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© 2002 American Society for Clinical Oncology
The Early Rad Catches the Tumor?University of Pennsylvania Medical Center, Philadelphia, PA TAKADA ET AL,1 as well as the entire Japan Clinical Oncology Group (JCOG), should be congratulated on completing this important randomized trial comparing early concurrent versus delayed sequential radiotherapy in limited-stage small-cell lung cancer. There have been multiple randomized studies addressing the issue of the timing of radiotherapy, not including several studies examining alternating schedules of chemotherapy and radiotherapy. Two trials demonstrate a statistically significant advantage to early concurrent therapy,2,3 one (the current Takada article) shows a strong trend toward better outcome with early concurrent therapy,1 and three reveal no advantage to early radiotherapy.4-6 Is a meta-analysis far behind? A careful look at all of these important trials (Table 1) can only lead to the conclusion that a meta-analysis would be wholly inappropriate, because the methodologies of the studies differ greatly. Viewed in retrospect, none of these studies have an optimal design.
The JCOG trial used a maximally intensive radiation dose-fractionation schedule (45 Gy in 1.5 Gy bid fractionation over 3 weeks) in both arms. The randomization was between early concurrent (radiation with the first cycle of chemotherapy) versus delayed sequential therapy (radiation after the fourth cycle of chemotherapy). However, as discussed by the authors, there was a second important difference between the arms: in the early concurrent arm, the chemotherapy was given at 4-weekly intervals, compared with the more traditional 3-weekly intervals used in the sequential arm. The use of 4-weekly chemotherapy intervals might explain the modest rate of severe toxicity in the concurrent arm, with a 9% rate of grade 3 to 4 esophagitis but may also be a clinically significant decrease in chemotherapy dose-intensity. Perhaps this explains the failure of the study to achieve statistical significance. The JCOG study1 and the National Cancer Institute of Canada study by Murray et al2 share a very interesting finding, namely that early concurrent therapy seems to reduce the risk of brain metastases as first failure. In contrast, neither study showed a significant impact of the timing of radiotherapy on local control. It is possible, as noted by the authors, that local control might actually be better in the concurrent arm, but available imaging technology is simply not accurate enough to quantitatively assess local control. However, even if occult local failures explain the results, the data still support the hypothesis that a local modality can influence the rate of distant metastases. The outcomes of these studies, furthermore, indirectly support the view that the brain is a sanctuary site for small-cell lung carcinoma, better managed with radiotherapy than with a more intensive chemotherapy schema. Another important finding from the JCOG trial is that the outcome in both arms was significantly better than expected. The trial design anticipated an increase in median survival from 12 to 18 months with early concurrent therapy. Actual results showed an increase from 19.7 to 27.2 months. Although the absolute magnitude of the difference was similar to that expected, the difference was not statistically significant, in part because of the sample size of 231 patients. The JCOG trial was thus underpowered to detect a clinically relevant difference in survival based on the timing of radiation, a common problem in limited-stage small-cell trials. Nonetheless, the statistically insignificant outcome of this trial reaffirms the importance of randomized clinical trials in oncology. As this trial demonstrated, the use of historical controls for survival is hazardous in this era of rapid changes in techniques of staging, supportive care, and even salvage therapies. As noted above, the rate of severe esophageal toxicity in the JCOG trial was a modest 9%, which is markedly lower than the 27% rate seen in the United States Intergroup study of accelerated radiation with chemotherapy.7 This is not explained by a difference in the toxicity grading scale because the Common Toxicity Criteria of the United States and the World Health Organization criteria are comparable. Could the difference be plausibly explained by the 4-weekly chemotherapy schedule? Were there subtle differences in radiation planning or delivery techniques that might have decreased esophagitis? Or are there features of Japanese patients’ esophageal mucosa or diet that lead to greater resistance to radiation injury? An alternative possibility might be cultural: could Japanese patients be more tolerant of or less likely to complain about significant side effects? Whatever the explanation, this issue definitely requires further study. The United States experience suggests that chemoradiation esophagitis and its con sequelae, such as malnutrition, dehydration, and treatment interruptions are a much bigger problem than the JCOG study would suggest. Some of the details of chemotherapy and radiotherapy from modern published randomized trials are shown in Table 1. An exhaustive review of all of the technical nuances of these studies is beyond the scope of this editorial, but several general principles emerge from reviewing these and other papers. The first is that the magnitude of any survival differences with respect to thoracic radiotherapy is small, but almost certainly clinically relevant. Second, the best results seen in large randomized trials for limited-stage small-cell lung cancer have been seen with early concurrent thoracic radiotherapy,1-3,7 particularly with hyperfractionated radiotherapy. Third, the definition of early remains controversial, but clearly means starting radiation therapy by the start of the fourth cycle of chemotherapy, and mandates concurrent, rather than sequential therapy. What questions should the major international cooperative groups answer next in limited-stage small-cell lung cancer? Because this disease seems to be less common than it used to be, it is most important to perform large-scale trials, to avoid underpowered studies. Second, as shown by the JCOG and other studies, the details of radiation therapy do seem to make a difference, both regarding treatment of the chest and the brain. Although there may still be a rationale for studying the timing of radiation, it is probably more appropriate to accept the usefulness of early thoracic irradiation and instead evaluate novel dose-fractionation schemes. For example, the Radiation Therapy Oncology Group (RTOG) is evaluating a concomitant boost accelerated thoracic radiotherapy schedule in a phase I/II trial, currently at 60+ Gy over 5 weeks. On a much larger scale, an international study comparing standard-dose prophylactic cranial irradiation (2.5 Gy x 10 fractions) versus increased-dose prophylactic cranial irradiation (2 Gy x 18 fractions or 1.5 Gy bid x 24 fractions) is underway and deserves the support of the world’s oncologic community. It is also important to integrate new imaging modalities, such as positron emission tomography scan, to assess tumor response after treatment.8 This may help clarify the role, if any, of maintenance therapy. Finally, it is critical to develop phase III studies that introduce new drugs into the treatment, both to improve therapy for small-cell cancer itself and to prevent second primary cancers, an emerging problem.9 At this time, unfortunately, there are no targeted or biologic therapies that appear ready for phase III testing in limited-stage disease. The conventional chemotherapy drug irinotecan (shown by the JCOG to improve survival in a modest-sized randomized trialin extensive-stage small-cell cancer10) is currently in phase I/II testing with platinum and radiation and requires rapid phase II/III assessment with radiotherapy. Perhaps we are only one or two drugs away from de-emphasizing, or even deposing, radiotherapy in limited-stage small-cell lung cancer. For now, though, thoughtfully planned and administered radiation therapy is an important contributor in the battle against this disease. REFERENCES
1. 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
2. Murray N, Coy P, Pater JL, et al: The importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer: The NCIC Clinical Trials Group. J Clin Oncol 11: 336-344, 1993
3. Jeremic B, Shibamoto Y, Acimovic L, et al: Initial versus delayed accelerated hyperractionated radiation therapy and concurrent chemotherapy in limited small cell lung cancer: a randomized study. J Clin Oncol 15: 893-900, 1997 4. Perry MC, Eaton WL, Propert KJ, et al: Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med 316: 912-918, 1987[Abstract]
5. Sklaros DV, Samantas E, Briassoulis E, et al: Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group. Ann Oncol 12: 1231-1238, 2001 6. Work E, Nielsen OS, Bentzen SM, et al: Randomized study of initial versus late chest irradiation combined with chemotherapy in limited-stage small-cell lung cancer: Aarhus Lung Cancer Group. J Clin Oncol 15: 3030-3037, 1997[Abstract]
7. Turrisi AT III, 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. Schumacher T, Brink I, Mix M, et al: FDG-PET imaging for the staging and follow-up of small cell lung cancer. Eur J Nucl Med 28: 483-488, 2001[CrossRef][Medline]
9. Heyne KH, Lippman SM, Lee JJ, et al: The incidence of second primary tumors in long-term survivors of small-cell lung cancer. J Clin Oncol 10: 1519-1524, 1994
10. Noda K, Nishiwaki Y, Kawahara M, et al: Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small cell lung cancer. N Engl J Med 346: 85-91, 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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