Affiliations: University Hospital Tuebingen, Germany,
Indiana Cancer Pavilion Indianapolis, IN
Correspondence to: Branislav Jeremic, MD, PhD, Department of Oncology, University Hospital, Zmaj Jovina 30, 34000 Kragujevac, Yugoslavia; e-mail: bjeremic@EUnet.yu
We have read with interest the recent article in CHEST by McGarry et al (April 2002)1 on three different treatment options in 128 patients with early stage non-small cell lung cancer (NSCLC). Although the authors acknowledge the limitations of their retrospective study, which showed no advantage for radiation therapy (RT) over observation only, we believe that additional aspects need to be brought to the attention of the readership of the journal, so as to leave no doubts regarding treatment choice in this patient population. These aspects are as follows:
More information about differences between the treatment groups regarding various pretreatment characteristics should have been disclosed, principally regarding patients’ refusal to surgery (14 refusals in the observation-only group vs no refusal in RT group; reason for radiotherapy referral not specified in 7 patients in the RT group). This may have seriously imbalanced prognosis, since it was shown that patients’ refusals inversely correlate with the incidence of intercurrent deaths,2–4 which, on the other side, directly correlate with increasing age and pre-existing comorbidity.5–6 Also, it is not clear whether patients were staged as having early NSCLC both initially and immediately before RT administration. If they were treated with RT because of symptom progression (majority of RT group), then they may have not been at an early stage before RT administration at all, but rather placed into a locally advanced group, which additionally undermines the effectiveness of RT.
While McGarry et al1 offer actuarial analysis using survival as an end-point, this patient population is notorious for having excessive cancer-unrelated deaths. It is mandatory, therefore, to have other end-points, such as cause-specific survival, to correct for these events. Indeed, when 5-year cause-specific survival/disease-specific survival rates in the RT series were reported,5–7 they were usually twice as high as rates of overall survival in the same studies, the difference being approximately 10% vs 20%. Also, no causes of death were offered in surgical patients who were younger and had smaller tumors and better lung function than RT patients. To extend this, perhaps patterns of failure and/or other end-points, such as local recurrence-free survival or distant metastasis-free survival, may have helped to gain better insight into possible differences in the treatment outcome.
Other issues may well have been quality-of-life and/or economic issues, because it is not unrealistic to expect that observation-only patients should have had more symptomatic (best supportive care) treatments, which are often prolonged and more expensive than RT alone. Additionally, information on postoperative treatment morbidity/mortality in this largely geriatric population is lacking, as well as RT-related toxicity, particularly with different RT regimens used and observed inconsistencies even within palliative RT.
It seems, therefore, that the somewhat inferior results obtained with RT, and particularly with high-dose RT, may be explained at least in part by an RT population that clearly has poor prognoses, as evidenced by low-RT doses frequently used, and most likely has higher stages of the disease. Thus, any reliable comparison to both observation-only and surgical group is almost impossible.
Finally, the authors state that local field RT is a standard RT approach in this disease. This is not so. First, there is not a single prospective randomized study evaluating the issue of optimal RT field in this patient population. Second, the studies achieving the best results are actually those using some elective nodal RT, that is, inclusion of uninvolved ipsilateral hilum and/or ipsilateral mediastinum,2–4 which can be seen as the radiotherapeutic equivalent of lobectomy.
Numerous studies have clearly documented the effectiveness of RT alone in this disease, with median survival times of > 30 months and a 5-year survival rate of > 30%,2–7 going up to 40% in T1N0 patients.8 This should assure referring physicians that we can offer our patients a “best treatment approach” which, we believe, in technically operable but medically inoperable early stage NSCLC, is RT alone. We are opponents, not advocates, of “therapeutic nihilism” in treating this disease and in this patient population. As we have observed the increase in patient numbers in recent years, discovery of successful treatment options must become one of our top priorities in the near future.
Thank you very much for allowing me to comment. I would like to take the opportunity to clarify some points raised in this review.
With respect to the various pretreatment characteristics between the groups, all patients at the Richard L. Roudebush VA Medical Center are assessed in both pulmonary medicine and surgery departments prior to a treatment decision. It often seems the case that these decisions occurred prior to patient presentation at the multidisciplinary chest conference attended by all the other services involved in the delivery of care. Patients who refused surgical treatment were not usually seen by the radiation therapy service to discuss this option.
All patients were staged according to the American Journal of Critical Care staging criteria by the multidisciplinary chest conference at the time of diagnosis and were entered as such into the institutional tumor data base. Dr. Jeremic raises an important point. Indeed, many of the patients classified as early stage lung cancer did not reach our service until their cancers had progressed to the point of requiring palliation; therefore, our estimation of mortality due to lung cancer for those who received no treatment early in their disease is an underestimate of the total misery resulting from observation.
Cause of death was obtained from the tumor registry that recorded the International Classification of Diseases, Ninth Revision code from death certificates. The detailed records of these patients, including patterns of failure, would be exceedingly hard to obtain. Indeed, a prospective study would likely provide better and more comprehensive information on patterns of failure and cause-specific survival, but it is unlikely that any such study will ever be attempted. The main point we can derive from our work is that many of these patients died of their cancers, many required palliation by radiotherapy resulting from progression of their early stage cancers and, in my opinion, observation or “best supportive care” is not the best strategy for management of these patients when radiotherapy can be delivered safely and effectively.
In the population reviewed here, no postoperative therapy was included. We used a review of those patients receiving surgery as the primary modality for their lung cancers mainly to confirm that the surgically treated patients had a overall better outcome. We agree that these patients probably represent the patients with best physiologic state; but at a time when screening for lung cancer is in vogue, some treatment policies for the management of the medically inoperable (often geriatric) patients must be addressed.
4. and 5. We cannot explain the reason for the lack of apparent benefit to radiotherapy in this study, except to postulate that the patient numbers were too low to reach an appropriate power. We cannot reach any conclusion with respect to the benefit of radiation therapy; however, many studies have suggested that primary radiation therapy in medically inoperable patients results in approximately a 30% 5-year survival, which is much greater than we see in the results presented in our group of untreated patients.
Unfortunately, it remains difficult to state what the standard of care is in these patients. No randomized study comparing observation only vs local field radiotherapy (“postage stamp”) vs limited nodal irradiation has been done. No institutional review board would ever approve a randomized study in which no therapy is an arm. With respect to nodal irradiation in T1/T2N0 patients, we also believe that local therapy may include nodes. For those patients with a solitary lung nodule and extremely poor pulmonary function, a postage-stamp field is commonly used. From many surgical series, it is apparent that the incidence of tumor metastasis to nodes is very low and is reflected in the good 5-year survival of these early stage patients treated surgically. For other patients, the advent of positron emission tomography scanning is improving our ability to truly assess mediastinal nodal tumor positivity, although studies are ongoing on the utility of positron emission tomography as a treatment planning modality to limit tissue volumes treated. Dose-escalation studies are now aimed at treating only suspicious nodes (≥ 1 cm).1–2 We agree with Dr. Jeremic that not only is it important to select patients appropriate for therapy, but that “local therapy” in these debilitated patients must encompass all disease if possible and include those nodes at risk on an elective basis.
We feel that this is an evolving area that is going to take on a new importance in the future as our methods for identifying and treating early stage disease improves. It remains important to understand the natural history of the disease to fully assess the impact of our therapies, and it was this thought that provoked our study.
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