Irinotecan Plus Cisplatin in Small-Cell Lung Cancer

September 2, 2002

The DNA topoisomerase inhibitor irinotecan (CPT-11, Camptosar) is being evaluated as a novel chemotherapeutic agent for small-cell lung cancer that may complement other agents and treatment modalities. Combination

ABSTRACT: The DNA topoisomerase inhibitor irinotecan (CPT-11, Camptosar) is beingevaluated as a novel chemotherapeutic agent for small-cell lung cancer that maycomplement other agents and treatment modalities. Combination chemotherapy isrecognized as the most effective means of improving survival in patients withextensive-stage small-cell lung cancer, but until recently, no one combinationhad emerged as superior. In a recent Japanese phase III study, irinotecan incombination with cisplatin significantly improved survival of previouslyuntreated patients with extensive small-cell lung cancer compared with standardetoposide/cisplatin therapy (median progression-free survival: 6.9 vs 4.8months, P < .001; median overall survival: 12.8 vs 9.4 months, P = .0021).Two additional phase III trials are planned to confirm these results in theUnited States, and to investigate how the irinotecan/cisplatin administrationschedule may be modified to improve therapeutic index. This article will reviewthe use of irinotecan in combination with cisplatin in patients with small-celllung cancer. [ONCOLOGY 16(Suppl 9):39-44, 2002]

Small-cell lung cancer accounts for approximately 20% to 25% of all cases oflung cancer and has an especially poor prognosis, resulting in about 25% of alllung cancer deaths.[1-3] Small-cell lung cancer is characterized by anaggressive clinical course with early dissemination of regional and distantmetastases. Tumors are initially chemosensitive but acquire drug resistanceduring disease progression.[4] About 30% to 40% of small-cell lung cancerpatients present with limited-stage disease that is confined to one hemithoraxand regional lymph nodes without pericardial or pleural effusion.[1] Themajority of patients are initially diagnosed with more advanced and lesstreatment-sensitive extensive-stage disease. The 5-year survival rate forsmall-cell lung cancer is only about 5% overall, and is negligible for patientswith extensive-stage disease.[1]

Combination chemotherapy is the most effective treatment modality forsmall-cell lung cancer. For patients with extensive-stage small-cell lungcancer, chemotherapy can increase median survival from approximately 1.5 monthsto 7 to 11 months, with 2-year survival uncommon.[1,5] Standard chemotherapyregimens for small-cell lung cancer include cyclophosphamide (Cytoxan, Neosar),doxorubicin (Adriamycin), and vincristine (CAV); cisplatin or carboplatin (Paraplatin)plus the DNA topoisomerase II inhibitor etoposide; or alternating these twocombinations (eg, CAV followed by cisplatin/etoposide).[6] Cisplatin/etoposideis the most widely used first-line regimen for patients with extensive-stagesmall-cell lung cancer, and results in survival comparable to that obtained withCAV or other early combinations (median overall survival: 7 to 11 months), butwith a more favorable toxicity profile.[1]

Several new agents, including paclitaxel, topotecan (Hycamtin), gemcitabine (Gemzar),and irinotecan (CPT-11, Camptosar), have exhibited significant activity assingle agents against small-cell lung cancer (Table1).[6] This review willfocus on the treatment of extensive-stage small-cell lung cancer with thetopoisomerase I inhibitor irinotecan when used alone and in combination withcisplatin.

Irinotecan Mechanism of Action and Preclinical Activity

Irinotecan hydrochloride, a semisynthetic derivative of the plant alkaloidcamptothecin, inhibits topoisomerase I activity. During DNA replication, theenzyme topoisomerase I relieves torsional strain by inducing reversiblesingle-strand breaks.[7,8] Irinotecan, and to a much greater extent its activemetabolite SN-38, prevents religation of those breaks by binding to thetopoisomerase I/DNA complex.[9] Irinotecan-induced cytotoxic death may occurthrough interaction of replication enzymes with this ternary molecular complex,possibly by arresting DNA replication and leading to lethal double-strand DNAbreaks.[10]

Antitumor activity of irinotecan has been demonstrated in preclinical studieswith a variety of mouse tumors and human tumor xenografts, includingdrug-resistant tumors, when administered either intravenously or orally.[11,12]Irinotecan also complements the antitumor activity of agents that act throughother effects on DNA replication (eg, cisplatin or gemcitabine) or interferewith other vital cell functions (eg, the taxanes), either additively orsynergistically.[13,14]

Single-Agent Irinotecan

Single-agent irinotecan has demonstrated antitumor activity as second-linetherapy in several phase II studies of patients with extensive-stage small-celllung cancer, achieving overall response rates of 13.6% to 47% with doses of 100to 125 mg/m² weekly and 350 mg/m² every 3 weeks (Table2).[15-17]

In a recent U.S. phase II study involving previously treated small-cell lungcancer patients, 45 patients received irinotecan at 125 mg/m² weekly for 4weeks, followed by a 2-week rest; the majority of patients received only onetreatment course.[18] The response rate was 14% overall, but 29% among 17patients with sensitive-relapse disease (ie, relapse more than 90 days aftercompleting chemotherapy). Similarly, topotecan, another camptothecin analog,achieved a 38% response rate among chemosensitive patients, but only 6% ofrefractory patients responded (ie, patients not initially responding tochemotherapy, or those with relapse less than 90 days after completingchemotherapy).[19]

Irinotecan With Cisplatin

The mechanisms of action of irinotecan are complementary to those ofcisplatin, which is highly active against small-cell lung cancer. Studies inpreclinical models have demonstrated synergistic activity of the two agents. Inaddition, there is minimal overlap in the toxicity profiles of irinotecan andcisplatin. For these reasons, irinotecan was an ideal candidate for clinicalstudies with cis-platin as first-line therapy.

Several dose-finding studies of the irinotecan/cisplatin combination inpatients with advanced lung cancer were conducted in Japan.[20-22] The maximumtolerated doses for phase II study were established as weekly irinotecan at 60to 80 mg/m² on days 1, 8, and 15 of each 28-day cycle, together with cisplatinat 60 to 80 mg/m² once every 28 days.[20-22] Partial responses were obtained in43% to 54% of patients treated in the three studies. Overall response durationwas 82 days for irinotecan at 30 to 70 mg/m² and cisplatin at 80 mg/m², and 128days for irinotecan at 60 to 90 mg/m² and cisplatin at 60 mg/m².

Major dose-limiting toxicities seen with irinotecan at 60 mg/m² and cisplatinat 80 mg/m² were grade 3 or 4 leukopenia and diarrhea; grade 3 nausea andvomiting were common at most dose levels but manageable with standard antiemeticmedication.[20] Less severe leukopenia and fewer other side effects resultedfrom irinotecan at 80 mg/m² and cisplatin at 60 mg/m².[21] The combination ofirinotecan at 70 to 90 mg/m² and cisplatin at 80 mg/m² was also studied with theaddition of granulocyte colony-stimulating factor, but the median time toprogression was not increased at 80 mg/m² of each agent compared with lowerdoses.[22]

Subsequently, a phase II study of irinotecan/cisplatin as first-line therapyin 35 patients with extensive-stage small-cell lung cancer was conducted by theWest Japan Thoracic Oncology Group. Both agents were administered at a dose of60 mg/m², irinotecan on days 1, 8, and 15 of each 28-day cycle and cisplatin onday 1, for up to six 4-week courses.[23] Overall response rate was 86%, with 29%of patients achieving complete responses. Median survival was 13.0 months, with2-year survival of 17.5%.[23]

Based on these results, the Japan Clinical Oncology Group (JCOG) conducted amulti-institutional randomized phase III trial (JCOG-9511) comparing irinotecan/cisplatinwith standard etoposide/cisplatin in patients with previously untreatedextensive-stage small-cell lung cancer (Figure1).[24] The experimental armconsisted of irinotecan at 60 mg/m² administered on days 1, 8, and 15 of each4-week cycle, with cisplatin at 60 mg/m² on day 1, for a total of four cycles.That treatment was compared to etoposide at 100 mg/m² administered on the firstthree days of each 3-week cycle, with cisplatin at 80 mg/m² on day 1, for atotal of four cycles. Projected accrual was 115 patients per arm. An interimanalysis conducted when 77 patients were accrued per arm revealed a significantsurvival advantage for the irinotecan/cisplatin arm. Enrollment in the trial wastherefore discontinued.[24]

Response rates were significantly higher for patients receiving irinotecan/cisplatinthan in those receiving etoposide/cisplatin (83% vs 68%; P < .01).Additionally, the irinotecan/cisplatin arm showed a statistically significantimprovement in progression-free survival (6.9 vs 4.8 months; P < .001) andmedian overall survival (12.8 vs 9.4 months; P = .0021) compared with theetoposide/cisplatin arm (Table 3, Figure2). The incidences of leukopenia,neutropenia, and thrombocytopenia were significantly higher (P ≤ .01) in theetoposide/cisplatin arm, whereas diarrhea was more frequent in the irinotecan/cisplatinarm.[24] The day 15 doses of irinotecan/cisplatin were omitted or reduced inabout 50% of treatment courses due to toxic side effects.

To maintain a weekly dose intensity that is better tolerated, drug deliveryon days 1 and 8 every 3 weeks may be an appropriate alternative. A modifiedregimen of weekly irinotecan for the first 2 weeks of each 3-week cycle,combined with every-3-week cisplatin, may allow for greater concurrent doseintensity and improved patient tolerance. This dosing schedule will be evaluatedin a multi-institutional randomized phase III trial that opened in June 2001 (Figure3). Cisplatin will be administered more frequently at lower doses (ie,to achieve dose-dense therapy), with irinotecan and etoposide at higher doses,in an attempt to decrease toxicity and increase activity. The Southwest OncologyGroup is also considering a confirmatory trial of the JCOG-9511 study, using thesame dosing and schedule as in the Japanese trial (D. Gandara, personalcommunication, September 2001).

Summary

Several new chemotherapy agents are being evaluated for the treatment ofsmall-cell lung cancer, including the topoisomerase I inhibitor irinotecan. Thisagent has demonstrated single-agent activity in both previously treated anduntreated small-cell lung cancer patients. It has also been evaluated incombination with cisplatin, an active agent in this disease, and with whichirinotecan has shown synergistic activity in preclinical models. An 86% overallresponse rate was achieved in a phase II study of the irinotecan/cisplatincombination in patients with extensive-stage small-cell lung cancer, with a 29%complete response rate. In a randomized phase III trial conducted in Japan, thecombination of irinotecan/cisplatin was compared with etoposide/cisplatin. Theirinotecan-containing regimen resulted in significantly higher response ratesand progression-free and overall survival. Confirmatory phase III trials of theregimen are ongoing.

References:

1. Ihde D, Pass H, Glatstein E: Small cell lung cancer, in DeVita VT Jr,Hellman S, Rosenberg SA (eds): Cancer: Principles & Practice of Oncology, pp911-949. Philadelphia, Lippincott-Raven, 1997.

2. Adjei AA: Management of small cell cancer of the lung. Curr Opin Pulm Med6:384-390, 2000.

3. Sandler AB: Current management of small cell lung cancer. Semin Oncol24:463-476, 1997.

4. Zöchbauer-Müller S, Pirker R, Huber H: Treatment of small cell lungcancer patients. Ann Oncol 10(suppl 6):83-91, 1999.

5. Kelly K: New chemotherapy agents for small cell lung cancer. Chest117:156S-162S, 2000.

6. Sandler A: Extensive small-cell lung cancer: A treatment overview.Oncology 14(suppl 5):49-55, 2000.

7. Hsiang Y-H, Liu LF: Identification of mammalian DNA topoisomerase I as anintracellular target of the anticancer drug camptothecin. Cancer Res48:1722-1726, 1988.

8. Hertzberg RP, Caranfa MJ, Hecht SM: On the mechanism of topoisomerase Iinhibition by camptothecin: Evidence for binding to an enzyme-DNA complex.Biochemistry 28:4629-4638, 1989.

9. Kawato Y, Aonuma M, Hirota Y, et al: Intracellular roles of SN-38, ametabolite of the camptothecin derivative CPT-11, in the antitumor effect ofCPT-11. Cancer Res 51:4187-4191, 1991.

10. Potmesil M: Camptothecins: From bench research to hospital wards. CancerRes 54:1431-1439, 1994.

11. Kawato Y, Furuta T, Aonuma M, et al: Antitumor activity of a camptothecinderivative, CPT-11, against human tumor xenografts in nude mice. CancerChemother Pharmacol 28:192-198, 1991.

12. Kudoh S, Takada M, Masuda N, et al: Enhanced antitumor efficacy of acombination of CPT-11, a new derivative of camptothecin, and cisplatin againsthuman lung tumor xenografts. Jpn J Cancer Res 84:203-207, 1993.

13. Kudoh S, Takada M, Masuda N, et al: Enhanced antitumor efficacy of acombination of CPT-11, a new derivative of camptothecin, and cisplatin againsthuman lung tumor xenografts. Jpn J Cancer Res 84:203-207, 1993.

14. Masumoto N, Nakano S, Esaki T, et al: Inhibition ofcis-diamminedichloroplatinum (II)-induced DNA interstrand cross-link removal by7-ethyl-10-hydroxy-camptothecin in HST-1 human squamous-carcinoma cells. Int JCancer 62:70-75, 1995.

15. Negoro S, Fukuoka M, Niitani S, et al: A phase II study of CPT-11, acamptothecin derivative, in patients with primary lung cancer. Jpn J CancerChemother 18:1013-1019, 1991.

16. Masuda N, Fukuoka M, Kusunoki Y, et al: CPT-11: A new derivative ofcamptothecin for the treatment of refractory or relapsed small-cell lung cancer.J Clin Oncol 10:1225-1229, 1992.

17. Le Chevalier T, Ibrahim N, Chomy P, et al: A phase II study of irinotecan(CPT-11) in patients with small cell lung cancer (SCLC) progressing afterinitial response to first line chemotherapy CT) (abstract 1). Proc Am Soc ClinOncol 16:450a, 1997.

18. DeVore RF III, Dowell JE, Denham CA, et al: A phase II study ofirinotecan (CPT-11) in patients with previously treated small cell lung cancer.Clin Cancer Res (in press).

19. Ardizzoni A, Hansen H, Dombernowsky P, et al: Topotecan, a new activedrug in the second-line treatment of small-cell lung cancer: A phase II study inpatients with refractory and sensitive disease. J Clin Oncol 15:2090-2096, 1997.

20. Fukuoka M, Masuda N: Clinical studies of irinotecan alone and incombination with cisplatin. Cancer Chemother Pharmacol 34:S105-S111, 1994.

21. Masuda N, Fukuoka M, Takada M, et al: CPT-11 in combination withcisplatin for advanced non-small-cell lung cancer. J Clin Oncol 10:1775-1780,1992.

22. Masuda N, Fukuoka M, Kudoh S, et al: Phase I and pharmacologic study ofirinotecan in combination with cisplatin for advanced lung cancer. Br J Cancer68:777-782, 1993.

23. Kudoh S, Fujiwara Y, Takada Y, et al: Phase II study of irinotecancombined with cisplatin in patients with previously untreated small-cell lungcancer. J Clin Oncol 16:1068-1074, 1998.

24. Noda K, Nishiwaki Y, Kawahara M, et al: Irinotecan plus cisplatincompared with etoposide plus cisplatin for extensive small-cell lung cancer. NEngl J Med 346:85-91, 2002.