Phase II study of weekly carboplatin and irinotecan as first-line chemotherapy for patients with advanced non-small cell lung cancer

Purpose

Platinum-based doublet chemotherapy has a major role in the treatment of patients with advanced non-small cell lung cancer (NSCLC). The weekly fractionated administration of cisplatin for patients with NSCLC has been shown to be active. Irinotecan and carboplatin are effective against NSCLC and demonstrated synergism with non-cross-resistance in preclinical studies. We conducted a phase II study of weekly combination of carboplatin and irinotecan as first-line chemotherapy for patients with advanced NSCLC.

Methods

From March 2009 to November 2011, 24 patients who were diagnosed with inoperable or metastatic NSCLC were enrolled. Treatment consisted of carboplatin at an AUC 2.5 mg/mL/min over 30-min intravenous infusion and irinotecan 65 mg/m² over 90-min intravenous infusion on day 1 and day 8, respectively. The treatment was repeated every 3 weeks.

Results

One patient (4.2 %) achieved complete response, and seven (29.2 %) showed partial response. Overall response rate was 33.3 %, with median response duration of 4.55 months. Nine patients had stable disease, and disease control rate was 70.8 %. With median follow-up of 12.8 months, median progression-free survival was 4.5 months (95 % CI 1.8–7.2), and median overall survival was 15.5 months (95 % CI 6.9–24.1). Major toxicity was myelosuppression. Grade 3–4 neutropenia and thrombocytopenia occurred in 50 and 20.8 % of patients, respectively. Two patients experienced febrile neutropenia. Non-hematologic toxicities were generally mild. One patient suffered grade 4 diarrhea, and one treatment-related death due to pneumonia was occurred.

Conclusion

The weekly combination of carboplatin and irinotecan showed favorable activity and manageable toxicity profiles in chemo-naïve patients with advanced NSCLC. Our results suggest that this regimen can be a reasonable chemotherapeutic option for patients with advanced NSCLC.     

Phase II study of nedaplatin and irinotecan for elderly patients with advanced non-small cell lung cancer

We conducted a phase II study of combination chemotherapy with nedaplatin (NP) with irinotecan (CPT) to determine the effects against unresectable non-small cell lung cancer (NSCLC) and to determine the qualitative and quantitative toxicities of this combination chemotherapy in 70 years or older patients. Thirty-eight patients received 100 mg/m2 NP on day 1 and 60 mg/m2 CPT on days 1 and 8 every four weeks. Twenty-five patients achieved PR, nine SD and three PD, and the overall response rate was 65.8%. Nineteen patients (50%) experienced grade 4 neutropenia. Neutropenic fever occurred in 11 patients (29%) and one of them died. Of other grade 3 non-hematologic toxicities, two patients experienced diarrhea; one interstitial pneumonitis; one liver injury; and one rash. The median survival time was 418 days and the one-year survival rate was 55.3%. In conclusion, NP combined with CPT is an active treatment for elderly patients with NSCLC.     

Phase II study of irinotecan and ifosfamide in patients with advanced non-small cell lung cancer

OBJECTIVES: This phase II study was conducted to investigate the efficacy and safety of irinotecan (CPT-11) and ifosfamide as first-line chemotherapy for advanced non-small cell lung cancer (NSCLC). METHODS: Eligibility criteria included histologically or cytologically confirmed NSCLC (stage IIIb or IV), no prior treatment, and measurable or evaluable disease. CPT-11 (80 mg/m(2)) was administered intravenously on days 1, 8, and 15, while ifosfamide (1.5 g/m(2)) was given on days 1 through 3 every 4 weeks. RESULTS: Forty-four patients (31 men) with a median age of 65 years (range 43-75) and a median ECOG performance status of 1 (range 0-2) were enrolled. The response rate was 29.5% [95% CI: 16.7-45.2%], with 13 partial responses. The median survival was 12.5 months, the median time to progression was 5.3 months, and the 1 and 2-year survival rates were 52.3 and 11.3%, respectively. Toxicity was generally mild; WHO grade 3-4 neutropenia was recorded in 38.6% of the patients, grade 3 diarrhea in 6.8%, and grade 3-4 nausea/vomiting in 0%. CONCLUSIONS: CPT-11 combined with ifosfamide demonstrated anti-tumor activity in advanced NSCLC, with response and survival rates similar to those of cisplatin-based chemotherapy but with a more favorable toxicity profile.     

Phase I/II study of weekly irinotecan and concurrent radiation therapy for locally advanced non-small cell lung cancer

A study was undertaken to determine the maximum tolerated dose, the dose-limiting toxicities, and the response rate of irinotecan administered weekly with concurrent thoracic radiation therapy in patients with locally advanced non-small-cell lung cancer. In a phase I/II clinical trial, patients with histologically documented, surgically unresectable stage IIIA or IIIB non-small cell lung cancer (NSCLC) were enrolled. Irinotecan was administered as a 90 min intravenous infusion once weekly for 6 weeks. The starting dose was 30 mg m(-2) and dose escalation was done in 15 mg m(-2) increments. Dose-limiting toxicity was defined as grade 3 nonhaematologic toxicity (excluding nausea, vomiting and alopecia) or grade 4 haematologic toxicity according to the WHO criteria. Radiation was delivered to the primary tumour and regional lymph nodes (40 Gy), followed by a boost to the primary tumour (20 Gy). Twenty-seven patients were entered into this study at three irinotecan dose levels (30, 45 and 60 mg m(-2)). Twenty-six eligible patients were evaluated for toxic effects and clinical outcome. Severe oesophagitis, pneumonitis, and diarrhoea occurred at 45 and 60 mg m(-2). Three of the five patients given 60 mg m(-2) developed grade 3 or 4 oesophagitis and pneumonitis. In addition, one patient died of pneumonitis after completing therapy at 45 mg m(-2) in the phase II study. The objective response rate was 76.9% (95% CI, 53.0-88.9%). Oesophagitis, pneumonitis, and diarrhoea are the dose-limiting toxicities of weekly irinotecan combined with thoracic irradiation. The maximum tolerated dose and the dose for the phase II study were 60 and 45 mg m(-2) wk(-1), respectively. This combined therapy for locally advanced non-small cell lung cancer is promising and shows acceptable toxicity.     

Phase II study of carboplatin combined with weekly docetaxel in patients with advanced non-small cell lung cancer

Purpose

This phase II study is performed to evaluate the safety, efficacy and tolerability of carboplatin combined with weekly docetaxel in patients with advanced non-small cell lung cancer (NSCLC).

Patients and methods

All patients were treated with the combination of docetaxel 35 mg/m² by IV infusion over 30–60 min weekly, on days 1, 8, and 15, for 3 weeks followed by 1 week of rest, with intravenous carboplatin (AUC 6) administered immediately afterward on day 1. Cycles were repeated every 28 days.

Results

Forty-seven (95.9%) of the 49 patients were assessable for response, one case of complete response and 17 cases of partial response were confirmed, giving an overall response rate of 36.7% (95% CI 23.2–50.2%). The median time to progression and overall survival (OS) for all patients were 5.2 months (95% CI 4.1–6.3 months) and 10.4 months (95% CI 7.3–13.5 months), respectively. The estimate of OS at 12 months was 37.6% (95% CI 24.0–51.2%). The most severe hematologic adverse event was anemia, which occurred with grade 3/4 intensity in 7 (14.9%) patients. Neutropenia occurred with grade 3 intensity in 4 (8.5%) patients. However, no grade 4 neutropenia was observed. Grade 3 nausea/vomiting, diarrhea, asthenia, nail changes, and skin reaction were observed in 6 (12.8%), 3 (6.4%), 2 (4.3%), 2 (4.3%) and 1 (2.1%) patients. Yet, no grade 4 non-hematologic toxicity was observed.

Conclusions

The combination of carboplatin with weekly docetaxel is a tolerated treatment modality with encouraging activity and survival outcome in previously untreated patients with advanced NSCLC.     

Phase I and pharmacologic study of irinotecan and amrubicin in advanced non-small cell lung cancer

Purpose We conducted a Phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with amrubicin, a topoisomerase II inhibitor. The aim was to determine the maximum tolerated dose (MTD) of amrubicin combined with a fixed dose of CPT-11 as well as the dose-limiting toxicities (DLT) of this combination in patients with advanced non-small cell lung cancer. Patients and methods Eleven patients with stage IIIB or IV disease were treated at 3-week intervals with amrubicin (5-min intravenous injection on days 1–3) plus 60 mg/m² of CPT-11 (90-min intravenous infusion on days 1 and 8). The starting dose of amrubicin was 25 mg/m², and it was escalated in 5 mg/m² increments until the maximum tolerated dose was reached. Results The 30 mg/m² of amrubicin dose was one dose level above the MTD, since three of the five patients experienced DLT during the first cycle of treatment at this dose level. Diarrhea and leukopenia were the DLT, while thrombocytopenia was only a moderate problem. Amrubicin did not affect the pharmacokinetics of CPT-11, SN-38 or SN-38 glucuronide. Except for one patient, the biliary index on day-1 correlated well with the percentage decrease of neutrophils in a sigmoid E _max model. There were five partial responses among 11 patients for an overall response rate of 45%. Conclusion The combination of amrubicin and CPT-11 seems to be active against non-small cell lung cancer with acceptable toxicity. The recommended dose for Phase II studies is 60 mg/m² of CPT-11 (days 1 and 8) and 25 mg/m² of amrubicin (days 1–3) administered every 21 days. This work was presented in part at the 41st Annual Meetings of the American Society of Clinical Oncology, Orlando, FL, USA May 13–17, 2005.     

Phase I/II dose finding study of paclitaxel and carboplatin in advanced non-small cell lung cancer.

INTRODUCTION: This phase I study was designed to establish the maximum tolerated dose (MTD) of the carboplatin paclitaxel combination, given without routine growth factor support to previously untreated patients with stage IIIB and IV non-small cell lung cancer. PATIENTS AND METHODS: Fifty patients (one stage IIIa, 31 stage IIIb and 18 stage IV) were sequentially assigned to one of 14 treatment groups in which paclitaxel and carboplatin were administered in doses ranging from 130 to 235 mg/m2 and from 230 to 375 mg/m2 , respectively. Paclitaxel was administered as a 3-h intravenous infusion using non-polyvinylchloride tubing and connectors. The carboplatin infusion, over 30 min, was administered at the completion of the paclitaxel infusion. RESULTS: The MTD for the combination has been reached at 235 mg/m2 of paclitaxel and at 375 mg/m2 of carboplatin. The combination shows a good safety profile with very few and brief episodes of neutropenia without any infectious episodes. At the doses tested thrombocytopenia did not occur at all. Among 47 assessable patients there was one complete response and 17 partial responses for an overall response rate of 38%. There has been a tendency to a dose-response relationship for the combination with only six partial responses (27%) reported in 22 patients who received paclitaxel at doses < or = 195 mg/m2 and carboplatin at doses < 350 mg/m2 and 12 partial responses in 25 patients (48%) receiving paclitaxel > 195 mg/m2 and carboplatin > or = 350 mg/m2, respectively. The median event-free survival time is 33 weeks (range, 4-156 +). With a minimum follow up duration of 57 weeks the median overall survival time is 51.81 weeks (range, 7-162 +) and the 1-year survival rate is 49%. CONCLUSION: In advanced NSCLC the carboplatin-paclitaxel combination can be safely administered at the doses of 375 and 225 mg/m2 every 4 weeks, it appears to be active and well tolerated.     

Phase I/II trial of vinorelbine and divided-dose carboplatin in advanced non-small cell lung cancer

Vinorelbine administered in a doublet with cisplatin has become a standard treatment in patients with advanced non-small cell lung cancer (NSCLC). However, carboplatin appears to provide comparable efficacy with a better nonhematologic safety profile than cisplatin. Herein we report the results of a phase I/II trial of weekly vinorelbine and divided-dose carboplatin in patients with stage IIIB/IV NSCLC, Eastern Cooperative Oncology Group performance status < or = 2, and adequate bone marrow. Patients received vinorelbine starting at 20 mg/m(2) (to 25 mg/m(2)) and carboplatin area under the curve (AUC) 2.5 in divided-doses, both given on Days 1 and 8 every 21-day cycle for up to 6 cycles or until disease progression. Dose-limiting toxicity was defined for Cycles 1 and 2. Tumor response and toxicity were assessed using standard criteria. Twenty-one patients with a mean age of 67 years (range, 43-79) and stage IIIB/IV (8/13) disease were enrolled. All but 1 patient were chemotherapy-nai;ve; the majority (n = 20) had good performance status (< or = 1). Seventy-nine courses (median, 4) were administered. The vinorelbine/carboplatin doublet was well tolerated, with 7 courses interrupted or delayed because of toxicity. Toxicities were generally mild and evenly divided between hematologic (i.e., neutropenia) and nonhematologic (i.e., fatigue). No growth factor support was required for hematologic toxicity. There was only one case of grade 2 alopecia, and no cases of > or = grade 2 neurotoxicity. There were 5 (24%) partial responses, and 9 (43%) patients had stable disease. Weekly vinorelbine 25 mg/m(2) and divided-dose carboplatin AUC 2.5 is a well tolerated regimen with activity in advanced NSCLC patients. Further evaluation of this regimen in combination with novel targeted biologic therapy is warranted.     

Phase I and pharmacokinetic study of paclitaxel and irinotecan for patients with advanced non-small cell lung cancer

We conducted a phase I study of paclitaxel and irinotecan (CPT-11) in advanced non-small cell lung cancer (NSCLC). This study aimed to determine the maximum tolerated doses (MTD). The pharmacokinetics of CPT-11 and its major active metabolite, SN-38, were also analysed. Patients received paclitaxel (day 1) followed by CPT-11 (days 1, 8 and 15), in a 4-week cycle, and paclitaxel and CPT-11 were escalated from 120 and 40 mg/m(2), respectively. 28 patients were enrolled, who were evaluated for toxicity. 2 of 6 patients at 210 mg/m(2) paclitaxel and 50 mg/m(2) CPT-11, and 2 of 4 at 180 and 60 mg/m(2) developed dose-limiting toxicity (DLT) (neutropenia, fever, neurotoxicity and diarrhoea). The area under the plasma concentration-time curve (AUC) of CPT-11 on day 1 was significantly higher than that on days 8 or 15 at each dose level (P=0.002). The AUC of SN-38 on day 1 was significantly increased using paclitaxel doses >or=150 mg/m(2). A preceding paclitaxel administration changed the pharmacokinetics of CPT-11 and SN-38. However, the toxicity was tolerable. Paclitaxel 180 mg/m(2) and CPT-11 50 mg/m(2) were the recommended doses for further phase II study of this combination.     

Phase II study of weekly irinotecan and cisplatin for refractory or recurrent non-small cell lung cancer

Even with the standard first-line chemotherapy, advanced non-small cell lung cancer (NSCLC) recurs in most cases. The purpose of this study is to develop a new chemotherapeutic regimen for patients with NSCLC that has relapsed or was refractory to previous chemotherapy. Patients with proven NSCLC refractory or recurrent after previous single-regimen chemotherapy, PS of 0-2, age of 15 years or older, adequate organ functions and measurable lesions were treated with irinotecan at 60 mg/m(2) and cisplatin at 25 mg/m(2) with 1000 ml hydration on day 1. This administration, considered as one cycle, was repeated every week without rest unless encountering defined skip and dose-reduction criteria. The treatment was administered for six cycles over a 49-day period, both median values, to 48 patients, with a response rate of 26%, progression free and median survival times of 3 and 11 months, respectively, and a 1-year survival rate of 46%. The most frequent grade 3 or 4 toxicities were neutropenia, anaemia and nausea, which were manageable. Subset analyses suggested that the response rate was independent of response to the first-line chemotherapy. In conclusion, second-line chemotherapy of weekly irinotecan and cisplatin with minimum hydration seemed effective, with tolerable toxicity, and is potentially useful irrespective of the outcome of previous chemotherapy.     

Phase II study of alternating chemotherapy regimens for advanced non-small cell lung cancer

PURPOSE: We assessed the use of alternating drugs with differing mechanisms of action as treatment for advanced non-small cell lung cancer. BACKGROUND: We hypothesized that the shape of a dose-response curve would be determined by the major mechanisms of resistance of a cancer to the drug being studied. Assessment of data from published clinical trials suggested that if our hypothesis were correct resistance of non-small cell lung cancer to most agents is due to "saturable passive" resistance mechanisms (non-competitive inhibition of drug effect due to deficiency of a factor required for drug effect) rather than to "active" resistance mechanisms (competitive inhibition of drug effect due to excess of a factor) or to "non-saturable passive resistance (due to factor alteration or mutation). Using drugs with differing mechanisms of action is a strategy that might be of value against passive resistance. METHOD: In patients with advanced non-small cell lung cancer, we used four alternating cisplatin-based regimens. In each regimen, cisplatin 80 mg/m(2) was given iv on day 1 of each course. The regimens were: cisplatin + vinorelbine 25 mg/m(2) days 1, 8 and 15, cisplatin + gemcitabine 1000 mg/m(2) days 1, 8 and 15, cisplatin + paclitaxel 200 mg/m(2) day 1 iv over 1h, and cisplatin + etoposide 100 mg/m(2) po days 1-6. Patients were assigned randomly to different regimen sequences. Patients first received 1 course of each of these 4 regimens, then received 1 further course of each of single agent vinorelbine, gemcitabine, paclitaxel and etoposide (at the same doses as in courses 1-4), without cisplatin. (Cisplatin was omitted from courses 5-8 to limit cumulative toxicity.) Change in tumor size was measured after each course. RESULTS: Thirty-six patients were entered. One patient achieved complete remission and nine achieved partial remissions, for an objective response rate of 28% (95% confidence intervals, 13-43%). Nineteen patients (53%) (95% confidence intervals, 37-69%) had stable disease. Eleven patients had growth of >10% on one regimen followed by tumor shrinkage of >10% on a later one. Median survival was 8.1 months, 1-year survival was 28% and 2-year survival was 6%. No unexpected toxicity was seen. CONCLUSIONS: The use of four alternating regimens is feasible in advanced non-small cell lung cancer. Response rates and survival times were comparable to those observed for standard chemotherapy approaches, suggesting that this strategy does not offer any major advantage. We plan to explore the hypothesis that this approach failed since tumor cells surviving first exposure to chemotherapy rapidly down-regulate their ability to undergo apoptosis.     

Phase I/II study of S-1 plus carboplatin in patients with advanced non-small cell lung cancer

The objective of this phase I/II study was to determine the recommended dose (RD) of S-1 and carboplatin (CBDCA), and to evaluate the efficacy and safety of this combination in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Chemotherapy-naïve patients were treated with S-1 given orally on days 1–14, and CBDCA infused intravenously on day 1, repeated every 3 weeks. RD was AUC5 of CBDCA and 80 mg/m² of S-1. Nineteen patients were treated at the RD. The overall response was 30.8% (95% confidence interval: 17.1–58.3%). The response rate in the RD was 36.8% (95% CI: 16.3–61.6%). The median overall survival time was 11.1 months (95% CI: 8.1–15.3 months) and the median progression-free survival time was 5.0 months (95% CI: 3.6–6.0 months). Major grades 3–4 toxicities were thrombocytopaenia (47%), anaemia (26%) and infection (16%). This is the first report to show promising activity of this combination in phase II, including survival data and manageable toxicity, especially in outpatients receiving treatment for advanced NSCLC.     

Phase II study of paclitaxel and carboplatin for advanced non-small-cell lung cancer

A prospective phase II study was conducted to determine the response, toxicity and survival rate of lung cancer patients treated with combination paclitaxel and carboplatin in stage IIIB and IV NSCLC. Eligible patients required measurable and/or evaluable diseases; performance status (ECOG) 0-2; no previous chemotherapy; adequate hepatic, renal and bone marrow function. Paclitaxel was administered at a dose of 200 mg/m2, 3 h infusion, followed by carboplatin at an AUC of 6. Treatment was repeated every 3 weeks for six courses. G-CSF 5 microgram/kg was subcutaneously injected during subsequent courses if there was grade 3-4 leucopenia or granulocytopenia in the previous course. From April 1996 through July 1997, 53 patients were enrolled; all are assessable for toxicity and response. The median age was 56 years (range, 20-77 years). Sixty four percent were male, 64% had adenocarcinoma and 62% had stage IV disease. Two hundred and seventy two courses were administered; 36 patients (68%) completed all six cycles. Two patients achieved a complete response (4%) and 27 patients achieved a partial response (51%), for an overall response rate of 55%. Sixteen patients had stable disease (30%) and 8 patients had progressive disease (15%). The median progression free survival time for all patients, stage IIIB and stage IV patients was 28 weeks (range, 18-37 weeks), 31 weeks (range 21-41 weeks) and 22 weeks (range 16-29 weeks), respectively. The median survival time and 1 year survival rate for all patients was 55 weeks (range, 51-59 weeks) and 55%, respectively. Stage IIIB patients had better median survival time and 1-year survival rate than stage IV patients (75 vs. 46 weeks, P = 0.007; 80% vs. 42%, P = 0.003). Grade 3 and 4 granulocytopenia, anemia and thrombocytopenia were observed in 25, 3, and 1%, respectively, of the 272 courses administered. G-CSF was required in 28% of the 272 courses. There were four episodes of febrile neutropenia (1.5%), three episodes of angina pectoris (1%) and one episode of anaphylaxis (0.4%). Other common toxicities, generally mild, included myalgia, arthralgia, peripheral neuropathy and asthenia. Most toxicities showed cumulative effect. Paclitaxel plus carboplatin is a moderately active regimen in advanced NSCLC. Toxicities of this regimen are well tolerated.     

Phase II study of weekly irinotecan and carboplatin for refractory or relapsed small-cell lung cancer

We designed a phase II study of weekly irinotecan (CPT-11) and carboplatin for refractory or relapsed small cell lung cancer (SCLC) and assessed the response rate, survival, and toxicity. Twenty-nine patients with refractory or relapsed SCLC were entered onto the trial. The median time off chemotherapy was 3.5 months (range: 0.8-12.9). Patients were treated at 4-week intervals using CPT-11 (50 mg/m(2) intravenously on days 1, 8 and 15) plus carboplatin (AUC = 2 mg/ml min, intravenously on days 1, 8, 15). All patients were assessable for toxicity and survival; 28 patients were assessable for response. There were nine partial responses (PRs). Overall response rate was 31.0% (95% CI: 15.3-50.8%). The median time to progression was 3.5 months. Median survival time was 6.1 months. Major toxicity was myelosuppression. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 52 and 21% of patients, respectively. Grade 3-4 diarrhea was observed in 7%. There was one treatment-related death due to febrile neutropenia and sepsis. This combination of CPT-11 and carboplatin seems to be active second-line regimen with acceptable toxicity against small cell lung cancer.     

Phase I study of gemcitabine and carboplatin in advanced non-small cell lung carcinoma

BACKGROUND: This phase I study was designed to determine the maximum tolerated dose of carboplatin with a fixed dose of gemcitabine without growth factor or hematopoietic precursor support. METHODS: Nineteen patients with previously untreated non-small cell lung cancer (NSCLC) were treated at three dose levels. Initially, the gemcitabine dose was 1000 mg/m(2) given on days 1 and 8. Of the first five patients treated with carboplatin AUC 4, three experienced dose limiting toxicity (DLT). The study was, therefore, amended to decrease the dose of gemcitabine to 800 mg/m(2) given on days 1 and 8 in a 21-day cycle. RESULTS: Dose limiting toxicity (neutropenia and thrombocytopenia) were seen at dose level 2A (carboplatin AUC=5). Thus, no further dose escalation was performed. Grade 3 and 4 toxicities were seen as follows: leukopenia in five of 18 (28%); neutropenia, four of 18 (22%); and thrombocytopenia, four of 18 (22%) evaluable patients. Grade 3 or 4 anemia occurred in one of 18 (6%) patients and no neutropenic fever or treatment related mortality was observed. Partial responses were seen in six patients and one patient with evaluable disease had an objective response. The overall response rate was 37% (seven of 19). Six other patients had stable disease. A total of 89 courses were administered with a median of five courses per patient (range: two to six courses). The median time to progression for all patients was 3.7 months. The median overall survival was 7.4 months with four patients still alive (median follow up 13.5 months). The survival at 6 months and 1 year is 64 and 23%, respectively. CONCLUSION: The maximum tolerated dose (MTD) in this group of patients was defined as carboplatin AUC 4 when administered with gemcitabine 800 mg/m(2) on days 1 and 8 of a 21-day schedule.     

Phase II study of combination of gemcitabine and carboplatin in advanced non-small cell lung cancer (an interim report)

A phase II study of combination therapy with gemcitabine and carboplatin was performed in 24 patients with advanced non-small cell lung cancer to evaluate the efficacy and safety of the therapy. Patients were treated at 3-week intervals with two courses or more of the regimen consisting of gemcitabine 1,000 mg/m(2) and carboplatin AUC 2 on day 1 and day 8. Response rate was 37.5% (9/24) (95% confidence interval: 18.8-59.4%). The median number of courses was 3(range 1-8). The time to progressive disease was 147 days and the median survival was 338 days. The one-year survival rate was 45.8%. The major toxicity was hematotoxicity, and >or=grade 3 neutropenia(58.3%)and thrombocytopenia (45.8%) occurred. None of >or=grade 3 non-hematotoxicities were evident, but grade 2 rash (8.3%) and fever (8.3%), nausea (4.2%), vomiting (4.2%) occurred. None of the other severe toxicities appeared. In conclusion, this combination therapy was suggested to be tolerable with a high response rate and safety, and we plan to continue testing.     

Phase I/II and pharmacologic study of irinotecan and carboplatin for patients with lung cancer

PURPOSE: To determine the maximum tolerated dose (MTD) of irinotecan combined with carboplatin, to evaluate its efficacy and toxicity for patients with lung cancer, and to examine its pharmacokinetics and pharmacodynamics. METHODS: The dose of irinotecan was escalated from 40 mg/m2 per week in increments of 10 mg/m2. Carboplatin was fixed at 300 mg/m2. Multivariate regression models with an interaction term were used to evaluate synergistic pharmacodynamic interactions. RESULTS: The MTD and recommended dose of irinotecan were 60 and 50 mg/m2, respectively. Dose-limiting toxicities were grade 4 neutropenia and grade 3 or 4 diarrhea. In phase II studies, response rates were 81.3% (95% confidence interval 61.8-100%) in 16 patients with small-cell lung cancer and 22.2% (2.7-41.8%) in 18 patients with non-small-cell lung cancer. Two patients (6%) experienced grade 4 neutropenia, thrombocytopenia, and grade 3 diarrhea. The area under the plasma concentration versus time curve (AUC) of carboplatin ranged from 2.87 to 9.31 mg x min/ml, with a median of 4.66 mg x min/ml. In pharmacodynamic analyses, the log-transformed surviving fraction in platelet count (SFp) showed a significant association with the AUC of carboplatin (P=0.010), while that in neutrophil count (SFn) was not significantly correlated with any pharmacokinetic parameter. The interaction term was not significant in either case. CONCLUSIONS: These results indicate that AUC-based dosing of carboplatin is still rational in combination chemotherapy. A more sensitive method for predicting life-threatening toxicities is needed, however, because traditional pharmacokinetic parameters were not adequate tools for identifying patients at high risk of severe neutropenia and diarrhea. This combination regimen has only modest activity, and further studies are necessary to evaluate a different dose schedule.