Lung cancer is the leading cause of cancer-related death in both men and women in the United States. In 2002, an estimated 169,400 new cases of lung cancer will be diagnosed, and the disease will cause 154,900 deaths. Non-small-cell histologies account for approximately 80% of new lung cancer cases, and the majority of these patients initially present with advanced or metastatic disease. The long-term survival prognosis for patients with advanced non-small-cell lung cancer (NSCLC) remains poor. In recent years, however, more effective chemotherapy regimens have improved the survival outlook, and hopefully progress will continue with the development of new agents.
The benefit of platinum-based therapy in the treatment of patients with advanced NSCLC was demonstrated in a meta-analysis of clinical trials that compared chemotherapy to best supportive care. With the use of cisplatin(Drug information on cisplatin)-based regimens, median overall survival improved to 6 months compared to 4 months with best supportive care, and the 1-year survival rate rose from 15% to 25%. Based on these data, platinum-based regimens have been considered a standard of care for advanced NSCLC.
In an effort to further improve survival, investigators have evaluated the efficacy of combining platinum agents with several newer drugs that have demonstrated promising single-agent activity in NSCLC, including paclitaxel(Drug information on paclitaxel), docetaxel (Taxotere), gemcitabine(Drug information on gemcitabine) (Gemzar), vinorelbine (Navelbine), irinotecan(Drug information on irinotecan) (CPT-11, Camptosar), and topotecan (Hycamtin). In the United States, efforts have focused on platinum agents combined with taxanes, gemcitabine, and vinorelbine.
Major US Trials
The preliminary results of two US randomized phase III trials evaluating platinum-based regimens in advanced NSCLC were recently reported. A four-arm study conducted by the Eastern Cooperative Oncology Group (ECOG) compared doublets of cisplatin and paclitaxel, cisplatin and gemcitabine, cisplatin and docetaxel(Drug information on docetaxel), and carboplatin(Drug information on carboplatin) (Paraplatin) and paclitaxel; a two-arm study conducted by the Southwest Oncology Group (SWOG) compared the combination of cisplatin and vinorelbine to carboplatin and paclitaxel.
In each of these trials, no differences in median overall survival or 1-year survival were reported between arms. However, some differences did emerge with respect to specific toxicities. At present, platinum doublet combinations such as those used in the ECOG and SWOG trials can be expected to produce a median overall survival of approximately 8 months and 1-year survival rates ranging from 30% to 35% in patients with advanced NSCLC. Although these results indicate progress in terms of survival, room for improvement remains, and the evaluation of newer agents and combinations is necessary.
Irinotecan, a camptothecin analog, has demonstrated meaningful clinical activity in a number of solid tumors, including colorectal and other gastrointestinal cancers and both small-cell lung cancer (SCLC) and NSCLC. In SCLC, single-agent irinotecan has produced response rates of 50% in previously untreated patients and 16% to 33% in previously treated patients.[8-10] With the combination of irinotecan and cisplatin as first-line therapy, overall response rates of 83% and 86% were reported in patients with limited and extensive SCLC, respectively.
Based on this activity, the Japan Clinical Oncology Study Group conducted a randomized phase III trial comparing the combination of irinotecan and cisplatin to a standard regimen of etoposide(Drug information on etoposide) and cisplatin in patients with extensive SCLC.[12,13] The median overall survival of 13.5 months in the irinotecan/cisplatin arm was significantly longer than the 9 months observed in the etoposide/cisplatin arm (P = .0021). The combination of irinotecan and cisplatin has been adopted as the standard of care in Japan for patients with extensive SCLC and is currently being evaluated in phase III randomized trials in the United States.
Given its high degree of activity in SCLC, the potential of irinotecan in the treatment of NSCLC was considered. Investigators in Japan have been the first to systematically evaluate the role of irinotecan in NSCLC, and interest in the agent has recently been increasing in both the United States and Europe.
In patients with previously untreated advanced NSCLC, phase II studies of single-agent irinotecan have evaluated both weekly administration and once-every-3-week dosing schedules (Table 1).[14-17] Fukuoka et al reported an overall response rate of 32% in 72 evaluable patients, 40 of whom had stage IV disease, and achieved a response rate of 32.5% with a weekly irinotecan dose of 100 mg/m2. The median duration of response for all patients was 3.5 months, and median overall survival was 10 months. Leukopenia, nausea and vomiting, and diarrhea were the most common toxicities, with grade 3/4 toxicity occurring in 20% to 25% of patients.
In a study reported by Baker et al, irinotecan, 100 mg/m² administered weekly for 4 weeks of a 6-week cycle, produced an overall response rate of 15% in 41 evaluable patients, with a median response duration of 4.7 months and a median overall survival of 6 months. Grade 3 neutropenia was noted in 15% of patients, and grade 3/4 diarrhea in 17%.
Two studies evaluated irinotecan administered on an every-3-week schedule. Nakai et al reported an overall response rate of 20% in 35 evaluable patients given 200 mg/m² of irinotecan every 3 weeks, while a study by Douillard et al reported an overall response rate of 22% in 19 patients receiving a dose of 350 mg/m² every 3 weeks.[16,17] Major toxicities included leukopenia, diarrhea, nausea, and vomiting.
Given the promising single-agent activity of irinotecan in advanced NSCLC, current studies are investigating platinum-based and nonplatinum doublet and triplet regimens with irinotecan (Table 2).
Irinotecan and Cisplatin
Preclinical studies, lung cancer cell lines, and tumor xenograft models have indicated a potential synergism between irinotecan and cisplatin.[18,19] Given the established role of platinum agents in the treatment of NSCLC, their subsequent combination with irinotecan was a logical step. The combination of cisplatin and irinotecan has been studied most frequently.
Numerous phase I studies evaluating various administration schedules of irinotecan and cisplatin have been conducted in patients with previously untreated NSCLC.[20-27] In a series of trials, Masuda et al evaluated combinations of cisplatin at a fixed dose on day 1 with escalating doses of irinotecan on days 1, 8, and 15 of a 28-day cycle in patients with advanced NSCLC. Their initial study used a fixed cisplatin dose of 80 mg/m², and dose-limiting toxicities (diarrhea and leukopenia) occurred at an irinotecan dose of 70 mg/m². Among 26 evaluable patients, 14 achieved partial responses, for an overall response rate of 54%.
A second study decreased the cisplatin dose to 60 mg/m² on day 1, and diarrhea was found to be dose-limiting at an irinotecan dose of 90 mg/m². The overall response rate was 43% among the 14 evaluable patients, with one complete and five partial responses.
In an effort to increase dose intensity, a third study used a fixed cisplatin dose of 80 mg/m² with escalating doses of irinotecan, and granulocyte colony-stimulating factor (G-CSF, Neupogen) added on days 4 to 21 except on the days that irinotecan was administered. Dose-limiting diarrhea and leukopenia developed at an irinotecan dose of 90 mg/m², and a partial response rate of 50% was noted in 20 evaluable patients.
Using fractionated doses of both cisplatin and irinotecan on days 1, 8, and 15, Kobayashi et al reported a maximum tolerated cisplatin dose of 33 mg/m² in combination with a fixed irinotecan dose of 60 mg/m². Leukopenia was dose-limiting, and 7 of 13 patients (54%) achieved partial responses. Ueoka et al administered a fixed dose of cisplatin (60 mg/m²) on days 1 and 8 with escalating doses of irinotecan. The maximum tolerated dose of irinotecan was 60 mg/m², with diarrhea being dose-limiting; partial responses were seen in 13 of 17 evaluable patients, for an objective response rate of 76%.
Mori et al evaluated escalating doses of irinotecan in combination with a 5-day infusion of cisplatin. Maximum tolerated doses were cisplatin at 20 mg/m²/d × 5 in combination with irinotecan at 80 mg/m² on day 1 without G-CSF, and irinotecan at 160 mg/m²/d with G-CSF; overall response rates ranged from 47% to 55%.[25,26]
Phase II Trials
With the promising overall response rates (43% to 76%) reported in phase I trials for the combination of irinotecan and cisplatin, several phase II trials evaluating various regimens were initiated (Table 3).[28-36] Masuda et al administered irinotecan, 60 mg/m² on days 1, 8, and 15, in combination with cisplatin, 80 mg/m² on day 1. Of the 64 patients evaluable for response, 1 achieved a complete response and 32 had a partial response for an overall response rate of 52%. The median overall survival of the 69 enrolled patients was 10 months, and the 1-year survival rate, 33%. Predominant toxicities included leukopenia, neutropenia, and diarrhea, although all were considered manageable.
In the United States, DeVore et al evaluated the combination of irinotecan at 60 mg/m² on days 1, 8, and 15 and cisplatin at 60 mg/m² on day 1. Irinotecan was preferentially dose-reduced for toxicity, and actual delivered dose intensities were 75% for irinotecan and 100% for cisplatin. Among the 52 evaluable patients, 29% achieved an objective response, with a median survival of 10 months and a 1-year survival rate of 37%. Grade 3/4 neutropenia, which occurred in 46% of patients, was the most common serious toxicity.
As a follow-up to their phase I trial, Mori et al conducted a phase II trial of irinotecan at 160 mg/m² on day 1 with cisplatin at 20 mg/m² on days 1 to 5, with G-CSF support. The overall response rate was 56% for the 41 evaluable patients, the median survival was 10 months, and the 1-year survival rate was 44%. Grade 3/4 toxicities included diarrhea in 23%, granulocytopenia in 20%, and thrombocytopenia and anemia in 15% of patients.
Coadministration of irinotecan and cisplatin on a weekly schedule, facilitating potential synergism between these agents, has also been evaluated. Based on previous clinical experience, Jagasia et al administered irinotecan at 65 mg/m² with cisplatin at 30 mg/m²/wk for 4 weeks of a 6-week cycle. Ueoka et al administered irinotecan at 50 mg/m² with cisplatin at 60 mg/m² on days 1 and 8 of a 28-day cycle.[31,32] Overall response rates of 36% and 41%, median survivals of 12 and 13 months, and 1-year survival rates of 46% and 58%, respectively, were reported for the two studies. Both regimens were reasonably well tolerated. Jagasia et al reported a 26% incidence of grade 3/4 neutropenia and diarrhea, while grade 3/4 toxicities reported by Ueoka et al included leukopenia in 48%, thrombocytopenia in 43%, anemia in 42%, diarrhea in 27%, and nausea and vomiting in 26%.
Cardenal and associates opted to administer an intensive irinotecan dose of 200 mg/m² with cisplatin at 80 mg/m², both on day 1. Grade 3/4 neutropenia occurred in 51% of patients, with an 11% rate of febrile neutropenia, and grade 3/4 delayed diarrhea occurred in 31% of patients. Preliminary data indicated an overall response rate of 41%.
Phase III Trials
Two multicenter randomized phase III trials evaluating irinotecan and cisplatin have been completed by Japanese investigators (Table 3).[28-36] The first was a three-arm trial comparing combination irinotecan/cisplatin to vindesine(Drug information on vindesine)/cisplatin or irinotecan alone. The second trial compared irinotecan/cisplatin to vindesine/cisplatin. Updated response and survival analyses for both studies have recently been presented.[33,37]
In the three-arm study, the combination of irinotecan and cisplatin produced an overall response rate of 43%, with a median survival of 12 months and a 1-year survival rate of 49%. For the vindesine/cisplatin arm and the single-agent irinotecan arm, overall response rates were 31% and 40%, respectively, and 1-year survival rates were 21% and 44%, with a median overall survival of 11 months in both arms. In the two-arm study, irinotecan and cisplatin produced an overall response rate of 29%, median survival of 10 months, and 1-year survival rate of 36%, compared to an overall response rate of 22%, median survival of 10 months, and 1-year survival rate of 41% for vindesine and cisplatin.
There was a trend toward improved survival in the irinotecan/cisplatin arm of the three-arm study that was not apparent in the two-arm study. More recently, a combined analysis of the two studies indicated that the combination of irinotecan and cisplatin significantly improved survival over the vindesine/cisplatin regimen in patients with metastatic disease. Notably, the median survival in the irinotecan/cisplatin arms was 10 months or longer.
Irinotecan and Carboplatin
The activity of carboplatin appears to be similar to that of cisplatin in the treatment of lung cancer, and given the drug’s favorable toxicity profile and ease of administration, the use of carboplatin may be preferable. Investigation of carboplatin-based regimens is necessary, and several studies of the combination of irinotecan and carboplatin have recently been reported (Table 4).[39-42]
Okamoto et al performed a phase I study of escalating doses of both irinotecan and carboplatin with G-CSF support. Diarrhea was dose-limiting at an irinotecan dose of 70 mg/m² administered on days 1, 8, and 15 with carboplatin at an area under the concentration-time curve (AUC) of 5. Of 20 evaluable patients, 7 (35%) achieved an objective response, and the median overall survival was 8 months.
Fukuda et al conducted a phase I trial of irinotecan plus carboplatin without G-CSF in untreated patients with advanced solid tumors, primarily lung cancer patients. Escalating doses of irinotecan were administered starting at 40 mg/m² on days 1, 8, and 15 with carboplatin at AUC 5 on day 1 of a 28-day cycle. Dose-limiting toxicities, including neutropenia, thrombocytopenia, and diarrhea, occurred at an irinotecan dose of 60 mg/m². Of the 11 evaluable patients, 4 (36%) with NSCLC achieved an objective response. On this schedule, irinotecan at 50 mg/m² with carboplatin at AUC 5 was recommended for future testing.
Two phase II studies using this regimen were conducted by Mukohara et al and Kinoshita et al.[41,42] In the preliminary reports, overall response rates of 25% and 35%, median survivals of 11 and 9 months, and 1-year survival rates of 39% and 34%, respectively, were reported for the two studies. Mukohara et al reported the following grade 3/4 toxicities: neutropenia (77%), thrombocytopenia (47%), anemia (25%), and nausea or vomiting (36%). Febrile neutropenia developed in four patients. Investigators were concerned that less than 50% of patients received the day 15 dose of irinotecan, possibly contributing to the lower than expected response rate. Kinoshita et al observed grade 3/4 neutropenia, thrombocytopenia, and diarrhea in 55%, 22%, and 5% of patients, respectively.
At the University of Colorado Cancer Center, we are currently conducting a phase I dose-escalation trial of irinotecan administered on days 1 and 8 with carboplatin administered on day 1 every 21 days in previously treated patients with solid tumors. The current dose level being explored is irinotecan, 50 mg/m², and carboplatin, AUC 5.