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Irinotecan in Combination With Radiation Therapy for Small-Cell and Non-Small-Cell Lung Cancer

Irinotecan in Combination With Radiation Therapy for Small-Cell and Non-Small-Cell Lung Cancer

ABSTRACT: Lung cancer is the leading cause of cancer-related death in the United States. There was rapid progress in the treatment of lung cancer during past decades, but local control and survival rates are still poor. Radiation therapy has been an indispensable part of the management of lung cancer, and a recent paradigm is concurrent chemoradiation therapy. Many novel chemotherapeutic agents were recently developed to improve both local and systemic control of cancer, including camptothecin derivatives, which are topoisomerase I inhibitors. Irinotecan (CPT-11, Camptosar) is a semisynthetic water-soluble derivative of camptothecin. Irinotecan is active as a single agent against lung cancer, and is also a potent radiosensitizing agent in human lung cancer cell lines and xenografts. There have been many phase I and II clinical trials demonstrating promising results of single-agent irinotecan and combination with concurrent therapy. This article reviews irinotecan’s mechanism of action of cytotoxicity and of radiation-sensitizing effects, as well as recent clinical data regarding combining radiation therapy and irinotecan for both non-small-cell and small-cell lung cancer. [ONCOLOGY 16(Suppl 9):13-18, 2002]

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.[4]
DNA/topoisomerase I/camptothecin cleavable complexes also affect the repair of
potentially lethal damage in plateau-phase cells.[4] 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 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.[7] 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.[12] Irinotecan showed potent radiosensitizing effects in
human lung tumor xenografts which were related to the cell cycle.[13] 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.[14] In addition, irinotecan and platinum
agents are not cross resistant, and do not possess overlapping toxicity
profiles.[15]

Non-Small-Cell
Lung Cancer: Current Treatment Approaches

Lung cancer is the leading cause of cancer death in the United
States in both men and women over 35 years old.[16] 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.[17] 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.[18]

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.[19] 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.[20]

A meta-analysis of 11 randomized clinical trials showed that
cisplatin-based combinations plus radiation therapy reduced the risk of death by
10% compared with radiation therapy alone.[21] Therefore, a combined-modality
approach has been standard.[22]

Studies have examined the optimal timing of chemotherapy
relative to radiation therapy. For example, Furuse et al[23] conducted a phase
III study using cisplatin, vindesine (Eldisine), and 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.[24] 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 (Taxotere),
paclitaxel, gemcitabine (Gemzar), vinorelbine (Navelbine), and irinotecan with
radiation.[25-28]

Concurrent
Irinotecan and Radiation for Non-Small-Cell Lung Cancer

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.[29]
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.[32] 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),[30] 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.[28] 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.[33] 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
6 weeks.

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,[29] 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.[34] 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.[35] 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 and irinotecan.[36] 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.[37] 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

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