Bogart, Jeffrey A. MD
Department of Radiation Oncology, State University of New York, Upstate Medical University, Syracuse, New York
Disclosure: The author declares no conflicts of interest.
Address for correspondence: Jeffrey A. Bogart, MD, Upstate Medical University, Department of Radiation Oncology, 750 East Adams Street, Syracuse, NY 13210. E-mail: BogartJ@Upstate.Edu
In this issue of Journal of Thoracic Oncology, Gielda et al.1 report their extensive single-institution experience treating stage III non-small cell lung cancer (NSCLC) with split-course radiotherapy (SCR) concurrent with chemotherapy. By far, the most interesting observation is the favorable outcome for patients with poor-risk features such as pretreatment weight loss and poor performance status. In fact, the median survival of the poor-risk cohort numerically eclipsed that of standard-risk patients. Although the authors suggest that these results were not likely influenced by selection of a favorable cohort of poor-risk patients, whether selection bias, happenstance, or the treatment approach itself is responsible for outcomes is a matter for speculation. Nevertheless, these data would suggest that a reassessment of SCR may be warranted.
The history of SCR is quite muddied with the mention of SCR (in the curative setting) often reflexively met with criticism in the radiotherapy community. The intent of including rest days during the course of radiotherapy is to allow for recovery of normal tissues and improve the tolerability of intensive therapy. However, serious concerns have been raised because the rest period may facilitate accelerated repopulation of resistant tumor clones with a resultant loss of local tumor control.2 Clinical evidence supporting a detrimental impact of radiation treatment breaks is largely circumstantial and is based in part on data from patients who required unplanned radiation treatment interruptions. This association has been observed in several epithelial malignancies. For example, a retrospective review of Radiation Therapy Oncology Group (RTOG) studies in NSCLC demonstrated worse outcomes when the time to complete radiotherapy was protracted,3 although this observation may simply emphasize that patients not able to tolerate continuous course treatment do poorly. Prospective randomized trials that tested “accelerated” radiotherapy regimens with a planned treatment break have been interpreted as further indirect evidence of the negative impact of SCR—the assumption being that the accelerated regimen would have been beneficial if a break had not been given. A frequently cited example is the differing results of trials assessing twice-daily radiotherapy (BID RT) versus conventional radiotherapy for limited-stage small cell lung cancer: continuous BID RT improved survival on Intergroup trial 0096, whereas a North Central Cancer Treatment Group trial did not find a benefit for split-course BID RT.4,5 There are less data available describing the impact of a planned treatment break when standard fractionation is given (∼2 Gy daily fractions) simultaneously with systemic chemotherapy. The bulk of experience in this regard comes from the treatment of anal carcinoma, which appears to be a more radiosensitive tumor than NSCLC, with conflicting reports in sequential phase II trials as to the impact of a planned treatment break.6,7 Despite the strong bias against the use of SCR, an overview of 13 randomized studies and numerous additional retrospective studies found no clinically relevant differences between continuous radiotherapy and SCR.8
Unlike poor-risk patients, outcomes for standard-risk patients in the current report are in-line with results expected with other approaches. This underscores the notion that the therapeutic balance is not meaningfully shifted for this population. Although the split-course approach may be associated with less acute toxicity (particularly esophagitis) than traditional combined modality treatment, standard-risk patients usually recover fully from severe acute esophagitis without long-term sequelae. On the other hand, poor-risk patients may have less reserve capacity and more difficulty overcoming severe acute toxicity. Sequential studies conducted by the Southwest Oncology Group support the contention that poor-risk patients can only be pushed so hard before diminishing returns are seen. An initial Southwest Oncology Group trial assessing concurrent chemotherapy and continuous fractionated radiotherapy reported a median survival of 13 months, encouraging for a poor-risk population, but a follow-up protocol adding adjuvant paclitaxel chemotherapy resulted in increased toxicity and worse survival.9,10 So the hypothesis that recovery from acute reactions during a planned break could substantially shift the therapeutic ratio would appear to be tenable in the poor-risk population. One of the most remarkable findings in the current report is the high percentage of poor-risk patients completing the entire planned course of chemotherapy and radiotherapy.
Larger population-based studies also seem to emphasize the delicate balance that must be respected when designing treatment strategies for poor-risk patients. In a report from Davidoff et al.,11 published in last issue of the Journal, Surveillance, Epidemiology, and End Results data for more than 6000 patients older than 65 years with stage III NSCLC were analyzed. Despite using a conservative definition of “elderly,” patients treated with concurrent chemoradiotherapy had increased mortality compared with treatment with radiotherapy alone. On the other hand, sequential chemotherapy followed by radiotherapy was associated with improved survival compared with radiotherapy alone. These sentiments were echoed in a quality-adjusted survival analysis of more than 900 patients enrolled on RTOG prospective studies for NSCLC between 1983 and 1995. Patients less than 70 years had improved survival with more aggressive therapy, whereas older patients fared best with standard radiotherapy alone.12 In stark contrast to these reports are the results from a landmark prospective phase III study, RTOG 9410, comparing sequential and concurrent chemoradiotherapy in locally advanced NSCLC, which suggest that patients aged 70 and older actually derive the greatest benefit from concurrent therapy.13 These contradictory results strongly caution against using chronologic age alone in selecting a treatment approach for patients with locally advanced NSCLC.
Whether SCR has sufficient merit to carry forward with new prospective trials in the 21st century is debatable. In addition to biologic concerns, a key drawback of the SCR program is the time to complete therapy (approximately 70 days). This can place a logistical burden on poor-risk patients, who frequently have multiple comorbidities, and the extended course of treatment may be associated with increased costs. We are now in an era where advances in radiotherapy technology, such as 3D planning, image guided therapy, and respiratory gating, have greatly improved the ability to conform the radiation dose to the intended target while protecting surrounding normal structures. These advances have facilitated an evolution toward delivering fewer treatments in a shorter time period. Stereotactic body radiotherapy, used in early stage NSCLC, is the most extreme example, but trials of hypofractionated radiotherapy for stage III disease are planned in both the RTOG and Cancer and Leukemia Group B. Other novel strategies under investigation aim to exploit the biologic differences between cancer cells and normal cells by combining radiotherapy with molecular targeted agents that preferentially sensitize tumor.14,15 In the end, it may be more rewarding to work toward developing regimens that are less likely to cause toxicity severe enough to require interruptions of therapy rather than reducing treatment intensity for the sake of allowing patients to complete a prescribed course of therapy.
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9. Lau DH, Crowley JJ, Gandara DR, et al. Southwest Oncology Group phase II trial of concurrent carboplatin, etoposide, and radiation for poor-risk stage III non-small cell lung cancer. J Clin Oncol 1998;16:3078–3081.
10. Davies AM, Chansky K, Lau DM, et al. Phase II study of consolidation paclitaxel after concurrent chemoradiation in poor-risk stage III non-small cell lung cancer: SWOG S9712. J Clin Oncol 2006;24:5242–5246.
11. Davidoff AJ, Gardner JF, Seal B, et al. Population-based estimates of survival benefits associated with combined modality therapy in elderly patients with locally advanced non-small cell lung cancer. J Thorac Oncol In press.
12. Movsas B, Scott C, Sause W, et al. The benefit of treatment intensification is age and histology-dependent in patients with locally advanced non-small cell lung cancer (NSCLC): a quality-adjusted survival analysis of radiation therapy oncology group (RTOG) chemoradiation studies. Int J Radiat Oncol Biol Phys 1999;45:1143–1149.
13. Langer CJ, Hsu C, Curran WJ, et al. Elderly patients (pts) with locally advanced non-small cell lung cancer (LA-NSCLC) benefit from combined modality therapy: secondary analysis of Radiation Therapy Oncology Group (RTOG) 94-10. Proc Am Soc Clin Oncol 2002;21:Abstr 1193.
14. Ready N, Janne PA, Bogart J, et al. Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptors and KRAS mutation analysis: Cancer and Leukemia Group B (CALGB) 30106, a CALGB-stratified phase II trial. J Thorac Oncol 2010;5:1382–1390.
15. Jatoi A, Schild SE, Foster N, et al. A phase II study of cetuximab and radiation in elderly and/or poor performance status patients with locally advanced non-small-cell lung cancer (N0422). Ann Oncol 2010;21:2040–2044.