Hong-gyun Wu, MD

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]

amptothecin is analkaloid obtained from plants such as the Camptotheca acuminata tree. The targetof camptothecin and its derivatives is topoisomerase I, an enzyme that relievespositive 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 thecleaved strand, which inhibits DNA synthesis and results in cell death. X- orgamma-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 ofpotentially lethal damage in plateau-phase cells.[4] An additional mechanism ofthe synergistic effect of the combination of camptothecin and radiation therapymay be the synchronizing effect of irradiation itself, which preferentiallykills G2- through M-phase cells and leaves camptothecin-sensitive S-phasecells.[5,6]

Irinotecan hydrochloride (CPT-11, Camptosar) is a semisyntheticwater-soluble derivative of camptothecin. Irinotecan is a prodrug that isconverted in vivo primarily by hepatic microsomal carboxylesterases to an activemetabolite, SN-38. Substantial individual variability in irinotecanpharmacokinetics has been observed.[7] Irinotecan is active as a single agent inlung cancer treatment, producing response rates ranging from 11% to 34% inpatients with advanced non-small-cell lung cancer.[8-11] Major toxicities ofirinotecan are myelosuppression and early- or late-onset diarrhea, which aregenerally manageable.[12] Irinotecan showed potent radiosensitizing effects inhuman lung tumor xenografts which were related to the cell cycle.[13] However,the optimum timing of topoisomerase I inhibitor treatment for maximizingradiosensitizing effects remains controversial. Combination therapy withirinotecan/cisplatin has also been shown to cause significantly greater tumorregression (as compared with either agent alone) in small-cell and non-small-celllung cancer xenografts in nude mice.[14] In addition, irinotecan and platinumagents are not cross resistant, and do not possess overlapping toxicityprofiles.[15]

Non-Small-CellLung Cancer: Current Treatment Approaches

Lung cancer is the leading cause of cancer death in the UnitedStates in both men and women over 35 years old.[16] Depending on clinicalcircumstances, the principal treatment for stage III non-small-cell lungcancer includes radiation therapy, chemotherapy, surgery, and theircombinations. The highest rate of cure for non-small-cell lung cancer has beenachieved with surgery; however, fewer than 20% of non-small-cell lung cancerpatients are considered candidates for surgical resection.[17] The 5-yearsurvival rate with surgical resection for stage I/II non-small-cell lungcancer is 60% to 70%, but falls to 5% to 20% for stage III non-small-cell lungcancer.[18]

Radiation therapy to the primary tumor and regional lymph nodeshas been the traditional treatment for locally advanced stage III non-small-celllung cancer.[19] Although a complete response is rare, 5% to 10% of patientshave a long-term survival benefit and palliation with standard fractionation to60 Gy.[20]

A meta-analysis of 11 randomized clinical trials showed thatcisplatin-based combinations plus radiation therapy reduced the risk of death by10% compared with radiation therapy alone.[21] Therefore, a combined-modalityapproach has been standard.[22]

Studies have examined the optimal timing of chemotherapyrelative to radiation therapy. For example, Furuse et al[23] conducted a phaseIII study using cisplatin, vindesine (Eldisine), and mitomycin (Mutamycin) inaddition to thoracic radiation therapy and showed superior response rate andmedian survival duration in patients receiving concurrent chemotherapy andradiation compared with those receiving sequential therapy. Another phase IIIstudy, conducted by the Radiation Therapy Oncology Group (RTOG), compared twoconcurrent chemotherapy and thoracic radiation therapy regimens to a standardsequential chemotherapy and thoracic radiation approach.[24] Preliminary resultsdemonstrated a promising median survival rate for the concurrent platinum-basedchemotherapy and radiation therapy arm.

Lung cancer is relatively chemotherapy resistant and newchemotherapeutic agents are needed, especially against non-small-cell lungcancer. Recently, many phase I and II studies have evaluated docetaxel (Taxotere),paclitaxel, gemcitabine (Gemzar), vinorelbine (Navelbine), and irinotecan withradiation.[25-28]

ConcurrentIrinotecan and Radiation for Non-Small-Cell Lung Cancer

Concurrent Thoracic Radiation With Single-Agent Irinotecan

Several phase I/II trials of concurrent treatment withsingle-agent irinotecan and thoracic radiation therapy have been conducted inpatients with locally advanced non-small-cell lung cancer (Table1). Aninitial phase I study of the irinotecan/cisplatin combination with concurrentthoracic 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 irinotecanadministered weekly for 6 weeks and concurrent radiotherapy in locally advancednon-small-cell lung cancer.[32] Dose-limiting toxicities were esophagitis,pneumonitis, and diarrhea, and the maximum tolerated dose was 60 mg/m

. In aphase II trial of the Japan Clinical Oncology Group (JCOG),[30] 24 eligiblepatients received irinotecan at 60 mg/m

 weekly with 60 Gy of chestradiotherapy. The response rate was 79%, with pneumonitis and esophagitis as themajor toxicities.

Takeda and colleagues examined escalating doses of weeklyirinotecan with concurrent thoracic radiation.[28] The starting irinotecan dosewas 30 mg/m

 IV weekly for 6 weeks. The maximum tolerated dose was 60 mg/m

; atthis dose level (n = 5), there were two cases of grade 3/4 esophagitis and threecases of grade 3/4 pneumonitis. A total of 17 patients received an irinotecandose of 45 mg/m

 (7 in the phase I portion and 10 in the phase II portion of thetrial). Toxicities in the phase II portion (45 mg/m

) included fatal pneumonitis(n = 1) and grade III diarrhea (n = 1). Overall objective response rate was76.9%, and 1-year survival rate was 62% with 22 months of follow-up.

Choy et al reported results of a phase I study of weeklyirinotecan at 30 to 50 mg/m

 and concurrent radiation therapy for stage IIIunresectable non-small-cell lung cancer.[33] Among 13 treated patients, 58%responded. Nausea, vomiting, and esophagitis were the major toxicities. Themaximum tolerated dose of irinotecan is 40 mg/m

Concurrent Thoracic Radiation and Irinotecan/PlatinumCombinations

The promising results achieved with irinotecan and concurrentthoracic radiation therapy led to incorporation of platinum compounds, whichhave demonstrated, in addition to antitumor activity, radiosensitizing effectsin non-small-cell lung cancer (Table 2).[29,31,34-39] In a phase I trial ofirinotecan/cisplatin plus radiotherapy in stage III non-small-cell lungcancer, conducted by Yokoyama and colleagues in the JCOG,[29] the response ratewas 67%, but 1-year survival rate was only 33%.

Another Japanese trial of concurrent cisplatin, irinotecan, andradiation in non-small-cell lung cancer was reported by Fukuda et al, in whichpatients received two chemotherapy courses with split-course radiation.[34] Theoverall response rate in 23 evaluable patients was 65%, with some cases ofneutropenia, thrombocytopenia, and esophagitis. The Japanese Lung Cancer Groupconducted a follow-up study with induction cisplatin and irinotecan for twocycles, followed by concurrent weekly irinotecan and thoracic radiation.[35] Thesignificant 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 withcarboplatin and irinotecan.[36] Irinotecan was administered weekly, carboplatinwas given at a dose of 20 mg/m

 daily for 5 days a week, and both were repeatedfor 4 weeks. Radiation dose was 60 Gy in 2-Gy fractions for 6 weeks. The maximumtolerated dose of irinotecan was 60 mg/m

, and dose-limiting toxicities werepneumonitis, esophagitis, neutropenia, and thrombocytopenia. The response ratewas 60%, median survival has not been reached, but the 2-year survival rate was51%. Oka and colleagues conducted a phase I study of irinotecan and cisplatinwith concurrent split-course radiation therapy in patients with locally advancedstage III non-small-cell lung cancer.[37] Only one patient experienced adose-limiting toxicity (neutropenia and diarrhea) at 60 mg/m

 of cisplatin. The response rate was 70%. Recommended doses for phase IIstudy were 60 mg/m

The regimen of weekly irinotecan/carboplatin with concurrentradiation therapy is likely to be adopted by RTOG as one treatment arm in a newrandomized phase II trial in patients with locally advanced non-small-celllung cancer

CurrentApproaches to Small-Cell Lung Cancer

Small-cell lung cancer accounts for about 20% of new lung cancerdiagnoses annually in the United States,[40] and one-third of those patientspresent with limited-stage disease confined to the chest. Combinationchemotherapy and radiation therapy is the cornerstone of treatment. Mediansurvival is limited to 15 to 20 months and the 2-year survival rate is 40% forpatients with limited-stage disease who receive chemotherapy and radiationtherapy.[41] The treatment goal for limited-stage small-cell lung cancer is thecontrol of both local disease and distant metastases by using optimalchemotherapy and radiation therapy approaches. There are still unansweredquestions with regard to combining chemotherapy and radiation therapy, includingadministration sequence, early vs late radiotherapy, and once-daily vstwice-daily radiation.

Takeda et al conducted a phase III study examining the sequenceof chemotherapy (cisplatin plus etoposide) and radiation therapy inlimited-stage small-cell lung cancer.[42] Median survival time was 31 months forpatients receiving concurrent chemotherapy radiation and 21 months for thosereceiving sequential treatment. Murray et al also reported that in patientsreceiving concurrent chemotherapy/radiotherapy, early administration of thoracicradiation therapy (concurrent with the first cycle of etoposide/cisplatin, week3) vs late administration (last cycle of etoposide/cisplatin, week 15)significantly improved median survival.[43]

Radiation therapy can be delivered once daily in larger fractions   or twice daily in lower fractions. The multiple daily fractions result in less   normal tissue damage, no radiobiological shoulder of small-cell lung cancer,   redistribution of tumor cells between fractions, sublethal repair of normal   tissue, and greater antitumor efficacy. Turissi et al reported results of once-daily   vs twice-daily radiation therapy with four cycles of cisplatin and etoposide.   Results showed that median survival was superior in the twice-daily arm (23   vs 19 months, 

The optimal once-daily radiation dose in combined-modalitytherapy is unknown, although a dose of at least 50 Gy is probably necessary tocontrol a tumor.[45] In a pilot study by Choi et al,[46] the maximum tolerateddose of twice-daily radiotherapy was 45 Gy given in 30 fractions over 3 weeks;in contrast, the maximum tolerated dose of daily radiation was 70 Gy in 35fractions over 7 weeks. In this study, however, radiation treatment began atcycle 4 of chemotherapy.

The combination of cisplatin/etoposide has been the treatment ofchoice for limited-stage small-cell lung cancer.[42,47-51] Development of newdrugs and more effective combination regimens is necessary for furtherimprovement in outcome for small-cell lung cancer patients.

Irinotecan-Containing Combinations and Thoracic Radiation forLimited-Stage Small-Cell Lung Cancer

Phase I and II trials of irinotecan have demonstrated clinicalactivity in patients with previously untreated and treated small-cell lungcancer.[28,50] Cisplatin, one of the most active drugs in this disease, is beingcombined with irinotecan and concomitant radiotherapy for treating patients withsmall-cell lung cancer.

Masuda et al reported a phase I study of irinotecan/cisplatinwith concurrent radiation for limited-stage small-cell lung cancer.[52] Theradiation dose was 60 Gy with conventional fractionation, and the cisplatin dosewas 60 mg/m

. Fatigue was the dose-limiting toxicity and the recommendedirinotecan dose for the phase II study was 40 mg/m

A phase I study conducted by Masuda et al of the irinotecan/cisplatincombination in patients with small-cell lung cancer showed antitumor activitywith acceptable toxicity.[52] The radiation dose was 60 Gy with conventionalfractionation, and the cisplatin dose was 60 mg/m

 IV on day 1, every 28 days.Irinotecan was given on days 1, 8, and 15. In a subsequent phase II study, Kudohet al assessed irinotecan plus cisplatin in patients with both limited-stage andextensive small-cell lung cancer.[14] Limited-stage patients received irinotecanat 60 or 80 mg/m

 days 1, 8, and 15 and cisplatin at 60 mg/m

 day 1 every 28days for two courses. Responders received two additional chemotherapy coursesfollowed by 50 Gy of thoracic irradiation. The overall response rate was 84% andthe complete remission rate was 29%. Median survival time was 14.3 months, andthe 2-year survival rate was 22%. Hematologic toxicity was the most commontoxicity observed; nausea and diarrhea were the principal nonhematologictoxicities.

Noda et al conducted a phase III study comparing irinotecan/cisplatinvs etoposide/cisplatin for extensive small-cell lung cancer.[53] The study wasterminated early due to a statistically significant survival difference atinterim analysis favoring the irinotecan/cisplatin arm. The conclusion was thatirinotecan plus cisplatin was an effective treatment for metastatic small-celllung cancer.

Locally advanced non-small-cell lung cancer presentstherapeutic challenges in terms of both local control and systemic treatment.The combination of chemotherapy and radiation therapy has resulted in improvedoutcome for such patients. Many phase I/II studies demonstrated the single-agentactivity of irinotecan against advanced non-small-cell lung cancer, similar tothat reported for other new active agents such as vinorelbine, gemcitabine,paclitaxel, and docetaxel. The synergistic effect of irinotecan and cisplatinwas also observed in both in vitro and clinical studies, and phase I/II studiesof radiation therapy and concurrent irinotecan and cisplatin demonstratedencouraging response and survival rates with acceptable toxicities. This regimenneeds to be compared with other combined-modality approaches in locally advancednon-small-cell lung cancer in randomized phase II or III trials.

While irinotecan is a promising agent for use in combinedchemotherapy and radiation therapy for advanced non-small-cell lung cancer,the best combination, dose, and timing of chemotherapy and radiation therapyremains unclear. Such patients should be encouraged to participate in theclinical trials.

Studies in patients with small-cell lung cancer havedemonstrated that concurrent chemotherapy and radiation therapy is better thansequential chemotherapy and radiation therapy, early thoracic radiotherapy isbetter than late radiotherapy, and twice-daily radiation is better thanonce-daily treatment. The optimal radiation dose still needs to be defined forsmall-cell lung cancer. The cisplatin/etoposide combination is currently thestandard chemotherapy for regimen for limited-stage small-cell lung cancer. Fewclinical trials have evaluated combination chemotherapy including irinotecanwith radiation for limited-stage small-cell lung cancer, thus trials are neededto explore the potential role of irinotecan for patients in this diseasesetting.

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Articles

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.

Hong-gyun Wu, MD

Articles

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