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© 2002 American Society for Clinical Oncology
Small-Cell Lung Cancer, High Growth Rate, High Response Rate to Chemotherapy: Ideal for High-Dose Chemotherapy?Guy’s Hospital, London, United Kingdom SMALL-CELL lung cancer (SCLC) provides clinicians with a paradox. The majority of patients respond to chemotherapy, but such responses are of relatively short duration and overall survival has not significantly increased over the last two decades. There is a pressing need for new approaches; one of those studied has been dose-intensive chemotherapy. The concept of dose-response is well established in tumors associated with a high fraction of dividing cells, and the biology of SCLC makes this an appropriate group in which to study this hypothesis. Dose-intensity may be defined as dose per meter squared per week.1 This can be increased either by increasing the dose or by shortening the interval between cycles (dose-density). In this issue of the Journal of Clinical Oncology, Ardizzoni et al2 present a prospective multicenter phase III study performed by the European Organization for Research and Treatment of Cancer Lung Cancer Study Group. It is the first study to examine the impact on overall survival of increasing both the dose and dose-density. Two hundred forty-four chemotherapy-naive patients with limited or extensive SCLC and a performance score of 0 or 1 were randomized to standard cyclophosphamide, doxorubicin, and etoposide (CDE) or intensified CDE with granulocyte colony-stimulating factor support. By increasing the dose by 25%, and the dose-density by 33%, a 90% increase of the dose-intensity was planned. In fact, a 70% increase in the dose-intensity was achieved, a reasonable outcome. Overall there was no statistically significant difference in response rate (79% v 84%), median survival (54 v 52 weeks), or 2-year survival rates (15% v 18%) between the standard and the high-dose arms. The sample size of this study was planned to reliably detect a 50% increase in median survival; clearly this was not achieved. A 2 x 2 factorial design was also used to test the use of prophylactic antibiotics. Relatively small numbers became smaller. Nevertheless this was a well-designed trial that produced a negative result. How does this complement the literature to date? Fifteen years ago we summarized the data available at that time.3 Despite the well-recognized bias against the publication of negative studies, similar negative results have been reported by other groups. The Southeast Cancer Study Group compared the standard dose of cyclophosphamide, doxorubicin, and vincristine (CAV) with a higher dose of CAV in 298 patients with extensive SCLC.4 Although the high-dose arm had higher response rates, this did not translate to a significant improvement in median survival (29.3 v 35.7 weeks) or 1-year survival (20% in both arms). Furthermore, the high-dose arm was more toxic. Almost identical results have been presented by Ihde et al.5 Ninety patients with extensive disease were randomized to receive either standard-dose or higher-dose cisplatin and etoposide. Despite the small size of the study, the authors concluded that a dose escalation of 67% in the first two cycles was associated with worse toxicity and no therapeutic benefit. Other trials have reported similar results.6-8 These results are in contrast with a study performed by Arriagada et al.9 This trial was in patients with limited SCLC. One hundred five patients, with an initial Karnofsky score greater than 60 (in fact, 75% had a Karnofsky score > 90), were randomized to receive a standard dose of cisplatin, cyclophosphamide, doxorubicin, and etoposide or the same regimen with a 20% increase of cisplatin and a 25% increase of the cyclophosphamide dose for the first cycle only. This relatively minor dose escalation resulted in a statistically significant survival benefit (2-year survival rate 43% in the high-dose arm v 26% in the standard arm). However, the question is whether this study tested "insufficient" against "sufficient" chemotherapy. Dose-intensity can also be achieved by increasing the dose-density alone. Steward et al10 increased dose-density by reducing the interval between the cycles from 4 to 3 weeks. Three hundred patients with "good" or "intermediate" prognosis disease were randomized to receive either three or four weekly treatments with ifosfamide, carboplatin, etoposide, and vincristine. There was a significant improvement in the clinical outcome (median survival 443 v 351 days and 2-year survival rates 33% v 18%, both in favor of the three-weekly-treatments arm) but no significant difference in toxicity. Similar conclusions were reported by a Medical Research Council trial, in which 403 patients with limited or extensive disease were randomized to receive six cycles of doxorubicin, cyclophosphamide, and etoposide, in two or three weekly treatments.11 In this trial, there was an escalation of dose-intensity by 50%. The survival was significantly longer in the intensified arm (1-year survival was 47% v 39% and 2-year survival was 13% v 8%). Although the survival benefit was small, this was not associated with a decrease in quality of life in the experimental arm. On the other hand, a randomized trial of 233 patients, by Sculier et al,12 did not show a survival advantage by increasing dose-density. Have we reached the end of the road of dose intensification in SCLC? The evidence from other solid tumors would suggest we have.13,14 Nevertheless, one has to question the methodologies of some of the trials. Ardizzoni et al2 sought a 50% improvement in survival by increasing dose-intensity. Would a lesser level of benefit be of interest to our patients or to the oncologic community? What degree of benefit is acceptable to justify the toxicity and the cost of this approach? Would attempting to increase the survival at 18 months or 2 years by five- or 10-fold be acceptable, even if median survival was not improved? Are we missing potential benefits by inappropriate patient selection? Are we diluting the results by including all (extensive disease and limited disease) patients with SCLC? Is it reasonable to use traditional staging methods defining limited disease or extensive disease or even good performance score, good prognosis, or intermediate prognosis, as entry criteria? Are we going to see greater benefit by determining the molecular profile of these tumors? Will pharmacogenomics enable us to move forward and generate molecular criteria for individualized chemotherapy? Certainly, in non–small-cell lung cancer the work by Rosell et al15-17 on oncogenomics does seem to show that some subgroup of patients benefit to a greater level. That the dose-intensity trials to date do not consistently show the degree of benefit that most of us could find acceptable is not a reason for abandoning dose intensification forever. The new agents targeting specific sites in tumorigenesis (epidermal growth factor receptor antagonists, tyrosine kinase inhibitors, antiagiogenic agents, monoclonal antibodies) are now being used. The integration of these agents into research protocols may be the most appropriate way of shifting the survival of patients with SCLC. It is clear that additional, well-designed, well-sized trials are needed. REFERENCES 1. Hryniuk W, Bush H: The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol 2: 1281-1288, 1984[Medline]
2. 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 3. Harper PG, Souhami RL: Intensive chemotherapy with autologous bone marrow transplantation in small cell carcinoma of the lung. Recent Results Cancer Res 97: 146-156, 1985[Medline]
4. Johnson DH, Einhorn LH, Birch R, et al: A randomized comparison of high-dose versus conventional-dose cyclophosphamide, doxorubicin, and vincristine for extensive-stage small-cell lung cancer: A phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 5: 1731-1738, 1987
5. Ihde DC, Mulshine JL, Kramer BS, et al: Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol 12: 2022-2034, 1994 6. Figueredo AT, Hryniuk WM, Strautmanis I, et al: Co-trimoxazole prophylaxis during high-dose chemotherapy of small-cell lung cancer. J Clin Oncol 3: 54-64, 1985[Abstract]
7. Pujol JL, Douillard JY, Riviere A, et al: Dose-intensity of a four-drug chemotherapy regimen with or without recombinant human granulocyte-macrophage colony-stimulating factor in extensive-stage small-cell lung cancer: A multicenter randomized phase III study. J Clin Oncol 15: 2082-2089, 1997 8. Hong WK, Nicaise C, Lawson R, et al: Etoposide combined with cyclophosphamide plus vincristine compared with doxorubicin plus cyclophosphamide plus vincristine and with high-dose cyclophosphamide plus vincristine in the treatment of small-cell carcinoma of the lung: A randomized trial of the Bristol Lung Cancer Study Group. J Clin Oncol 7: 450-456, 1989[Abstract]
9. Arriagada R, Le Chevalier T, Pignon JP, et al: Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 329: 1848-1852, 1993 10. 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]
11. 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—Medical Research Council Lung Cancer Working Party. J Clin Oncol 18: 395-404, 2000 12. Sculier JP, Paesmans M, Lecomte J, et al: A three-arm phase III randomised trial assessing, in patients with extensive-disease small-cell lung cancer, accelerated chemotherapy with support of haematological growth factor or oral antibiotics. Br J Cancer 85: 1444-1451, 2001[CrossRef][Medline]
13. Hortobagyi GN: High-dose chemotherapy for primary breast cancer: Facts versus anecdotes. J Clin Oncol 17: 25-29, 1999
14. Schrama JG, Faneyte IF, Schornagel JH, et al: Randomized trial of high-dose chemotherapy and hematopoietic progenitor-cell support in operable breast cancer with extensive lymph node involvement: Final analysis with 7 years of follow-up. Ann Oncol 13: 689-698, 2002 15. Rosell R, Monzo M, O’Brate A, et al: Translational oncogenomics: Toward rational therapeutic decision-making. Curr Opin Oncol 14: 171-179, 2002[CrossRef][Medline] 16. Rosell R, Monzo M, Alberola V, et al: Determinants of response and resistance to cytotoxics. Semin Oncol 29: 110-118, 2002[CrossRef][Medline]
17. Lord RV, Brabender J, Gandara D, et al: Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non–small cell lung cancer. Clin Cancer Res 8: 2286-2291, 2002
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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