Correspondence

Radiotherapy for Small-Cell Lung Cancer

N Engl J Med 1999; 340:2002-2004June 24, 1999

Article

To the Editor:

In their study of the treatment of small-cell lung cancer with radiotherapy and concurrent cisplatin and etoposide, Turrisi et al. (Jan. 28 issue)1 concluded, “Twice-daily treatment significantly improved survival as compared with concurrent once-daily radiotherapy.” Some readers might take this to mean that twice-daily fractionation was superior to once-daily treatment for such patients. Nothing could be further from the truth. What was demonstrated in this study is that twice-daily treatment at doses that were barely tolerable (grade 3 esophagitis developed in 27 percent of these patients) were slightly more effective than what we know to be inadequate doses of once-daily therapy. An appropriate test of twice-daily fractionation would be to compare it with a tolerable total dose of 70 Gy delivered at 2 Gy per daily fraction,2 a dose approximately 50 percent higher than that used in the reported trial.

The results reported by Turrisi et al. do not mean that once-daily fractionation for limited small-cell lung cancer is obsolete. It is the current standard of practice and will continue to be the standard until proved otherwise in an appropriately designed clinical trial.

Rushdy Abadir, M.D.
Boone Hospital, Columbia, MO 65201

Colin Orton, Ph.D.
Wayne State University, Detroit, MI 48201

2 References

1
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 1999;340:265-271
Full Text | Web of Science | Medline

2
Choi NC, Herndon JE II, Rosenman J, et al. Phase I study to determine the maximum-tolerated dose of radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer. J Clin Oncol 1998;16:3528-3536
Web of Science | Medline

To the Editor:

Turrisi et al. gave no evidence that variables in radiation therapy were evenly distributed between the two treatment groups in their study, and some important information was not supplied.

The method of treatment planning (the technical design of the treatment) for lung cancer is critical and may affect the therapeutic ratio. The technique can be based on simple manual calculations or on more sophisticated, computerized techniques such as those used for three-dimensional conformal radiation therapy. The determination of dose-fractionation schedules would require some form of treatment planning, so it is necessary to have these details in a report of this type of trial.

John G. Armstrong, M.D.
St. Luke's Hospital, Dublin 6, Ireland

To the Editor:

Turrisi et al. state that prophylactic cranial irradiation was offered to patients who had a complete response to therapy, but they do not tell us how many patients in each group actually received it. Furthermore, to evaluate their results, it is important to know whether the groups were well balanced with respect to therapeutic interventions such as prophylactic cranial irradiation. In a meta-analysis of individual data from seven trials involving 987 patients randomly assigned to receive or not to receive prophylactic cranial irradiation, the relative risk of death in the group that received this prophylaxis as compared with the control group was 0.84, corresponding to a reduction in mortality of 16 percent.1

Turrisi and colleagues show that improvement in local control of small-cell lung cancer may also influence survival. However, since more than half the patients in the control group had local recurrence, 45 Gy of thoracic radiotherapy given in 25 daily fractions is most likely a suboptimal treatment. Whether optimal thoracic radiotherapy for limited small-cell lung cancer consists of 45 Gy given in accelerated, twice-daily doses or given according to another, biologically similar dose schedule is an important question.

Damian A. Laber, M.D.
Baylor College of Medicine, Houston, TX 77096

1 References

1
Arrigada R, Auperin A, Pignon JP. Prophylactic cranial irradiation overview in patients with small cell lung cancer in complete remission. Prog Proc Am Soc Clin Oncol 1998;17:1758-1758 abstract.

Author/Editor Response

The authors reply:

To the Editor: In response to Dr. Laber: the value of prophylactic cranial irradiation was unclear during the period of our trial (May 1989 through July 1992), many doctors and patients refused it, and we did not register patients for this treatment. Only 10 of the patients who were given prophylactic cranial irradiation had a subsequent relapse in the brain: 2 in the group that had undergone once-daily thoracic radiotherapy and 8 in the twice-daily group. When no prophylactic cranial irradiation was administered, 28 had brain relapse: 7 and 21 of the once-daily and twice-daily groups, respectively. More patients in the twice-daily group than in the once-daily group did not receive prophylactic cranial irradiation. However, most had local or systemic relapses, leaving few patients at risk for a first relapse in the brain.

Dr. Armstrong requests more technical detail. The radiotherapy field included the tumor and regional ipsilateral hilar and mediastinal nodes, with a 1.0-to-1.5-cm margin. Supraclavicular nodes were not treated. In the once-daily group, the dose to the spinal cord was limited to 45 Gy, and in the twice-daily group the limit was 35 to 36 Gy. Parallel opposed oblique portals, with avoidance of radiation to the spinal cord, were used to treat the target area in the afternoon sessions during the second and third weeks.

The occurrence of severe esophagitis, mentioned by Drs. Abadir and Orton, requires comment. We can be faulted for not recording the duration of esophagitis. However, this condition is reversible, and “barely tolerable” seems an overstatement. Choi et al. found similar rates of esophagitis when 45 Gy was given in twice-daily treatments or 70 Gy in once-daily treatments; they called this esophagitis “maximally tolerated.”1 Bonner et al. have studied the quality of life with regimens of once-daily as compared with twice-daily thoracic radiotherapy.2 Despite the higher frequency of acute esophagitis in the twice-daily group, esophagitis was shorter in duration, and there were no reported differences in the quality of life.

To test the efficacy and toxicity of 45-Gy, twice-daily thoracic radiotherapy, we compared it with a standard regimen (45 Gy given once daily). The recent investigation by Choi et al., a phase 1 dose-escalation study, included only six patients treated with up to 70 Gy.1 There are no other data advocating 70 Gy; it is not standard therapy.

Comparisons among radiotherapy time–dose–fraction schemes use mathematical models, details of which are too complex to describe here. The repair of surviving cells occurs after each fractional dose of radiation. The cells of small-cell lung tumors die exponentially, even after small radiotherapy fractions, which cause damage that is repairable in most normal tissues. Abadir and Orton dismiss any potential benefit from such accelerated schedules, ignoring repair and assuming that 1.5 Gy given twice daily is the same as 3 Gy given in one dose.

Andrew T. Turrisi, III, M.D.
Medical University of South Carolina, Charleston, SC 29425

KyungMann Kim, Ph.D.
University of Wisconsin, Madison, WI 53792

David H. Johnson, M.D.
Vanderbilt University, Nashville, TN 37232

2 References

1
Choi NC, Herndon JE II, Rosenman J, et al. Phase I study to determine the maximum-tolerated dose of radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer. J Clin Oncol 1998;16:3528-3537
Web of Science | Medline

2
Bonner JA, Sloan JA, Hillman SH, Shanahan TG, Brooks BJ, Marks RS. A quality-adjusted re-analysis of a phase III trial comparing once-daily thoracic radiotherapy versus twice-daily thoracic radiotherapy in patients with limited stage small-cell lung cancer. Prog Proc Am Soc Clin Oncol 1999;18:466A-466A abstract.

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