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In Reply

Department of Medicine, Division of Oncology, Indiana University, Indianapolis, Indiana

Takigawa and colleagues consider the fractionated schedule of irinotecan and cisplatin (IP) to be inferior to the original schedule given in the study by Noda et al¹ and point to this as one possible explanation for the lack of survival advantage for the IP regimen in our study² published in the May 1, 2006, issue of the Journal of Clinical Oncology. A second point raised by these authors is that salvage chemotherapy may have affected the survival outcomes and suggest the best outcomes may be achieved with the combination of all three agents (cisplatin, etoposide, and irinotecan).

Regarding the first point, we acknowledged in our paper that the fractionated regimen of IP may be inferior to the regimen in the study by Noda et al.¹ The authors cite their own study of fractionated IP as evidence of this point.³ However, the response rate of 80% and median time to progression of 5.6 months in their study (n = 15) was similar to that seen with the Noda IP regimen. In addition, as the authors acknowledge the dose intensity of irinotecan was 1.8 times greater with irinotecan in our study compared with theirs. The Southwest Oncology Group is completing a much larger trial in patients with extensive disease small-cell lung cancer utilizing the two arms of the Noda trial.¹ The results from this trial will provide the answer to this question of dose/schedule of IP. However, given the lack of positive phase III trials testing a number of active agents in various combinations, schedules, and dosages in extensive disease small-cell lung cancer over the last 25 years, it seems unlikely that a change in schedule of IP which provides less dose intensity (as does the original schedule of IP compared with our regimen) will positively affect survival outcomes.

Regarding the second point, it seems equally unlikely that differences in salvage therapy resulted in negating a positive effect by the IP regimen in our study. It should be noted that the response rates and time to disease progression (indicators of the effect of first-line therapy) are nearly identical on the two arms. Furthermore, a higher percentage of patients on the IP arm received salvage chemotherapy compared with the etoposide and cisplatin (EP) arm (69.9% v 60.4%). It would be difficult to argue that salvage etoposide would be superior to salvage topoisomerase I inhibition if one is also making the case that the IP arm is more effective than the EP arm.

Finally, regarding the last point that the best regimen may be a combination of all three agents, I would caution that several other three-drug regimens are more toxic but not more effective than EP.^4-6 Given the significant toxicity of both IP and EP regimens, major dose reductions of each agent would likely be required for this combination to be safely given.

Author's Disclosures of Potential Conflicts of Interest

The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Nasser H. Hanna Pfizer Inc

REFERENCES

1. Noda K, Nishiwaki Y, Kawahara M, et al: Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small cell lung cancer. N Engl J Med 346 : 85 -91, 2002[Abstract/Free Full Text]

2. Hanna N, Bunn PA Jr, Langer C, et al: Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 24 : 2038 -2043, 2006[Abstract/Free Full Text]

3. Takigawa N, Fujiwara K, Ueoka H, et al: Fractionated administration of irinotecan and cisplatin for treatment of extensive-disease small-cell lung cancer: A phase II study. Anticancer Res 23 : 557 -560, 2003[Medline]

4. Roth B, Johnson D, Einhorn L, et al: Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small cell lung cancer: A phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 10 : 282 -291, 1992[Medline]

5. Sundstrom S, Bremnes R, Kaasa S, et al: Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small cell lung cancer: Results from a randomized phase III trial with 5 years' follow-up. J Clin Oncol 20 : 4665 -4672, 2002[Abstract/Free Full Text]

6. Neill H, Herndon J, Miller A, et al: Randomized phase III Intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B trial 9732. J Clin Oncol 23 : 3752 -3759, 2005[Abstract/Free Full Text]

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Related Correspondence

• Fractionated Administration of Irinotecan and Cisplatin in Japanese Patients With Extensive-Stage–Disease Small-Cell Lung Cancer
  Nagio Takigawa, Katsuyuki Kiura, Masahiro Tabata, and Mitsune Tanimoto
  JCO 2006 24: 5175 [Full Text]

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