|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2001 American Society for Clinical Oncology Risk of Death From Intercurrent Disease Is Not Excessively Increased by Modern Postoperative Radiotherapy for High-Risk Resected Non–Small-Cell Lung CarcinomaByFrom the Departments of Radiation Oncology and Thoracic Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA. Address reprint requests to Mitchell Machtay, MD, Department of Radiation Oncology, 2 Donner Building, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104; email: machtay{at}xrt.upenn.edu
PURPOSE: Some studies report a high risk of death from intercurrent disease (DID) after postoperative radiotherapy (XRT) for non–small-cell lung cancer (NSCLC). This study determines the risk of DID after modern-technique postoperative XRT. PATIENTS AND METHODS: A total of 202 patients were treated with surgery and postoperative XRT for NSCLC. Most patients (97%) had pathologic stage II or III disease. Many patients (41%) had positive/close/uncertain resection margins. The median XRT dose was 55 Gy with fraction size of 1.8 to 2 Gy. The risk of DID was calculated actuarially and included patients who died of unknown/uncertain causes. Median follow-up was 24 months for all patients and 62 months for survivors.
RESULTS: A total of 25 patients (12.5%) died from intercurrent disease, 16 from confirmed noncancer causes and nine from unknown causes. The 4-year actuarial rate of DID was 13.5%. This is minimally increased compared with the expected rate for a matched population (approximately 10% at 4 years). On multivariate analysis, age and radiotherapy dose were borderline significant factors associated with a higher risk of DID (P = .06). The crude risk of DID for patients receiving less than 54 Gy was 2% (4-year actuarial risk 0%) versus 17% for XRT dose CONCLUSION: Modern postoperative XRT for NSCLC does not excessively increase the risk of intercurrent deaths. Further study of postoperative XRT, particularly when using more sophisticated treatment planning and reasonable total doses, for carefully selected high-risk resected NSCLC is warranted.
THERE IS NO consensus regarding the use of adjuvant therapy for resected non–small-cell lung carcinoma (NSCLC). This is particularly frustrating to physicians and patients because it is well-known that the survival rate for NSCLC, with the exception of pathologic T1N0M0 disease, is poor. Although distant metastases account for most recurrences, local failure in the ipsilateral chest and/or mediastinum is common in stage II and IIIA (node-positive) NSCLC.1 Thus, there has been considerable interest in studying adjuvant thoracic radiotherapy (XRT), with nonrandomized studies showing a significant improvement in local control and survival with postoperative XRT2-6 compared with surgery alone. In contrast, randomized studies of postoperative XRT have not shown a survival benefit; a recent meta-analysis of nine randomized trials in fact was interpreted to show a detrimental effect of postoperative XRT for NSCLC that was statistically significant.7 The implication of these data, best documented in the large randomized trial by Dautzenberg et al,8 is that postoperative XRT, although acutely well tolerated, significantly increases the risk of deaths from intercurrent disease (DID).8 These non–cancer-related deaths overwhelm any possible local control and/or cancer-specific survival benefits that XRT delivers. The above described meta-analysis and its component trials have been criticized in editorials because of design flaws.9,10 These studies, which are accepted by many as conclusive because of their randomized design, included many patients with stage I disease who are known to have a low risk of local failure11-13 and offered little information about the type and extent of surgery performed. Furthermore, Cobalt-60 irradiation, which has been shown to be suboptimal for lung irradiation,14 was used in many, if not most, of the patients in these trials. Lateral radiation portals, which expose a large portion of total lung tissue, were used in many of the PORT (postoperative radiation therapy) meta-analysis trials. Total radiation dose and/or fraction size was not standardized and often excessively high. Modern computerized treatment planning was used for few patients. In light of the provocative conclusions of the meta-analysis and the Groupe d’Etude et de Traitement des Cancers Bronchiques (GETCB) trial, we analyzed our series of patients treated with postoperative XRT for NSCLC since 1982, a time corresponding to the use of computerized dosimetry, uniform linear accelerator therapy, and conventional dose fractionation techniques. We have previously reported data on survival and patterns of failure;15 we now include a detailed analysis of intercurrent deaths not related to lung cancer.
Chart review of all patients treated with postoperative XRT for NSCLC from 1982 to 1998 was performed. In general, in our institution, patients were referred for postoperative XRT for one or more of the following reasons: (1) positive mediastinal (N2) nodes; (2) extensive hilar/peribronchial (N1) nodes, particularly if a complete mediastinal lymph node dissection was not performed; or (3) compromised resection margins. Patients whose surgery consisted solely of wedge resection were excluded from this series, leaving a total of 202 assessable patients. Median age was 61 years, and 60% of the patients were male. Histology was confirmed squamous in 33%, adenocarcinoma in 52%, and large-cell or poorly differentiated NSCLC–not otherwise specified in 15% of patients. Pathologic stage characteristics are listed in Table 1, and general patient characteristics are listed in Table 2. Resection margin status was confirmed negative in 59%, positive in 21%, close in 13%, and unknown/uncertain in 7% of patients.
The details of XRT have been previously reported.15 All patients were treated with standard fractionation XRT (1.8 to 2 Gy once daily fractionation). All patients were treated in the supine position on a linear accelerator (6 MV or higher energy), and all patients underwent simulation for initial and cone-down fields. Fields encompassed the mediastinum, ipsilateral hilum, bronchial stump, and in some cases, the supraclavicular fossa. Cone-down field resimulation using anterior and posterior oblique fields to avoid the spinal cord was performed after 40 to 46 Gy. The median total dose for all patients was 55 Gy (range, 30 to 68 Gy). The rates of DID, overall survival, local control, and freedom from distant metastases were calculated actuarially.16 For the analysis of DID, a patient who suffered a lung cancer recurrence was considered censored at the time of recurrence. Every patient who died of unknown cause, with no known recurrence of cancer, was considered to have died of intercurrent disease, even if the death certificate stated that he/she died of lung cancer. For further analysis, the observed rate of DID in this population was compared with the expected mortality for age- and sex-matched control persons, derived from United States vital statistics. For each subject’s age and sex, annual mortality rates were obtained from vital statistics reports from the year of diagnosis.17 The expected age- and sex-matched mortality for the entire cohort was calculated as the mean of each individual subject’s expected mortality. These raw data from the United States vital statistics office include a mix of smokers and nonsmokers and, thus, may not be relevant to our observed study population. We presumed that the vital statistics mortality tables reflect the national United States smoking rate, approximately 30% for men and 25% for women. Based on the relative risk reported by Peto et al,18 the relative risk for smokers varied by age group from 1.58 to 3.38 in males and 1.10 to 2.37 in females. Finally, to obtain the expected DID rate, the 20% of deaths in smokers related to lung cancer were excluded. We assumed the prevalence of smokers and the proportion of deaths caused by lung cancer were constant for all age groups. The determination of the expected DID rate in this population is shown below:
Subgroup analysis was performed with comparisons using the log-rank test for univariate analysis and a Cox regression model for multivariate analysis. The median follow-up for all patients was 24 months. The median follow-up for surviving patients was 62 months.
DID A total of 25 patients (12%) died of intercurrent disease at intervals ranging from 4 to 128 months after treatment. Table 2 lists the patients who died of intercurrent disease. The 4-year actuarial rate of DID was 13.5%. Of these 25 patients, 16 were confirmed to have died from non–lung-cancer causes, whereas nine died of unknown causes. Some of these nine unknown deaths may in fact have been caused by lung cancer; for the purposes of this report, however, they are considered to have died from intercurrent disease. Comparison of the study population rate of DID (13.5% at 4 years) shows a slight but statistically insignificant difference from the expected rate of DID (10%) (Fig 1).
Because the observed rate of DID was somewhat higher than expected and given the data from other series, analysis of potential factors associated with DID was performed. The risk of DID was associated with higher total XRT dose. The risk of DID was 2% for patients treated with an XRT dose less than 54 Gy (n = 50) versus 16% for patients treated with higher XRT doses (n = 152). Actuarially, the 4-year rate of DID was 0% for XRT dose less than 54 Gy versus 17% for XRT dose  54 Gy. By Cox regression analysis, in which XRT dose is considered as a continuous variable, this was considered borderline statistically significant (P = .06). Age (also a continuous variable) was also borderline statistically significant in this model (P = .06). Other factors, including sex, stage, type of surgery (pneumonectomy v lobectomy), and side of the chest irradiated (left v right) were not predictive of DID. On univariate analysis, histology was significant, with squamous cell more likely to suffer DID than nonsquamous cell histology (P = .04), but this was not significant on the Cox multivariate analysis after age and radiation dose were accounted for. Most of the DIDs were felt to be unlikely to be clearly related to XRT toxicity. There was one case of a fatal chest wall sarcoma near the irradiated field 7.5 years after irradiation. One patient died from a bronchopleural fistula 6 months after treatment, and one additional patient died of pneumonia/sepsis 5 months after treatment. It is likely that radiation contributed to the deaths of these three patients.
Overall Survival and Patterns of Failure
Thoracic XRT is an invasive procedure, with attendant risks of morbidity and even mortality. Over the past half century, extensive clinical research in lymphomas and breast cancer has characterized the type and magnitude of the risks for those diseases.19-22 This has allowed for improvements in treatment techniques to minimize these risks and thus optimize the benefits of XRT for those illnesses. There is considerably less literature on this problem in patients treated to the chest for lung cancer, probably because the poor survival in this disease has made it a very difficult topic to study. Patients with lung cancer are generally older and have considerably more underlying intercurrent disease than patients with most other types of malignancies. Nonetheless, the PORT meta-analysis and the GETCB trial concluded that postoperative XRT for NSCLC is contraindicated for all patients except perhaps those with pathologic N2 disease because of its significantly adverse effect on overall survival and survival free of DID.7,8 Our analysis shows that with modern XRT, the risk of DID is considerably less than that reported in the GETCB trial and, in fact, only slightly increased compared with the expected figures. We hypothesize that this is because of the following differences in our series compared with the GETCB trial and the meta-analysis: (1) Patients in our institution were carefully selected for postoperative radiotherapy based on the potential risk for local recurrence; margin-negative, stage I disease was not irradiated. (2) In our institution, every effort is made to avoid pneumonectomy. Although controversial,23 pneumonectomy may be associated with decreased long-term survival. (3) All XRT in our institution was delivered via linear accelerator (6 MV or greater), with two-dimensional or three-dimensional computerized dosimetry planning. (4) Lateral radiation fields were not used. All fields used customized blocking. (5) Radiation fraction size was 1.8 to 2 Gy once daily. (6) Attempts were made to minimize the total XRT dose (median dose 55 Gy in our series) when possible. (7) Patients were carefully and rigorously observed by the radiation oncologist and an internist, with frequent office examinations and chest x-rays. Office visits included smoking cessation counseling. In our practice, referrals to pulmonologists and/or cardiologists are frequently ordered, even for seemingly minor complaints and symptoms. Our conclusion that the risk of DID is not much greater than the expected risk is based on a comparison of an actual, observed rate against a hypothetical risk based on vital statistics. These populations are of course inherently different because the observed group consists entirely of lung cancer patients. This is an inherent limitation of our analysis. We would suggest, however, that if anything, the group of patients with lung cancer would be at a higher risk of DID than a group of smokers who did not have a previous diagnosis of lung cancer. Despite these precautions, the rate of DID was higher than the expected value and is slightly higher than the figure reported by the GETCB and the Lung Cancer Study Group in the surgery-alone arms of their trials. In our series, the observed 4-year DID rate was 13.5% compared with an expected rate of 10%. With our sample size of 202 patients, a statistically significant result (P < .05) would require an observed DID rate of approximately 17%.24 Conversely, if the absolute 3.5% difference in DID were true, a sample size of approximately 650 patients would be necessary for statistical significance.24
We did observe a radiation dose response with respect to DID. Patients treated to a total XRT dose Because even the most meticulous radiation planning and dose conservatism may lead to some excess in DID, postoperative XRT can only be justified in settings where its expected benefits outweigh these risks. This would specifically exclude the vast majority of patients with stage I disease, who have a low rate of local failure with surgery alone. In contrast, patients with node-positive NSCLC, particularly IIIA/N2 disease, have a relatively high rate of local failure with surgery alone.6,27 If XRT reduces that risk sufficiently to outweigh the increased risk of DID that it causes, an advantage in overall survival should appear. In the meta-analysis, XRT did not decrease overall survival for the N2 subgroup; in fact, the odds ratio slightly favored XRT but not significantly.7 The extent to which postoperative XRT can decrease the rate of local recurrence is uncertain and probably depends on multiple factors, including surgical details, XRT techniques and dose, and the definition of local recurrence. In the Lung Cancer Study Group study, XRT virtually eliminated local failures (decreased from approximately 20% with extensive surgery alone to 3% with postoperative XRT).25 Randomized trials from China28 and Austria29 also showed a dramatic effect of postoperative XRT on local control. In contrast, the large European randomized studies by the British Medical Research Council30 and the French GETCB8 showed only a modest effect of XRT on local control. The reason for this is uncertain. The Medical Research Council trial reported local control in two different ways; in one methodology, patients with suspected but unproven local failure were scored, whereas in a second analysis, only confirmed local failures were considered. In the latter analysis (requiring confirmation), XRT did decrease local failure significantly but not in the former methodology. Neither study had rigorous surgical requirements. The GETCB study altered its schema after the first 189 patients, changing from very rigorous requirements for quality assurance, data reporting, and follow-up procedures, to a simplified version of the protocol. In our series, local control was excellent, with only 11% (crude) of patients suffering local failure and a 4-year actuarial local failure rate of 16%. Survival in our series also compared favorably with other data, with a 4-year survival of 34%. This is lower than the observed survival rate for surgery alone (43% at 5 years) in the GETCB randomized trial; however, there was a marked difference in the patient population between that study and ours. In our series, only 3% of all patients had stage I disease compared with 30% of the patients in the GETCB trial. Furthermore, our series included patients with positive margins (21% of the population), close margins (13%), and uncertain/unknown margins (7%). In contrast, the GETCB study and most other prospective trials excluded patients who did not have confirmed negative margins. The survival rates in our series were considerably better than the survival reported for postoperative XRT in the GETCB study or the meta-analysis, likely because of the improved local control and the decreased rate of DID in our study. The most sobering statistic in our analysis, as is the case with most lung cancer studies, is the extremely high rate of distant metastases. The rate of distant metastses vastly surpassed the risk of local failure plus DID combined. To date, efforts to decrease the risk of DM in this patient population with adjuvant chemotherapy have been disappointing, as noted in the recent Intergroup trial. Trials with newer chemotherapy agents as well as biologically designed therapies are proceeding swiftly. We hypothesize that when these treatments begin to succeed at preventing or delaying distant metastases, achieving permanent local control will become paradoxically more, not less, important in the overall treatment of NSCLC. While these clinical trials of new systemic agents develop, it is vital to integrate new techniques in radiation technology and medical care to lessen the toxicity of thoracic XRT.
1. Wagner H: Postoperative adjuvant therapy for patients with resected non-small cell lung cancer: Still controversial after all these years. Chest 117: 110S-118S, 2000 2. Choi NC, Grillo HC, Gardiello M, et al: Basis for new strategies in postoperative radiotherapy of bronchogenic carcinoma. Int J Radiat Oncol Biol Phys 6: 31-35, 1980[Medline] 3. Chung CK, Stryker JA, O’Neill M Jr, et al: Evaluation of adjuvant postoperative radiotherapy for lung cancer. Int J Radiat Oncol Biol Phys 8: 1877-1880, 1982[Medline] 4. Green N, Kurohara SS, George FW: Postresection irradiation for primary lung cancer. Radiology 116: 405-407, 1975[Abstract] 5. Kirsh MM, Rotman H, Argenta L, et al: Carcinoma of the lung: Results of treatment. Ann Thor Surg 21: 371-377, 1976[Abstract] 6. Sawyer TE, Bonner JA, Gould PM, et al: The impact of surgical adjuvant thoracic radiation therapy for patients with nonsmall cell lung carcinoma with ipsilateral mediastinal lymph node involvement. Cancer 80: 1399-1408, 1997[Medline] 7. PORT: Postoperative radiotherapy in non-small cell lung cancer: Systematic review and meta-analysis of individual patient data from nine randomised controlled trials. Lancet 352: 257-263, 1998[Medline] 8. Dautzenberg B, Arriagada R, Chammard AB, et al: A controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma: Groupe d’Etude et de Traitement des Cancers Bronchiques. Cancer 86: 265-273, 1999[Medline]
9.
Machtay M, Kaiser L, Glatstein E: Is meta-analysis really meta-physics? Chest 116: 539-542, 1999 10. 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 (editorial). Cancer 86: 195-196, 1999[Medline] 11. Feld R, Rubenstein L, Weisenburger T, et al: Sites of recurrence in resected stage I non-small cell lung cancer: A guide for future studies. J Clin Oncol 2: 1352-1358, 1984[Abstract] 12. Sawyer TE, Bonner JA, Gould PM, et al: Patients with stage I non-small cell lung carcinoma at postoperative risk for local recurrence, distant metastases, and death: Implications related to the design of clinical trials. Int J Radiat Oncol Biol Phys 45: 315-321, 1999[Medline] 13. Thomas P, Rubinstein L: Cancer recurrence after resection: T1N0 non-small cell lung cancer—Lung Cancer Study Group. Ann Thor Surg 49: 242-246, 1990[Abstract] 14. Philips P, Rocmans P, VanHoutte P: Postoperative radiotherapy after pneumonectomy: Impact of modern treatment facilities. Int J Radiat Oncol Biol Phys 27: 525-529, 1993[Medline]
15.
Lee JH, Machtay M, Kaiser LR, et al: Non-small cell lung cancer: Prognostic factors in patients treated with surgery and postoperative radiation therapy. Radiology 213: 845-852, 1999 16. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 17. National Center for Health Statistics: NCHS-Life Tables. Atlanta, GA, Centers for Disease Control, 2000 18. Peto R, Lopez AD, Boreham J, et al: Mortality from tobacco in developed countries: Indirect estimation from national vital statistics. Lancet 339: 1268-1278, 1992[Medline] 19. Donaldson SS, Hancock SL, Hoppe RL: The Janeway Lecture: Hodgkin’s disease—Finding the balance between cure and late effects. Cancer J Sci Am 5: 325-333, 1999[Medline] 20. Eriksson F, Gagliardi G, Liedberg A, et al: Long-term cardiac mortality following radiation therapy for Hodgkin’s disease: Analysis with the relative seriality model. Radiother Oncol 55: 153-162, 2000[Medline] 21. Gagliardi G, Lax I, Ottolenghi A, et al: Long-term cardiac mortality after radiotherapy of breast cancer: Application of the relative seriality model. Br J Radiol 69: 839-846, 1996[Abstract] 22. Hurkmans CW, Borger JH, Bos LJ, et al: Cardiac and lung complication probabilities after breast irradiation. Radiother Oncol 55: 145-151, 2000[Medline]
23.
Ferguson MK, Karrison T: Does pneumonectomy for lung cancer adversely influence long-term survival? J Thor Cardiovasc Surg 119: 440-448, 2000 24. Lilienfeld AM, Lilienfeld DE: Selected statistical procedures, in Foundations of Epidemiology (ed 2). New York, NY, Oxford Univ Press, 1980, pp 323-354. 25. 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[Abstract]
26.
Keller SM, Adak S, Wagner H, et al: Mediastinal lymph node dissection improves survival in patients with stage II and IIIA non-small cell lung cancer: Eastern Cooperative Oncology Group. Ann Thor Surg 70: 358-365, 2000 27. Martini N, Flehinger B: The role of surgery in N2 lung cancer. Surg Clin NA 67: 1037-1049, 1987 28. Feng QF, Wang M, Wang LJ, et al: A study of postoperative radiotherapy in patients with non-small cell lung cancer: A randomized trial. Int J Radiat Oncol Biol Phys 47: 925-929, 2000[Medline] 29. Smolle-Juettner FM, Mayer R, Pinter H: Adjuvant external radiation of the mediastinum in radically resected non-small cell lung cancer. Eur J Cardiac Surg 10: 947-951, 1996 30. 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[Medline] Submitted December 5, 2000; accepted June 13, 2001. This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
