|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 24, No 7 (March 1), 2006: pp. 1020-1022 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.9676
Scheduling of Radiation and Chemotherapy for Limited-Stage Small-Cell Lung Cancer: Repopulation As a Cause of Treatment Failure?Princess Margaret Hospital and University of Toronto, Toronto, Ontario, Canada The meta-analyst can cast a broad net to gain statistical power, possibly obtaining results clouded by the combining of heterogeneous trials, or can focus on more homogeneous data, thereby sacrificing power. In this issue, De Ruysscher et al1 have chosen the latter approach to test the plausible hypothesis that initial chemotherapy or protracted radiotherapy can trigger repopulation of surviving cells in limited-stage small-cell lung cancer (LSCLC), thus decreasing the effectiveness of treatment. Repopulation of cells in critical normal tissues between individual dose fractions of either radiotherapy or chemotherapy is important for recovery or retention of normal organ function, thereby improving tolerance to treatment. Thus, a schedule of radiotherapy administered over 6 to 7 weeks leads to less normal tissue reaction than a similar total dose administered over a shorter time, and the kinetics of repopulation in the bone marrow allow repetitive scheduling of cycle-active chemotherapy at approximately 3-week intervals. However, repopulation of surviving tumor cells also occurs between dose fractions of either radiation or chemotherapy and effectively decreases tumor-cell kill (Fig 1). 2,3 There is evidence in several tumor types for an increase in the rate of repopulation during the latter part of a course of radiation treatment, which is an effect long recognized as a mechanism of clinically significant resistance to treatment.4 There are few data on the role of repopulation in the longer intervals between cycles of chemotherapy, but accelerating repopulation probably occurs and can lead to clinical resistance, even if there is no change in the inherent sensitivity of the cancer cells.2
To test their hypothesis that initial treatment triggers repopulation, De Ruysscher et al1 calculated the start of any treatment to end of radiation therapy (SER) for the study arms in four published randomized trials of LSCLC. Studies were selected that reported at least 5 years of follow-up and that evaluated regimens using cisplatin-based chemotherapy and continuous radiation schedules of varying duration and timing.5-8 A shorter SER was found to be associated with better long-term survival, such that a survival decrement of approximately 1.8% per week occurred when SER was extended beyond 3 weeks. A notable exclusion from the analysis is a large trial performed in the United Kingdom, which has been reported only in abstract form9; presumably, this trial was excluded because 5-year survival was not reported. Early data from this trial do not demonstrate differences in survival at 3 years in relation to SER. However, the rather low reported median survival rates raise the possibility of inclusion of relatively poor prognosis patients. For radiation to influence survival of patients with LSCLC, it must presumably improve local control of gross disease, thereby preventing or delaying subsequent metastasis. Thus, an unexpected conclusion of the analysis by De Ruysscher et al1 is a significant association between SER and long-term survival, without a significant association between SER and local control. The authors are probably correct in attributing this anomaly to difficulties in the assessment of local failure in LSCLC. Residual disease can be difficult to distinguish from post-treatment fibrosis, and in the Intergroup study,7 patients who were coded as partial responders were just as likely to live 5 years as complete responders in the accelerated fractionation arm. Current estimates of local failure rates for the two arms of this trial are approximately 15% for accelerated radiotherapy compared with approximately 40% for conventional fractionation (A. Turrisi, personal communication, November 2005), instead of the published estimates of 36% and 52%, respectively.7 A major implication of the analysis of De Ruysscher et al1 is that repopulation of clonogenic tumor cells triggered by neoadjuvant chemotherapy inhibits the effectiveness of subsequent radiotherapy and, thus, contributes to treatment failure in LSCLC. This effect is illustrated in Figure 1.3 Therefore, limiting tumor-cell repopulation might improve outcome. One strategy is to minimize SER by delivering radiation early in the course of treatment using an accelerated fractionation schedule, as evaluated in the trials that were reviewed. However, this strategy also leads to increased toxicity; the hazard ratio for survival estimated by De Ruysscher et al1 from using regimens with short (compared with longer) SER was 0.62, whereas for severe acute esophagitis, it was 0.55. Thus, there is no evidence of improvement in therapeutic index; rather, improved survival was gained at the expense of greater toxicity. Whether a regimen using a higher dose of conventionally fractionated radiotherapy could reduce acute toxicity while maintaining a similar survival advantage is a key question that has not yet been addressed by randomized studies. Regardless, the increased acute toxicity that accompanies altered radiation fractionation or concurrent chemotherapy/radiotherapy regimens delivered with curative intent has been widely accepted in a number of other tumor sites (eg, head and neck, esophagus, and cervical cancers). It also seems likely that integration of modern radiotherapy planning and delivery techniques, such as intensity modulation and adaptive image-guided approaches,10 will reduce toxicity and allow application of accelerated treatment regimens in a larger proportion of patients with LSCLC. An ideal therapeutic strategy for targeting repopulation would involve selective inhibition of proliferation of tumor cells during treatment, with less or no inhibition of repopulation in critical normal tissues. There are promising examples of such strategies. Signaling through the epidermal growth factor receptor may be a mediator of accelerated repopulation in squamous cell cancer of the head and neck,11 and concurrent use of cetuximab with radiation therapy has improved survival for patients with this disease.12 Dose-dense chemotherapy, whereby the treatment interval is shortened with concurrent use of hematologic growth factors to stimulate repopulation of bone marrow, has led to improved survival in breast cancer and lymphoma,13,14 although confirmatory trials are needed (and are in progress). There are molecular perturbations that may provide targets for novel therapies directed toward selective inhibition of repopulation in SCLC, but two recent clinical trials illustrate the difficulty in selecting targets in SCLC; imatinib failed to provide clinical benefit for patients with metastatic SCLC overexpressing c-kit, despite promising preclinical data.15,16 Study of drug scheduling in such strategies will be crucial to avoid interference with conventional treatments while reducing repopulation. The analysis presented by De Ruysscher et al1 is consistent with the hypothesis that neoadjuvant chemotherapy may induce resistance to subsequent radiation through repopulation in LSCLC but does not provide proof. The analysis encourages further research in which cytostatic agents capable of targeting repopulation in LSCLC are combined with existing therapies. The analysis is perhaps most important in drawing attention to repopulation as a potential cause of treatment failure. Although this has been recognized for a long time by radiation oncologists, repopulation between courses of chemotherapy may be equally or more important as a cause of clinical drug resistance. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. Author Contributions
REFERENCES
1. De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al: Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol 24:1052-1056, 2006 2. Kim JJ, Tannock IF: Repopulation of cancer cells during therapy: An important cause of treatment failure. Nat Rev Cancer 5:516-525, 2005[CrossRef][Medline] 3. Tannock IF: Treatment of cancer with radiation and drugs. J Clin Oncol 14:3156-3174, 1996[Abstract] 4. Withers HR, Taylor JM, Maciejewski B: The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 27:131-146, 1988[Medline] 5. Murray N, Coy P, Pater JL, et al: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer: The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11:336-344, 1993 6. Jeremic B, Shibamoto Y, Acimovic L, et al: Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small-cell lung cancer: A randomized study. J Clin Oncol 15:893-900, 1997 7. Turrisi AT, Kim K, Blum R, et al: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340:265-271, 1999 8. Takada M, Fukuoka M, Kawahara M, et al: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: Results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 20:3054-3060, 2002 9. James L, Spiro S, O'Donnell, KM, et al: A randomized study of timing of thoracic irradiation in small cell lung cancer (SCLC): Study 8. Lung Cancer 41(suppl 2):S23, 2003 10. Jaffray DA: Emergent technologies for 3-dimensional image-guided radiation delivery. Semin Radiat Oncol 15:208-216, 2005[CrossRef][Medline] 11. Bentzen SM, Atasoy BM, Daley FM, et al: Epidermal growth factor receptor expression in pretreatment biopsies from head and neck squamous cell carcinoma as a predictive factor for a benefit from accelerated radiation therapy in a randomized controlled trial. J Clin Oncol 23:5560-5567, 2005 12. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for locoregionally advanced squamous cell carcinoma of head and neck. N Engl J Med (in press) 13. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431-1439, 2003 14. Pfreundschuh M, Trumper L, Kloess M, et al: Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: Results of the NHL-B1 trial of the DSHNHL. Blood 104:626-633, 2004 15. Dy GK, Miller AA, Mandrekar SJ, et al: A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: A CALGB and NCCTG study. Ann Oncol 16:1811-1816, 2005 16. Krug LM, Crapanzano JP, Azzoli CG, et al: Imatinib mesylate lacks activity in small cell lung carcinoma expressing c-kit protein: A phase II clinical trial. Cancer 103:2128-2131, 2005[CrossRef][Medline]
Related Article
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
