Irinotecan for malignant mesothelioma A phase II trial by the Cancer and Leukemia Group B

PURPOSE: The Cancer and Leukemia Group B (CALGB) conducted a multi-center phase II trial to evaluate the activity of irinotecan in malignant mesothelioma (CALGB protocol 9733). PATIENTS AND METHODS: Twenty-eight patients accrued between January 1998 and January 1999 received irinotecan 125 mg/m2 by intravenous infusion over 90 min weekly for 4 weeks, every 6 weeks. Eligibility included a performance status of 0-2 by CALGB criteria, and no prior chemotherapy. Twenty-five patients had pleural mesothelioma; two patients had peritoneal mesothelioma, and one patient had pericardial mesothelioma. Sixty-one percent of patients had epithelial histology. RESULTS: There were no complete or partial responders. Thirty-three percent of patients had stable disease and 52% were shown to have progressive disease at the first reassessment. One patient was not evaluable for response. Median survival from study entry was 9.3 months (95% CI 4.5-13.2 months); 1-year survival was estimated at 46% (95% CI 28-65%). Toxicity was moderately severe. Grade 3 or 4 toxicities included neutropenia in 28% of patients, lymphopenia in 43%, and diarrhea in 18%. Three patients died of treatment-related toxicities. All three experienced grade 4 diarrhea, two also had neutropenic sepsis. CONCLUSION: Single-agent irinotecan in this dose and schedule has considerable toxicity in patients with malignant mesothelioma and has no anti-tumor activity. The relatively long median survival seen in this study principally reflects the prognostic features of the accrued patients.     

High-dose paclitaxel plus G-CSF for malignant mesothelioma: CALGB phase II study 9234

Background: New agents with activity in mesothelioma are sorely needed. The Cancer and Leukemia Group B (CALGB) therefore performed a phase II study of high-dose paclitaxel in patients with malignant mesothelioma who had no prior chemotherapy.Patients and methods: Thirty-five patients accrued to this multi-institutional phase II study of paclitaxel given as a 24-hour infusion at 250 mg/m2 every three weeks plus filgrastim (G-CSF) 300 mcg subcutaneously days 3–18.Results: There were three (9%) regressions of evaluable disease. The median survival was five months (95% confidence interval (95% CI): 1.9–9.6 months), the one-year survival rate was 14% and the two-year survival rate was 6%. Toxicity was tolerable with one death from pneumonia (without neutropenia) on day 18 and a 23% rate of grade 4 granulocytopenia.Conclusions: The level of activity seen with paclitaxel is similar to that seen in other CALGB trials of the single agents carboplatin, trimetrexate and 5-azacytidine. Future studies of of paclitaxel (at lower doses) in combination with synergistic agents could be considered.     

Capecitabine in malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B (39807)

PURPOSE: The CALGB performed a phase II multicenter study to evaluate the activity of oral capecitabine in patients with malignant mesothelioma (CALGB 39807). PATIENTS AND METHODS: Between November 15, 2000 and August 31, 2001, 27 patients with mesothelioma were enrolled in this study. Capecitabine was administered at 2500 mg/m(2) per day divided in two doses for 14 days followed by a seven-day break. Cycles were repeated every 21 days with restaging performed every two cycles and therapy continuing for up to six cycles. One patient withdrew from the study prior to receiving therapy and is removed from further analysis. Eligibility criteria included no prior treatment, PS 0-1 by CALGB criteria and histologically documented mesothelioma. Patient characteristics: gender; male 19 (73%), female seven; median age 70 (range 40-81); histology: epithelial 15 (58%), mixed eight (31%), unclassified three; site of origin pleura, 25 (96%); weight loss in previous six months of more than 10% in seven (27%), symptoms longer than six months in five (19%). RESULTS: One patient (4%) had a confirmed PR while 10 (38%) achieved SD for 2-6 cycles. Ten patients (38%) had PD as their best response. There were three patients unevaluable for response and two early deaths. Median survival and failure free survival were 4.9 (95% CI 4-10.8) and 2.4 (95% CI 1.5-4.2) months respectively with a one-year survival of 23% (95% CI 11-49%). Grade three or greater toxicities encountered by at least 10% of patients included lymphopenia (12%), fatigue (12%), dehydration (12%) and diarrhea (15%). Three patients (12%) had grade three skin toxicity or hand-foot syndrome. One patient died of treatment related toxicity during cycle one. CONCLUSION: The antitumor activity of capecitabine is insufficient to warrant further exploration in patients with malignant mesothelioma.     

A multicenter phase II study of gemcitabine and oxaliplatin for malignant pleural mesothelioma

We conducted a phase II multicenter trial to evaluate the activity of combined gemcitabine and oxaliplatin in malignant pleural mesothelioma. Twenty-five patients were recruited between May 1999 and December 2001 and received gemcitabine 1000 mg/m2 intravenously over 30 minutes and oxaliplatin 80 mg/m2 intravenously over 3 hours on days 1 and 8 of a 21-day cycle for a maximum of 6 cycles. Eligibility criteria included an Eastern Cooperative Oncology Group performance status of 0-2 and no prior chemotherapy. Best objective responses achieved were as follows: partial response, 10 patients (40%, 95% CI, 21%-61%); stable disease, 6 patients (24%, 95% CI, 9%-45%); and progressive disease, 9 patients (36%, 95% CI, 18%-57%). Median time to disease progression was 7 months, and median survival was 13 months. One-year survival was 60% (95% CI, 31%-72%). There were 2 deaths from disease progression. Toxicity was mainly hematologic. Grade 3/4 nausea and vomiting occurred in 8% of patients, neuropathy occurred in 8% of patients, and diarrhea occurred in 4% of patients. The combination of gemcitabine and oxaliplatin was shown to be active in malignant pleural mesothelioma and to exhibit tolerable toxicity in an outpatient setting.     

Gemcitabine and cisplatin in unresectable malignant mesothelioma of the pleura: a phase II study of the Southwest Oncology Group (SWOG 9810)

PURPOSE: The purpose of this open-label phase II SWOG study was to evaluate the activity of gemcitabine (Gemzar; Eli Lilly, Indiana, USA) and cisplatin combination therapy, in patients with unresectable malignant mesothelioma of the pleura. PATIENTS AND METHODS: Fifty eligible chemotherapy na?ve patients with histologically proven malignant mesothelioma of the pleura, and a SWOG performance status 0-2 were enrolled between February 1999 and August 2000. Treatment consisted of gemcitabine 1000mg/m(2) and cisplatin 30mg/m(2) on days 1, 8 and 15 of a 28-day cycle, until progression of disease or two cycles beyond complete response. RESULTS: Using SWOG response criteria, one patient had a confirmed complete response and five patients had a confirmed partial response, for a total response rate of 12% (95% CI 5-24%). All the responses were seen in patients with epithelioid or unspecified histology. Stable disease was seen in 25 patients (50%). The median overall survival was 10 months (95% CI 7-15 months), with a median progression-free survival of 6 months. Sixteen patients experienced Grade 4 toxicity. Twelve of these Grade 4 toxicities were hematologic. There were no treatment-related deaths. CONCLUSIONS: Cisplatin-gemcitabine combination chemotherapy has modest activity with an acceptable toxicity profile, as first line treatment for patients with malignant mesothelioma.     

Edatrexate (10-ethyl-deaza-aminopterin) (NSC #626715) with or without leucovorin rescue for malignant mesothelioma. Sequential phase II trials by the cancer and leukemia group B

BACKGROUND: The Cancer and Leukemia Group B (CALGB) conducted sequential Phase II multicenter trials to evaluate the activity of edatrexate alone (E) or with leucovorin rescue (EL) in patients with malignant pleural mesothelioma (CALGB Protocol 9131). METHODS: Twenty patients were accrued to the E portion of the study and received edatrexate, 80 mg/m(2), intravenously over 20-30 minutes weekly. After a protocol amendment precipitated by excessive toxic events with E, 40 patients were enrolled in the EL arm and received the same dose of edatrexate with leucovorin, 15 mg orally, every 6 hours for 4 doses beginning 24 hours after edatrexate. Eligibility criteria included a CALGB performance status of 0-2 and no prior chemotherapy. A central pathology review was performed. Of the 58 patients included in this analysis (20 receiving E and 38 receiving EL), 36 had epithelial cell type and 22 had mixed or sarcomatous cell types. There were 31 patients with measurable disease and 27 with evaluable disease. RESULTS: The overall response rate was 25% for E (95% confidence interval [95% CI], 9-49%) and 16% for EL (95% CI, 6-31%). There was a 5% complete response [CR] rate, a 10% partial response [PR] rate, and a 10% regression [R] rate for E and a 0% CR rate, a 3% PR rate, and a 13% R rate for EL. The median survival duration from study entry was 9.6 months and 6.6 months, respectively, for E and EL; 1-year survival was 50% and 32%, respectively, for E and EL. There were four early deaths with the E regimen (including two from neutropenic sepsis) and one early death with the EL regimen (from progressive disease). Principal toxicities included mu cositis, myelosuppression, and rash, which were less frequent with leucovorin rescue. CONCLUSIONS: Moderate antitumor activity has been observed with both regimens. Leucovorin rescue ameliorated the mucosal, hematologic, and dermatologic toxicities of edatrexate, but also may have reduced its efficacy.     

A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma

Our previous phase II study of cisplatin and gemcitabine in malignant mesothelioma showed a 47.6% (95% CI 26.2-69.0%) response rate with symptom improvement in responding patients. Here we confirm these findings in a multicentre setting, and assess the effect of this treatment on quality of life and pulmonary function. Fifty-three patients with pleural malignant mesothelioma received cisplatin 100 mg m(-2) i.v. day 1 and gemcitabine 1000 mg m(-2) i.v. days 1, 8, and 15 of a 28 day cycle for a maximum of six cycles. Quality of life and pulmonary function were assessed at each cycle. The best response achieved in 52 assessable patients was: partial response, 17 (33%, 95% CI 20-46%); stable disease, 31 (60%); and progressive disease, four (8%). The median time to disease progression was 6.4 months, median survival from start of treatment 11.2 months, and median survival from diagnosis 17.3 months. Vital capacity and global quality of life remained stable in all patients and improved significantly in responding patients. Major toxicities were haematological, limiting the mean relative dose intensity of gemcitabine to 75%. This schedule of cisplatin and gemcitabine is active in malignant mesothelioma in a multicentre setting. Investigation of alternative scheduling is needed to decrease haematological toxicity and increase the relative dose intensity of gemcitabine whilst maintaining response rate and quality of life.     

Multicentre phase II study of gemcitabine and cisplatin in malignant pleural mesothelioma

Malignant pleural mesothelioma is a notoriously chemoresistant tumour. However, a recent single institution study showed an impressive activity of gemcitabine and cisplatin. Our aim is to investigate the efficacy and toxicity of a gemcitabine and cisplatin combination in selected and chemo-naive patients with histologically proven malignant pleural mesothelioma. METHOD: Gemcitabine 1250 mg m(-2) was administered on day 1 and day 8 and cisplatin 80 mg m(-2) was administered on day 1 in a 3-week cycle with a maximum of six cycles. Response and toxicity evaluations were performed according to WHO and NCIC-CTC criteria. Pathology and radiology were centrally reviewed. Results show that in 25 evaluable patients, four PR were observed (ORR 16%, 95% CI 1-31%). Responses of seven patients were unevaluable. No unexpected toxicity occurred. Time to progression was 6 months (5-7 months) with a median survival from registration of 9.6 months (95% CI 8-12 months). In conclusion this trial excludes with 90% power a response rate of greater than 30% in patients with malignant pleural mesothelioma using a combination of gemcitabine and cisplatin at the proposed dose and schedule.     

Carboplatin and pemetrexed in the management of malignant pleural mesothelioma: a realistic treatment option?

BACKGROUND: Malignant pleural mesothelioma is an aggressive cancer. Chemotherapy with cisplatin and pemetrexed can improve overall survival but has a toxic profile. Substitution of cisplatin with carboplatin may avoid some potential side-effects. Therefore, we undertook a retrospective review to assess the effectiveness and tolerability of carboplatin and pemetrexed in patients with malignant pleural mesothelioma in clinical practice. METHODS: Patients with malignant pleural mesothelioma who had been treated with carboplatin and pemetrexed were retrospectively identified from pharmacy databases. The endpoints were disease control rate, time to treatment failure, clinical improvement rate and overall survival. We also evaluated any significant haematological and non-haematological toxicities. RESULTS: A total of 49 patients were identified. Of 45 evaluable cases, the disease control rate was achieved in 34 patients (69%, 95% CI 55-82, intention to treat analysis). The clinical response rate was achieved in 34 out of 49 patients (69%, 95% CI 55-82). The median time to treatment failure was 4.6 months (95% CI 3.4-5.8) and median overall survival was 14 months (95% CI 9.5-18.5). Grade 3/4 haematological toxicities were observed in 7 patients (14.3%). Grade 3/4 non-haematological toxicities were seen in 12 patients (24.5%). No toxic deaths were recorded. CONCLUSION: The combination of carboplatin and pemetrexed may be a viable option in the treatment of malignant pleural mesothelioma.     

A phase II study evaluating the cisplatin and epirubicin combination in patients with unresectable malignant pleural mesothelioma

Few chemotherapeutic agents have demonstrated their efficacy in malignant mesothelioma. The cisplatin plus doxorubicin combination has one of the highest response rates. Epirubicin is an anthracyclin, analogous to doxorubicin, with a different toxicologic pattern. As there are no data on the activity of the combination cisplatin plus epirubicin in malignant mesothelioma, the European Lung Cancer Working Party (ELCWP) designed a phase II study with response rate as primary objective. Sixty-nine eligible patients with malignant pleural mesothelioma were centrally registered. The majority of the patients were male (n=59), had a Karnofsky performance status of 80 or more (n=62) and presented with an epithelial histologic subtype (n=43). Median age was 62 years. In nine patients, metastases were documented at the initial work-up, mainly in bone, lung and skin. Three hundred and twenty-four cycles of chemotherapy were administered. The main toxicities were nausea and vomiting, neutropenia and alopecia. Among 63 assessable patients, response rate was 19.0% (95% confidence interval [CI] 9-29%). Median survival was 13.3 months. In multivariate analysis, poor prognostic factors for survival were neutrophil count and CALGB groups 4-6. In conclusion, cisplatin plus epirubicin appears as an effective regimen in malignant mesothelioma, with a favourable toxicity profile. However, it does not demonstrate superior activity to other active regimens in this disease.     

High-dose ifosfamide with mesna and granulocyte-colony-stimulating factor (recombinant human G-CSF) in patients with unresectable malignant mesothelioma

BACKGROUND: The current study was conducted to assess the activity and toxicity of high-dose ifosfamide and mesna with recombinant human granulocyte-colony-stimulating factor (rhG-CSF), given in an outpatient setting, in the treatment of patients with unresectable malignant mesothelioma. METHODS: Between September 1994 and September 1996, 41 patients with histologically verified, unresectable malignant mesothelioma were registered, 38 of whom were analyzable (2 were ineligible and 1 was nonanalyzable). Patients received intravenous ifosfamide at a dose of 2.8 g/m2 over 3 hours (total dose of 14 g/m2), plus mesna at a dose of 0.56 g/m2 prior to and at 4 hours and 8 hours after ifosfamide infusion daily for 5 days every 21 days. rhG-CSF at a dose of 5 microg/kg/day was administered subcutaneously on days 6-15. RESULTS: Response assessment could be determined adequately in 21 patients. Two patients obtained responses; 1 was a confirmed partial response (3%; 95% confidence interval [95% CI], 0-14%) and 1 was an unconfirmed response (3%; 95% CI, 5-14%). Eleven patients had stable disease (29%), 7 patients developed disease progression (18%), 1 patient had an early death (3%), and 17 patients had inadequate assessment (45%). At the time of last follow-up, 36 of the 38 eligible patients had developed disease progression, with a median progression-free survival of 5 months (95% CI, 3-7 months) and 34 patients had died with a median survival of 7 months (95% CI, 6-9 months). Twenty-four patients (63%) and 7 patients (18%), respectively, had Grade (according to Southwestern Oncology Group Toxicity Criteria) 4 hematologic toxicities and Grade 4 nonhematological toxicities. There was one treatment-related death, the result of infection, pulmonary edema, and renal failure. CONCLUSIONS: This regimen demonstrated a low overall objective response rate with substantial toxicity, and in the opinion of the authors does not warrant further investigation in the treatment of patients with unresectable malignant mesothelioma.     

A phase II study of combined intravenous and subcutaneous interleukin-2 in malignant pleural mesothelioma

A total of 29 previously untreated patients with histologically proven malignant pleural mesothelioma, with an ECOG score of < or = 2 and UICC stage I-II disease, were enrolled between May 1994 and October 1996. On days 1 and 2, 18 x 10(6) IU/day of rIL-2 was administered by continuous intravenous infusion, and 6 x 10(6) IU/day of rIL-2 by subcutaneous injection on days 5--20 inclusive of a 42-day cycle. Further treatment was administered if no radiological disease progression was demonstrated. A total of 29 patients were assessable for toxicity and 25 for response, and 49 cycles of IL-2 were administered with a median of one per patient (range, < 1-4). Toxicity included mild fever, nausea and vomiting, and skin rashes, < grade II. Three patients failed to complete one cycle of treatment because of toxicity and one died of disease before response evaluation. Two patients achieved a partial response (8%, 95% CI 1-26%) surviving 18.1 and 18.7 months from diagnosis. A total of 11 patients (44%, 95% CI 24-65%) with stable disease had a median survival of 13.6 months (range 6.5-33.8). The median survival was 8.6 months (range 3.7-34.5) for the 12 patients with progressive disease (48%, 95% CI 28-69%). This regimen of rIL-2 is well tolerated and shows limited activity in mesothelioma.     

Gefitinib in patients with malignant mesothelioma: a phase II study by the Cancer and Leukemia Group B.

PURPOSE: The Cancer and Leukemia Group B conducted a phase II study of gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, in patients with previously untreated malignant mesothelioma. EXPERIMENTAL DESIGN: Eligible patients had unresectable pleural or peritoneal mesothelioma, measurable disease, no prior therapy, and performance status 0-1 by Cancer and Leukemia Group B criteria. Gefitinib (500 mg p.o.) was administered once a day for 21 days. Patients underwent restaging after every two cycles. Therapy was continued until disease progression or unacceptable toxicity. RESULTS: The most common grade 3 toxicities were diarrhea (16%) and nausea (12%). Of 43 patients enrolled, 1 patient (2%) had a complete response, 1 patient (2%) had a partial response, 21 (49%) had stable disease lasting two to eight cycles, 15 (35%) had progressive disease, and 5 (12%) had early deaths. One-year survival was 32% [95% confidence interval (CI), 21-50%]. Median survival and failure-free survival were 6.8% (95% CI, 3.5-10.3) and 2.6 months (95% CI, 1.5-4.0), respectively. The 3-month failure-free survival was 40% (95% CI, 25-56%). EGFR expression score by immunohistochemistry done in 28 patients was categorized as low (EGFR 1+ or 2+) or high (EGFR 3+) expression: 97% had EGFR overexpression (2+ or 3+). The median and 3-month failure-free survival were 3.6 months and 40% for those patients with low EGFR expression compared with 8.1 and 40% for those with high EGFR expression. CONCLUSIONS: Although 97% of patients with mesothelioma had EGFR overexpression, gefitinib was not active in malignant mesothelioma. EGFR expression does not correlate with failure-free survival.     

Erlotinib plus bevacizumab in previously treated patients with malignant pleural mesothelioma

BACKGROUND: We conducted a phase 2, multicenter, open-label study of erlotinib plus bevacizumab in patients with malignant pleural mesothelioma who had previously received 1 prior chemotherapy regimen. These agents have activity in non-small cell lung cancer, but their role in mesothelioma is unclear. The primary endpoint is response rate. Secondary endpoints include time to progression, survival, and toxicity. METHODS: Eligible patients with mesothelioma who had previously received 1 chemotherapy regimen were treated with erlotinib 150 mg per os daily and bevacizumab 15 mg/kg administered intravenously on Day 1 of a 21-day cycle. Treatment continued until disease progression or development of significant toxicity. Tumor response was assessed after every 2 cycles using previously established mesothelioma response criteria from Byrne and Nowak. RESULTS: Twenty-four eligible patients initiated therapy with erlotinib and bevacizumab between February 2004 and October 2006. There were no complete or partial responses, although 12 patients achieved stable disease for at least 2 cycles of treatment. The median time to progression was 2.2 months (95% confidence interval [CI], 1.4 months-5.9 months). The median survival was 5.8 months (95% CI, 2.8 months-10.1 months). The most common toxicities were rash and diarrhea. There were no treatment-related deaths, intracranial bleeding, or hemoptysis. CONCLUSIONS: The combination of erlotinib and bevacizumab was tolerated reasonably well, but there was no evidence of radiographic response. This study demonstrates the feasibility of conducting trials in mesothelioma patients who have failed first-line therapy. More therapeutic studies with effective agents are needed for these patients.     

PS-341 and gemcitabine in patients with metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group (NCCTG) randomized phase II study.

BACKGROUND: PS-341 is a proteasome inhibitor with preclinical activity in pancreatic cancer tumor models and synergistic activity with gemcitabine. This randomized phase II study determined the tumor response rate (RR) for PS-341 alone and the 6-month survival and RR for the combination of gemcitabine and PS-341 in patients with metastatic pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients were randomized to receive 3-week cycles of either arm A: PS-341 1.5 mg/m(2) i.v. bolus (over 3--5 s) on days 1, 4, 8 and 11 or arm B: PS-341 1.0 mg/m(2) (same as arm A otherwise) plus gemcitabine 1,000 mg/m(2) i.v. on days 1 and 8. Patients progressing on arm A were allowed to receive arm B treatment. RESULTS: Arm A: 42 evaluable patients were enrolled with a confirmed RR of 0% (95% CI 0% to 8%), median survival of 2.5 months (95% CI 2.0-3.3), and median time to progression (TTP) of 1.2 months (95% CI 1.1--1.3). Twelve of 43 evaluable patients (28%) experienced at least one grade 4+ AE. Arm B: 39 evaluable patients yielded a 6-month survival rate of 41% (16/39, 95% CI 29.8% to 67.0%), median survival of 4.8 months (95% CI 2.4--7.4), median TTP of 2.4 months (95% CI 1.5--3.1), and confirmed RR of 10% (4 partial responses/0 complete responses, 95% CI 3% to 24%). Eleven of 43 evaluable patients (26%) experienced at least one grade 4+ AE. One patient had grade 5 hypotension. CONCLUSION: The use of PS-341 alone or in combination with gemcitabine did not result in an overall survival and RR better than that expected for gemcitabine alone. Based on the lack of efficacy and the toxicity seen in our trial, there does not appear to be a role for PS-341 in pancreatic adenocarcinoma with either of the schedules used in this trial.     

Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma

Objectives

Pemetrexed-cisplatin is the only FDA-approved regimen for malignant pleural mesothelioma (MPM), and the impact on survival is modest. No drugs have been shown to improve survival as second-line therapy, yet vinorelbine and gemcitabine are prescribed based on the results of small phase II trials. To augment the existing limited data, we examined our institutional experience with vinorelbine and gemcitabine in patients with previously treated MPM.

Materials and methods

We reviewed charts of patients with MPM treated with vinorelbine and/or gemcitabine as second- or third-line therapy between 2003 and 2010. Toxicity was graded according to the Common Terminology Criteria for Adverse Events Version 4.0. CT scans were reviewed with a reference radiologist according to modified RECIST criteria.

Results

Sixty patients were identified: 33 treated with vinorelbine, 15 gemcitabine, and 12 both agents. Eighty-three percent initially received pemetrexed-platinum. Toxicity was substantial: 46% experienced at least one episode of grade 3–4 toxicity. Of 56 patients evaluable radiologically, there was 1 partial response (gemcitabine) giving a response rate of 2% (95% CI: 0–10%). Forty-six percent had stable disease. Median progression free survival was 1.7 months for vinorelbine and 1.6 months for gemcitabine. Median overall survival was 5.4 and 4.9 months, respectively.

Conclusions

Response to second- or third-line vinorelbine or gemcitabine is rare. The high rate of stable disease warrants the continued use of these agents in this setting, though the impact on survival is questionable. These data justify the choice of placebo control arms in randomized trials of novel agents in previously treated patients.     

Activity of gemcitabine and carboplatin in advanced non-small cell lung cancer: a phase II trial

This phase II trial was designed to investigate the efficacy and tolerability of gemcitabine combined with carboplatin in patients with advanced or metastatic NSCLC. Patients were treated with gemcitabine 1000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle and carboplatin AUC 5 mg/ml/min on day 2 of each cycle. Fifty patients (Zubrod-ECOG-WHO performance status 0/1 in 70/30%, stage IV disease in 64%) entered the study and were evaluable for response and toxicity. There was 1 complete response and 24 partial responses among 50 evaluable patients, for a response rate of 50% (95% CI: 36.0-64.1%). The median survival time was 13 months (range: 6-22 months), and the 1-year survival rate was 54%. Hematologic toxicities included grades 3 and 4 neutropenia in 24 and 8% of patients, respectively, and grades 3 and 4 thrombocytopenia in 48 and 8% of patients, respectively. These were without clinical sequelae. Seven (14%) patients had grade 3 nausea and vomiting. The combination of gemcitabine and carboplatin is highly active and well tolerated in patients with advanced or metastatic NSCLC.     

Phase II trial of a single weekly intravenous dose of ranpirnase in patients with unresectable malignant mesothelioma.

PURPOSE: A multicenter phase II trial of ranpirnase (Onconase; Alfacell Corp, Bloomfield, NJ) as a single agent was conducted to further assess the safety and clinical efficacy of this novel antitumor ribonuclease. Patients with unresectable and histologically confirmed malignant mesothelioma (MM) were eligible. PATIENTS AND METHODS: One hundred five patients with Eastern Cooperative Oncology Group performance status 0 to 2 were enrolled onto the study. Thirty-seven percent of patients had not responded to prior chemotherapy. The primary end point of the study was survival. Tumor responses and time to progression were also assessed. The Cancer and Leukemia Group B (CALGB) prognostic group criteria were used to define a treatment target group (TTG). Both the intent-to-treat (ITT) and the TTG populations were analyzed for survival. RESULTS: Median survival times of 6 months for the ITT and 8.3 months for the TTG populations were observed. The 1- and 2-year survival rates were 34.3% and 21.6% for ITT, respectively, and 42% and 26.8% for TTG, respectively. Among the 81 patients assessable for tumor response, four had partial responses, two had minor regressions, and thirty-five experienced stabilization of previously progressive disease. Patients with responses and stable disease demonstrated markedly prolonged survival. Ranpirnase was well tolerated in the majority of patients, and there were no drug-related deaths. CONCLUSION: Ranpirnase demonstrated activity and a tolerable toxicity profile in patients with unresectable MM. The prognostic value of the CALGB groups was confirmed.     

Weekly gemcitabine and cisplatin combination therapy in patients with transitional cell carcinoma of the urothelium: A phase II clinical trial

Purpose: To determine the efficacy of gemcitabine and cisplatin combination therapy in patients with advanced and/or metastatic transitional cell urothelial carcinoma.Patients and methods: Forty-two chemonaïve patients with Karnofsky performance status (KPS) 70 were treated with cisplatin 35 mg/m² followed by gemcitabine 1000 mg/m² (30 min i.v. infusion) on days 1, 8, and 15 every twenty-eight days.Results: Thirty-eight patients were evaluable for efficacy. Half had visceral disease. There were seven complete (18%) and nine partial responses (24%), for a response rate of 42% (95% confidence interval (95% CI): 26%–59%). Responses were independently reviewed. Median response duration was 13.5 months (95% CI: 8.5–18.1 months), median time to progressive disease 7.2 months (95% CI: 4.0–9.1 months) and median survival 12.5 months (95% CI: 8.1–18.7 months); one-year survival was 52%. Laboratory toxicities included leucopenia (44% grade 3; 17% grade 4), neutropenia (25% grade 3; 33% grade 4) and thrombocytopenia (29% grade 3; 49% grade 4). Four patients had grade 4 symptomatic toxicity (three nausea and vomiting, one diarrhoea). There were no grade 4 infections and no toxic deaths.Conclusions: The combination of gemcitabine and cisplatin is active in patients with locally advanced and/or metastatic urothelial carcinoma. The weekly schedule of cisplatin is considered inappropriate.     

Divided dose of cisplatin combined with gemcitabine in malignant mesothelioma

Malignant mesothelioma is a rare but notoriously chemoresistant tumor. An impressive activity of gemcitabine and cisplatin combination in malignant mesothelioma has been shown. However, the hematological toxicity and nephrotoxicity related to this regimen affect the patient's life negatively. The aim of this study is to investigate the efficacy and toxicity of divided dose of cisplatin combined with gemcitabine in chemo-na?ve patients with malignant mesothelioma. Twenty-six eligible patients with malignant mesothelioma were enrolled onto the study. Cisplatin 35 mg/m(2) and gemcitabine 800 mg/m(2) were administered on days 1 and 8 as intravenous infusion in a 3-week cycle, up to maximum 6 cycles. Response and toxicity evaluations were performed in 26 patients. Male-female ratio was 11/15 with a mean age of 50.5 years (37-70). Locations of tumor were pleura in 16 patients, and peritoneum in 10 patients. All patients had epitheloid subtype of malignant mesothelioma. The partial response and stable disease were observed in 6 patients (23.1%) and in 13 patients (50%), respectively, with an overall tumor control rate of 73.1%. Seven patients (26.9%) had progressive disease. Median time to disease progression and survival were 4 and 19.5 months, respectively. Grade 3 nausea and vomiting were observed in one patient (3.8%), grade 4 neutropenia developed in one patient (3.8%) and grades 3-4 thrombocytopenia and nephrotoxicity did not develop. There was no treatment related death. Divided dose of cisplatin combined with gemcitabine, at the current dosage and schedule, appears to be an active regimen in chemotherapy-na?ve patients with malignant mesothelioma, and well-tolerated.