Adjuvant Radiation Therapy After Complete Resection of Non–Small-Cell Lung Cancer
Authors: Eric Vallières, Mitchell Machtay, Eli Glatstein, James A. Bonner
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.5.1427 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11870193 Adjuvant Radiation Therapy After Complete Resection of Non–Small-Cell Lung Cancer Eric VallièresxEric VallièresSearch for articles by this author Mitchell MachtayxMitchell MachtaySearch for articles by this author , Eli GlatsteinxEli GlatsteinSearch for articles by this author James A. BonnerxJames A. BonnerSearch for articles by this author Show More University of Washington, Seattle, WAUniversity of Pennsylvania Medical Center, Philadelphia, PAWallace Tumor Institute, University of Alabama at Birmingham, Birmingham, AL https://doi.org/10.1200/JCO.2002.20.5.1427 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01032002Response01032002Reply 1:We appreciate the opportunity to respond to Dr Vallières’ letter to the editor. Most of the issues he raises are valid and were addressed previously in the Discussion section of our article.1 Postoperative radiotherapy (XRT) for N2R0 lung cancer remains controversial and will remain so unless further prospective studies are performed. The two prospectively randomized studies quoted by Vallières were not merely “possibly too small,” as described by him, but grossly underpowered. In the Lung Cancer Study Group, 44 N2 patients were randomized to XRT versus control; results showed no overall survival difference but a trend toward better disease-free survival (P = .03).2 In the Medical Research Council study, 106 N2 patients were randomized to XRT versus control; although the median and 1-year survival rates were virtually identical, the 2- and 3-year survival data favored XRT (43% v 33% at 2 years; 36% v 21% at 3 years; P = .18).3 It is unreasonable to expect statistically significant differences with so few N2 patients randomized in these two studies.Because the prospective data show a trend toward improved outcome with postoperative XRT for N2 disease, and given the well-documented decrease in local failure (which is an extremely morbid event) with postoperative XRT, we continue to endorse its use if it can be given safely. We agree with Vallières that distant metastases remain the greatest challenge in this disease, but we believe there remains a role for studies evaluating postoperative XRT as well.Reply 2:In 1992, Pignon et al1 reported a meta-analysis addressing the role of thoracic radiotherapy (TRT) in small-cell lung cancer. Although this publication discussed small-cell lung cancer, it provides several lessons about lung cancer in general. The authors began the article by stating that the role of this treatment (TRT) “is controversial.” Over the years that followed the publication of the meta-analysis by Pignon et al, TRT became the standard of care for patients with limited-stage small-cell lung cancer. Recently, trials have shown that the timing and fractionation (or biologic dose) of TRT may also be important.2,3 However, a striking aspect of the 1992 meta-analysis deserves comment. The statistically significant survival advantage, that was associated with the use of TRT, pertained to an improvement in 3-year survival from only 8.9% ± 0.9% to 14.3% ± 1.1%.1 Although both survival estimates were disappointing, most patients would still prefer the 14% chance of survival over the 9% chance of survival.The oncology community learned several general concepts about lung cancer from the 1992 meta-analysis of small-cell lung cancer. For instance, individual trials of patients with lung cancer have frequently lacked the power to address the desired question. Most phase III trials involving patients with lung cancer have included less than 1,000 patients even though there is not a paucity of these patients in our clinics. Pignon et al1 mentioned that more than 1,000 patients would be required to detect a survival advantage of 16% compared with 10%. In this issue of the Journal of Clinical Oncology, Dr Vallières has suggested, in a letter to the editor, that the Lung Cancer Study Group trial (LCSG 773)4 and the Medical Research Council Lung Cancer Working Party trial5 may provide sufficient information to demonstrate the ineffective results of postoperative radiotherapy (PORT) for patients who have had a complete resection of non–small-cell lung cancer (NSCLC), even if involvement of the N2 lymph nodes is demonstrated. Unfortunately, these two trials included only 149 patients with N2 disease. If one heeds the information that Pignon et al1 have provided regarding adequate sample sizes, it is unlikely that a PORT-associated survival advantage would be detectable with a population of 149 patients.Next, Vallières considers the biology of lung cancer and questions whether there is any reason to perform further studies of PORT for patients with N2 disease. He suggests that the treatment “will not improve” outcome for these patients. After considering the biology of lung cancer, he states, “The main reason why adjuvant RT has failed to improve the survival of our patients after R0 resection is not because the wrong RT was given or the wrong populations were studied. It is because our patients die of systemic disease.” Once again, it is possible to make an analogy between published results in small-cell lung cancer1 and similar aspects of NSCLC in order to address Vallières’ concerns. It is a fact that most patients with NSCLC will die of systemic disease. However, it is also true that a vast majority of patients with small-cell lung cancer die of systemic disease. However, it seems that the use of appropriate locoregional TRT can reduce the risk of locoregional recurrences in a manner that results in improved survival for these patients.1 It is entirely possible that appropriate doses of PORT may also reduce the risk of locoregional recurrences and improve survival for patients with completely resected NSCLC with N2 disease. The Mayo Clinic Group determined that this latter group of patients had a 60% rate of locoregional recurrences at 4 years after surgery and observation.6 Also, they found that the use of PORT reduced this rate to 17%.Therefore, it may be premature to conclude that PORT will not improve survival in any group of patients. With respect to patients with N2 disease, the retrospective review of the Mayo Clinic showed a very compelling suggestion that some patients may benefit from PORT.6 However, the phase III trials that have addressed this issue have left the question unanswered.7Finally, Vallières outlines the potential impracticality of attempting to perform additional studies of PORT. He states that our previous editorial described two failed attempts to study this issue8 and suggests that physician bias may prevent the completion of additional studies. Hopefully, this sentiment is not fact. There is precedent in medicine that unforeseen events often change physicians’ past biases. These changes can lead to the completion of trials that were deemed to be not feasible before the change. For instance, the recent publication of a meta-analysis demonstrating benefit for the use of prophylactic cranial irradiation (PCI) for patients with small-cell lung cancer9 has changed many physicians’ views of PCI. The oncology community is now able to study different methods of delivering PCI. Additionally, it is possible that this meta-analysis has indirectly influenced the current enthusiasm to study PCI in certain groups of patients with NSCLC. Therefore, the fact that investigators have had difficulty accruing patients to trials that include a randomization to PORT versus observation may not mean that this concept should be abandoned in the future.1. Machtay M, Lee JH, Shrager JB, et al: Risk of death from intercurrent disease is not excessively increased by modern postoperative radiotherapy for high-risk resected NSCLC. J Clin Oncol 19:: 3912,2001-3917, Link, Google Scholar2. Lung Cancer Study Group: Effects of post-operative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. N Engl J Med 315:: 1377,1986-1381, Crossref, Medline, Google Scholar3. Stephens RJ, Girling DJ, Bleehan NM, et al: The role of post-operative radiotherapy in non-small cell lung cancer: A multicentre randomised trial in patients with pathologically staged T1-2, N1-2, M0 disease. Br J Cancer 74:: 632,1996-639, Crossref, Medline, Google Scholar1. Pignon JP, Arriagada R, Ihde DC, et al: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327:: 1618,1992-1624, Crossref, Medline, Google Scholar2. Murray N, Coy P, Prater JL, et al: The importance of timing for thoracic irradiation in the combined modality treatment of limited-state small-cell lung cancer. J Clin Oncol 11:: 366,1993-344, Google Scholar3. 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:: 265,1999-271, Crossref, Medline, Google Scholar4. Weisenburger TH, Gail M: The Lung Cancer study Group: Effects of postoperative mediastinal radiation on completely resected stage II and stage II epidermoid cancer of the lung. N Engl J Med 315:: 1377,1986-1381, Crossref, Medline, Google Scholar5. Stephens RJ, Girling DJ, Bleehen NM, et al: The role of post-operative radiotherapy in non-small-cell lung cancer: A multicentre randomized trial in patients with pathologically staged T1-2, N1-2, M0 disease—Medical Research Council Lung Cancer Working Party. Br J Cancer 74:: 632,1996-639, Crossref, Medline, Google Scholar6. Sawyer TE, Bonner JA, Gould PM, et al: Effectiveness of postoperative irradiation in stage IIIA non-small cell lung cancer according to regression tree analyses of recurrence risks. Ann Thorac Surgery 64:: 1402,1997-1407, Crossref, Medline, Google Scholar7. Bonner JA: The role of postoperative radiotherapy for patients with completely resected non-small cell lung carcinoma: Seeking to optimize local control and survival while minimizing toxicity. Cancer 86:: 195,1999-196, Crossref, Medline, Google Scholar8. Bonner JA, Tincher SA, Fiveash JB: Balancing the possible effectiveness of postoperative radiotherapy for non–small-cell lung cancer against the possible detriment of radiation-induced toxicity. J Clin Oncol 19:: 3905,2001-3907, (editorial) Link, Google Scholar9. Auperin A, Arriagada R, Pignon JP, et al: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med 341:: 476,1999-484, Crossref, Medline, Google Scholar