I am a little surprised that Ganti et al question or caution about issues for which a fair amount of level I evidence is available. Having just worked with the late John Murren and George Simon on the American College of Chest Physicians' evidence-based guideline, and having written with Nevin Murray a concise review of first-line treatment for small-cell lung cancer (SCLC) in the new Journal of Thoracic Oncology, I find a lot more consensus than controversy on most of these issues.
A review needs to identify the mainstream of information important to today's therapy, including the controversial areas, but needs to point a way out of the thicket of conflicting trials with rational guiding principles. Authors have the duty to provide clear prose and balanced information, but must distinguish ideas that represent their point of view from that which is historically true or established fact. Unless they have some prevailing currency, old issues and old trials need to be allowed to settle to the bottom of the stream, and should not be dredged up to muddy the waters.
Background, Incidence, and Staging
As our review pointed out, the incidence of SCLC as a clinical entity seems to be decreasing, from about 20%-25% in the 1970s to as low as 13.8% now. In 1980, there were about 50 American Society of Clinical Oncology (ASCO) lung cancer abstracts for each cell type, ie, small-cell and non-small-cell lung cancer (NSCLC). In 2004, there were still 50 SCLC abstracts, but the upsurge in interest in NSCLC resulted in 350 abstractsa sevenfold increase. Industry realized that lung cancer offered a big market for selling many products, but SCLC is too small a niche for them, and clinical research in this setting has been retarded and suppressed. Due to the lack of modern trials, older trials are "immortalized," never being eclipsed by newer trials, so the meta-analyses go back 20 to 30 years to find "evidence," often neglecting that staging tools have changed as well as the basics of standard therapy.
Writing about what constitutes limited disease as opposed to extensive disease can be a contentious business. With a financial grant from Eli Lilly, the International Association for the Study of Lung Cancer (IASLC) has invested resources to redefine stages for SCLC and NSCLC. That report is due out any day now. Pleural effusions, as seen on chest x-ray, are clearly extensive disease and have been dealt with in this fashion for 20 years (the era in which the role of thoracic radiotherapy has been ensconced). The argument about pleural effusion and stage periodically arises and stirs debates that have no clinical relevance. When older trials looked at pleural fluid as a prognostic marker for survival in chemotherapy trials, it did not seem to make a difference. Once we accept the evidence that thoracic radiotherapy improves local control and survivaland that evidence is supported by two meta-analyses, as well as guidelines from the National Comprehensive Cancer Network (NCCN) and American College of Chest Physicians (ACCP)one cannot treat the entire hemithorax with radiotherapy; it is not a "reasonably sized" target.
Another piece of evidence that did not fit into the New England Journal of Medicine report of the Intergroup trial was that although pleural effusions were specifically excluded, a few patients enrolled in the study had pleural fluid. The survival for the pleural effusion subset was significantly worse. We see cases otherwise limited with bulky central disease, and computed tomography (CT) scans are much more capable of detecting pleural fluid. On the other hand, they can also detect pleural studding and small nodules. Whether we call these cases limited or extensive may have importance for clinical trials, but these factors may influence other aspects of clinical management as well.
Management of Limited Disease
The Intergroup study set the high-water mark for survival and brought to light some rather interesting factors that I feel the need to reemphasize. The study compared two pilot studies that were roundly accepted as demonstrating the best outcomes that people had seen up until that time. The exception from the original pilot studies was chemotherapy duration and the agents used. We used only four cycles of cisplatin/etoposide. We did not use the "alternating" tactic with cyclophosphamide, doxorubicin [Adriamycin], and vincristine (the components of the widely used CAV regimen). Interestingly, none of the meta-analyses on the role of thoracic radiotherapy used cisplatin/etoposide as upfront treatment. When one looks back at this time, the term "alternating therapy" was prevalent; however, it has now fallen completely away.
When the study was designed, no one used doses of more than 50 Gy. Nonetheless, the disease melted, and as Ganti et al noted in their paper, it was considered a step forward to prove that 37 Gy was better than 25 Gy. No one considered using a dose greater than 50 Gy in the era without CT-based treatment planning, because esophagitis was very debilitating and commonly led to stricture. Rapid early response and excessive toxicity was attributed to the thoracic radiotherapy, and there was controversy about whether there was any role for it in a disease that disseminated early. When CAV or the alkylator-based treatments were used, esophageal strictures were common, and concurrent therapy was damned by "intolerable" toxicity.
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