Small-cell lung cancer differs from
other types of lung cancer in its
more aggressive clinical course and in its superior responsiveness to
chemotherapy and radiotherapy. Chemotherapy is currently the main treatment for
all stages of small-cell lung cancer.
In phase III investigations by the Japan Clinical Oncology Group
(JCOG) in extensive disease (JCOG 9106), current combination chemotherapy
regimens 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 12
months (N = 227). In a phase III study of 228 evaluable patients with limited
disease (JCOG 9104), a regimen of etoposide/cisplatin with early concurrent
thoracic radiotherapy twice daily (30 fractions, 45 Gy each) produced response
rates of 85% to 95%, complete response rates of 40% to 60%, and a median
survival of 24 months. However, these therapeutic outcomes still leave
substantial room for improvement.
One of the most important approaches in the treatment of
small-cell lung cancer is new drug development. In the 1990s, drugs with novel
mechanisms of actionsuch as paclitaxel (Taxol), irinotecan (Camptosar,
CPT-11), and gemcitabine (Gemzar)were introduced (see Table
1). Irinotecan, a
water-soluble camptothecin derivative developed in Japan, acts by inhibition of
topoisomerase I; it is one of the most active agents against small-cell lung
In a phase II multicenter study of irinotecan in small-cell lung
cancer on a weekly schedule at a dose of 100 mg/m2, Negoro and colleagues reported response rates of 33% in 27 previously
treated patients and 50% in 8 previously untreated patients, resulting in an
overall response rate of 37.1%. Two complete and 13 partial responses were
observed. The major toxicities were leukopenia and diarrhea (which were dose
limiting, but reversible), nausea/vomiting, anorexia, and alopecia. The authors
concluded that irinotecan was highly effective against small-cell lung
In a prospective nonrandomized phase II single-institution
study, Masuda and collaborators assessed irinotecan at 100 mg/m2/wk in 16
patients who had been pretreated heavily with cisplatin-based combination
chemotherapy. 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 were
myelosuppression (predominantly grade 3/4 leukopenia in 33%), diarrhea, and
pulmonary toxicity. The authors concluded that irinotecan was an active agent
against refractory or relapsed small-cell lung cancer, and the data warranted
further study in single-agent and combination therapy.
In a phase II trial, the combination of irinotecan at 60 mg/m2
on days 1, 8, and 15 (80 mg/m2 for the first 10 patients), and cisplatin at 60
mg/m2 on day 1, every 4 weeks, was assessed in previously untreated small-cell
lung cancer patients. The overall response rate was 84%, with a complete
response rate of 29%. The median survival time was 14.3 months for 40
limited-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% for
extensive disease. The response rates are enumerated in Table
1. Major grade 3/4
toxicities were neutropenia (77%), leukopenia (45%), anemia (39%), and diarrhea
(19%). The authors concluded that the combination of irinotecan/cisplatin was a
new active regimen for small-cell lung cancer (especially extensive disease),
with acceptable toxicity.
Based on these results, the JCOG conducted a phase III study of
irinotecan/cisplatin vs etoposide/cisplatin in extensive-disease small-cell lung
cancer (JCOG 9511, Chairman Nagahiro Saijo).[6,7] The primary end point was
survival. Patients in the study arm received a combination of irinotecan at 60
mg/m2 on days 1, 8, and 15, and cisplatin at 60
mg/m2 on day 1, on an
every-4-week schedule. The standard arm consisted of etoposide at 100 mg/m2 on days 1, 2, and 3, and cisplatin at 80
mg/m2 on day 1, every 3 weeks,
for four courses.
After accrual of 154 patients between November 1995 and November
1998, the study was stopped in December 1998 because of a large, statistically
significant difference in survival at the second interim analysis. Median
survival was 411 days for the new combination of irinotecan/cisplatin and 282
days for standard etoposide/cisplatin. Also, there was a trend toward a higher
response rate in patients receiving the irinotecan-containing regimen (83.1% vs
67.5%), as well as significant increases (P = .0021) in both 1-year (58.4% vs
37.7%) and 2-year survival (18.9% vs 6.5%) with the new combination. A summary
of these responses is shown in Table 2.
Hematologic toxicity was less pronounced in patients receiving
irinotecan/cisplatin compared to etoposide/cisplatin, with significantly less
JCOG grade 3/4 leukopenia (27% vs 52%; P = .003), grade 3/4 neutropenia (66% vs
92%; P = .0002), and grade 3/4 thrombocytopenia (5% vs 19%; P = .0001). Among
nonhematologic toxicities, only the incidence of grade 3/4 diarrhea was
increased in the irinotecan/cisplatin arm (16% vs 0%; P = .0001); others did not
differ significantly between the two arms.
The authors concluded that in patients with extensive-disease
small-cell lung cancer, the four cycles of irinotecan plus cisplatin regimen
every 4 weeks yielded a significant improvement in survival over standard
etoposide/cisplatin, and resulted in less myelosuppression.
Two North American randomized phase III trials are being planned
that will attempt to reproduce and extend these promising results. One will
utilize the JCOG 9511 trial design, and the second will employ a study arm in
which the schedule is modified to irinotecan at 65 mg/m2 on days 1 and 8, plus
cisplatin at 30 mg/m2 on days 1 and 8, every 3 weeks.
Irinotecan/cisplatin is superior to etoposide/cisplatin in
survival with tolerable toxicity, and irinotecan/cisplatin regimens are a new
standard treatment for extensive-disease small-cell lung cancer (see Table
1. Furuse K, Fukuoka M, Nishiwaki Y, et al: Phase III study of
intensive weekly chemotherapy with recombinant human granulocyte
colony-stimulating factor versus standard chemotherapy in extensive-disease
small-cell lung cancer. The Japan Clinical Oncology Group. J Clin Oncol
2. Goto K, Nishiwaki Y, Takada M, et al: Final results of a
phase III study of concurrent versus sequential thoracic radiotherapy (TRT) in
combination with cisplatin (P) and etoposide (E) for limited-stage small cell
lung cancer (LD-SCLC): The Japan Clinical Oncology Group (JCOG) study (abstract
1805). Proc Am Soc Clin Oncol 18:468a, 2000.
3. Negoro S, Fukuoka M, Niitani H, et al: A phase II study of
CPT-11, a camptothecin derivative, in patients with primary lung cancer. CPT-11
Cooperative Study Group [in Japanese]. Gan To Kagaku Ryoho 18:1013-1019, 1991.
4. Masuda N, Fukuoka M, Kusunoki Y, et al: CPT-11: A new
derivative of camptothecin for the treatment of refractory or relapsed
small-cell lung cancer. J Clin Oncol 10:1225-1229, 1992.
5. Kudoh S, Fujiwara Y, Takada Y, et al: Phase II study of
irinotecan combined with cisplatin in patients with previously untreated
small-cell lung cancer. West Japan Lung Cancer Group. J Clin Oncol 16:1068-1074,
6. Noda K, Nishiwaki Y, Kawahara M, et al: Randomized phase III
study of irinotecan (CPT-11) and cisplatin in extensive-disease small-cell lung
cancer: Japan Clinical Oncology Group Study (JCOG9511) (abstract 1887). Proc Am
Soc Clin Oncol 19:483a, 2000.
7. Negoro K, et al: A randomized phase III study of irinotecan
and cisplatin (CP) versus etoposide and cisplatin (EP) in extensive-disease
small-cell lung cancer (ED-SCLC): Japan Clinical Oncology Group Study (JCOG
9511). Lung Cancer 29(suppl 1):30, 2000