PHASE-II STUDY OF MITOXANTRONE IN ADVANCED BREAST-CANCER - AN EASTERN COOPERATIVE ONCOLOGY GROUP PILOT-STUDY
LEVIN, M; PANDYA, KJ; KHANDEKAR, JD; HORTON, J; GLICK, JH; BENNETT, JM; MUGGIA, FM; FALKSON, G
1984 ;68(12):1511-1512, Cancer treatment reports
— id: 41259, year: 1984, vol: 68, page: 1511, stat: Journal Article,

ACTIVITY OF MITOLACTOL IN CANCER OF THE UTERINE CERVIX
LIRAPUERTO, V; MORALESCANFIELD, F; WERNZ, J; MUGGIA, FM
1984 ;68(4):669-670, Cancer treatment reports
— id: 40947, year: 1984, vol: 68, page: 669, stat: Journal Article,

ROLE OF CHEMOTHERAPY IN THE TREATMENT OF LUNG-CANCER - EVOLVING STRATEGIES FOR NON-SMALL CELL HISTOLOGIES
MUGGIA, FM; BLUM, RH; FOREMAN, JD
1984 ;10(1):137-145, International journal of radiation oncology biology physics
— id: 41099, year: 1984, vol: 10, page: 137, stat: Journal Article,

ACIVICIN - PHASE-II STUDIES WITH A 72-HOUR INFUSION SCHEDULE
MUGGIA, FM; EARHART, RH
1984 ;2(1):115-115, Investigational new drugs
— id: 40968, year: 1984, vol: 2, page: 115, stat: Journal Article,

WORKSHOP ON CHEMOPREVENTION OF BREAST-CANCER
MUGGIA, FM; GREENSPAN, EM
1984 ;44(7):3151-3154, Cancer research
— id: 40941, year: 1984, vol: 44, page: 3151, stat: Journal Article,

THERAPEUTIC STRATEGIES UTILIZING RECOMBINANT ALPHA-2-INTERFERON IN EPIDEMIC KAPOSIS SARCOMA
MUGGIA, FM; KRIGEL, RL; WERNZ, JC; SPIEGEL, RJ
1984 ;2(1):107-107, Investigational new drugs
— id: 40967, year: 1984, vol: 2, page: 107, stat: Journal Article,

PHASE-II TRIAL OF PALA IN LYMPHOMA - AN EASTERN-COOPERATIVE-ONCOLOGY-GROUP STUDY
MUGGIA, FM; TSIATIS, AA; OCONNELL, MJ; GLICK, JH; OPFELL, RW; COREN, A
1984 ;68(3):551-553, Cancer treatment reports
— id: 40964, year: 1984, vol: 68, page: 551, stat: Journal Article,

CARBOPLATIN - ACTIVITY IN PATIENTS WITH HEAD AND NECK (H+N), RENAL-CELL (RC) AND OVARIAN CARCINOMAS
OHNUMA, T; LEYVRAZ, S; COFFEY, V; BILLER, H; MUGGIA, F; HOLLAND, JF
1984 ;25(MAR):179-179, Proceedings (American Association for Cancer Research)
— id: 40805, year: 1984, vol: 25, page: 179, stat: Journal Article,

Phase II trial of cyclophosphamide and cis-platinum for non-small cell bronchogenic carcinoma
Schmidt AM; Blum RH; Clayton M; Speyer JL; Bottino J; Muggia FM
1984 Dec;7(6):725-727, American journal of clinical oncology
We hypothesized that cyclophosphamide and cis-platinum, without adriamycin, which had been used in previous studies, may be equally efficacious, but less toxic. We treated 27 patients with non-small cell bronchogenic carcinoma with the combination of cyclophosphamide and cis-platinum. We report six responses (25% response rate), with median survival of 79 weeks as compared to 28 weeks in nonresponders (p less than 0.01). Our regimen had acceptable hematologic toxicity and tolerable gastrointestinal toxicity. However, cumulative nephrotoxicity and neurotoxicity were observed. We conclude that cyclophosphamide and cis-platinum may compare favorably to the cyclophosphamide, adriamycin and cis-platinum combination, with respect to response and toxicity
— id: 35105, year: 1984, vol: 7, page: 725, stat: Journal Article,

HUMAN-TUMOR CLONOGENIC-ASSAY - CHEMOSENSITIVITY TESTING IN SOFT AGAR AND CLINICAL CORRELATION IN MALIGNANT-MELANOMA
CUMPS, E; BOWEN, J; HARRIS, M; ROSES, D; GOLOMB, F; VALENTINE, F; MUGGIA, F; LEVIN, M
1983 ;31(2):A405-A405, Clinical research
— id: 40682, year: 1983, vol: 31, page: A405, stat: Journal Article,

COMBINATION CHEMOTHERAPY CONTAINING SEMUSTINE (MECCNU) IN PATIENTS WITH ADVANCED COLORECTAL-CANCER PREVIOUSLY TREATED WITH 5-FLUOROURACIL (5-FU)
Engstrom, PF; Macintyre, JM; Douglass, HO; Muggia, F; Mittelman, A
1983 ;6(2):175-180, American journal of clinical oncology
— id: 30663, year: 1983, vol: 6, page: 175, stat: Journal Article,

A PILOT-STUDY OF THE CONCURRENT USE OF CIS-PLATINUM AND RADIATION-THERAPY IN ADVANCED HEAD AND NECK-CANCER
GREEN, MD; COOPER, JS; MUGGIA, FM; COHEN, N
1983 ;6(2):148-148, American journal of clinical oncology
— id: 40700, year: 1983, vol: 6, page: 148, stat: Journal Article,

KAPOSIS SARCOMA - A NEW STAGING CLASSIFICATION
Krigel, RL; Laubenstein, LJ; Muggia, FM
1983 ;67(6):531-534, Cancer treatment reports
— id: 30625, year: 1983, vol: 67, page: 531, stat: Journal Article,

A SEQUENTIAL FLUOROURACIL-HYDROXYUREA (5 FU/HU) REGIMEN FOR BOWEL AND PANCREATIC CANCERS
LERNER, WA; MUGGIA, FM; WERNZ, JC; SPEYER, JL; BLUM, RH; SPIEGEL, RJ
1983 ;31(2):A410-A410, Clinical research
— id: 40683, year: 1983, vol: 31, page: A410, stat: Journal Article,

IMPROVED QUALITY OF LIFE OF PATIENTS WITH SMALL-CELL CARCINOMA OF THE LUNG BY ELECTIVE IRRADIATION OF THE BRAIN
MUGGIA, FM
1983 ;9(7):1099-1100, International journal of radiation oncology biology physics
— id: 40663, year: 1983, vol: 9, page: 1099, stat: Journal Article,

N-ACETYLCYSTEINE (NAC) - A SIGNIFICANT CHEMOPROTECTIVE ADJUNCT - PROCEEDINGS OF A SYMPOSIUM - SE
MUGGIA, FM
1983 ;10(1):1-1, Seminars in oncology
— id: 40698, year: 1983, vol: 10, page: 1, stat: Journal Article,

PATTERNS OF HEMATOLOGIC TOXICITIES FROM ANTI-CANCER DRUGS
MUGGIA, FM
1983 ;1(11):741-741, Journal of clinical oncology
— id: 40602, year: 1983, vol: 1, page: 741, stat: Journal Article,

PULMONARY TOXICITY OF ANTITUMOR AGENTS
MUGGIA, FM; LOUIE, AC; SIKIC, BI
1983 ;10(4):221-243, Cancer treatment reviews
— id: 41032, year: 1983, vol: 10, page: 221, stat: Journal Article,

PRE-CLINICAL STUDIES - DISCUSSION
MUGGIA; UNVERFERTH; LEVY; JOHNSTON; GURTOO; HARRISON
1983 ;10(1):46-48, Seminars in oncology
— id: 50983, year: 1983, vol: 10, page: 46, stat: Journal Article,

CLINICAL-STUDIES - DISCUSSION
MUGGIA; UNVERFERTH; MYERS; MORGAN; LEVY; SLAVIK; HOLOYE; MILLER; KIM
1983 ;10(1):89-92, Seminars in oncology
— id: 50984, year: 1983, vol: 10, page: 89, stat: Journal Article,

Repeated femoral vein cannulation for administration of chemotherapeutic agents
Nidus BD; Speyer JL; Bottino J; Green M; Levin M; Muggia FM
1983 Feb;67(2):185-186, Cancer treatment reports
A cannulation set has been designed for repeated short-term infusion of vesicant chemotherapeutic agents via the femoral vein. The major complication was thrombophlebitis in 2.1% of infusions. The procedure provides reliable venous access when therapeutic plans are changed or when the inability to provide catheter care makes an indwelling catheter unwarranted
— id: 28278, year: 1983, vol: 67, page: 185, stat: Journal Article,

COMBINATION CHEMOTHERAPY OF ADVANCED COLORECTAL-CANCER UTILIZING 5-FLUOROURACIL, SEMUSTINE, DACARBAZINE, VINCRISTINE, AND HYDROXYUREA - A PHASE-III TRIAL BY THE EASTERN-COOPERATIVE-ONCOLOGY-GROUP (EST-4275)
ENGSTROM, PF; MACINTYRE, JM; DOUGLASS, HO; MUGGIA, F; MITTELMAN, A
1982 ;48(7):1555-1560, Cancer
— id: 40433, year: 1982, vol: 48, page: 1555, stat: Journal Article,

Phase I clinical trial of 9,10-anthracene dicarboxaldehyde (Bisantrene) administered in a five-day schedule
Spiegel RJ; Blum RH; Levin M; Pinto CA; Wernz JC; Speyer JL; Hoffman KS; Muggia FM
1982 Jan;42(1):354-358, Cancer research
Bisantrene is a substituted anthracene derivative which preclinically demonstrated a spectrum of activity similar to that of doxorubicin but without associated cardiotoxicity. A Phase I evaluation of the drug has been performed using daily i.v. administrations for 5 days. Sixty courses of treatment were administered to 23 patients at doses from 2.5 to 90 mg/sq m/day. Courses were repeated at 4-week intervals. Dose-limiting toxicities were leukopenia and local cutaneous reactions. The leukopenia was dose related, noncumulative, and of brief duration. Local reactions occurred in 14 of 37 courses administered at doses greater than 60 mg/sq m and in 13 patients resulted in clinical cellulitis of the infused extremity. Gastrointestinal side effects were mild. No alopecia or cardiotoxicity was observed. Two mixed responses were obtained in patients with hypernephromas. Using a daily schedule for 5 days, approximately 40% more drug can be delivered per course than by single-day i.v. administration. However, with this schedule, local cutaneous reactions may prove additionally dose limiting. Phase II studies of Bisantrene in a daily i.v. schedule for 5 days are planned at a dose of 80 mg/sq m/day to be repeated every 4 weeks
— id: 15704, year: 1982, vol: 42, page: 354, stat: Journal Article,

PHASE-II TRIAL OF DAILY X5 BISANTRENE IN RENAL-CELL CARCINOMA
Spiegel, RJ; Levin, M; Blum, R; Speyer, J; Wernz, J; Pinto, C; Muggia, F
1982 ;23(MAR):111-111, Proceedings of the annual meeting of the American Association for Cancer Research
— id: 30412, year: 1982, vol: 23, page: 111, stat: Journal Article,

A TRIAL OF N-(PHOSPHONACETYL)-L-ASPARTATE (PALA) AND 5-FLUOROURACIL (FU) IN PATIENTS (
CAMACHO, FJ; MUGGIA, FM; KAPLAN, BH
1981 ;22(MAR):457-457, Proceedings (American Association for Cancer Research)
— id: 40185, year: 1981, vol: 22, page: 457, stat: Journal Article,

CURRENT RESULTS OF THE SCREENING-PROGRAM AT THE DIVISION OF CANCER-TREATMENT, NATIONAL CANCER INSTITUTE
GOLDIN, A; VENDITTI, JM; MACDONALD, JS; MUGGIA, FM; HENNEY, JE; DEVITA, VT
1981 ;17(2):129-142, European journal of cancer
— id: 40351, year: 1981, vol: 17, page: 129, stat: Journal Article,

LUNG-CANCER - CHEMOTHERAPY AS CURATIVE TREATMENT
HOWARD, LM; BLUM, RH; MUGGIA, FM
1981 ;81(6):919-921, New York state journal of medicine
— id: 50361, year: 1981, vol: 81, page: 919, stat: Journal Article,

Future clinical investigations with anthracycline antibiotics in relation to daunorubicin
Muggia FM; Blum RH; Wernz JC
1981 ;65 Suppl 4:35-37, Cancer treatment reports
Future studies with daunorubicin involve mainly comparative evaluations with other anthracycline antibiotics and related compounds. Efforts are ongoing to improve the therapeutic index of these drugs. This includes not only laboratory development but also clinical evaluation of analogs, manipulations in dose schedules, and the use of protectors of toxic manifestations, primarily of cardiomyopathy. Technological advances in the clinical area permit, for example, the exploration of daunorubicin and related compounds by continuous infusion under more precise pharmacologic and cardiologic monitoring than was possible when they were initially introduced
— id: 15705, year: 1981, vol: 65 Suppl 4, page: 35, stat: Journal Article,

ANTI-CANCER DRUG DEVELOPMENT AND FEDERAL-REGULATION - PROTECTION AGAINST PROGRESS
MUGGIA, FM
1981 ;71(3):341-344, American journal of medicine
— id: 40313, year: 1981, vol: 71, page: 341, stat: Journal Article,

THE CANCER-THERAPY EVALUATION PROGRAM OF THE NATIONAL-CANCER-INSTITUTE
MUGGIA, FM; CARTER, SK; MACDONALD, JS
1981 ;8(4):394-402, Seminars in oncology
— id: 40298, year: 1981, vol: 8, page: 394, stat: Journal Article,

ADRIAMYCIN (ADM) 24 HOUR INFUSION - A PHASE-I TRIAL
SPEYER, JL; BOTTINO, J; NIDUS, B; BLUM, R; WERNZ, JC; LEVIN, M; HYMES, K; MUGGIA, FM
1981 ;22(MAR):363-363, Proceedings (American Association for Cancer Research)
— id: 40183, year: 1981, vol: 22, page: 363, stat: Journal Article,

PHASE-I TRIAL OF 9,10-ANTHRACENEDICARBOXALDEHYDE (CL216,942)
SPIEGEL, R; BLUM, R; PINTO, C; WERNZ, J; LEVIN, M; HOFFMAN, K; BLANK, J; MUGGIA, F
1981 ;22(MAR):357-357, Proceedings (American Association for Cancer Research)
— id: 40182, year: 1981, vol: 22, page: 357, stat: Journal Article,

CISPLATINUMDIAMMINODICHLORIDE (CPDD) IN CHEMOTHERAPY OF CANCERS - A PHASE-II THERAPEUTIC TRIAL
HAYAT, M; BRULE, G; CAPPELAERE, P; CATTAN, A; CHAUVERGNE, J; CLAVEL, B; GUERRIN, J; MISSET, JL; POMMATAU, E; RIBAUD, P; MUGGIA, FM; ROZENCWEIG, M; MATHE, G
1980 ;74(5):139-145, Recent results in cancer research = Fortschritte der Krebsforschung = Progres dans les recherches sur le cancer
— id: 40451, year: 1980, vol: 74, page: 139, stat: Journal Article,

TESTICULAR CANCER - RISK-FACTORS AND THE ROLE OF ADJUVANT CHEMOTHERAPY
Jacobs, EM; Muggia, FM
1980 ;45(7):1782-1790, Cancer
— id: 27887, year: 1980, vol: 45, page: 1782, stat: Journal Article,

THE REDISCOVERY OF DON (6-DIAZO-5-OXO-L-NORLEUCINE)
KISNER, DL; CATANE, R; MUGGIA, FM
1980 ;74(5):258-263, Recent results in cancer research = Fortschritte der Krebsforschung = Progres dans les recherches sur le cancer
— id: 40454, year: 1980, vol: 74, page: 258, stat: Journal Article,

LOCALLY INOPERABLE PANCREATIC-CANCER - FURTHER OBSERVATIONS ON A COMBINED RADIOTHERAPY-CHEMOTHERAPY APPROACH
Levin, B; Wernz, J; Kinzie, J; Moossa, A; Newall, J; Blum, R; Muggia, F
1980 ;21(MAR):419-419, Proceedings (American Association for Cancer Research)
— id: 27995, year: 1980, vol: 21, page: 419, stat: Journal Article,

TREATMENT OF PRIMARY BREAST-CANCER - SUMMARY OF THE NATIONAL-INSTITUTES-OF-HEALTH CONSENSUS DEVELOPMENT CONFERENCE
MOXLEY, JH; ALLEGRA, JC; HENNEY, J; MUGGIA, F
1980 ;244(8):797-800, JAMA
— id: 98657, year: 1980, vol: 244, page: 797, stat: Journal Article,

GENERAL PROGRESS IN CLINICAL CHEMOTHERAPY OF ADVANCED DISEASE
MUGGIA, FM; HENNEY, J; DEVITA, V
1980 ;74(5):1-7, Recent results in cancer research = Fortschritte der Krebsforschung = Progres dans les recherches sur le cancer
— id: 40448, year: 1980, vol: 74, page: 1, stat: Journal Article,

ROLE OF CHEMOTHERAPY IN HEAD AND NECK-CANCER - SYSTEMIC USE OF SINGLE AGENTS AND COMBINATIONS IN ADVANCED DISEASE
Muggia, FM; Rozencweig, M; Louie, AE
1980 ;2(3):196-205, Head & neck surgery
— id: 27934, year: 1980, vol: 2, page: 196, stat: Journal Article,

CLINICAL IMPLICATIONS OF CISPLATIN PHARMACOLOGY
MUGGIA, FM; ROZENCWEIG, M; PENTA, J
1980 ;74(5):132-138, Recent results in cancer research = Fortschritte der Krebsforschung = Progres dans les recherches sur le cancer
— id: 40450, year: 1980, vol: 74, page: 132, stat: Journal Article,

COMMENTS ON THE CARCINOGENIC, MUTAGENIC, AND TERATOGENIC PROPERTIES OF ANTICANCER DRUGS
MUGGIA, FM; ZIEGLER, J
1980 ;74(5):306-311, Recent results in cancer research = Fortschritte der Krebsforschung = Progres dans les recherches sur le cancer
— id: 40455, year: 1980, vol: 74, page: 306, stat: Journal Article,

PRE-CLINICAL AND PHASE-I STUDIES OF MALONATOPLATINUM
RIBAUD, P; KELSEN, DP; ALCOCK, N; GARCIAGIRALT, E; DUBOUCH, P; YOUNG, CC; MUGGIA, FM; BURCHENAL, JH; MATHE, G
1980 ;74(5):156-162, Recent results in cancer research = Fortschritte der Krebsforschung = Progres dans les recherches sur le cancer
— id: 40452, year: 1980, vol: 74, page: 156, stat: Journal Article,

N-(PHOSPHONACETYL)-L-ASPARTATE (PALA) - CURRENT STATUS
ROZENCWEIG, M; ABELE, R; PICCART, M; VONHOFF, DD; MUGGIA, FM
1980 ;74(5):72-77, Recent results in cancer research = Fortschritte der Krebsforschung = Progres dans les recherches sur le cancer
— id: 40449, year: 1980, vol: 74, page: 72, stat: Journal Article,

M-AMSA - A NEW ANTICANCER AGENT
ROZENCWEIG, M; VONHOFF, DD; LEGHA, SS; CYSYK, RL; MUGGIA, FM
1980 ;74(5):250-257, Recent results in cancer research = Fortschritte der Krebsforschung = Progres dans les recherches sur le cancer
— id: 40453, year: 1980, vol: 74, page: 250, stat: Journal Article,

Therapeutic progress in ovarian cancer, testicular cancer, and the sarcomas
van Oosterom, AT; Muggia, Franco M; Cleton, FJ
Hingham, MA : Kluwer, 1980,
— id: 2245, year: 1980, vol: , page: , stat: ,

LONG-TERM SEQUELAE OF CANCER-CHEMOTHERAPY
ZIEGLER, J; MUGGIA, FM
1980 ;74(5):312-315, Recent results in cancer research = Fortschritte der Krebsforschung = Progres dans les recherches sur le cancer
— id: 40456, year: 1980, vol: 74, page: 312, stat: Journal Article,

Lung cancer : progress in therapeutic research
Muggia, Franco M.; Rozencweig, Marcel
New York : Raven Press, 1979,
— id: 172, year: 1979, vol: , page: , stat: ,

Hypercalcemia in cancer
Horton, J; Olsen, K B; Muggia, F M; Heinemann, H O
1970 Dec;73(6):1047-1048, Annals of internal medicine
— id: 135840, year: 1970, vol: 73, page: 1047, stat: Journal Article,

Hypercalcemia associated with neoplastic disease
Muggia, F M; Heinemann, H O
1970 Aug;73(2):281-290, Annals of internal medicine
— id: 135841, year: 1970, vol: 73, page: 281, stat: Journal Article,

Lysozymuria and renal tubular dysfunction in monocytic and myelomonocytic leukemia
Muggia, F M; Heinemann, H O; Farhangi, M; Osserman, E F
1969 Sep;47(3):351-366, American journal of medicine
— id: 135843, year: 1969, vol: 47, page: 351, stat: Journal Article,