Risk of death from intercurrent disease is not excessively increased by modern postoperative radiotherapy for high-risk resected non-small-cell lung carcinoma. Machtay M, Lee JH, Shrager JB, et al. 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 > or = 54 Gy. The 4-year actuarial overall survival was 34%; local control was 84%; and freedom from distant metastases was 37%. 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. J Clin Oncol. 2001 Oct 1;19 (19):3912-3917. PMID: 11579111 CogentMedicine.com EDITOR'S COMMENT One of the axioms of logic is that you cannot prove a negative. Retrospective studies may formulate hypothesis, but it takes a prospective trial to test it and prove it or deny it. One of the truths of oncology is that you should not try to confuse people with the facts when they have already made up their mind. The above two papers boldly attempts to prove that bad things do not happen, and the editorial accompanying it is written by the people who are convinced by their own post-operative retrospective analysis that post operative therapy is indicated. Where does all of the sturm and drang come from? The PORT analysis, a so-called meta-analysis published in the Lancet midsummer 1998. The 2000 ASTRO had an organized group of experts that should have been penalized at least fifteen yards for unnecessary roughness. The real problem with the after-hours sneak attack was that it did not invite the authors of the PORT to defend their analysis. There have been countless assaults on the PORT by those that would have you believe that the evidence is invalid -- radiotherapy is not so bad for you, and the trials used the wrong patients, the wrong equipment and the wrong dose. The Mayo retrospective trial showed a sizeable benefit to treatment, but how can we be convinced that the doctors that picked treatment for the elite group able to afford to travel to the Mayo were somehow comparable to the group that they selected to not treat? And does this experience in anyway apply to patients we see in daily practice? Machtay goes after the fact that radiotherapy causes morbidity and death. The Penn retrospective series is quite interesting, and does show a lower rate of treatment mortality than in the PORT analysis. Rightly, there are few patients that are N-0. However, a few unexpressed caveats about the Penn series. During the first half of the analysis period, surgeons at Penn refused mediastinal sampling or dissection. I know this, because I tried time and time again as a very junior assistant professor to convince the very senior surgeons at Penn that a dissection was important. Not all of these patients even had CT scans pre-op. Surely, none had PET scans. The editorial assumes that the authors of the Penn report used fairly consistent target volumes. Perhaps the authors do, but the I know that I treated most of these cases between January 1982 and April 1989 and I evolved into a method of treating nodes during these years. The dose range of 30 - 60 Gy is typical, and the target volumes were quite variable. It is a retrospective analysis, and this is to be expected. Since the cases did not have mediastinal dissection, now outside the standard of care, can we really compare the outcome to today's cases managed with modern surgical standards, staging procedures and multidisciplinary integrated care? I would waggishly argue that meta-analysis may enshrine the mistakes of the past, but using clearly old case studies with outdated methodologies cannot guide us to enlightenment either. If post operative radiotherapy works, why can't prospective trials show it? While PORT may have its flaws, particularly the large segments of the analyzed group that do not have reasonable indications for surgery: true surgical and pathologic N-0 patients, the final conclusions cannot be really argued away with weaker retrospective evidence. If we throw out evidence of well staged patients, how can we really be convinced by evidenced tainted by mere gross N-0 patient from the Penn series? Can the time at risk with these understaged patients really be sufficient to assure us that bad things do not happen to them from the treatment? The positive observation that higher than 54 Gy seems to cause more trouble counts as evidence, but do we really know the benefit or the risk with the 50 Gy dose from retrospective analysis done with an ax to grind? While we have tried to look prospectively, we have failed. Why? Most of the world views the largest risk to be systemic, so trials have been done that look at chemotherapy. Patients were allowed to have radiotherapy, and while not randomized, the ALPI and IALT trials from Europe allowed patient to receive radiotherapy. Many of these trials included the N-0 to N-2 category of patients, but they were all resected. The technical radiotherapy variables may still exist. However, if no benefit is seen in prospective trials, albeit non-randomized, many will not be dissuaded because they are already convinced from the retrospective reports. My bias is that radiotherapy offers only toxicity risk to N-0 patients, little benefit in local control or survival in N-1 patients, and a very small local control benefit and tiny survival advantage in N-2 patients. If the patient has not been staged surgically, the current standard, or has not had a CT scan and PET scan, all bets are off. If one insists that post-operative therapy is worth the risk despite the lack of evidence, one needs to be cautious about target volume. Particularly in right pneumonectomy, but in any patient with limited lung capacity, limiting the target volume at least limits the pulmonary risk. The ECOG study by Keller et al prove that concurrent chemoradiotherapy is more toxic than radiotherapy alone. Retreating to the very foundations of medicine, we must remember to first do no harm, and I would say especially when evidence points away from even a fig leaf of benefit. While I'll freely admit my bias, I can be convinced by a prospective trial, and I would be willing to enter patients, or even enter a study myself if it were available. However, I will not trump prospective evidence with weaker retrospective case studies. I do not think you can prove that there is no toxicity, or that it is insignificant, with a retrospective study. Especially when the study shows risk, and the selection variables and various other flaws remain hidden. See also 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 2001 Oct 1;19(19):3905-7; PMID 11579109. ANDREW T. TURRISI III, M.D. - 5/1/2002 J Lung Cancer, 7/03 Cancer, 3/06 Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.