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Originally published as JCO Early Release 10.1200/JCO.2006.05.8560 on June 12 2006 © 2006 American Society of Clinical Oncology.
Postoperative Radiotherapy in Non—Small-Cell Lung Cancer Warrants Further Exploration in the Era of Adjuvant Chemotherapy and Conformal RadiotherapyUniversity of Alabama Birmingham, Birmingham, AL There has been a debate for more than 40 years regarding the appropriate use of postoperative radiotherapy (PORT) for patients with completely resected non–small-cell lung cancer (NSCLC).1,2 As with almost all technologies, this time span has allowed for significant advancements in the quality of radiotherapy and the understanding of the effects of various methods of delivering radiotherapy.3,4 Therefore, it may be a serious error to make conclusions about the efficacy of PORT based on older trials that used equipment (cobalt machines), radiotherapy dose regimens, or radiotherapy volumes that are not part of currently accepted practices. The radiation oncology community has learned much about radiotherapy during these last 40 years.3-5 In 1998, the impact of PORT for NSCLC was analyzed in a meta-analysis of phase III trials that randomly assigned patients to either surgery alone or surgery and PORT.1 This analysis included all available randomized trials, with the initiation of some trials dating back to 1965. (An additional trial has since been published.6) The meta-analysis showed that PORT was not associated with an overall improvement in survival and was associated with a detrimental effect on survival for the subgroup of patients with stage I and II disease. Numerous authors have examined the trials that were included in the meta-analysis. These analyses have concluded that many trials lacked appropriate methodology for randomized trials or appropriate treatment regarding recent standards for care.2,5,7-11 The PORT meta-analysis included trials in which a majority of patients received treatment with cobalt machines, and some groups of patients were treated with just one radiotherapy field each day (an anterior field one day and a posterior field the next). It has been shown that these treatments result in suboptimal dose distributions, which may potentially increase toxicity.2,4,7 Additionally, a large proportion of the patients who were included in the meta-analysis (more than 30%) were participants in one randomized trial of Dautzenberg et al.12 This trial allowed physicians to treat patients with daily fractions of 2.50 Gy and total doses of 60 Gy. These doses exceed the doses that have been considered the standard of care in North America for many years.5,8-10 These high doses do not comply with recent practices because physicians have had concerns about dose-related toxicity and the potential for treatment-related deaths. Both of these suboptimal outcomes were augmented by PORT in the study of Dautzenberg et al. Additionally, a majority of patients who were entered onto the randomized trial of Dautzenberg et al were part of an effort to increase accrual by relaxing the protocol requirements (simplified protocol). It is possible that this simplification detracted from the balance that was sought with the randomization procedure. The analysis of the Surveillance, Epidemiology, and End Results (SEER) database, as highlighted in this issue, demonstrated several similar findings compared with the meta-analysis, with the striking exception of the results for patients with involvement of N2 lymph nodes (N2 disease). Overall, PORT did not have a significant effect on survival and was associated with a survival decrement for patients with N0 or N1 disease. However, PORT was associated with an improvement in survival for patients with N2 disease, unlike the meta-analysis. Therefore, how does the clinician assess the available literature regarding PORT in resected NSCLC and make rational treatment recommendations for patients?
One can start by examining the study of Dautzenberg et al.12 This study illustrated an increased risk of intercurrent death with the use of PORT as delivered in their trial. One must assess whether more modern techniques might have been able to overcome this problem. And if so, has PORT proven to be efficacious with modern treatments? Unfortunately, both of these assessments are difficult. However, several authors have evaluated optimal radiotherapy techniques, and recent phase II studies are beginning to provide some information about the efficacy of modern techniques. The group from the University of Pennsylvania has reviewed their experience with PORT in patients with resected NSCLC.5 They used United States vital statistics and assessed the rate of intercurrent deaths in their treated population relative to expected rates in the general population. They also used modern techniques that included linear accelerator machines, three-dimensional planning in many patients, and volumes that excluded the contralateral hilum and only included the supraclavicular area in some patients. They found that the modern delivery of PORT, with a median dose of 55 Gy, resulted in a slightly higher rate of death from intercurrent disease (13.5%) compared with the expected rate (10%), but this difference was not statistically significant. However, patients were treated with a range of doses from 30 to 68 Gy, thus allowing an assessment of intercurrent death relative to radiation dose. Further analysis revealed a suggestion of increased intercurrent deaths with doses Clinicians need to discuss the possible detrimental effects of PORT in the context of the available literature and provide rational consultation for patients regarding the potential risks and benefits of PORT for individual patients. One question arises: How do patient outcomes of modern series relate to the outcomes of older series? As eluded to earlier, the assessment of the efficacy of modern PORT is difficult. This assessment is complicated by the fact that no recent trials have randomly assigned patients to PORT or observation. In addition, over the last 5 years, adjuvant chemotherapy has become part of the standard of care after resection of NSCLC.17-19 Therefore, current evaluations of PORT must be performed in the context of optimizing adjuvant chemoradiotherapy regimens.19 The SEER analysis of Lally et al16 did not provide information about chemoradiotherapy because information about chemotherapy was not available. Therefore, the use of chemotherapy may be a confounding factor that hinders interpretation of the SEER analysis. It could be hypothesized that the lack of this information is a minor issue because the analysis included patients from 1988 to 2002, and chemotherapy began to enter standard practice after the year 2000.17-19 The Eastern Cooperative Oncology Group (ECOG) performed a noteworthy trial during the early 1990s.21 This trial randomly assigned patients with resected NSCLC (with N1 or N2 disease) to either PORT alone or PORT plus concomitant chemotherapy (cisplatin and etoposide). The two treatments did not differ with respect to survival. Recently, the Radiation Therapy Oncology Group (RTOG) conducted a phase II trial of PORT with concomitant paclitaxel and carboplatin in a group of patients with similar characteristics (age, stage, and performance status) compared with the 181 patients who were entered onto the earlier ECOG trial through the auspices of the RTOG.22 The outcomes of those patients who received PORT with paclitaxel and carboplatin (on the RTOG phase II trial) were compared with the outcomes of patients who were entered onto the earlier ECOG trial. The patients who received PORT with paclitaxel and carboplatin had a statistically significant improvement in survival compared with patients entered onto the earlier trial (P = .03). Additionally, the trial of PORT plus paclitaxel and carboplatin produced an improvement in intrathoracic failure compared with the earlier trial (15% v 28% to 29%, respectively). This improvement in local control and survival may be related to a synergistic effect between PORT and the paclitaxel and carboplatin regimen. Others have shown promising results combining PORT with similar chemotherapy regimens.23 Recent trials of this nature are encouraging, but it is important to consider the possibility that better results are being achieved as a result of better patient selection. However, it is possible that these improved outcomes can be attributed to better techniques of combining PORT and chemotherapy. It will be important to re-evaluate PORT in the modern era of improved radiotherapy technology and improved regimens of adjuvant chemotherapy for patients with resected NSCLC who are at high risk for locoregional failure. Recently, the Lung Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence-Based Care9 concluded that, "Postoperative radiotherapy may therefore be considered for some patients with stage III disease, although the potential advantages and disadvantages would need to be discussed with the patient when deciding on a final treatment recommendation." The work from the Mayo Clinic would suggest that patients with an intermediate or high risk of locoregional failure are most likely to benefit from PORT. They used a regression tree analysis to determine risk groups.24 In this study, the patients at highest risk for locoregional failure were those patients with involvement of upper and lower mediastinal levels. Patients with involvement of multiple N2 lymph nodes and involvement of mediastinal nodes that were discordant with the location of the primary tumor (such as upper lobe and lower mediastinum or vice versa) were the highest risk groups with respect to diminished survival. It will be important to explore risk groups in the treatment era that now includes adjuvant chemotherapy. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. Author Contributions
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Strauss G, Herndon J, Maddaus M, et al: Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage IB non-small cell lung cancer: Report of Cancer and Leukemia Group B (CALGB) protocol. Proc Am Soc Clin Oncol 22:621s, 2004 (abstr 7019) 20. Erman M, Moretti L, Soria JC, et al: Adjuvant chemotherapy and radiotherapy in non-small cell lung cancer. Semin Radiat Oncol 14:315-321, 2004[Medline] 21. Keller SM, Adak S, Wagner H, et al: A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer: Eastern Cooperative Oncology Group. N Engl J Med 343:1217-1222, 2000 22. Bradley JD, Paulus R, Graham MV, et al: Phase II trial of postoperative adjuvant paclitaxel/carboplatin and thoracic radiotherapy in resected stage II and IIIA non-small-cell lung cancer: Promising long-term results of the Radiation Therapy Oncology Group—RTOG 9705. J Clin Oncol 23:3480-3487, 2005 23. 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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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54 Gy compared with doses less than 54 Gy (P = .06). At the Mayo Clinic, when PORT doses of 50 Gy were used for patients with resected NSCLC and N2 disease, there was no suggestion of a detrimental effect, but survival was enhanced.
