Lung Cancer, 1993; 9 (Suppl. 2): S31-S37 0 1993 Elsevier Scientific Publishers Ireland
s31 Ltd. All rights reserved.
Preoperative chemotherapy for locally advanced non-small cell lung cancer E. Carmack Holmes” and John C. Ruckdeschelb ‘Professor of Surgery, Department of Surgery, Division of Oncology, UCLA Medical Center, Los Angeles, California and bProfessor of Medicine and Head, Division of Medical Oncology, Albany Medical College, Albany, New York, USA
Summary Recently, the field of preoperative chemotherapy for non-small cell lung cancer (NSCLC) has been the focus of Phase II trials. Extensive experience with preoperative therapy has been reported by such study groups as the Rush-Presbyterian group, Memorial Sloan-Kettering Cancer Center, the Dana Farber Institute, the University of Toronto, and the Lung Cancer Study Group. The studies by these and other investigative groups are reviewed here and, although all but one of the studies was flawed by the lack of a control arm, results are encouraging. Comparison of data from the various studies is difficult due to differences in preoperative staging, but it appears that 60-75% of patients may be expected to respond to one of a number of preoperative regimens, the majority of responders will be able to go on to surgical resection and about 10% of patients initially entered into a study are likely to attain histologic complete response, with correspondingly higher rates for those who undergo surgery. Toxicity rates are significant and survival data are not yet conclusive, however, and it is clear that a controlled trial is needed.
Key words: Lung cancer; Adjuvant therapy
Among all who treat patients with lung cancer it is an article of faith that the benefits of surgery outweigh the results of other treatment modalities [I]. Indeed, all efforts at early detection are directed toward increasing the proportion of patients potentially
Correspondence to: E. Carmack Angeles, CA 90024, USA.
curable by surgical resection; only recently has chemoprevention become a possibility . The overall results of surgical resection are mixed, however, due to our inability to accurately stage patients. Whereas 70% or more of pathologic Stage I patients appear cured [3,4] and 20% of selected Stage IIIA patients may be cured by surgery alone, [5,6] the overall impact of surgery on more advanced disease is marginal at best . Despite a variety of rationales more hopeful than proven, the field of preoperative chemotherapy for non-small cell lung cancer (NSCLC) has moved ahead in numerous Phase II trials. Disturbingly, such preoperative treatment is also routinely considered by community oncologists in the nonstudy setting, despite its lack of proven efficacy . The following is a review of a variety of neoadjuvant studies from several different groups. This review describes the ‘state-of-the-art’ as we now know it and comments on the future research directions in this area.
Current Results of Preoperative Therapy The Rush-Presbyterian experience
Aside from the combined Lung Cancer Study Group (LCSG) reports, [9-l l] the RushPresbyterian group has the most extensive experience with preoperative therapy for NSCLC [12,13]. Their initial group of 64 patients, all described as Stage III, MO in the earlier staging system, [ 141 received continuous infusion 5-fluorouracil (5-FU), cisplatin, and 40 Gy of radiation, Follow-up surgery was possible in 61% of the initial patient group and 23% of the resected patients (14% of the initial 64 treated patients), achieved histologic complete response (CR). Median survival was not given, but the l-year survival was reported at 58% . In a subsequent study by Bonomi et al.,  etoposide was added to the regimen and 73% of 32 patients responded to the combined therapy, with 38% subsequently able to undergo surgery. Ultimately, half of the resected patients and 12.5% of the overall patient population were histologically disease-free. Median and l-year survival were not reported. This group has examined their complete data set for significant prognostic factors and have focused on the histologic CR rate as the most significant . The Memorial Sloan-Kettering Cancer Center experience
Several reports from the Memorial Sloan-Kettering group have appeared in both the surgical and medical literature. The most recent report from Gralla and colleagues  summarizes results with 68 patients and includes the earlier report of Martini et al. . These investigators employed high-dose cisplatin and mitomycin, with either vinblastine or vindesine, given for two to three cycles prior to surgery. These patients had no preoperative radiotherapy and all were defined as having clinical N2 disease by the presence of mediastinal adenopathy on chest X-ray. A total of 68 patients were studied and 69% responded to the chemotherapy. The same percentage of patients went on to surgery, with 19% of the resected patients and 13% of the total group attaining histologic CR. The median survival was 19.5 months and the l-year survival was 68%. This report serves as the benchmark for chemotherapy-only trials in this area.
The Dana-Farber experience
Skarin and colleagues  reported on their experience with CAP (cyclophosphamide/doxorubicin/cisplatin) in 41 patients with Stage III MO NSCLC. At 34%, their rates of partial response and CR were significantly lower than others discussed, but 90% of their patients went on to surgery and the median survival was 32 months. Elias and coworkers [ 191then increased the doses of CAP and radiotherapy in a subsequent group of patients. Unfortunately, patients who did not respond to the chemotherapy were given preoperative radiotherapy prior to an attempt at resection, which confused the survival data. Nevertheless, it appeared that 43% of their patient population responded to the CAP chemotherapy and 34% of patients could go on to surgery. Histologic CR rates were not given. The LCSG experience
LCSG has published the results of two Phase II trials on preoperative therapy for NSCLC [9,10]. The first study, reported by Eagan and associates,  explored a regimen of CAP plus 30 Gy split-course radiation in 39 patients. All patients had Stage III MO disease according to the old staging system, and 51% responded to the combined therapy, with 33% able to go on to resection. The median survival for the group was 11 months, with 43% of patients alive at 1 year. No comment was made on the extent of histologic CR. A late study by Weiden and Piantadosi [lo] explored a program similar to that of the Rush-Presbyterian regimen, consisting of continuous infusion 5-FU with cisplatin and concurrent radiotherapy (total dose, 30 Gy). Of 95 patients with Stage IIIA disease originally entered into this trial, 50% (56% of eligible patients) responded to the therapy, and 46% and 51%, respectively, were able to go on to surgery. Fifteen percent of those who went on to surgery achieved histologic CR. Considering only those patients who had a complete resection, 28% of patients had histologic CR, but only 8.4% of the total group of 95 initial patients demonstrated histologic CR. Median survival for the entire group of patients was 13 months, and the l-year survival was 53%. The Toronto experience
The University of Toronto group replicated the Memorial Sloan-Kettering Cancer Center experience using MVP (mitomycin/vindesine/cisplatin) prior to surgery . In total, 39 patients with Stage IIIA disease took part in their study, but four were ultimately inevaluable. Similar to the New York results, 69% of patients responded to the therapy, with 60% able to undergo surgery. Of those who underwent surgery, 14% (8% of the total group) attained histologic CR and the median survival had not yet been reached at the time of the report. Unfortunately, the toxicity reported for this study was significant, and several preoperative deaths were attributed to the chemotherapy. As a result, it has been recommended that patients with active pulmonary infection prior to therapy should not be started on MVP chemotherapy. (F. Shephard, M.D., personal communication, September 1990). Given the high rate of clinical and subclinical obstructive pneumonia in patients with Stage IIIA disease, however, this may be a difficult recommendation to follow.
Several other institutions have reported their experience with varying regimens. Henriquez et al.  in Spain described 53 patients treated with MVP. In this group with mixed Stages IIIA and IIIB disease, 68% responded to the chemotherapy, and 62% went on to surgery. Of the patients who underwent surgery 33% (21% of the total group) demonstrated histologic CR with a 15-month median survival; l-year survival was not given. Pujol et al.  in France described 30 patients (24 of whom were eligible) treated with cisplatin/ifosfamide/etoposide for three courses. Of the total patient group, 53% responded (67% of eligible patients) and 46% of the total group went on to surgery. Twenty-nine percent of resected patients and 13% of the total patients demonstrated histologic CR; neither median nor l-year survival was given. Wozniak et al.  at Wayne State reported on 15 surgical patients who received etoposide by continuous infusion, along with cisplatin and concurrent radiotherapy. Fiftyseven percent of patients responded, and 40% went on to surgery. Median survival had not been reached at the time of reporting, but it must be kept in mind that the study included a large number of patients with Stage IIIB disease. Vokes et al.  from the University of Chicago reported that 40% of 27 patients treated with etoposide/vindesine/cisplatin responded to therapy and 15% went on to surgery. The median survival was only 8 months. No comment was made as to why these particular results were seemingly so inferior to other reports. Chapman et al.  at the Henry Ford Hospital in Detroit have reported a 67% response among 33 patients who received combination vinblastine/cisplatin, with 77% of patients going on to surgery. Median survival had not been reached, but the l-year survival was estimated at 87%. At the Second International Conference on Neoadjuvant Therapy, Gouva et al.  reported on a regimen of bleomycin/cisplatin in 21 patients. These patients, however, were chosen on the basis of having responded to chemotherapy, so the denominator is not known. By definition, all patients underwent resection. No estimate of histologic CR was given, and median survival was listed as 17 months. LCSG randomized Phase ZZstudy
Confronted with this array of Phase II data, including results of its own two studies, LCSG set out to clarify the role of preoperative therapy with respect to standard therapy [ 111.It was recognized that the most appropriate study would compare preoperative treatment to standard therapy alone, but there was an initial disagreement over the definition of standard therapy in a potential control arm. Most investigators felt that radiotherapy alone should be considered standard treatment for patients with marginally resectable disease. The results of the Cancer and Leukemia Group B trial of vinblastine/cisplatin prior to radiotherapy were not yet mature,  but it was agreed that the best arm from that study might become the control arm for comparison to preoperative therapy. It was considered vital that comparable patients be studied in each arm. The nuances of referral patterns to radiotherapists and surgeons are such that different types of disease are referred to different practitioners. In general, for example, patients referred to radiotherapists have either bulkier disease or poorer pulmonary status than those who go to surgeons.
Thus, it would be highly unlikely that an unselected referral population from either group could be compared to patients of the other. In order to thoroughly compare preoperative therapy with radiotherapy alone, it was felt that patients must be thoroughly staged before treatment and that their treatment be randomly assigned to avoid the bias of the various modalities. LCSG launched study 88 1 with a thorough mediastinal evaluation required in advance of randomization, but it did not initially address its planned study of preoperative therapy versus standard radiotherapy. An argument supervened that required a preliminary study to determine the relative role of chemotherapy and radiotherapy in the responses seen in the various Phase II studies of preoperative therapy. The MVP data from the Memorial Sloan-Kettering Cancer Center, confirmed by the Toronto group, seemed to imply an equal efficacy for chemotherapy compared with combined modality therapy. It was argued, however, that preoperative radiation alone could offer similar response rates and that the 15% long-term survival seen by Komaki et al.  in patients with good performance status and Stage III disease treated with radiation alone was consistent with at least a 15% rate of histologic CR. Consequently, it was decided to conduct a randomized Phase II study in order to assure that comparable patients in each arm received either radiation alone (44 Gy) or MVP chemotherapy in random assignment. This evaluation was not designed to compare radiation alone with chemotherapy alone, but to ensure proper patient distribution. Each arm was to be evaluated for its ability to induce an approximately 15% rate of histologic CR. The patient group comprised 64 patients randomized to either MVP or radiotherapy in 22 fractions to both the primary tumor and mediastinum. There were surprisingly few differences in the results of the two regimens. Approximately half of the patients responded to each regimen, and median survival for the entire group - and for each of the treatment subgroups - was approximately 1 year. Only 1 patient had histologic CR and that patient received radiotherapy. There were 4 postoperative deaths among the patients who underwent surgery. These were equally distributed between the chemotherapy and radiotherapy arms. The LCSG concluded that neither regimen could be recommended as the standard for preoperative therapy.
With the exception of LCSG 88 1, all of the previously reported studies were single arm Phase II studies. All were flawed by their lack of a control arm, but none was designed as more than an exploratory study. Unfortunately, few data from these studies can be compared because of the differences in preoperative staging. Despite that drawback, however, 60-75% of patients may respond to any of several preoperative regimens, the vast majority of responders - and about half of all patients - will probably go on to surgical resection, and about 10% of patients initially entered into a study are likely to attain histologic CR. The histologic CR rates for those who actually undergo surgery are, of course, correspondingly higher. The median and l-year survival data are not yet suffciently mature to draw any conclusions. This type of therapy clearly is not appropriate for routine use in the community. Toxicity rates are substantial, even in the best of hands. There is little question that controlled trial is needed. The Southwest Oncology Group is
beginning a Phase III randomized trial comparing chemotherapy or without surgery.
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