Camptothecin is an alkaloid obtained from plants such as the Camptotheca acuminata tree. The target of camptothecin and its derivatives is topoisomerase I, an enzyme that relieves positive and negative supercoiling of DNA by cleaving a single DNA strand.[1-4] This drug binds the topoisomerase I/DNA complex and blocks religation of the cleaved strand, which inhibits DNA synthesis and results in cell death. X- or gamma-irradiation causes thousands of single-strand breaks per cell per gray. These sites are bound by topoisomerase I in the presence of camptothecin. DNA/topoisomerase I/camptothecin cleavable complexes also affect the repair of potentially lethal damage in plateau-phase cells. An additional mechanism of the synergistic effect of the combination of camptothecin and radiation therapy may be the synchronizing effect of irradiation itself, which preferentially kills G2- through M-phase cells and leaves camptothecin-sensitive S-phase cells.[5,6]
Irinotecan hydrochloride (CPT-11, Camptosar) is a semisynthetic water-soluble derivative of camptothecin. Irinotecan(Drug information on irinotecan) is a prodrug that is converted in vivo primarily by hepatic microsomal carboxylesterases to an active metabolite, SN-38. Substantial individual variability in irinotecan pharmacokinetics has been observed. Irinotecan is active as a single agent in lung cancer treatment, producing response rates ranging from 11% to 34% in patients with advanced non-small-cell lung cancer.[8-11] Major toxicities of irinotecan are myelosuppression and early- or late-onset diarrhea, which are generally manageable. Irinotecan showed potent radiosensitizing effects in human lung tumor xenografts which were related to the cell cycle. However, the optimum timing of topoisomerase I inhibitor treatment for maximizing radiosensitizing effects remains controversial. Combination therapy with irinotecan/cisplatin has also been shown to cause significantly greater tumor regression (as compared with either agent alone) in small-cell and non-small-cell lung cancer xenografts in nude mice. In addition, irinotecan and platinum agents are not cross resistant, and do not possess overlapping toxicity profiles.
Lung cancer is the leading cause of cancer death in the United States in both men and women over 35 years old. Depending on clinical circumstances, the principal treatment for stage III non-small-cell lung cancer includes radiation therapy, chemotherapy, surgery, and their combinations. The highest rate of cure for non-small-cell lung cancer has been achieved with surgery; however, fewer than 20% of non-small-cell lung cancer patients are considered candidates for surgical resection. The 5-year survival rate with surgical resection for stage I/II non-small-cell lung cancer is 60% to 70%, but falls to 5% to 20% for stage III non-small-cell lung cancer.
Radiation therapy to the primary tumor and regional lymph nodes has been the traditional treatment for locally advanced stage III non-small-cell lung cancer. Although a complete response is rare, 5% to 10% of patients have a long-term survival benefit and palliation with standard fractionation to 60 Gy.
A meta-analysis of 11 randomized clinical trials showed that cisplatin(Drug information on cisplatin)-based combinations plus radiation therapy reduced the risk of death by 10% compared with radiation therapy alone. Therefore, a combined-modality approach has been standard.
Studies have examined the optimal timing of chemotherapy relative to radiation therapy. For example, Furuse et al conducted a phase III study using cisplatin, vindesine(Drug information on vindesine) (Eldisine), and mitomycin(Drug information on mitomycin) (Mutamycin) in addition to thoracic radiation therapy and showed superior response rate and median survival duration in patients receiving concurrent chemotherapy and radiation compared with those receiving sequential therapy. Another phase III study, conducted by the Radiation Therapy Oncology Group (RTOG), compared two concurrent chemotherapy and thoracic radiation therapy regimens to a standard sequential chemotherapy and thoracic radiation approach. Preliminary results demonstrated a promising median survival rate for the concurrent platinum-based chemotherapy and radiation therapy arm.
Lung cancer is relatively chemotherapy resistant and new chemotherapeutic agents are needed, especially against non-small-cell lung cancer. Recently, many phase I and II studies have evaluated docetaxel(Drug information on docetaxel) (Taxotere), paclitaxel, gemcitabine(Drug information on gemcitabine) (Gemzar), vinorelbine (Navelbine), and irinotecan with radiation.[25-28]
Concurrent Thoracic Radiation With Single-Agent Irinotecan
Several phase I/II trials of concurrent treatment with single-agent irinotecan and thoracic radiation therapy have been conducted in patients with locally advanced non-small-cell lung cancer (Table 1). An initial phase I study of the irinotecan/cisplatin combination with concurrent thoracic radiation therapy resulted in excessive diarrhea and myelosuppression. Other trials demonstrated the feasibility of irinotecan/carboplatin (Paraplatin) with concurrent radiation.[30-32]
Kodoh and colleagues conducted a phase I/II trial of irinotecan administered weekly for 6 weeks and concurrent radiotherapy in locally advanced non-small-cell lung cancer. Dose-limiting toxicities were esophagitis, pneumonitis, and diarrhea, and the maximum tolerated dose was 60 mg/m2. In a phase II trial of the Japan Clinical Oncology Group (JCOG), 24 eligible patients received irinotecan at 60 mg/m2 weekly with 60 Gy of chest radiotherapy. The response rate was 79%, with pneumonitis and esophagitis as the major toxicities.
Takeda and colleagues examined escalating doses of weekly irinotecan with concurrent thoracic radiation. The starting irinotecan dose was 30 mg/m2 IV weekly for 6 weeks. The maximum tolerated dose was 60 mg/m2; at this dose level (n = 5), there were two cases of grade 3/4 esophagitis and three cases of grade 3/4 pneumonitis. A total of 17 patients received an irinotecan dose of 45 mg/m2 (7 in the phase I portion and 10 in the phase II portion of the trial). Toxicities in the phase II portion (45 mg/m2) included fatal pneumonitis (n = 1) and grade III diarrhea (n = 1). Overall objective response rate was 76.9%, and 1-year survival rate was 62% with 22 months of follow-up.
Choy et al reported results of a phase I study of weekly
irinotecan at 30 to 50 mg/m2 and concurrent radiation therapy for stage III
unresectable non-small-cell lung cancer. Among 13 treated patients, 58%
responded. Nausea, vomiting, and esophagitis were the major toxicities. The
maximum tolerated dose of irinotecan is 40 mg/m2 weekly for
Concurrent Thoracic Radiation and Irinotecan/Platinum Combinations
The promising results achieved with irinotecan and concurrent thoracic radiation therapy led to incorporation of platinum compounds, which have demonstrated, in addition to antitumor activity, radiosensitizing effects in non-small-cell lung cancer (Table 2).[29,31,34-39] In a phase I trial of irinotecan/cisplatin plus radiotherapy in stage III non-small-cell lung cancer, conducted by Yokoyama and colleagues in the JCOG, the response rate was 67%, but 1-year survival rate was only 33%.
Another Japanese trial of concurrent cisplatin, irinotecan, and radiation in non-small-cell lung cancer was reported by Fukuda et al, in which patients received two chemotherapy courses with split-course radiation. The overall response rate in 23 evaluable patients was 65%, with some cases of neutropenia, thrombocytopenia, and esophagitis. The Japanese Lung Cancer Group conducted a follow-up study with induction cisplatin and irinotecan for two cycles, followed by concurrent weekly irinotecan and thoracic radiation. The significant toxicities were neutropenia (6% of patients with grade 4), esophagitis (4% grade 3), and hypoxia (2% grade 4). The response rate was 63%, and the estimated 1-year survival rate was 72%.
Another Japanese trial examined use of thoracic radiation with carboplatin(Drug information on carboplatin) and irinotecan. Irinotecan was administered weekly, carboplatin was given at a dose of 20 mg/m2 daily for 5 days a week, and both were repeated for 4 weeks. Radiation dose was 60 Gy in 2-Gy fractions for 6 weeks. The maximum tolerated dose of irinotecan was 60 mg/m2, and dose-limiting toxicities were pneumonitis, esophagitis, neutropenia, and thrombocytopenia. The response rate was 60%, median survival has not been reached, but the 2-year survival rate was 51%. Oka and colleagues conducted a phase I study of irinotecan and cisplatin with concurrent split-course radiation therapy in patients with locally advanced stage III non-small-cell lung cancer. Only one patient experienced a dose-limiting toxicity (neutropenia and diarrhea) at 60 mg/m2 of irinotecan and 60 mg/m2 of cisplatin. The response rate was 70%. Recommended doses for phase II study were 60 mg/m2 of irinotecan and 60 mg/m2 of cisplatin.
The regimen of weekly irinotecan/carboplatin with concurrent radiation therapy is likely to be adopted by RTOG as one treatment arm in a new randomized phase II trial in patients with locally advanced non-small-cell lung cancer