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Eur J Cardiothorac Surg 1999;14:263-264
© 1999 Elsevier Science NL
Editorial comment |
Department of Thoracic Surgery, University of Torino, 3, Via Genova, 10126 Torino, Italy
Corresponding author. Fax: +39 11 6960170.
The role of chemotherapy in the treatment of patients with non-small cell lung cancer has been a matter of debate among oncologists and thoracic surgeons for decades. Although surgery is universally considered the only therapy with curative intent, preoperative (neoadjuvant) or postoperative (adjuvant) chemotherapy have alternatively or in combination been proposed to improve the results of surgery. Proponents of postoperative chemotherapy based their assumption on the fact that in all stages of completely resected non-small cell lung carcinoma (NSCLC) the most frequent sites of failure are systemic, and for this reason they maintain that a systemic therapy is required.
Unfortunately, despite a number of studies, to date no active single agent or combination therapy has been proven to be effective in large, prospective, randomized collaborative trials [1] [2] [3]. The small number of patients recruited when divided by stages, the patients selection to surgery, the often not comparable treatment arms, the different drugs deliveries all may contribute to explain the conflicting results.
As surgeons, we are not asked to test new chemotherapeutic agents nor to personally prescribe the drugs regimens, which belong to medical oncologists; nonetheless, due to our major role in the management of lung cancer patients, we must know the pros and cons of non-surgical therapies, which patients are expected to benefit from them, and the cost/benefit ratio of any aggressive chemotherapy following surgical intervention.
We therefore look with interest any study testing new agents with a potential survival efficacy, low toxicity and a good compliance. As everyone knows, however, the skepticism and conservatism proverbial to surgeons make us prudent towards any published `sensational' results, particularly if they look strikingly different from the historical controls.
In this issue of The European Journal of Cardio-thoracic Surgery, a Japanese group reports their experience on postoperative chemotherapy based upon oral administration of a 5-fluorouracil derivative drug (UFT) in all-stages completely resected NSCLC patients [3].
A medline of the subject revealed no more than 20 papers in the last 7 years, most from Japanese groups and almost all for inoperable patients.
UFT is not a new chemotherapeutic agent, having been employed in the past for a variety of solid tumors, including those of the head and neck, digestive tract, breast with good compliance and acceptable toxicity [4].
The drug is a combination of Tegafur, a prodrug which continuously releases 5-FU maintaining constant 5-FU concentration and Uracil which inhibits 5-FU degradation.
Two previous prospective randomized studies on UFT from Japanese groups [5] [6] have shown encouraging results, with a response rate of 35%, a good compliance and a significant survival advantage as compared to the control group consisting of patients submitted to surgery alone: 64% vs. 49% 5-year survival for all stage patients. At that time no detailed description of the surgical staging was provided by the authors and a 64% survival is indeed high for a population of Stage I through IIIa lung carcinoma patients.
The present report seems to present similar limits, with a 61% 5-year survival for the all stages population of NSCLC patients. This figure is in contrast to most large series studies published in the recent literature which report an overall survival rate not exceeding 35% [7] [8].
A major limit of the present study includes the time period examined which ranges between 1976 and 1992, which means that until the early 1980s patients were studied without CT scan and with an obsolete TNM staging system (although subsequently restaged); also, the authors made little use of mediastinoscopy for preoperative selection of N2 patients. In such a poorly preoperatively studied population, the authors identified 53% of patients in Stage I, 11% in Stage II, 35% in Stage IIIa (of whom 21%, 139, N2). A possible explanation for their excellent all-stages 5-year survival may be the high percentage of Stage I patients.
When focusing on the group of patients by stage, however, and when considering the patients with locally advanced disease (Stage IIIa) some considerations arise: it is difficult for most thoracic surgeons to figure out how a group of poorly preoperatively selected N2 patients from a 10- through 20-years ago series can achieve a 34% 5-year survival; even more difficult seems to accept an astounding 54% 5-year survival rate among the small subgroup of 24 patients receiving UFT. If these data are confirmed in larger prospective studies, a major improvement comparable to that achieved following the introduction of cisplatin-based regimens might be anticipated, and the outcome of patients with bronchogenic carcinoma might be dramatically improved.
In every scientific publication and in clinical papers in particular, in most cases the results obtained largely depend upon the selection criteria in the patients recruitment.
Beyond any consideration about the statistical tests employed, which are otherwise appropriate and valid, some intrinsic limits are evident from the paper. (1) The authors did not mention when they started to employ UFT: if the agent was used in the second part of the time period considered, the reported better survival of the UFT group might have resulted from a general improvement in surgical techniques and postoperative care along with a decrease in the rate of exploratory thoracotomies and operation-related deaths; (2) the UFT group does not seem a consecutive series (the authors stated that the drug was administered to those patients who gave informed consent) and this may pose a significant bias in the interpretation of the results; (3) after two previous prospective randomized trials, the present retrospective study looks like a backward step in the natural progression of the scientific evaluation of a potential new therapeutic procedure.
We thoracic surgeons and physicians surely welcome and favor any potentially beneficial therapeutic adjunct to surgery in the management of patients with resectable NSCLC and the authors of the present study are to be congratulated for their results. If their excellent survival rates stand the test of time and are reproducible in a larger number of patients with a careful selection criteria and surgical staging, a major step forward will be made for a new and more definite role of systemic chemotherapy in the management of lung cancer patients.
So let us wait and see! At the eve of the new millennium we all hope that good news may be heard and a real progress may be made in this field.
References
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