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© 2002 American Society for Clinical Oncology
Adjuvant Radiation Therapy After Complete Resection of Non–Small-Cell Lung CancerUniversity of Washington, Seattle, WA To the Editor:The 1998 postoperative radiotherapy (PORT) meta-analysis once again seriously questioned the role of adjuvant radiotherapy (RT) in the management of R0 resected non–small-cell lung cancer (NSCLC), and it is still being debated 3 years later.1 A recent review from the University of Pennsylvania has attempted to further address the safety of adjuvant RT.2 In this single-institution review of 202 patients treated with surgery followed by adjuvant RT, the authors conclude that as long as the dose of postoperative RT was less than 54 Gy, there was no excessive increase in the risk of intercurrent deaths. The authors suggest the need for an additional randomized trial to again readdress the role of adjuvant RT in patients who have had an R0 resection of their NSCLC.2 An editorial in the same issue of the Journal of Clinical Oncology also supports the need for such a trial where one would limit the dose of adjuvant RT to a dose of less than 54 Gy and target patients with N2R0 disease and possibly a select group of N1R0 patients.3 Two such trials have already been completed and have been published now for quite some time. The Lung Cancer Study Group phase III randomized trial LCSG 773 targeted patients with R0 resected T2N1, T3 chest wall, and/or N2 squamous cell carcinomas: 108 patients were observed, 102 patients received 50 Gy of adjuvant RT. Although there was a significant decrease in the locoregional recurrence rate in the RT group, there was absolutely no difference in the survival of the two groups.4 Ten years later, the Medical Research Council Lung Cancer Working Party published another phase III trial targeting patients with R0 resected N1 and N2 NSCLC of all histologies. The radiation group in this study received 40 Gy of RT given in 15 fractions. This trial also concluded that there was no clear indication for postoperative RT in N1 disease but that the question remained unresolved in N2 disease, whereas patients with N2 disease on this study seem to gain 1 month in survival with adjuvant RT.5 Both of these trials used doses of RT under the 54-Gy threshold suggested by the University of Pennsylvania group. Both, in phase III randomized designs, have failed to show a survival advantage for patients receiving adjuvant RT after R0 resections of N1 and N2 NSCLC. tk;2Despite this, adjuvant RT is still considered the standard of care by many in the United States. The only data that have ever suggested a potential benefit of postoperative radiotherapy have been retrospective phase II data with all of their inherent weaknesses. Critics have argued that in the two randomized trials described above, the number of patients with N2 disease was possibly too small and not powered to show a positive effect (20% N2 in the LCSG 773 trial, 37% in the Lung Cancer Working Party study) and that subset analysis of patients with N2 disease in these trials suggested a possible survival benefit. The fact remains that there are absolutely no randomized data that clearly confirm a survival benefit for adjuvant RT after a R0 resection of NSCLC. The editorial by Bonner et al3 describes two recent failed attempts at restudying the question of adjuvant therapy in patients with resected N2 disease. Both have failed because of poor patient accrual. I would submit that the reason for these failures lies in the fact that, in the United States, patients are receiving adjuvant RT off trial despite the lack of data to support its use. In fact, in Eastern Cooperative Oncology Group Trial 3590 (INT 0115), the last completed North American cooperative trial that addressed the question of adjuvant therapy after surgery for N1 and N2 disease, adjuvant RT was given to both arms on the trial—where was the control arm?6 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. New strategies of delivering the RT will not improve on this. The hypothesis of Machtay et al2 that "when these treatments begin to succeed at preventing or delaying distant metastases, achieving permanent local control will become paradoxically more, not less, important. . . " is interesting. However, until this has been achieved, there is no proven curative role for the use of adjuvant RT after the R0 resection of an NSCLC, nor is there a need to repeat the studies that have already addressed the question. REFERENCES 1. PORT Meta-Analysis Trialists Group: Postoperative radiotherapy in NSCLC: Systematic review and meta-analysis of individual patient data from nine randomized controlled trials. Lancet 352: 257-263, 1998[CrossRef][Medline]
2.
Machtay M, Lee JH, Schrager JB, et al: Risk of death from intercurrent disease is not excessively increased by modern postoperative radiotherapy for high-risk resected non–small-cell lung cancer. J Clin Oncol 19: 3912-3917, 2001
3.
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: 3905-3907, 2001 (editorial) 4. Weisenburger TH, Gail M: Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung (LCSG 773): The Lung Cancer Study Group. N Engl J Med 315: 1377-1381, 1986[Abstract] 5. Stevens RJ, Girling DJ, Bleehen NM, et al: The MRC Lung Cancer Working Party: The role of postoperative radiotherapy in non small cell lung cancer—A multi center randomized trial in patients with pathologically staged T1-2, N1-2, M- 0 disease. Br J Cancer 74: 632-639, 1996[Medline]
6.
Keller SM, Adak S, Wagner H, et al: A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA NSCLC. N Engl J Med 343: 1217-1222, 2000
ResponseUniversity of Pennsylvania Medical Center, Philadelphia, PA Reply 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. REFERENCES 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: 3912-3917, 2001 2. 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: 1377-1381, 1986 3. 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: 632-639, 1996
ResponseWallace Tumor Institute, University of Alabama at Birmingham, Birmingham, AL 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.7 Finally, 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. REFERENCES 1. Pignon JP, Arriagada R, Ihde DC, et al: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327: 1618-1624, 1992[Abstract] 2. 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: 366-344, 1993
3.
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 4. 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: 1377-1381, 1986 5. 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: 632-639, 1996
6.
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: 1402-1407, 1997 7. 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: 195-196, 1999[CrossRef][Medline] 8. 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: 3905-3907, 2001 (editorial)
9.
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: 476-484, 1999
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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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