Phase I-II study of gemcitabine and carboplatin in stage IIIB-IV non-small-cell lung cancer.

PURPOSE: Platinum-based chemotherapy currently represents standard treatment for advanced non-small-cell lung cancer. Gemcitabine is one of the most interesting agents currently in use in advanced non-small-cell lung cancer, and high response rates have been reported when it is administered in combination with cisplatin. The aim of the present study was to evaluate the combination of gemcitabine and carboplatin in a phase I-II study. PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB-IV non-small-cell lung cancer received carboplatin at area under the concentration-time curve (AUC) 5 mg/mL/min and gemcitabine at an initial dose of 800 mg/m2, subsequently escalated by 100 mg/m2 per step. Gemcitabine was administered on days 1 and 8 and carboplatin on day 8 of the 28-day cycle. Dose escalation proceeded up to dose-limiting toxicity (DLT), which was defined as grade 4 neutropenia or thrombocytopenia or grade 3 nonhematologic toxicity. RESULTS: Neutropenia was DLT, inasmuch as it occurred in three of five patients receiving gemcitabine 1,200 mg/m2. Nonhematologic toxicities were mild. Gemcitabine 1,100 mg/m2 plus carboplatin AUC 5 was recommended for phase II studies. An objective response was observed in 13 (50%) of 26 patients, including four complete responses (15%) and nine partial responses (35%). Median duration of response was 13 months (range, 3 to 23 months). Median overall survival was 16 months (range, 3 to 26 months). CONCLUSION: The combination of gemcitabine and carboplatin is well tolerated and active. Neutropenia was DLT. The observed activity matches that observable in cisplatin-gemcitabine studies, whereas duration of response and survival are even higher. A phase II trial is under way.     

Combination Cisplatin and Carboplatin in Advanced Squamous Cell Carcinoma of the Head and Neck

Twenty-three patients with advanced squamous cell carcinoma of the head and neck who had received no prior chemotherapy were treated with carboplatin 350 mg/m² followed by cisplatin 50 mg/m² every 28 days. Twenty-one of 23 patients were evaluablefor response and toxicity. Eight patients (38%) achieved complete response (CR) or partial response (PR) with 2 CR and 6 PR. The overall median survival was 8.4 months (range 19 days-56% months). The major toxicity was hematological with grade III/IV granulocytopenia in 32% and grade III/IV thrombocytopenia in 32%. There was very little nonhematological toxicity and no nephrotoxicity. There were no therapy-related deaths. The combination carboplatin/cisplatin is tolerable in patients with squamous cell carcinoma of the head and neck, with objective responses in 38%; however, the response rate was not superior to single-agent carboplatin or cisplatin. Further studies with a higher dose of cisplatin should be considered.     

Survival advantage for carboplatin substituting cisplatin in combination with vindesine and mitomycin C for stage IIIB and IV squamous-cell bronchogenic carcinoma: a randomized phase III study

This communication represents the definitive report of a randomized phase III study comparing cisplatin and carboplatin, in combination with vindesine and mitomycin C in stage IIIB and IV squamous-cell bronchogenic carcinoma. A total of 221 patients entered the study and were randomized into two arms. Of these, 114 patients (109 evaluable for activity) were randomized to arm A, receiving cisplatin 120 mg/m(2), mitomycin C 8 mg/m(2) and vindesine 3 mg/m(2) per cycle; 107 patients (101 evaluable for activity) were randomized to arm B receiving carboplatin 500 mg/m(2) with the same doses of mitomycin C and vindesine per cycle. Patients with progressive disease (PD) were excluded from the study after the 2nd cycle, and those with stable disease (SD), partial response (PR) and complete response (CR) received six cycles of chemotherapy (or less in case of early progression). Patients were stratified according to the clinical stage (IIIB vs. IV), performance status (0+1 vs. 2+3) and tumor histological grade (I+II vs. III). In the cisplatin arm two patients (1.9%) achieved a CR, 38 (34.9%) a PR, 45 (41.2%) a SD and 24 (22.0%) had PD; the overall response rate was 40/109 (36.8%). In the carboplatin arm five patients (5.0%) achieved a CR, 31 (30.7%) a PR, 40 (39.6%) a SD, and 25 (24.7%) had PD; the overall response rate was 36/101 (35.7%). No statistically significant difference in response rate was present between the two arms, and the response rate was not influenced by performance status, histological grade or clinical stage. The Kaplan-Meyers curves displayed a significant advantage both for time to progression (P=0.005) and overall survival (P=0.008) for patients in the carboplatin arm. The advantage for patients receiving carboplatin instead of cisplatin appeared evident in univariate setting for patients with a good performance status and clinical stage IV, and occurred irrespectively of tumor histological grade; response duration and survival of responders was identical in the two arms. Patients achieving a stable disease survived longer in the carboplatin than in the cisplatin arm (P=0.012). Thus, substitution of cisplatin by carboplatin in the combination chemotherapy regimen, although more hematologically toxic (but less emetogenic) resulted in a similar response rate, but a significantly longer time to progression and overall survival.     

A combination chemotherapy of cisplatin and etoposide in small cell lung cancer

Fourteen patients with small cell lung cancer were treated with cisplatin (80 mg/m2 i.v.) and etoposide (300, 400, 500 mg/m2 i.v.). This combination chemotherapy was administered over a three- or four-week period. Eleven of 13 evaluable patients showed a greater than 50% tumor reduction, but there were 3 complete responses and 5 partial responses, giving a response rate of 61%. Four patients who were initially treated achieved major responses. In 9 patients who had received prior chemotherapy, 4 achieved a major response. Of 3 complete responders, 2 patients had previously received etoposide treatment alone. The renal toxicity of this regimen was minimal and no patients developed any clinical symptoms. Nausea and vomiting were well controlled by high-dose metoclopramide and methylprednisolone. All patients, however, experienced appetite loss after treatment. The dose-limiting toxic effect of this regimen was hematologic toxicity. We therefore concluded that the combination of etoposide (300 mg/m2 i.v.) and cisplatin (80 mg/m2 i.v.) is repeatable at 3 or 4 week intervals and effective in patients with small cell lung cancer.     

A phase II trial of weekly intravenous gemcitabine and cisplatin with continuous infusion fluorouracil in patients with metastatic renal cell carcinoma.

BACKGROUND: We reported previously that the combination of gemcitabine and continuous infusion fluorouracil (5-FU) has activity in renal cell carcinoma. Based upon in vitro synergy of gemcitabine/cisplatin and 5-FU/cisplatin, we hypothesized that the addition of cisplatin could improve the objective response rate of gemcitabine and 5-FU with manageable toxicity. PATIENTS AND METHODS: Twenty-one patients with metastatic renal cell carcinoma (RCC) and a Cancer and Leukemia Group B performance status of 0 to 2 were enrolled. Ten had received prior systemic therapy. Treatment consisted of gemcitabine 600 mg/m2 and cisplatin 20 mg/m2 on days 1, 8 and 15 of each 28-day cycle. Continuous infusion 5-FU was given from day 1 to day 21. RESULTS: No complete responses and one partial response were observed for an objective response rate of 5% (95% confidence interval 0% to 24%). Two minor responses (25% to 50% regression) were also observed. The median overall survival was 10 months with 35% of patients surviving at 1 year. Grade 3-4 myelosuppression (mostly thrombocytopenia) occurred in nine (43%) patients. Nausea/vomiting and neuropathy were dose-limiting in an additional five patients. Only 51% of treatment cycles were delivered on time and without dose reduction. CONCLUSIONS: The addition of cisplatin to gemcitabine and 5-FU did not improve the objective response rate of gemcitabine and 5-FU alone and added to the toxicity. Due to the cumulative toxicity, further trials with this cisplatin-containing regimen in RCC are not indicated.     

A comparison of the toxicity and efficacy of cisplatin and carboplatin in advanced ovarian cancer. The Swons Gynaecological Cancer Group

Eighty-eight patients with stage IIB-III epithelial ovarian cancer were randomised to receive first line single agent cisplatin (100 mg/m2) monthly or carboplatin (400 mg/m2) monthly for up to 5 cycles. Crossover to the opposite analogue occurred with progression or lack of response. All patients were premedicated with i.v. methylprednisolone (500 mg at 0 hours and 250 mg at 3 hours) and the first 20 patients in both groups received lorazepam and prochloperazine for nausea and vomiting. The median number of vomiting episodes per cycle with cisplatin was 16 and with carboplatin 2 (p less than 0.001). In the cisplatin arm 27/40 (67.5%) developed mild renal toxicity, 9/40 (22.5%) WHO grade I neurotoxicity and 18/40 (45%) evidence of ototoxicity at audiometry. To date we have seen no neuro- or ototoxicity with carboplatin and 1/40 (2.5%) have developed WHO grade I renal toxicity. Myelosuppression and anaemia was more common with carboplatin but only 1 episode of grade IV thrombocytopenia has been seen with first line carboplatin. The clinical response rate (CR+PR) for cisplatin was 19/40 and for carboplatin 27/40. Actuarial survival for cisplatin group at 24 months was 50% and for carboplatin group 58% with no significant difference. Carboplatin appears less toxic than cisplatin producing to date similar survival and response as a single agent.     

Carboplatin (JM 8), adriamycin and cyclophosphamide (JAC) in advanced ovarian carcinoma: a pilot study

Eleven untreated patients with advanced ovarian cancer were studied for tolerance and response to combination treatment with fixed doses of adriamycin (45 mg/m2) and cyclophosphamide (600 mg/m2) + escalating doses of carboplatin. At the first dose level of carboplatin (200 mg/m2), toxicity was acceptable. With carboplatin at 300 mg/m2, severe hematologic toxicity was observed. The dose-limiting toxicity was leukopenia. Although carboplatin was administered without any hydration, no patient experienced renal toxicity. Eight objective responses were observed in 9 clinically evaluable patients. At second look surgery, 3 complete responses and 4 partial responses were documented. Polychemotherapy with JAC (carboplatin, 200 mg/m2, adriamycin, 45 mg/m2, and cyclophosphamide, 600 mg/m2) is administrable with acceptable toxicity.     

Phase I study of acivicin and cisplatin in non-small-cell lung cancer. A National Cancer Institute of Canada study

Seventeen previously untreated patients with metastatic non-small-cell lung cancer were entered in this phase I trial. Treatment consisted of a combination of acivicin and cisplatin at a starting dose of 12 and 15 mg/m2, respectively, given i.v. during 5 days and repeated every 28 days. A total of 46 cycles was given. Renal function abnormality was the dose-limiting toxicity of cisplatin with a maximum tolerated dose of 12 mg/m2. This toxicity occurred at a dose lower than expected, indicating a possible potentiation of platinum renal toxicity by acivicin. Myelosuppression was the dose-limiting toxicity of acivicin, with a maximum tolerated dose of 12 mg/m2. Other side effects included generalized weakness and gastrointestinal and neurological symptoms. In 15 patients evaluable for response seven progressed, six were stable for a median duration of 13 weeks, and two patients achieved a partial remission lasting 8 and 24 weeks, respectively. The overall response rate was 13%. The recommended phase II dose of both agents in this schedule was 12 mg/m2. The possible enhancement of cisplatin toxicity might have compromised the overall response rate of the combination and further studies using these drugs in this schedule are not recommended.     

Dose intensification of platinum compounds with glutathione protection as induction chemotherapy for advanced ovarian carcinoma.

Based on previous clinical experience indicating the tolerability and efficacy of high-dose cisplatin with glutathione protection in the treatment of advanced ovarian cancer, this study was undertaken to explore the efficacy and feasibility of an alternative high-dose, platinum-based approach including a combination of high-dose cisplatin plus carboplatin as induction chemotherapy of advanced ovarian carcinoma and intervention surgery. Fifty consecutive eligible patients with untreated stage III or IV epithelial ovarian cancer received 40 mg/m(2) cisplatin daily on days 1-4 and 160 mg/m(2) carboplatin on day 5. The cycle was repeated after 28 days. Patients received glutathione (2,500 mg) before each cisplatin or carboplatin administration and standard intravenous hydration. After 2 courses of induction chemotherapy, the patients underwent surgical reevaluation with debulking, when possible, followed by a further 3 cycles of 120 mg/m(2) cisplatin (i.e. 40 mg/m(2) daily for 3 consecutive days plus 600 mg/m(2) cyclophosphamide on day 3) except in instances of lack of response. All eligible patients were assessed for response and toxicity. The toxicity was moderate with lack of significant nephrotoxicity. Neurotoxicity and ototoxicity were acceptable and in no patient was treatment discontinued for those toxic effects. Myelotoxicity was somewhat more severe than that observed with our previous study with high-dose cisplatin and probably related to the addition of carboplatin. Of the 40 responsive patients, 23 (46%) had a pathological complete response and 4 (8%) had a clinical complete response (without second-look laparotomy). The efficacy of the present protocol was also documented by overall survival (median survival >48 months), which appeared to be better than expected with the current therapy in this group with advanced/bulky disease. The impressive efficacy suggests a possible contribution of reduced glutathione itself in improving the outcome, as supported by preclinical studies. The results of this study should be placed in context with current platinum-based therapy including paclitaxel.     

Dose-intensive chemotherapy in refractory germ cell cancer--a phase I/II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation

Between September 1986 and March 1988, 33 patients with refractory germ cell cancer were entered on a phase I/II trial of two courses of high-dose carboplatin plus etoposide with autologous bone marrow support. All patients had extensive prior treatment and had either cisplatin-refractory disease (67%) defined as progression within 4 weeks of the last cisplatin dose or failed at least two cisplatin-based regimens (35%) including a cisplatin-ifosfamide salvage regimen. Patients received a fixed total dose of etoposide of 1,200 mg/m2 with each cycle. The carboplatin dose ranged from 900 mg/m2 to 2,000 mg/m2. Twenty of the 33 patients received the second cycle of therapy. Despite extensive prior therapy with cisplatin, neurotoxicity, nephrotoxicity, or hearing impairment with high-dose carboplatin and etoposide was unusual. The most common nonhematologic toxicity was moderate enterocolitis. The hematologic toxicity of this regimen was substantial at each dose level. All 53 courses were accompanied by granulocytopenic fevers. Seven of the 33 patients (21%) died from treatment. All of these deaths occurred during the granulocyte nadir, and five were related to documented sepsis. Overall, 14 of 32 patients (44%) evaluable for response obtained an objective response, including eight complete remissions. Four patients remain in complete remission, with three patients being continuously free of disease in excess of 1 year. Eight responders (including four complete remissions) had progressed while receiving cisplatin. We conclude that carboplatin and etoposide can be administered in combination at high dosages and this regimen may have curative potential for patients with germ cell tumors resistant to conventional-dose cisplatin-based therapies.     

Gemcitabine and Cisplatin is a highly effective combination chemotherapy in patients with advanced cancer of the gallbladder

We evaluated the efficacy and toxicity of gemcitabine with or without cisplatin in 11 chemonaive patients with histologically confirmed advanced gallbladder cancer. All were symptomatic and had stage IV disease. Eight patients received gemcitabine 1 g/m2 on days 1 and 8 along with cisplatin 70 mg/m2 on day 1. Three received gemcitabine alone. Treatment cycles were repeated every 21 days. One patient (9%) had complete remission of disease and 6 (55%) achieved a partial response to chemotherapy with an overall response rate of 64%. Median time to progression was 28 weeks and median overall survival was 42 weeks. Toxicity was easily manageable, and no treatment-related deaths occurred. We conclude that gemcitabine in combination with cisplatin may be one of the most effective therapies for patients with advanced gallbladder cancer. If confirmed by others, it may provide an important therapeutic option in managing these patients who otherwise have a dismal prognosis.     

Paclitaxel, cisplatin, and epirubicin first-line chemotherapy in stage III and IV ovarian carcinoma: long-term results of a phase II study

BACKGROUND: The combination of paclitaxel with cisplatin or carboplatin has become the preferred chemotherapy regimen in the treatment of epithelial ovarian carcinoma. Anthracyclines also have activity in this disease. We conducted a Phase II study by using the combination of paclitaxel, cisplatin, and epirubicin for the treatment of advanced ovarian carcinoma. METHODS: Forty consecutive patients with optimally (n = 7) or suboptimally (n = 33) debulked advanced ovarian carcinoma (International Federation of Gynecology and Obstetrics (FIGO) Stage III or IV) were treated with paclitaxel, 135 mg/m(2), as a 3-hour intravenous infusion, cisplatin 75 mg/m(2) intravenously (i.v.), and epirubicin 50 mg/m(2) i.v. every 3 weeks on an outpatient basis. Granulocyte-colony stimulating factor was administered at a dose of 5 microg/kg/day on Days 5-9. RESULTS: Among 28 patients with measurable disease, 24 (86%%) achieved an objective response including 19 complete and 5 partial responses. Among 18 patients who underwent reassessment laparotomy, pathologic complete response was confirmed in 9 patients. At a minimum follow-up of 40 months, the median overall survival had not been reached whereas the median time to progression for all patients was 18.7 months. The median remission duration for women with measurable disease who responded to treatment was 14 months. The treatment was well tolerated without toxic deaths; the most common toxicity was Grade 3/4 neutropenia that occurred in 30% of patients. Significant neuropathy (Grade 2 or higher) developed in only 8% of patients. CONCLUSIONS: The combination of paclitaxel, cisplatin, and epirubicin is a well tolerated outpatient regimen with significant activity in the treatment of advanced epithelial ovarian carcinoma.     

Phase I trial of the combination of irinotecan, paclitaxel, and carboplatin in patients with advanced non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated dose, toxicities, and dose suitable for phase II/III trials of irinotecan (CPT-11) combined with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC were enrolled to this multicenter, phase I study. The initial regimen was paclitaxel 225 mg/m(2)/3 h, followed by carboplatin area under the curve (AUC) 6 over 30 minutes on day 1, and CPT-11 starting at 40 mg/m(2) over 90 minutes, days 1 and 8, every 3 weeks. Dose-limiting toxicity occurred in three of seven patients. The regimen was amended, with doses reduced to paclitaxel 175 mg/m(2)/3 h, carboplatin AUC 5 and CPT-11 at 40 mg/m(2), all on day 1 every 3 weeks. Dose escalation of CPT-11 proceeded to 80 mg/m(2) then 125 mg/m(2) before dose-limiting toxicities were experienced. Subsequent patients received an intermediate CPT-11 dose of 100 mg/m(2). RESULTS: Thirty-three patients were enrolled; 32 patients were assessable for safety, and 31 were assessable for tumor response. The primary first-cycle dose-limiting toxicities were neutropenia and diarrhea. The most common grade 3/4 toxicity observed during all cycles was neutropenia (16 patients [50%], with six [19%] developing neutropenic fever). Objective tumor response was observed in 39% (12/31, 95% confidence interval, 22% to 58%). The median time to tumor progression was 6.8 months, median survival 11.0 months, and 1-year survival probability 0.46. CONCLUSION: CPT-11 100 mg/m(2), paclitaxel 175 mg/m(2), and carboplatin AUC 5 given every 3 weeks can be safely administered in patients with advanced NSCLC. Neutropenia and diarrhea are the dose-limiting toxicities. The combination shows appreciable activity, and survival data are favorable.     

Phase I trial, including pharmacokinetic and pharmacodynamic correlations, of combination paclitaxel and carboplatin in patients with metastatic non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated dose of paclitaxel with carboplatin with and without filgrastim support in patients with metastatic non-small-cell lung cancer (NSCLC) and to investigate the pharmacokinetics of paclitaxel and carboplatin and correlate these with the pharmacodynamic effects. PATIENTS AND METHODS: Thirty-six chemotherapy-naive patients with metastatic NSCLC were entered into this phase I dose-escalation and pharmacokinetic study. Paclitaxel was initially administered as a 24-hour infusion at a fixed dose of 135 mg/m2, and the carboplatin dose was escalated in cohorts of three patients, using Calvert's formula [dose(mg) = area under the concentration time curve (glomerular filtration rate + 25)], to target areas under the concentration time curve (AUCs) of 5, 7, 9, and 11 mg/mL x minute. A measured 24-hour urinary creatinine clearance was substituted for the glomerular filtration rate. Once the maximum-tolerated AUC (MTAUC) of carboplatin was reached, the paclitaxel dose was escalated to 175, 200, and 225 mg/m2. When the paclitaxel dose escalation began, the AUC of carboplatin was reduced to one level below the MTAUC. RESULTS: Myelosuppression was the major dose-limiting toxicity. Thrombocytopenia was observed at a carboplatin AUC of 11 mg/mL x minute after course 2 and thereafter. End-of-infusion plasma paclitaxel concentrations and median duration of time above 0.05 microM were similar in course 1 versus course 2 at the 135 and 175 mg/m2 dose levels. The neutropenia experienced by patients was consistent with that observed in patients who had received paclitaxel alone. Measured carboplatin AUCs were approximately 12% (20% v 3% with course 1 v course 2, respectively) below the desired target, with a standard deviation of 34% at all dose levels. A sigmoid-maximum effect model describing the relationship between relative thrombocytopenia and measured free platinum exposure indicated that patients who received the combination of carboplatin with paclitaxel experienced less severe thrombocytopenia than would be expected from carboplatin alone. Of the 36 patients entered onto the study, one experienced a complete response and 17 had partial responses, for an overall response rate of 50%. The recommended doses of paclitaxel (24-hour infusion) and carboplatin for future phase II studies of this combination are (1) paclitaxel 135 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL x minute without filgrastim support; (2) paclitaxel 135 mg/m2 with a carboplatin dose targeted to achieve an AUC of 9 mg/mL x minute with filgrastim support; and (3) paclitaxel 225 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL x minute with filgrastim support. CONCLUSION: The regimen of paclitaxel and carboplatin is well-tolerated and has promising activity in the treatment of NSCLC. There is no pharmacokinetic interaction between paclitaxel and carboplatin, but there is a pharmacodynamic, platelet-sparing effect on this dose-limiting toxicity of carboplatin.     

Phase I and pharmacological study of an oxaliplatin and carboplatin combination in advanced malignancies.

BACKGROUND: Phase I and pharmacokinetic study to determine the maximal tolerated dose and the recommended dose, as well as the optimal sequence of a carboplatin/oxaliplatin combination delivered every 3 weeks. PATIENTS AND METHODS: Patients received either carboplatin [area under the curve (AUC)-based individually calculated dose (starting dose AUC 4 mg.min/ml), 1 h intravenous (i.v.) infusion] followed by oxaliplatin (110 mg/m(2), 2 h i.v. infusion), every 3 weeks, or the reverse sequence. RESULTS: Sixteen patients were included and only one dose level was assessed. In group A, 10 patients received 23 cycles of carboplatin followed by oxaliplatin. In group B, 6 patients received 20 cycles with the reverse sequence. Delayed recovery from hematological toxicities was treatment-limiting, with mainly moderate thrombocytopenia and neutropenia as dose-limiting toxicities for group A (5 of 10 patients for each) and thrombocytopenia for group B (3 of 6 patients). No febrile neutropenia or grade 3/4 non-hematological toxicity occurred. Pharmacokinetic analysis showed similar mean total platinum AUCs for the two groups: 37.2 +/- 13.7 and 33.6 +/- 9.9 mg.h/l, respectively. One complete response and two partial responses (World Health Organization-International Union Against Cancer criteria, response rate 18.8%) were seen in ovarian, Fallopian and neuroendocrine carcinomas, respectively. CONCLUSIONS: This platinum combination appears feasible and active at the dose of AUC 4 mg.min/ml for carboplatin (Chatelut formula) and oxaliplatin 110 mg/m(2); however, it does not allow a significant increase in platinum dose-intensity delivery.     

Southwest Oncology Group Study of paclitaxel and carboplatin for advanced transitional-cell carcinoma: the importance of survival as a clinical trial end point.

PURPOSE: The combination of paclitaxel and carboplatin for the treatment of advanced transitional-cell carcinoma (TCC) of the urothelium has promising activity and acceptable toxicity. The purpose of this trial was to evaluate the efficacy of this regimen in a cooperative group setting. PATIENTS AND METHODS: Twenty-nine patients with advanced TCC were treated every 21 days with paclitaxel 200 mg/m(2), administered as a 3-hour infusion, followed by carboplatin dosed to an area under the curve of 5. Prior systemic adjuvant or neoadjuvant platinum-based therapy was not permitted unless completed at least 1 year before enrollment. Patients were evaluated for response every three cycles, and follow-up was conducted to determine survival. RESULTS: Twenty-nine patients were enrolled and were assessable. Four (14%) had received prior adjuvant or neoadjuvant therapy. Node-only disease was present in 24%, and 76% of patients had extranodal disease. The median number of cycles received was five. Grade 4 toxicity consisted primarily of neutropenia (38% of patients). Neurologic toxicity was noted in 16 patients (grade 1 in four patients, grade 2 in five patients, grade 3 in six patients, and grade 4 in one patient). Six partial responses and no complete responses were noted, for a response proportion of 20.7% (95% confidence interval, 8% to 40%). Median progression-free survival time was 4 months, and overall survival time was 9 months. CONCLUSION: The combination of paclitaxel and carboplatin for the treatment of advanced TCC is reasonably well tolerated. However, a response proportion considerably lower than that previously reported was noted. In addition, the median survival time of 9 months was less than the survival time previously reported for patients treated with the combination of methotrexate, vinblastine, doxorubicin, and cisplatin. Although our results may reflect enrollment of patients with poor prognostic features, they also call into question the utility of this regimen.     

Gemcitabine combined with carboplatin in patients with malignant pleural mesothelioma: a multicentric phase II study

BACKGROUND: Malignant pleural mesothelioma (MPM) is increasing rapidly worldwide. Currently, pemetrexed plus cisplatin chemotherapy showed a survival advantage versus cisplatin alone. No impact on patient survival of surgery, radiotherapy, or their combination has been demonstrated. METHODS: Eight centers in northeastern Italy participated in a Phase II multicenter study. Chemotherapy was comprised of carboplatin area under the concentration-time curve 5 on Day 1 and gemcitabine 1000 mg/m(2) on Days 1, 8, and 15. This cycle was repeated every 4 weeks. RESULTS: Between July 1996 and September 2000, 50 patients were treated. Of the sample, 68% were males, 88% had a Eastern Cooperative Oncology Group performance status score of 0-1, 56% had Stage I-II disease, 68% had epithelioid histology, and 62% had no previous treatments. The delivered dose intensity of gemcitabine was 617 mg/m(2) per week, which was 82% of the planned dose (750 mg/m(2) per week). For carboplatin, the delivered dose intensity was 80 mg/m(2) per week. Overall, 44% of 15th day doses were omitted or reduced. Twenty-six percent of the patients had partial responses (95% confidence interval: 15-40%) and 24% had disease progression. None of the patients had complete responses. The median response duration was 55 weeks (range, 13-113 weeks). Patients had good clinical benefit. For example, 46% had improved dyspnea, 40% improved in weight, and 26% experienced pain reduction. Patients developed Grade 3-4 leukopenia during 18 cycles (11%) of chemotherapy. Grade 3-4 thrombocytopenia occurred more frequently, i.e., there were 24 episodes (15%) among 17 patients. Grade 3 anemia developed among patients during eight cycles (5%). None of the patients developed Grade 3-4 nonhematologic toxicity. The median survival of this sample of patients was 66 weeks with 53%, 30%, and 20% of patients alive at 1, 2, and 3 years, respectively. The median progression-free survival period was 40 weeks. CONCLUSIONS: The gemcitabine/carboplatin combination is a valid option in the treatment of MPM due to its acceptable toxicity profile, the good response rate, and the clinical benefit to patients. Minor adjustments in schedule (3-week cycles instead of 4-week cycles) would permit a more optimal treatment administration.     

Cisplatin, etoposide, and paclitaxel in the treatment of patients with extensive small-cell lung carcinoma.

PURPOSE: The combination of cisplatin, etoposide, and paclitaxel was studied in patients with extensive small-cell lung cancer in a phase I component followed by a phase II trial to determine the maximum-tolerated dose (MTD), characterize toxicity, and estimate response and median survival rates. PATIENTS AND METHODS: Forty-one patients were treated between October 1993 and April 1997. Doses for the initial cohort were cisplatin 75 mg/m(2) on day 1, etoposide 80 mg/m(2)/d on days 1 to 3, and paclitaxel 130 mg/m(2) on day 1 over 3 hours. Cycles were repeated every 3 weeks for up to six cycles. The MTD was reached in the first six patients. In these six patients and in the next 35 patients, who were entered onto the phase II trial, response and survival were estimated. RESULTS: At the initial dose level, one of six patients developed febrile neutropenia, and five of six achieved targeted neutropenia (nadir absolute granulocyte count, 100 to 1,000/microL) without any other dose-limiting toxicity, defining this level as the MTD. Grade 4 neutropenia was observed in 88 (47%) of 188 total courses administered at or less than the MTD. Neutropenia was associated with fever in only 17 (9%) of 188 courses, but two patients experienced neutropenic sepsis that was fatal. Nonhematologic toxicity greater than grade 2 was observed in 10 (5%) of 188 total courses, with fatigue, peripheral neuropathy, and nausea/vomiting most common. The overall objective response rate was 90% of 38 assessable patients: six complete responses (16%) and 28 partial responses(74%). Median progression-free and overall survival durations were 31 and 47 weeks, respectively. CONCLUSION: The combination of cisplatin, etoposide, and paclitaxel produced response and survival rates similar to those of other combinations and was well tolerated.     

A phase I study of high-dose ifosfamide and escalating doses of carboplatin with autologous bone marrow support.

The dose-limiting toxicity in two separate phase I trials of the high-dose single agents ifosfamide and carboplatin was renal insufficiency at 18 g/m2 and hepatic and ototoxicity at 2,400 mg/m2, respectively. In this phase I study, 16 adults were treated with ifosfamide at 75% of the single-agent maximum-tolerated dose (MTD) (12 g/m2) and escalating doses of carboplatin (400 to 1,600 mg/m2) to determine the nonhematologic dose-limiting toxicity and the maximum-tolerated dose of the combination. Both drugs as well as mesna for uroprotection were given by continuous infusion over 4 days with an additional day of mesna (total dose per course, 15 g/m2). Autologous bone marrow support was stipulated for subsequent dose levels once granulocytes remained less than 500/microL for more than 14 days in two of three to five patients entered at a given dose level. Autologous bone marrow support was used at doses above the 400 mg/m2 carboplatin dose level. At the maximum-tolerated dose level of 1,600 mg/m2 of carboplatin, renal toxicity precluded further dose escalation. Of the five patients entered at this dose level, reversible creatinine elevation greater than 2 mg/dL (median peak, 2.6 mg/dL) was observed in three patients, and irreversible renal failure occurred in an additional patient (peak creatinine, 6.9 mg/dL. Transient gross hematuria appeared more common with the combination than with ifosfamide alone. Two patients developed severe somnolence and confusion associated with a rising creatinine. There were two complete (CRs) and four partial responses (PRs) in 14 heavily pretreated assessable patients (including four partial or complete responses in eight assessable patients with advanced refractory sarcoma, and one CR in two patients with germ cell carcinoma). Carboplatin and ifosfamide appear to have overlapping renal toxicity. Nevertheless, carboplatin and ifosfamide can be combined at 80% and 75% of the single-agent maximum-tolerated doses, respectively, with acceptable nonhematologic toxicity. Ifosfamide and carboplatin are an attractive core combination for further studies in the treatment of sarcoma, germ cell, ovarian, and lung carcinomas.     

Paclitaxel, carboplatin, and gemcitabine in the treatment of patients with advanced transitional cell carcinoma of the urothelium

BACKGROUND: The objective of the current study was to evaluate the efficacy and toxicity of combination chemotherapy with paclitaxel, carboplatin, and gemcitabine in patients with advanced urothelial carcinoma. METHODS: Patients with metastatic or locally unresectable transitional cell carcinoma of the urothelium who had received either no or one previous systemic chemotherapy regimen were eligible. All patients received chemotherapy with intravenous paclitaxel at a dose of 200 mg/m(2) on Day 1, intravenous carboplatin at an area under the serum concentration-time curve of 5.0 on Day 1, and intravenous gemcitabine at a dose of 1000 mg/m(2) on Days 1 and 8. Treatment courses were repeated every 21 days. Patients were evaluated for response after they completed two treatment courses; patients who achieved an objective response and stable disease continued treatment for a total of six courses or until tumor progression. RESULTS: Sixty patients were treated between January 2000 and September 2003. Thirty-five patients (58%) had > or = 1 visceral sites of metastases, and only 4 patients (7%) had received any previous systemic chemotherapy. Twenty-six patients (43%) had achieved objective responses to treatment (12% complete responses). The median actuarial survival was 11 months, and the actuarial 1-year and 2-year survival rates were 46% and 27%, respectively. Myelosuppression was the most frequent toxicity, and Grade 3-4 neutropenia (using the National Cancer Institute Common Toxicity Criteria [version 2.0]) occurred in 72% of patients (46% of courses). Ten patients were hospitalized for the treatment of neutropenia and fever, and 1 patient died of treatment-related causes. Nonhematologic toxicities were relatively uncommon. CONCLUSIONS: The combination of paclitaxel, carboplatin, and gemcitabine was an active and tolerable regimen for patients with advanced urothelial carcinoma. However, the regimen was more toxic and showed no obvious incremental increase in efficacy compared retrospectively with various two-drug regimens.