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© 2003 American Society for Clinical Oncology
Shorter is not BetterA. Prévost, Institut Jean-Godinot, Centre Régional de Lutte Contre le Cancer, Reims, France To the Editor: In their study, Ardizzoni et al1 compared in patients with small-cell lung carcinoma (SCLC) the standard CDE (cyclophosphamide, etoposide, and doxorubicin) protocol with an intensified version of this protocol without improvement of response rate or 2-year overall survival, despite a 70% increase in the actual dose-intensity. This increase in dose-intensity was performed by augmenting the doses of each drug of the chemotherapy regimen as well as by reducing intervals between cycles. However, with the purpose of delivering near-equivalent cumulative doses in standard and intensified treatments, the authors designed a trial comparing a control arm of five cycles of standard CDE given every 3 weeks, which had a theoretical duration of 15 weeks, with an experimental arm lasting only 8 weeks (four cycles every 2 weeks of intensified CDE). In a given neoplastic disease, the concept of dose-intensity needs to be tested with an estimation of the threshold level on the dose-response curve for each drug (to avoid comparing insufficient with sufficient chemotherapy) and of the ideal overall duration of the treatment course, which is not synonym of ideal cumulative dose. We can assume that the standard CDE protocol has delivered doses of each drug that were close to their threshold level, but we would like to discuss the issue of treatment duration, which has been pointed out neither by the authors nor by the accompanying editorial.2 Although it is widely accepted in many neoplastic diseases that chemotherapy should last between 4 and 6 months, optimal duration of chemotherapy in SCLC has not been clearly established. Neither extending the initial treatment beyond the median number of six cycles of chemotherapy nor maintenance treatment have so far resulted in increase in survival.3 But is shorter-term treatment better with equivalent cumulative doses? Can we expect obtaining long-lasting responses with a 2-month protocol, whatever its cumulative dose can be? Except for the study of Ardizzoni et al,1 duration of chemotherapy of no less than 4 months has been the rule even in intensified protocols,4 and thus, arguments are also converging for a chemotherapy no longer than 6 months but also no shorter than 4 months. Lessons drawn from other cancers can also be integrated in this discussion. In breast cancer it has been shown that 12 weeks of conventional adjuvant chemotherapy did worse than 36 weeks of treatment.5 In poor prognosis high-grade non-Hodgkin’s lymphoma (NHL), shortened high-dose chemotherapy has been tested in first-line therapy in a large randomized trial against standard treatment: The 2-month investigational regimen including high-dose chemotherapy with autologous stem-cell support was associated with a 5-year overall survival 15% lower than the 6-month control arm.6 Growth rate and immediate chemosensitivity of SCLC resemble that of NHL, but relapses after major responses are much more frequent in SCLC, and it is conceivable that if shortened chemotherapy, even at maximal tolerated doses, is insufficient in NHL, such strategies cannot be applied to SCLC. Thus, if the trial of Ardizzoni et al1 indicates that dose intensification over a short duration cannot yield a 50% improvement in survival, it does not mean that cytotoxic drugs given above their threshold level with acceptable toxicity (as can be achieved with the support of hematopoietic growth factors) for a sufficient duration of time are not better than nonaggressive therapy such as CDE. In this study, shorter was not worse, but a 2-month chemotherapy may have missed the benefit of intensified CDE with an acceptable tolerance. If we still believe that SCLC, a disease with high growth rate and high response rate to chemotherapy, should benefit from further investigation of the concept of dose-intensity, we need to compare active standard regimens to intensified protocols without compromise on therapy duration, keeping in mind that SCLC are associated with high incidence of second primary malignancies.7 REFERENCES
1. Ardizzoni A, Tjan-Heijnen VCG, Postmus PE, et al: Standard versus intensified chemotherapy with granulocyte colony-stimulating factor support in small-cell lung cancer: A prospective European Organization for Research and Treatment of Cancer-Lung Cancer Group phase III trial-08923. J Clin Oncol 20:3947–3955, 2002
2. Galani E, Ellis PA, Harper PG: Small-cell lung cancer, high growth rate, high responses rate to chemotherapy: ideal for high-dose chemotherapy? J Clin Oncol 20:3941–3942, 2002 3. Schuette W: Chemotherapy as treatment of primary and recurrent small cell lung cancer. Lung Cancer 33:99–107, 2001[CrossRef][Medline] 4. Steward WP, von Pawel J, Gatzemeier U, et al: Effects of granulocyte-macrophage colony-stimulating factor and dose intensification of V-ICE chemotherapy in small-cell lung cancer: A prospective randomized study of 300 patients. J Clin Oncol 16:642–650, 1998[Abstract] 5. Levine MN, Gent M, Hryniuk WM, et al: A randomized trial comparing 12 weeks versus 36 weeks of adjuvant chemotherapy in stage II breast cancer. J Clin Oncol 8:1217–1225, 1990[Abstract]
6. Gisselbrecht C, Lepage E, Molina T, et al: Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 20:642–650, 2002
7. Sagman U, Lishner M, Maki E, et al: Second primary malignancies following diagnosis of small-cell lung cancer. J Clin Oncol 10:1525–1533, 1992
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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