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Here is info on chemo treatments. Is Irinotecan/Cisplatin the best?

SCLC: Progress After Years of Stagnation or Still a Medical Chimera?

Corey J. Langer, MD Disclosures

For the first time in several years, small cell lung cancer (SCLC) papers presented at the SCLC plenary session at ASCO demonstrated the utility of newer agents, particularly epirubicin and irinotecan, in the treatment of small cell carcinoma of the lung. On the other hand, consolidation with topotecan yielded no significant survival benefit; and at least one study evaluating paclitaxel in combination with standard etoposide-cisplatin demonstrated the need for careful interim toxicity analysis. In addition, some studies have highlighted the crucial importance of patient selection in treatment outcome.

Dr. Pujol and colleagues of the FNCLCC[1] mounted a phase III study in extensive SCLC comparing etoposide and cisplatin with cyclophosphamide 400 mg/m2 on days 1 to 3 and epirubicin 40 mg/m2 in combination with the same doublet. The etoposide and cisplatin doses were fixed in each arm at 100 mg/m2 on days 1 to 3, and 100 mg/m2 on day 2, respectively. Hematopoietic growth factors were not used routinely. A total of 226 patients were accrued. Arms were well balanced with respect to demographics. The response rate for the 4-drug regimen was 76%, vs 61% for etoposide-cisplatin alone (P=.02). This translated into commensurate improvement in median survival (10.5 vs 9.3 months), 1-year survival (40% vs 29%), and 18-month survival (18% vs 9%), with a P value of .006. Not surprisingly, in the absence of hematopoietic support, the incidence of febrile neutropenia was nearly 4-fold in the 4-drug regimen (66% vs 18%), statistically significant at a P value of less than .0001, although this did not translate into a statistically significant increase in toxic deaths: 9% vs 5.5% (P=.10) Quality-of-life parameters were equivalent in both arms, with similar, if not better, improvement in the 4-drug regimen. Despite the apparent benefits, many investigators would question whether a 2 out of 3 risk of neutropenic fever in the palliative treatment of advanced cancer is too high a price to pay.

The most promising data come from a Japanese study.[2] Dr. Noda and colleagues compared irinotecan and cisplatin with etoposide and cisplatin. The doses of etoposide and cisplatin were fairly standard at 100 mg/m2 on days 1 to 3, and 80 mg/m2 on day 1. The cisplatin dose in the new agent combination was slightly lower at 60 mg/m2. Irinotecan was dosed at 60 mg/m2 on days 1, 8, and 15. Both regimens were dosed at 4-week intervals. The response rate for the new agent combination was significantly higher at 89% vs 67% (P=.013), with statistically significant improvement in survival: 14 vs 10 months (P=.0047), 1- and 2-year survival rates (58.4% and 18.9%, respectively, for irinotecan-cisplatin vs 37.7% and 6.5%, respectively, for standard etoposide-cisplatin). Moreover, with the exception of diarrhea, toxicity was less pronounced in the irinotecan combination; it caused significantly less neutropenia and thrombocytopenia. Accrual to this study was suspended early after 154 patients were enrolled because of statistically significant divergence in survival curves. Dr. Giuseppe Giaccone, the discussant of the session, questioned the early closure of the trial and the use of a one-sided P value to delineate a survival difference. Hence, it is imperative that this randomization be reproduced in North America, where etoposide-cisplatin still remains the standard of treatment. Two separate North American trials are being contemplated: one recapitulating the Japanese trial and the other comparing 2 separate 3-week regimens, with day 1 and 8 irinotecan administered in the experimental arm and day 15 treatment omitted.

Dr. Gatzemeier and colleagues[3] compared the German standard of carboplatin, etoposide, and vincristine (CEV) with the paclitaxel combination of taxol, etoposide, and carboplatin (TEC). The carboplatin dose in both regimens was fixed at area under the curve (AUC) 5. In the standard arm, etoposide phosphate was given at a dose of 160 mg/m2 on days 1 to 3, vincristine 2 mg intravenously (IV) on days 1 and 8. In the experimental arm, paclitaxel was dosed at 175 mg/m2 on day 4, in combination with carboplatin, following etoposide phosphate at a somewhat higher dose: 225 mg/m2 on days 1 to 3. Eligibility stipulated performance status 0-2, and normal hematologic, renal, and hepatic function. Both limited and extensive small cell disease patients were enrolled. Anemia, thrombocytopenia, and peripheral sensory neuropathy were less pronounced for the TEC regimen, and treatment delays were less common. The incidence of neutropenia and overall response rates (93% for TEC and 87% for CEV) were similar. Disappointingly, time to progression and survival data, although promised, were not yet available for analysis.

On the other hand, another study assessing the utility of paclitaxel added to standard etoposide and cisplatin failed to yield an advantage. Dr. Mavroudis and colleagues from the Greek Lung Cancer Cooperative Group[4] compared cisplatin 80 mg/m2 on day 1 and etoposide 120 mg/m2 on days 1 to 3 (cisplatin-etoposide [EP]) with a combination of etoposide-cisplatin and paclitaxel (TEP). In an experimental regimen, the cisplatin dose was fixed at 80 mg/m2, the etoposide dose lowered to 80 mg/m2 IV on days 2 and 4, and paclitaxel dosed at 175 mg/m2. Prophylactic granulocyte colony-stimulating factor 5 mcg/kg/d on days 5 to 15 was used routinely in the experimental arm. Treatment was repeated at 4-week intervals. A total of 133 patients were randomized, and 108 were evaluable for response and toxicity. Slightly more limited stage patients were enrolled on the experimental arm (47% vs 42%). There was no difference in response rate: 50% for TEP, 48% for EP; or in the median and 1-year survival rates (10.5 months and 46% for TEP vs 11.5 months and 46% for EP). Accrual was stopped early because of an untoward incidence of cytotoxic deaths in the TEP arm (13% vs 0%). There was no particular pattern with respect to performance status. The cycle-specific incidence of febrile neutropenia was 6% for TEP vs 3% for EP. Patients in the experimental arm sustained significantly more thrombocytopenia, diarrhea, and asthenia. In conclusion, the experimental regimen was substantially more toxic than standard EP. The results of this study have major implications for the current North American Intergroup trial, which virtually recapitulates the doses used in this effort. To date, however, the toxic death rate observed during the Greek trial has not been seen in the current intergroup trial. Nevertheless, based on these results, it is imperative that supportive measures and patient selection be carefully evaluated.

Finally, topotecan, despite its promise in chemo-sensitive relapsed SCLC, does not work as consolidation after standard treatment. ECOG 7593[5] randomized extensive disease patients to standard etoposide and cisplatin (125 mg/m2 on days 1 to 3, and 60 mg/m2 on day 1) at 3-week intervals, +/- consolidation therapy with topotecan (1.5 mg/m2 daily x 5) for 4 additional cycles. A total of 405 patients were registered in this trial; 277 were eligible for step 2, with an equal distribution between observation and topotecan. The overall response rate was 33%. Additional responses were observed in 7% of those randomized to topotecan. A statistically significant improvement in progression-free survival (3.4 months vs 2.3 months) was observed for topotecan, but this observation did not translate into a survival benefit: 9.3 months vs 8.9 months, respectively, from the time of randomization. Hence, 4 cycles of etoposide-cisplatin remain the gold standard of comparison for patients with extensive stage SCLC with good performance status.

There are multiple potential explanations for this apparent lack of benefit. Crossover to topotecan or other salvage agents at the time of progression might have nullified any potential survival advantage. Unfortunately, data on second-line treatment were not solicited. Alternatively, the concept itself may be flawed. Maintenance therapy in the past has yielded no benefit in terms of survival. Consolidation, despite the use of an alternative agent, may be tantamount to maintenance, particularly if cross-resistance exists between topoisomerase-1 and topoisomerase-2 inhibitors. Finally, the sequence called for in this study, topoisomerase-2 inhibition preceding topoisomerase-1 inhibition, may potentially represent a suboptimal integration of topoisomerase-1 and topoisomerase-2 inhibitors. Ongoing efforts are evaluating the alternative sequence: topoisomerase-1 inhibitors administered before topoisomerase-2 inhibition. But it remains to be seen whether alternative sequences will translate into benefit.

In conclusion, for extensive stage SCLC, irinotecan has proven superior to etoposide, in combination with cisplatin. But the observations from the Japanese study need to be confirmed in the United States. The addition of cyclophosphamide and epirubicin to EP has also proven superior to EP alone, in terms of survival, but considerably more toxic. However, the addition of paclitaxel to the same regimen, at least in one study, yielded an unacceptable rate of toxic deaths, and no apparent survival benefit. Similarly, consolidation with topotecan in patients whose disease has responded or stabilized on EP fails to yield a survival benefit.

Nevertheless, for the first time in several years, randomized studies in extensive disease have demonstrated some promise. Whether cycle compression with hematopoietic support or the integration of new biologics (eg, angiogenesis inhibitors, monoclonal antibodies directed against small cell-specific growth factors, and so forth) will introduce further benefit requires carefully conducted, rigorously controlled scientific trials.


Pujol J. Doublet etoposide - cisplatin (EP) versus quadruplet cisplatin - cyclophosphamide - epirubicin - etoposide (PCDE) in extensive disease small cell lung cancer (Ed-SCLC): a FNCLCC phase III multicentre study. In: Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 1892.

Noda K, Nishiwaki Y, Kawahara M, et al. Randomized phase III study of irinotecan (CPT-11) and cisplatin versus etoposide and cisplatin in extensive- disease small-cell lung cancer: Japan Clinical Oncology Group (JCOG9511). In: Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 1887.

Gatzemeier U, von Pawel J, Macha H, et al. A phase III trial of taxol, etoposide phosphate and carboplatin (TEC) versus carboplatin, etoposide phosphate and vincristine (CEV) in previously untreated small cell lung cancer (SCLC). In: Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 1889.

Mavroudis D, Papadakis E, Veslemes M, et al. A multicenter randomized phase III study comparing paclitaxel-cisplatin-etoposide (TEP) versus cisplatin-etoposide (EP) as front-line treatment inpatients with small cell lung cancer (SCLC). In: Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 1894.

Johnson DH, Adak S, Cella DF, et al. Topotecan (T) vs. observation (OB) following cisplatin (P) plus etoposide (E) in extensive stage small cell lung cancer (ES SCLC) (E7593): a phase III trial of the Eastern Cooperative Oncology Group (ECOG). In: Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 1886.

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