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© 1999 American Society for Clinical Oncology
Increased Dose-Intensity in Small-Cell Lung Cancer: A Failed Strategy?Division of Hematology and Oncology, Department of Medicine, Vanderbilt University School of Medicine, The Vanderbilt-Ingram Cancer Center, Nashville, TN I HAVE NOT failed. I've just found 10,000 ways that won't work. —Thomas Edison For several decades, dating back to the pioneering work of Schabel et al,1 the concepts of dose response and dose escalation have greatly influenced the thought processes of oncologists. These scientists noted improved cure rates in mice bearing chemosensitive neoplasms and given increasing doses of active drugs. Much of their early work became a how-to manual for clinical investigators planning experimental studies in humans. The principles espoused in their publications are sound and eminently understandable—more seems better. Other thoughtful investigators helped refine these concepts by clarifying the importance of dose-intensity, ie, the amount of drug delivered per unit of time2 and the relevance of tumor growth kinetics.3,4 A particularly appealing aspect of these principles is their immediate applicability to the clinic. One does not need to fully understand the intricacies of tumor biology to put these ideas into practice. Although there are many solid tumors in which one might attempt to exploit the principles of dose escalation and dose-intensity, none is more appealing than small-cell lung cancer (SCLC). SCLC is a highly responsive neoplasm sensitive to a broad spectrum of antineoplastic agents with varying mechanisms of action. In keeping with the preclinical models of Schabel et al, combination chemotherapy can effect increased complete and overall response rates in this disease, and overall survival is improved. Even more satisfying, there seems to be a dose response to some agents, according to early human studies.5 These observations prompted investigators to continue dose escalation trials in hopes that the results achieved in the preclinical studies of Schabel et al would be recapitulated in the clinic. However, to date, all such attempts have failed, even though in some instances higher complete remission rates have been achieved.6-8 Of note, the failure of higher complete response rates to translate into a better survival also could be predicted by the work of Schabel et al.1 The lack of good outcome in SCLC relates in part to another basic principle of combination chemotherapy, ie, each active drug should be used at its maximum effective dose.9 Because of overlapping toxicities, this is not always possible, even in this era of hematopoietic growth factor support. In the aforementioned dose escalation trials, toxicity was inevitably dose limiting in some manner. Even today, as we attempt to incorporate newer and presumably more active agents into combination regimens, the dose of one or all of the agents is often reduced. This is potentially problematic, as outlined in another classic article by Goldie and Coldman published some 15 years ago.10 They warned that even a slight reduction in the effective dose of an agent would reduce the fractional cell kill and raise the mutational rate to resistance for that particular drug. At some point, they admonished, this strategy becomes self-defeating. Once again, this concept is well illustrated in the mouse tumor models of Schabel et al, who found that a dose reduction of just 20% can result in cure rates that decrease as much as 50%.1 Given this dilemma, how can one maintain optimal dosing and simultaneously avoid unacceptable host toxicity? Norton11 has popularized the concept of "dose-dense" chemotherapy, ie, administering multiple cycles of escalated dose chemotherapy at short intervals. When administering drugs with overlapping toxicities, dose density can be increased by administering the agents sequentially. Among the first to use this strategy in SCLC were investigators at the British Columbia Cancer Agency. In 1991, Murray et al12 published the results of a pilot trial in which four active agents (cisplatin, vincristine, doxorubicin, and etoposide [CODE]) were administered using a weekly schedule with appropriate supportive measures. Myelosuppressive drugs were alternated with nonmyelosuppressive drugs. Eligibility was confined to extensive-stage patients younger than 66 years of age and included subjects with pleural effusions as their sole site of disease. These selection criteria resulted in a prognostically favorable study population. Nevertheless, the reported median survival time of 61 weeks and the 2-year survival rate of 30% were impressive and far in excess of what had previously been reported in extensive-stage SCLC.12 However, then, as now, there were reasons to be wary of these results. If as postulated by Hryniuk and others,2,9 scheduling of drugs is more relevant to toxicity and not so much related to treatment outcome, how could such a relatively minor change in drug scheduling result in so dramatic a change in survival? Presumably the answer lies in the principles underlying the notion of dose-intensity or dose density. To validate their results, the authors recommended a confirmatory randomized study comparing CODE to standard every-3-weeks chemotherapy. In this issue of the Journal of Clinical Oncology, Murray et al present the results of the proposed phase III trial conducted jointly by the National Cancer Institute of Canada (NCIC) and the Southwest Oncology Group (SWOG).13 Unfortunately, CODE proved no more effective than standard chemotherapy and was much more toxic, with a treatment-related fatality rate of 8% compared with a more acceptable 1% rate in the standard arm. This level of fatal toxicity is even more disturbing when one realizes that 90% of patients had a performance status of 0 or 1. On the basis of the level of lethal toxicity observed, a data-monitoring and safety committee appropriately recommended early stoppage of the study before the intended accrual goal could be met. The NCIC-SWOG study is actually one of several randomized trials comparing weekly therapy to every-3-weeks standard therapy.13-15 All results have been negative. While some experts may opine that the addition of granulocyte colony-stimulating factor could have reduced the incidence of neutropenia-related toxicity in the CODE trial, it is highly doubtful this strategy would have had a favorable impact on survival outcome.16 Thus, we can conclude that weekly therapy with the regimens used in these trials is of no value in extensive-stage SCLC. Where does this leave us vis-à-vis dose-intense chemotherapy for SCLC? Is this a failed strategy? Perhaps we have selected the wrong human "model" in which to test the concept. For example, it might be more appropriate to assess dose-intensity strategies in limited-stage SCLC patients. Here the tumor burden is somewhat less and presumably more amenable to the putative advantages of dose-intensity. There are tantalizing hints that such may be the case.17 Perhaps we need to spend more time rethinking the notion of drug scheduling as well. Changing the manner in which a drug is administered not only influences a drug's toxicity profile but may also have an impact on its mechanism of action, as illustrated by the common agents fluorouracil and paclitaxel.18,19 Clearly, the availability of several new agents with unique mechanisms of action means there will be numerous pilot trials forthcoming to test the impact of their inclusion in new regimens. However, it seems highly improbable that these traditional approaches will prove any more successful than past efforts. In our view, major improvements in therapeutic outcome are more likely to come from efforts designed to exploit the underlying biology of the malignancy. Combinations of maximally effective chemotherapy with antiangiogenic agents, such as antibodies to vascular endothelial growth factor (VEGF) or VEGF receptor tyrosine kinase inhibitors, hold real promise for therapeutic improvements. Molecular abnormalities in genes such as p53, Rb, and bcl-2 are commonplace in SCLC and may serve as additional targets for innovative therapies. For example, antisense strategies targeting bcl-2 in SCLC have shown intriguing results in vitro20 and are being tested in vivo. Overexpression of antigens, such as P53 and NY-ESO-1, and of gangliosides suggests that immunotherapy strategies also may play a meaningful role in SCLC treatment. Indeed, based on encouraging phase II results,21 a multicenter, randomized trial of chemotherapy followed by ganglioside-directed immunotherapy is underway. As we await the results of innovative treatment approaches, what should we recommend for our extensive-stage SCLC patients? We continue to believe the chemotherapy regimen of choice is a platinum agent (cisplatin or carboplatin) plus etoposide. To date, no regimen has yielded superior efficacy, nor has any been found to possess a truly superior toxicity profile compared with this combination. Furthermore, the regimen can be administered without the need for hematopoietic growth factors and with little nonhematologic toxicity.8,22 This is especially true if treatment is limited to no more than four to six cycles. Sadly, the overall survival in extensive-stage SCLC has improved little, if at all, during the past 10 to 15 years.23 We must continue efforts to design, implement, and complete relevant comparative trials. It is only through carefully executed studies, such as the one carried out by the NCIC and SWOG, that will we identify the best treatment for our patients. Though this be madness, yet there is method in 't. —William Shakespeare, Hamlet, Act II, Sc. ii REFERENCES 1. Schabel FM, Griswold DP, Corbett TH, et al: Testing therapeutic hypotheses in mice and man: Observations on the therapeutic activity against advanced solid tumors of mice treated with anticancer drugs that have demonstrated or potential clinical utility for treatment of advanced solid tumors in man, in DeVita VT, Busch H (eds): Methods in Cancer Research: Cancer Drug Development Part B. New York, NY, Academic Press, Inc, 1979, pp 4-52 2. Hryniuk WM: The importance of dose intensity in the outcome of chemotherapy. Important Adv Oncol 121-141, 1988 3. DeVita VT: The James Ewing Lecture: The relationship between tumor mass and resistance to chemotherapy—Implications for surgical adjuvant treatment of cancer. Cancer51:1207-1220, 1983 4. Gilewski T, Norton L: Cytokinetics and breast cancer chemotherapy, in Harris JR, Morrow M, Lippman ME, et al (eds): Disease of the Breast. Philadelphia, PA, Lippincott-Raven, 1996, pp 751-768 5. Cohen MH, Creaven PJ, Fossieck BE, et al: Intensive chemotherapy of small cell bronchogenic carcinoma. Cancer Treatment Rep61:349-354, 1977[Medline] 6. Figueredo AT, Hryniuk WM, Strautmanis I, et al: Co-trimoxazole prophylaxis during high-dose chemotherapy of small cell lung cancer. J Clin Oncol3:54-64, 1985[Abstract]
7.
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 Oncol5:1731-1738, 1987
8.
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 Oncol12:2022-2034, 1994 9. DeVita VT: Principles of cancer management: Chemotherapy, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles & Practice of Oncology (ed 5). Philadelphia, PA, Lippincott-Raven, 1997, pp 333-347
10.
Goldie JH, Coldman AJ: The genetic origin of drug resistance in neoplasms: Implications for systemic therapy. Cancer Res44:3643-3653, 1984 11. Norton L: Evolving concepts in the systemic drug therapy of breast cancer. Semin Oncol 24:S10-13, 1997 12. Murray N, Shah A, Osoba D, et al: Intensive weekly chemotherapy for the treatment of extensive-stage small cell lung cancer. J Clin Oncol9:1632-1638, 1991[Abstract]
13.
Murray N, Livingston RB, Shepherd FA, et al: Randomized study of CODE versus alternating CAV/EP for extensive-stage small- cell lung cancer: An Intergroup study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group. J Clin Oncol17:2300-2308, 1999
14.
Sculier JP, Paesmans M, Bureau G, et al: Multiple drug weekly chemotherapy versus combination regimen in small cell lung cancer: A phase III randomized study conducted by the European Lung Cancer Working Party. J Clin Oncol11:1858-1865, 1993
15.
Souhami RL, Rudd R, Ruiz de Elvira M-Cet al: Randomized trial comparing weekly versus 3-week chemotherapy in small cell lung cancer: A Cancer Research Campaign trial. J Clin Oncol12:1806-1813, 1994 16. Furuse K, Fukuoka M, Nishiwaki Y, et al: Phase III study of intensive weekly chemotherapy with recombinant human granulocyte colony-stimulating factor versus standard chemotherapy in extensive-disease small-cell lung cancer: The Japan Clinical Oncology Group. J Clin Oncol16:2126-2132, 1998[Abstract]
17.
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 Med329:1848-1852, 1993
18.
Sobrero AF, Aschele C, Bertino JR: Fluorouracil in colorectal cancer: A tale of two drugs—implications for biochemical modulation. J Clin Oncol15:368-381, 1997 19. Belotti D, Vergani V, Drudis T, et al: The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer Res2:1843-1849, 1996[Abstract]
20.
Ziegler A, Luedke GH, Fabbro D, et al: Induction of apoptosis in small-cell lung cancer cells by an antisense oligodeoxynucleotide targeting the Bcl-2 coding sequence [see comments]. J Natl Cancer Inst89:1027-1036, 1997
21.
Grant SG, Kris MG, Houghton AN, et al: Long survival of patients with small cell lung cancer after adjuvant treatment with the anti-idiotype antibody BEC2 plus Bacillus Calmette-Guerin. Clin Cancer Res5:1319-1324, 1999
22.
Bunn PA Jr, Crowley J, Kelly K, et al: Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: A prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol13:1632-1641, 1995 (erratum appears in J Clin Oncol 13:2860, 1995)
23.
Aisner J: Extensive-disease small cell lung cancer: The thrill of victory; the agony of defeat. J Clin Oncol14:658-665, 1996 This article has been cited by other articles:
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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