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In Reply:

Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

Dr Munck and Dr Prévost raise the concern that the lack of outcome differences in EORTC trial-08923 comparing intensified versus standard chemotherapy in small-cell lung carcinoma (SCLC) could be the result of an insufficient duration of chemotherapy in the intensified arm, counteracting a possible dose-intensity positive effect. Indeed, duration of chemotherapy in the intensified arm was 8 weeks versus 15 weeks in the standard dose-intensity arm.¹ The reasons for choosing a shorter chemotherapy duration in the intensified arm of this study were two-fold. First, we wanted to have the same total cumulative dose in both arms to tease out the real role of increasing dose-intensity by chemotherapy acceleration (shorter chemotherapy intervals) and dose-size increase. Second, in the pilot phase I and II studies performed earlier by our group to assess feasibility of such an intensified chemotherapy, accelerated chemotherapy, with or without dose size increase, led to a cumulative hematological toxicity (particularly thrombocytopenia and anemia), precluding the continuation of treatment beyond the fourth or fifth cycle.^2–4 Can this shorter chemotherapy duration be responsible for a worse outcome, therefore abolishing a possible benefit conferred by dose intensification? We believe it cannot. Optimal chemotherapy duration in SCLC is a controversial issue. Over 10 trials have been conducted on this subject, and most of them have shown no survival benefit with prolonged chemotherapy, although a time to progression prolongation has often been reported.⁵ Nevertheless, we agree with Drs Munck and Prévost that there is probably a "minimum duration" of chemotherapy under which treatment efficacy might be compromised. What the "minimum duration" is in the chemotherapy treatment of small-cell lung cancer (SCLC), however, has not yet been clearly defined. Contrary to what Drs Munck and Prevost suggest, there are data, in SCLC and other tumor types, indicating that a chemotherapy duration shorter than the usual 4 months may have similar efficacy. A British study compared six versus three courses of a standard chemotherapy regimen in patients with poor-risk SCLC, showing nondifference between standard duration and shorter chemotherapy in this group of patients.⁶ In the context of dose intensification, another British trial compared six courses of cyclofosfamide-doxorubicin-etoposide recycled every 3 weeks (15 weeks’ duration) versus six courses of the same regimen recycled every 2 weeks (10 weeks’ duration). As reported in the discussion of our article, this study showed a statistically significant survival prolongation in patients treated with the accelerated chemotherapy.⁷ In the context of other tumor types, a recent randomized study has shown superiority of accelerated chemotherapy in the adjuvant treatment of breast cancer.⁸

In conclusion, although we agree that duration of chemotherapy is an important factor in the treatment of SCLC and other tumor types, and that a minimum chemotherapy duration has to be given to achieve an optimal effect, this "minimum duration" has not yet been clearly defined, and the shorter chemotherapy duration used in the intensified arm of our study should have not compromised the effect of dose intensification. We still believe that, at this time, there is no sufficient evidence to justify the increase above the standard of chemotherapy dose-intensity in the standard management of SCLC.

REFERENCES

1. Ardizzoni A, Tjan-Heijnen VC, 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[Abstract/Free Full Text]

2. Ardizzoni A, Venturini M, Sertoli MR, et al: Granulocyte-macrophage colony stimulating factor (GM-CSF) allows acceleration and dose-intensity increase of CEF chemotherapy: A randomised study in patients with advanced breast cancer. Br J Cancer 69:385–391, 1994[Medline]

3. Ardizzoni A, Venturini M, Crinò L, et al: High dose-intensity chemotherapy, with accelerated cyclophosphamide-doxorubicin-etoposide and granulocyte-macrophage colony stimulating factor, in the treatment of small cell lung cancer. Eur J Cancer 29A:687–692, 1993[Medline]

4. Ardizzoni A, Pennucci MC, Danova M, et al: Phase I study of simultaneous dose-escalation and schedule-acceleration of cyclophosphamide-doxorubicin-etoposide using granulocyte colony stimulating factor with or without antimicrobial prophylaxis. Br J Cancer 74:1141–1147, 1996[Medline]

5. Ardizzoni A, Grossi F: Update on the treatment of small cell lung cancer (SCLC). Ann Oncol 11:101–108, 2000 (suppl 3)[Abstract/Free Full Text]

6. Bleehen NM, Girling DJ, Machin D, et al: A randomised trial of three or six courses of etoposide, cyclophosphamide, methotrexate and vincristine or six courses of etoposide and ifosfamide in small cell lung cancer (SCLC). I: Survival and prognostic factors. Medical Research Council Lung Cancer Working Party. Br J Cancer 68:1150–1156, 1993[Medline]

7. Thatcher N, Girling DJ, Hopwood P, et al: Improving survival without reducing quality of life in small-cell lung cancer patients by increasing the dose-intensity of chemotherapy with granulocyte colony-stimulating factor support: results of a British Medical Research Council Multicenter Randomized Trial. J Clin Oncol 18:395–404, 2000[Abstract/Free Full Text]

8. Citron M, Berny D, Cirrincione C, et al: Superiority of dose-dense over conventional scheduling and equivalence of sequential versus combination adjuvant chemotherapy for node positive breast cancer. CALGB 9741, INT c9741. Breast Cancer Res Treat 76:532, 2002 (suppl 1, abstr 15)

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