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Biomedical subjects

Franco Muggia

Publications and source records attributed to Franco Muggia.

At least 19 recordsLinked to original sources
PubMed2005

Prolonged topotecan infusion with cisplatin in the first-line treatment of ovarian cancer: an NYGOG and ECOG study.

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.

Adult↗
PubMed2005

Neoadjuvant chemotherapy, surgery, and adjuvant intraperitoneal chemotherapy in patients with locally advanced gastric or gastroesophageal junction carcinoma: a phase II study.

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.

Adenocarcinoma↗
PubMed2005

Investigational agents for epithelial ovarian cancer.

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.

Antineoplastic Agents↗
PubMed2005

Epidermal growth factor receptor inhibitors for the treatment of epithelial ovarian cancer.

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.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Phase II trial of carboplatin and infusional cyclosporine in platinum-resistant recurrent ovarian cancer.

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.

Adult↗
PubMed2004

Phase I clinical and pharmacokinetic study of BMS-247550, a novel derivative of epothilone B, in solid tumors.

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-naïve 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.

Adult↗
PubMed2004

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.

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.

Adult↗
PubMed2004

A phase II study of liposomal lurtotecan (OSI-211) in patients with topotecan resistant ovarian cancer.

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.

Adult↗
PubMed2004

A phase I and pharmacokinetic study of docetaxel combined with Doxil (pegylated liposomal doxorubicin) without and with granulocyte colony stimulating factor.

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.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Oxaliplatin with weekly bolus fluorouracil and low-dose leucovorin as first-line therapy for patients with colorectal cancer.

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.

Adenocarcinoma↗
PubMed2003

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.

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.

Adult↗
PubMed2003

A phase II study of 13-cis retinoic acid plus interferon alpha-2a in advanced stage penile carcinoma: an Eastern Cooperative Oncology Group study (E3893).

PURPOSE: Combined biological therapy with 13-cis-retinoic acid (13-cRA) and interferon alpha-2a (IFN alpha-2a) was reported to be highly effective in squamous cell carcinoma of the cervix and skin. Squamous cell carcinoma of the penis is rare in the United States, accounting for less than 1/2% of all male malignancies. Because of the association of infection with human papillomavirus with both carcinomas of the cervix and penis and their shared squamous cell histology, we carried out a phase II study of 13-cRA and IFN alpha-2a in carcinoma of the penis. MATERIALS AND METHODS: Eighteen ambulatory patients with surgically unresectable, recurrent, and/or metastatic squamous cell carcinoma of the penis were treated with IFN alpha-2a, 3MU/day administered subcutaneously and 13-cRA, 1 mg/kg orally daily for at least eight weeks, unless intolerable toxicity occurred. RESULTS: One patient was ineligible; one patient withdrew prior to treatment. Among the 16 eligible, treated patients, there was one complete response. Fourteen patients had progressive disease as their only treatment effect. Two patients were unevaluable for tumor response because they had no follow-up tumor measurements. No unexpected treatment-related toxicities were found on study. The only common form of grade 3 toxicity was hypertriglyceridemia found in eight of the 17 patients (47%). No toxicities above grade 3 were observed. CONCLUSION: In contrast to its benefit in squamous cell carcinomas of the cervix and skin, the combination of 13-cRA and IFN alpha-2a has low efficacy in advanced carcinoma of the penis.

Adult↗
PubMed2003

Emerging treatments for ovarian cancer.

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.

Animals↗