New State of the Art in Small-Cell Lung Cancer

ABSTRACT: Chemotherapy is currently the main treatment for all stages ofsmall-cell lung cancer. In extensive disease, etoposide/cisplatin (Platinol) isstandard treatment, and in limited disease, etoposide/cisplatin with earlyconcurrent thoracic radiotherapy twice daily is a typical regimen. Therapeuticoutcomes, however, leave substantial room for improvement. The topoisomerase Iinhibitor irinotecan (Camptosar, CPT-11) is one of the most active agentsagainst small-cell lung cancer. In a phase II study, irinotecan yielded responserates of 33% to 50%, depending on prior treatment status. Combinations withcisplatin have resulted in a median survival of 14.3 months in patients withlimited disease and 13.0 months in extensive disease. A phase III study inextensive-disease small-cell lung cancer compared irinotecan/cisplatin andstandard etoposide/cisplatin regimens, and demonstrated a significant differencein survival in the irinotecan-containing arm (411 vs 282 days). Planned phaseIII studies in North America will confirm and extend these results. Based onthese promising data, irinotecan/cisplatin regimens represent a new standardtreatment for extensive-disease small-cell lung cancer. [ONCOLOGY 15(Suppl1):8-10, 2001]

Introduction

Small-cell lung cancer differs fromother types of lung cancer in itsmore aggressive clinical course and in its superior responsiveness tochemotherapy and radiotherapy. Chemotherapy is currently the main treatment forall stages of small-cell lung cancer.

In phase III investigations by the Japan Clinical Oncology Group(JCOG) in extensive disease (JCOG 9106), current combination chemotherapyregimens such as etoposide/cisplatin (Platinol) produced response rates of 60%to 80%, complete response rates of 15% to 20%, and a median survival of 10 to 12months (N = 227).[1] In a phase III study of 228 evaluable patients with limiteddisease (JCOG 9104), a regimen of etoposide/cisplatin with early concurrentthoracic radiotherapy twice daily (30 fractions, 45 Gy each) produced responserates of 85% to 95%, complete response rates of 40% to 60%, and a mediansurvival of 24 months.[2] However, these therapeutic outcomes still leavesubstantial room for improvement.

One of the most important approaches in the treatment ofsmall-cell lung cancer is new drug development. In the 1990s, drugs with novelmechanisms of action—such as paclitaxel (Taxol), irinotecan (Camptosar,CPT-11), and gemcitabine (Gemzar)—were introduced (see Table1). Irinotecan, awater-soluble camptothecin derivative developed in Japan, acts by inhibition oftopoisomerase I; it is one of the most active agents against small-cell lungcancer.

Phase II Studies

In a phase II multicenter study of irinotecan in small-cell lungcancer on a weekly schedule at a dose of 100 mg/m², Negoro and colleagues[3] reported response rates of 33% in 27 previouslytreated patients and 50% in 8 previously untreated patients, resulting in anoverall response rate of 37.1%. Two complete and 13 partial responses wereobserved. The major toxicities were leukopenia and diarrhea (which were doselimiting, but reversible), nausea/vomiting, anorexia, and alopecia. The authorsconcluded that irinotecan was highly effective against small-cell lungcarcinomas.

In a prospective nonrandomized phase II single-institutionstudy, Masuda and collaborators[4] assessed irinotecan at 100 mg/m²/wk in 16patients who had been pretreated heavily with cisplatin-based combinationchemotherapy. In 15 assessable patients (14 relapsed and 1 refractory),investigators reported an overall response rate of 47% (95% confidence interval:21.4% to 71.9%), with seven partial responses. The major toxicities weremyelosuppression (predominantly grade 3/4 leukopenia in 33%), diarrhea, andpulmonary toxicity. The authors concluded that irinotecan was an active agentagainst refractory or relapsed small-cell lung cancer, and the data warrantedfurther study in single-agent and combination therapy.

In a phase II trial, the combination of irinotecan at 60 mg/m²on days 1, 8, and 15 (80 mg/m² for the first 10 patients), and cisplatin at 60mg/m² on day 1, every 4 weeks, was assessed in previously untreated small-celllung cancer patients. The overall response rate was 84%, with a completeresponse rate of 29%. The median survival time was 14.3 months for 40limited-disease patients and 13.0 months for 35 extensive-disease patients.Two-year survival rates were 17.5% for limited-disease patients and 21.7% forextensive disease. The response rates are enumerated in Table1. Major grade 3/4toxicities were neutropenia (77%), leukopenia (45%), anemia (39%), and diarrhea(19%). The authors concluded that the combination of irinotecan/cisplatin was anew active regimen for small-cell lung cancer (especially extensive disease),with acceptable toxicity.[5]

Phase III Study

Based on these results, the JCOG conducted a phase III study ofirinotecan/cisplatin vs etoposide/cisplatin in extensive-disease small-cell lungcancer (JCOG 9511, Chairman Nagahiro Saijo).[6,7] The primary end point wassurvival. Patients in the study arm received a combination of irinotecan at 60mg/m² on days 1, 8, and 15, and cisplatin at 60mg/m² on day 1, on anevery-4-week schedule. The standard arm consisted of etoposide at 100 mg/m² on days 1, 2, and 3, and cisplatin at 80mg/m² on day 1, every 3 weeks,for four courses.

After accrual of 154 patients between November 1995 and November1998, the study was stopped in December 1998 because of a large, statisticallysignificant difference in survival at the second interim analysis. Mediansurvival was 411 days for the new combination of irinotecan/cisplatin and 282days for standard etoposide/cisplatin. Also, there was a trend toward a higherresponse rate in patients receiving the irinotecan-containing regimen (83.1% vs67.5%), as well as significant increases (P = .0021) in both 1-year (58.4% vs37.7%) and 2-year survival (18.9% vs 6.5%) with the new combination. A summaryof these responses is shown in Table 2.

Hematologic toxicity was less pronounced in patients receivingirinotecan/cisplatin compared to etoposide/cisplatin, with significantly lessJCOG grade 3/4 leukopenia (27% vs 52%; P = .003), grade 3/4 neutropenia (66% vs92%; P = .0002), and grade 3/4 thrombocytopenia (5% vs 19%; P = .0001). Amongnonhematologic toxicities, only the incidence of grade 3/4 diarrhea wasincreased in the irinotecan/cisplatin arm (16% vs 0%; P = .0001); others did notdiffer significantly between the two arms.

The authors concluded that in patients with extensive-diseasesmall-cell lung cancer, the four cycles of irinotecan plus cisplatin regimenevery 4 weeks yielded a significant improvement in survival over standardetoposide/cisplatin, and resulted in less myelosuppression.

Two North American randomized phase III trials are being plannedthat will attempt to reproduce and extend these promising results. One willutilize the JCOG 9511 trial design, and the second will employ a study arm inwhich the schedule is modified to irinotecan at 65 mg/m² on days 1 and 8, pluscisplatin at 30 mg/m² on days 1 and 8, every 3 weeks.

Conclusion

Irinotecan/cisplatin is superior to etoposide/cisplatin insurvival with tolerable toxicity, and irinotecan/cisplatin regimens are a newstandard treatment for extensive-disease small-cell lung cancer (see Table3).[7]

References:

1. Furuse K, Fukuoka M, Nishiwaki Y, et al: Phase III study ofintensive weekly chemotherapy with recombinant human granulocytecolony-stimulating factor versus standard chemotherapy in extensive-diseasesmall-cell lung cancer. The Japan Clinical Oncology Group. J Clin Oncol16:2126-2132, 1998.

2. Goto K, Nishiwaki Y, Takada M, et al: Final results of aphase III study of concurrent versus sequential thoracic radiotherapy (TRT) incombination with cisplatin (P) and etoposide (E) for limited-stage small celllung cancer (LD-SCLC): The Japan Clinical Oncology Group (JCOG) study (abstract1805). Proc Am Soc Clin Oncol 18:468a, 2000.

3. Negoro S, Fukuoka M, Niitani H, et al: A phase II study ofCPT-11, a camptothecin derivative, in patients with primary lung cancer. CPT-11Cooperative Study Group [in Japanese]. Gan To Kagaku Ryoho 18:1013-1019, 1991.

4. Masuda N, Fukuoka M, Kusunoki Y, et al: CPT-11: A newderivative of camptothecin for the treatment of refractory or relapsedsmall-cell lung cancer. J Clin Oncol 10:1225-1229, 1992.

5. Kudoh S, Fujiwara Y, Takada Y, et al: Phase II study ofirinotecan combined with cisplatin in patients with previously untreatedsmall-cell lung cancer. West Japan Lung Cancer Group. J Clin Oncol 16:1068-1074,1998.

6. Noda K, Nishiwaki Y, Kawahara M, et al: Randomized phase IIIstudy of irinotecan (CPT-11) and cisplatin in extensive-disease small-cell lungcancer: Japan Clinical Oncology Group Study (JCOG9511) (abstract 1887). Proc AmSoc Clin Oncol 19:483a, 2000.

7. Negoro K, et al: A randomized phase III study of irinotecanand cisplatin (CP) versus etoposide and cisplatin (EP) in extensive-diseasesmall-cell lung cancer (ED-SCLC): Japan Clinical Oncology Group Study (JCOG9511). Lung Cancer 29(suppl 1):30, 2000