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Ann Thorac Surg 1998;66:300-301
© 1998 The Society of Thoracic Surgeons
a Department of Thoracic Surgery, Hôpitaux Universitaires de Strasbourg, F-67091 Strasbourg, France
e-mail: gilbert.massard{at}chru_strasbourg.fr
To the Editor
We read with great interest Dr Einhorn’s review on combined-modality treatment for primary non–small cell lung cancer [1]. This certainly is a hot topic, because many European colleagues from the oncology departments definitely believe that neoadjuvant treatment does improve long-term survival. As surgeons, we increasingly are referred patients who went through several cycles of chemotherapy for putative stage IIIA disease without histologic staging or multidisciplinary discussion; retrospective analysis of medical imaging studies often shows clearly resectable disease at the onset. We appreciate Dr Einhorn’s scientific honesty when concluding that available work fails to prove any undebatable survival advantage.
Induction chemotherapy trials have been founded on the hypothesis that neoadjuvant therapy should increase long-term survival by preventing metastatic progression, which is universally recognized as a primary cause of medium-term and long-term deaths after resection. Besides, chemotherapy should be the more effective when the tumor mass is smaller. Therefore, an increased efficacy of neoadjuvant therapy compared with adjuvant therapy is anticipated because it acts two to three doubling times earlier in the natural history of disease. Phase II studies of neoadjuvant therapy for bronchogenic cancer have been reviewed on several occasions and may be summarized as follows [1–3]. Neoadjuvant therapy, regardless of whether radiation therapy is added, results in an objective response rate of 50% to 60%; a histologic complete response is observed in 5% to 10% of cases. On the other hand, close to 15% of patients do not undergo subsequent operation, mainly because of progressive disease. Induction treatment-related mortality is 2% to 4%. Operation is delayed by an average of 3 months; a complete resection is achieved in 75% of patients. Global postoperative mortality is approximately 5%. However, many series show a dramatic increase in mortality after pneumonectomy, ranging up to 10% and even 17.5%. Increased mortality is the result of adult respiratory distress syndrome and explained by pulmonary toxicity of the various treatment regimens. Median survival is increased by 6 to 8 months; survival is substantially improved in complete responders [1–3].
Similarly to other authors, we felt most enthusiastic about our early results with a phase II trial conducted between 1987 and 1989 [4]. However, when reviewing the literature recently, we became doubtful about the real impact of this strategy [3]. Although available data suggest some efficacy of chemotherapy on an individual basis in responders, we hypothesized that results observed in a population as a whole might simply result from a selection process. Much previous work has demonstrated that a standard cohort of patients with resectable stage III disease usually achieves a 5-year survival of 15% to 20% after complete resection and adjuvant radiotherapy, with a median survival of 12 to 14 months. A sharp drop in the survival curve usually occurs during the first 6 months postoperatively; the corresponding deaths should occur in patients similar to those in whom progressive disease develops during induction therapy and who therefore are withdrawn from operation.
The following example illustrates the hypothesis of patient selection. A cohort of 20 patients followed up after resection for stage III lung cancer, drawn from a previous publication [4], was reanalyzed (Kaplan-Meier model) after 15% of the records, equaling 3 patients who died during the first 6 months postoperatively, were discarded. The discarded records were supposed to be those of patients whose disease progressed during adjuvant therapy. A further estimation was made under conditions of "interim analysis" with a maximal follow-up limited to 17 months. The basal 5-year survival rate of the cohort was 17%, with a median survival of 12 months [4]. After simulation of induction chemotherapy, 5-year survival rose to 20.6% and median survival increased to 18 months. Simulation of interim analysis led to a 5-year survival of 52.9%; the median survival had not been reached at the conclusion of the study (Fig 1)!
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Selection with neoadjuvant treatment is an expensive process, which delays surgical resection by 3 months and carries a substantial risk of increasing treatment-related mortality and morbidity. Major and minor complications are commonly reported during induction chemotherapy, and the postoperative course of patients requiring pneumonectomy may be jeopardized [2, 3]. Research aiming to define simplified criteria for adequate selection of long-term survivors should be applauded by both patients and physicians.
Analysis of published series reporting neoadjuvant treatment for stage III disease is further obscured by a varying panel of stage III subcategories such as pathologic stage III, clinically evident stage III, resectable stage III, and locally advanced tumors [3]. Further, there is a lack of consensus regarding the ideal extent of resection after induction therapy: should the surgeon remove the gross disease apparent at operation or resect the entire area of initial disease? The first concept would reduce resection to a second-range place of "adjuvant operation," whereas the latter challenges the definition of "marginally resectable tumor."
As quoted by Dr Einhorn, readily available phase III trials concern small sample sizes, and their methodology may be criticized. Although they anticipate a survival advantage for the neoadjuvant treatment arms, they cannot lead to a definitively valid conclusion directing any standard of practice for stage III disease.
References
This article has been cited by other articles:
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  P. A. Thomas Stage IIIA N2 non-small-cell lung cancer: current controversies in combined-modality therapy Eur. J. Cardiothorac. Surg., September 1, 2009; 36(3): 431 - 432. [Full Text] [PDF]
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H. Decaluwe, P. De Leyn, J. Vansteenkiste, C. Dooms, D. Van Raemdonck, P. Nafteux, W. Coosemans, and T. Lerut Surgical multimodality treatment for baseline resectable stage IIIA-N2 non-small cell lung cancer. Degree of mediastinal lymph node involvement and impact on survival Eur. J. Cardiothorac. Surg., September 1, 2009; 36(3): 433 - 439. [Abstract] [Full Text] [PDF]
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