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Ann Thorac Surg 1995;60:591-592
© 1995 The Society of Thoracic Surgeons
DR VALERIE W. RUSCH (New York, NY): I congratulate Dr Rice on an excellent presentation and thank him for sending me the manuscript to review in advance of the meeting. His study builds on a long series of neoadjuvant therapy trials reported during the past decade, all of which have tried to improve the poor prognosis of patients with stage III non–small cell lung cancer. I have a few comments about the trial that I hope will place it in perspective.
Neoadjuvant trials have used three treatment strategies: preoperative chemotherapy and radiation followed by surgical resection; preoperative chemotherapy alone followed by surgical resection; or chemotherapy followed by radiation without surgical resection. However, all trials recognize that the poor prognosis of stage III non–small cell lung cancer relates to the frequent development of distant metastases and that the pivotal part of neoadjuvant therapy is the use of high-dose chemotherapy.
Overall, neoadjuvant trials, both randomized and nonrandomized, have shown response and resectability rates of 50% to 75% and survival rates that appear to be superior to those seen with surgical resection or radiation alone.
The principal aim of this trial, namely to shorten the length of induction treatment while trying to preserve therapeutic intensity, is laudable and the regimen used is a novel variation on previous regimens. However, the toxicity of the induction regimen is significant; 19% of patients experienced grade III or IV esophagitis and 69% of patients developed grade IV neutropenia. In contrast, the Southwest Oncology Group and Rush-Presbyterian trials, both of which used induction chemoradiotherapy, but with markedly different regimens, were far less toxic, with response, resectability, and survival rates that were similar or superior to those recorded in this trial.
There are some other concerns about the trial. The follow-up is too short for the results to be as yet definitive. The dose of induction chemotherapy is low. Other neoadjuvant trials have generally used a total dose of 300 to 400 mg/m2 of cisplatin, whereas this trial used only 80 mg/m2. Yet one of the lessons learned from neoadjuvant therapy trials both in lung cancer and in other solid tumors is that optimal induction treatment includes two or three cycles of high-dose chemotherapy.
The radiation therapy was split between preoperative and postoperative treatment. In lung cancer, split course radiation has proven inferior to continuous high-dose radiation and the addition of a small dose of postoperative radiation is not generally considered effective and has been deleted from the current intergroup trial in lung cancer.
Hyperfractionated radiation is theoretically attractive but has not been proven consistently superior to standard fractionation radiation. Moreover, it is impractical for many patients and is a costly, labor-intensive approach to treatment.
In summary, the induction regimen used in this trial is cause for concern. The chemotherapy dose is low and the regimen focuses on optimizing the delivery of radiation, an approach that can be impractical and expensive and is probably not the most important feature of induction therapy for stage III disease. The regimen requires in-hospital treatment and is associated with toxicity significant enough to require additional hospitalization for treatment-related complications. I think it would be inadvisable to export this single institution experience, tolerable in one institution, to the community at large, because it is well known that response rates decrease and toxicity increases when similar institutional trials are extended to the multiinstitutional setting.
Attempts to optimize multimodality therapy for stage III disease should always be applauded. Sometimes phase II trials open the path to new and better treatment. In other instances they determine the limits of acceptable treatment and define what should not become standard care. I think that this trial falls into the latter category.
DR NICHOLAS V. AUGELLI (Madison, WI): In your pretreatment trial you started out with 42 patients and some of those patients subsequently died just of their chemotherapy and radiation, and yet in some of your final analyses the number that you consider for survival was not 42; I just wanted to have your comments on this.
DR JOHN R. BENFIELD (Sacramento, CA): If I heard you correctly, there were only 2 patients who had no evidence of residual cancer at the time of thoracotomy. My recollection is that the induction therapy of SWOG protocol 8805 was considerably more effective than your protocol in ridding stage III patients of their cancers. I wonder if you might comment on that.
Second, in our effort to do better with treating this disease, we are seeing an increasing number of patients referred from the community who have had induction therapy without complete staging by pathology, that is, without a mediastinoscopy. I find that a deplorable trend and I just wonder if you have encountered the same in your area.
DR RICE: In response to Dr Rusch's comments, the purpose of this study was to reduce the time required to administer induction therapy for those patients with poor prognosis stage III non–small cell lung carcinomas. The toxicity of this regime, although greater than some conventional trials, many of which include good prognosis stage III patients, allowed the majority of patients to proceed to operation in a timely fashion and complete the postoperative portion of the protocol. The toxicity was short lived and resolved in all but 1 patient.
The total dose of cisplatin for the complete trial was 160 mg/m2, 80 mg/m2 administered during induction and 80 mg/m2 administered postoperatively. The total chemotherapy dose given in two cycles was in the range of other trials and was administered in a similar time period. Additional courses of chemotherapy could have been given postoperatively, but we did not believe this was necessary in this setting.
Accelerated fractionated radiation allowed a biological equivalent dose of 40.5 Gy to be administered in the induction period, a dose in the range of other neoadjuvant protocols. If full-dose radiation therapy is to be given in a neoadjuvant regimen, split-course radiation therapy is necessary to allow operation to be conducted safely in fields that have received 35 to 45 Gy. As with other conventional trials, the remainder of the tolerable dose was available for postoperative administration.
Although this is more costly to administer initially, shortening the induction period by 2 to 3 months provides a significant cost saving. This approach has proven to be very practical and no more costly than conventional 3- to 4-month induction regimens. The in-hospital requirements for initiation of induction can probably be dropped as we gain more experience with this technique, further reducing cost.
Doctor Augelli, the survival calculations included treatment mortality.
In response to Dr Benfield's questions: 2 patients experienced complete pathologic response in this trial. I do not have the SWOG data available; however, the importance of complete pathologic response is not clear. Indeed, in this trial one of the patients with a complete pathologic response had recurrent disease. As well the time to operation is greatly reduced in this protocol, if the standard time period was allowed to elapse the number of patients with a complete pathologic response may be increased.
We too are seeing patients who have not been adequately staged and have been given some form of induction therapy. Every attempt should be made to stage patients adequately before they are placed in a neoadjuvant treatment protocol. This treatment must be conducted as part of an ongoing study.
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