Preoperative and Adjuvant Chemotherapy in Locally Advanced Non–Small Cell Lung Cancer

Surgical Treatment of Lung Carcinoma

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Preoperative and Adjuvant Chemotherapy in Locally Advanced Non-Small Cell Lung Cancer

Mark G. Kris, M.D.,* Richard]. Gralla, M.D.,t Nael Martini, M.D.);. Laura V. Stampleman, M.D.,§ and M. Thomasine Burke, R.N.II

Lung cancer remains the leading cause of cancer death in both men and women. 23 It is estimated that in 1987, 150,000 Americans will develop lung cancer and 136,000 will die from their disease. Although the vast majority of patients present with advanced intrathoracic or metastatic disease and experience short survival, patients who undergo complete resection of tUmors confined to the lung are a notable exception. Such patients with pathologically proven Stage I disease treated with a radical lobectomy and ~psilateral mediastinal lymph node dissection have 3-year survival rates as high as 77 per cent. 16 The results with surgery in early stage disease have led many investigators to attempt to reduce the size of locally advanced cancers in order to allow complete resection and, it is hoped, to afford those individuals with locoregional spread the same survival advantage enjoyed by patients undergoing complete resection at the time of diagnosis. In addition, patients who preoperatively are considered candidates for complete resection but who are found at surgery to have intrathoracic spread (and therefore to be at high risk for relapse despite From the Cornell University Medical College and the Memorial Sloan-Kettering Cancer Center, New York, New York

*Assistant Professor of Medicine,

and Assistant Attending Physician, Solid Tumor Service

t Associate Professor of Medicine, and Associate Attending Physician, Solid Tumor Service *Professor of Surgery, and Chief, Thoracic Surgery §Medical Oncology Research Fellow, Department of Medicine, Memorial Sloan-Kettering Cancer Center IIResearch Nurse/Clinician, Departments of Medicine and Surgery, Memorial Sloan-Kettering Cancer Center Supported in part by grant CA 05826 from the National Institutes of Health and by the TishberglMcGauley Fund. Dr. Kris is a recipient of an American Cancer Society Clinical Oncology Career Development Award.

Surgical Clinics of North America-Vol. 67, No.5, October 1987

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adequate surgery) have also been the subject of intense study. Although the approaches differ, the overall goals of both preoperative (neoadjuvant) and postoperative (adjuvant) treatment programs are the same: to confer upon individuals with intrathoracic spread the same long survival observed among patients with completely resected local lesions. Radiotherapy used in combination with potentially curative surgery has been the most widely used and studied modality. Impressive resection rates and improved survival have been demonstrated when preoperative radiation has been employed in patients with non-small cell lung cancer involving the superior sulcus. 20 A recent report also notes an apparent decrease in local recurrence rates for individuals with Stage II or III epidermoid carcinoma given mediastinal radiotherapy following a complete resection. 31 However, no survival advantage was seen for the patients receiving radiotherapy in that same randomized study. 31 Although radiotherapy, both preoperative and postoperative, clearly benefits selected patients and subsets of patients (i. e., those with superior sulcus tumors) with non-small cell lung cancer, this modality has not yet demonstrated a survival advantage for the group of lung cancer patients with locoregional spread as a whole. In general, radiation therapy is not routinely recommended either preoperatively or following a complete resection, and its use in this setting should be confined to clinical trials.

USE OF CHEMOTHERAPY WITH SURGERY With the ability of chemotherapy to induce tumor regressions in patients with metastatic non-small cell lung cancer and the inability of radiotherapy to improve resection and survival rates for most patients, there has been a long and increasing interest in using chemotherapy in the management of patients with locoregional non-small cell lung cancer. Trials of chemotherapy as an adjuvant to surgery in patients with nonsmall cell lung cancer have been reported for decades. 15 In these older trials of postoperative chemotherapy strategy, no clear benefit has emerged. In light of this experience, several pertinent questions arise: Are any further investigations indicated, and if so, are they warranted now? If more trials are performed, what groups of patients should be studied and how should such trials be designed? Can important information (i. e., survival benefit) beyond the feasibility of the adjuvant and preoperative approach be obtained?

CURRENT TRIALS OF POSTOPERATIVE CHEMOTHERAPY Two recent studies have been of particular interest. The Lung Cancer Study Group reported its results in patients with Stage II (hilar-Nllymph nodes involved or Stage III (ipsilateral mediastinal-N2-lymph nodes).8 One hundred thirty patients were randomly assigned to receive either immunotherapy with BCG plus levamisole, or CAP (cyclophosphamide, doxorubicin, cisplatin) chemotherapy. A significant difference in the

CHEMOTHERAPY IN LOCALLY ADVANCED NON-SMALL CELL LUNG CANCER

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relapse rate, favoring the chemotherapy arm, was observed. It has been suggested that the results of this study might be explained by adverse effects from the BCG plus levamisole rather than by improvement from chemotherapy. Moreover, the results obtained were seen in the entire group composed of both Stage II and III patients. The two groups have different 5-year survival percentages (43 per cent and 31 per cent, respectively),18 and it may not be appropriate to analyze the two groups together. Nonetheless, this is a well-conducted study that indicates a modest but significant improvement for patients receiving postoperative (adjuvant) chemotherapy. A similar result has been indicated in a preliminary report from Montreal. [ In this trial, patients with Stage II and III epidermoid carcinoma treated by resection were randomly assigned to receive either radiation therapy or radiation plus vindesine and cisplatin chemotherapy. At the time of reporting, the relapse rate and survival estimates favor the arm including chemotherapy. We await results of the completed trial, with greater patient accession and longer follow-up, to determine the value of this regimen for this patient population. At Memorial Sloan-Kettering Cancer Center, a study similar to that in Montreal continues to enlist patients. Eligibilty for this trial includes patients with operable Stage III (N2) disease of all histologic types of nonsmall cell lung cancer. This trial has yet to be analyzed by treatment arm (mediastinal radiation therapy alone versus radiation therapy plus vindesine and cisplatin), because it is still in progress. To date, however, some interesting observations have been made. The brain has been the most common site of first relapse in patients with adenocarcinoma, but recurrence in the brain has been unusual in those with an epidermoid histology. Similar findings were noted earlier by the Lung Cancer Study Groups and have important implications for this approach in patients with adenocarcinoma. A~ditionally, as observed in prior studies from our center,17 improved survival continues to be observed for those patients who are able to have both their primary tumors and their mediastinal lymph nodes completely resected, particularly those with only one level of malignant involvement of the mediastinal nodes. The results of these three studies highlight several points concerning the current role of postoperative (adjuvant) chemotherapy in patients with non-small cell lung cancer that was completely resected at surgery. First, a complete intraoperative assessment of the extent of disease, using the current staging system, [8 and an accurate determination of the histologic subtype of non-small cell lung cancer, using WHO criteria,33 are essential if the results of postoperative chemotherapy studies are to be compared. Second, all three of the studies mentioned employ some of the more active chemotherapy regimens. Only through the use of the most effective drug programs available can we first establish the validity of the concept of postoperative chemotherapy. Even if only modest gains are achieved in these trials, future treatment regimens of greater activity could be expected to result in further improvement. Third, the most active chemotherapy programs at present carry with them the greatest potential for acute and long-term adverse effects. Physicians conducting such trials must pay close

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Table 1. Chemotherapeutic Agents with Reported Major Objective Response Rates Higher Than 15 Per Cent in Non-Small Cell Lung Cancer* OBSERVED MAJOR

Cisplatin Ifosfamide Mitomycin Vinblastine Vindesine

PATlEl'."TS

TRIALS

RESPONSE RATE (%)

305 130 88 22 370

8 2 3 1 11

16 27 17 27 16

*These agents have been tested in at least fourteen patients during the period 19701983. See Reference 10.

attention to the control of treatment-associated side effects to maintain patient comfort and quality of life and at the same time assure adequate compliance with the overall treatment program. Fourth, if the central nervous system is indeed a "sanctuary site" leading to relapse in patients with adenocarcinoma, chemotherapy, which does not readily penetrate the blood-brain barrier, cannot be expected to adequately control disease at this site. Central nervous system "prophylaxis" may be a consideration in future studies involving this group of patients.

PREOPERATIVE CHEMOTHERAPY Lessons learned from chemotherapy of advanced non-small cell lung cancer and from the ongoing postoperative experience can be applied to preoperative chemotherapy studies. Accurate and complete staging, using the recent revision of the TNM system, is mandatory. Careful attention must also be paid to the presence or absence of the known independent, pretreatment prognostic factors that determine response and survival in patients with inoperable lung cancer irrespective of the therapy program employed. Several interesting reports concerning these factors are available. 5, 14, 19, 27 These studies, however, also include patients with distant metastases in addition to those individuals with inoperable intrathoracic disease only. Although no new agents active against non-small cell lung cancer have emerged in the 1980s, many chemotherapy combinations with higher response rates have been identified. Examination of the results of single agent phase II studies since 1970 shows that five agents (of 51 studied) have response rates higher than 15 per cent: cisplatin, mitomycin, vindesine, vinblastine, and possibly ifosfamide (Table 1).10 Regimens containing cisplatin have the highest and most reproducible response rates. 7 Especially interesting are the MVP combinations (mitomycin, vinca alkaloid, cisplatinj39, 12, 21, 22, 25 and regimens with fluorouracil infusions plus cisplatin. 28 , 32 To date, all large-scale MVP studies have reported response rates in excess of 30 per cent, with several trials noting substantially higher rates. Several factors may explain the discrepancies in response rates among the various MVP trials. Those studies with higher rates (50 to 60 per cent) tend to use the individual agents at or near the full doses established to be effective in

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Table 2. Major Objective Response Rates with Newer Cisplatin-Containing Combination Chemotherapy Regimens in Non-Small Cell Lung Cancer OBSERVED MAJOR REGIMEN

Cisplatin (120 mg/m2) + vindesine + mitomycin Cisplatin (100 mg/m2) + vinblastine + mitomycin Cisplatin (75 mg/m 2) + vinblastine + mitomycin Cisplatin (60 mg/m 2) + vindesine + mitomycin Cisplatin (40 mg/m 2) + vinblastine + mitomycin Cisplatin (100 mg/m 2) + fluorouracil + methotrexate Cisplatin (60 mg/m2) + fluorouracil + etoposide + vincristine

PATIENTS

RESPONSE RATE (%)

REFERENCE

87

60

Kris et al. l2

45

78

Folman et al. 3

26

46

Schulman et al?2

37

35

Joss et al. 9

121

31

Rukdeschel et al?l

21

66

Wheeler et al. 32

24

33

Yanagihara et al. 34

earlier phase II trials and in schedules similar to those used in "positive" studies. 3, 12 The trials with lower rates (30 to 40 per cent) employ doses lower than those reported to be active in phase II trials (one third to one half the doses used in the MVP studies with the higher response rates) and occasionally with infrequent and untested dosing schedules. 9• 21 Although the higher dose regimens have the potential to cause a greater degree of treatment-related toxicity, careful attention to supportive care through the judicious use of combination antiemetics l l and hydration/diuresis to prevent nephrotoxicity6 can allow the administration of the MVP combinations with maximum patient comfort and safety. Regimens containing multiple-day infusions of fluorouracil with cisplatin, although less well tested than MVP regimens, have been reported to have high response rates and manageable toxicity. 28. 34 If these rates can be confirmed, fluorouracil-cisplatin regimens may also be useful for preoperative and adjuvant trials. The main factors in selecting a chemotherapy regimen for use in preoperative combined modality studies are response rate and the lack of serious acute or chronic treatment-related toxicity. The preoperative approach can also assist in the development of chemotherapy programs in that it allows for the "in vivo" determination of tumor sensitivity. Moreover, regimens may be specifically designed for use prior to surgery. For example, "intensification" of the most active current regimens may increase the number of responsive tumors and improve the complete resection rate. Although the control of side effects is always a major concern, short-term toxicity in only one or two preoperative cycles becomes more acceptable if lasting benefit can be demonstrated, The types of chemotherapy regimens listed in Table 2 appear to be well suited for a preoperative approach. The response rates are sufficiently high (50 per cent or greater in several trials) so that a substantial proportion of patients so treated would experience major response. This would allow

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Table 3. Results of Recent Preoperative Chemotherapy Trials in Patients with Non-Small Cell Lung Cancer

CHEMOTHERAPY REGIMEN(S)

CAP + radiotherapy Mitomycin + vinblastine + cisplatin Mitomycin + vinblastine + cisplatin Etoposide + vindesine + cisplatin Various regimens containing cisplatin Fluorouracil + cisplatin + radiotherapy Vindesine + cisplatin + radiotherapy Mitomycin + vinblastine or vindesine + cisplatin

PATIENTS

CHEMO· THERAPY MAJOR RESPONSE RATE (%)

COMPLETE RESECTION

12 17

50 76

ll/12 2/3

28

65

20

70

44

MEDIAN SURVIVAL

(mo)

REFERENCE

9+ 8

Skarin et aI. 24 Folman et al. 3

3/4

22

Spain et aI.25

3/3

9

Bitran et aI. 2

29/-

30.5

Takita et al. 2.

59

61

27/33

14

Trybula et al. 30

22

55

12/13

14+

Strauss et aI.28

20

65

8110

15+

Kris et al. 13

testing of the hypothesis that the complete resection rate of advanced intrathoracic tumors could be improved by a response to chemotherapy. With only a short course of chemotherapy, pulmonary toxicity threatening operability is unlikely. Our experience and that of others has indicated that the use of preoperative mitomycin (8 mg per m2 ), with concomitant steroid administration, is rarely associated with pulmonary problems. 3, 13, 25 Only after sufficiently active chemotherapy regimens are identified and resection rates are increased will it be reasonable to pose questions concerning survival.

RESULTS OF PREOPERATIVE CHEMOTHERAPY TRIALS Listed in Table 3 are several recent reports of trials employing preoperative chemotherapy. Preoperative radiotherapy was also used in three of the studies. Although all of the above reports are preliminary, the overall results demonstrate two interesting points concerning this approach. Each study used a cisplatin-containing chemotherapy regimen and achieved a major objective response rate of at least 50 per cent with chemotherapy alone. Surgery following chemotherapy appears to be technically feasible and safe and is very likely to result in a complete resection when attempted. This latter fact is especially encouraging, in that a basic criterion for entering a patient in any of these programs was unresectability at diagnosis. CURRENT STATUS OF PREOPERATIVE CHEMOTHERAPY Because each of the current trials represents a feasibility study, it is appropriate that all are nonrandomized and that concurrent control groups

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are not included. Moreover, too many questions remain to be answered before randomized trials are warranted. Such unresolved issues include: Which chemotherapy regimen is best for preoperative use? How many courses of chemotherapy should be given prior to surgery? Should the number of chemotherapy courses be determined by the degree of objective regression observed with each chemotherapy course? How many cycles of chemotherapy should be given postoperatively, and should the decision be dictated by the operative findings? Is there a role for radiotherapy before, during, or after operation? If so, what doses, fractions, schedules, particles, and radiosensitizers should be employed? Even the most appropriate surgical approach and extent of resection have yet to be determined. With so many unresolved issues, more studies will be required, and the data from the current trials will need to mature before randomized trials can begin. Until the completion of the randomized trials of preoperative chemotherapy, its use should be confined only to controlled clinical trials. Despite the promise of preoperative therapy, it cannot as yet be recommended as standard treatment for patients with locally advanced intrathoracic non-small cell lung cancer deemed unresectable according to present standards of care.

CONCLUSIONS Although lung cancer remains a difficult and deadly illness, recent developments provide hope that control and cure are realistic goals. Advances in knowledge of the biology of lung cancer and potential new systemic therapies as well as refinements in surgery, radiation, and supportive care have contributed to an improved outlook. Combined modality therapy, which utilizes the best of surgery, radiation, and chemotherapy, provides an important area for investigation during the next several years. The results of the recently reported trials discussed indicate that the adjuvant approach deserves to be an area of active investigation in patients with non-small cell lung cancer. These trials are interesting and provocative, but there is still not sufficient evidence to recommend either preoperative or postoperative chemotherapy as part of standard practice. Although far from ideal, the most effective of currently available chemotherapy regimens are sufficiently active to be useful in combined modality programs. A methodical clinical research approach is needed to determine the relative contributions of each of the treatment modalities. Chemotherapy followed by radiation therapy is as valid an approach as preoperative chemotherapy. However, ifradiotherapy and chemotherapy are both given before surgery, it will be difficult to know whether both preoperative treatments are necessary. A reliable tumor marker would be particularly valuable in indicating when maximal response has been achieved prior to surgery. Although not the primary goal of investigations of preoperative chemotherapy, this approach allows for a pathologic determination of the effects of newer chemotherapy regimens. This knowledge may aid in more accurate assessments of the efficacy of systemic treatments in general. For the promise of multimodality therapy to be realized, medical,

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radiation, and surgical oncologists must test their respective approaches and decide which methods are most appropriate. The results of recent studies have been favorable, but complex questions related to the choice of which patient groups are best for preoperative and postoperative treatment and to the proper timing of the different modalities remain to be answered.

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20.

21. 22. 23. 24. 25.

26.

27. 28.

29. 30. 31. 32. 33. 34.

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pretreatment clinical characteristics in patients with advanced non-small cell lung cancer treated with combination chemotherapy. J Clin Oncol 4:1604-1614, 1986 Paulson DL: Combined pre-operative irradiation and extended resection for carcinoma in the superior pulmonary sulcus. In Bonica JJ, Venta-Fridda V, Pagni CA (eds): Management of Superior Sulcus Syndrome (Pancoast Syndrome). (Advances in Pain Research Therapy, vol 4). New York, Raven Press, 1982, pp 47-63 Ruckdeschel JC, Finkelstein DM, Ettinger DS, et al: A randomized trial of the four most active regimens for metastatic non-small cell lung cancer. J Clin OncoI4:14-22, 1986 Schulman P, Budman DR, Weiselberg L, et al: Phase II trial of mitomycin, vinblastine, and cisplatin (MVP) in non-small cell bronchogenic carcinoma. Cancer Treat Rep 67:943-945, 1983 Silverberg E, Lubera JA: A review of American Cancer Society estimates of cancer cases and deaths. CA 33:2-25, 1986 Skarin A, Veeder M, Malcolm A, et al: Chemotherapy (CAP) prior to radiotherapy (RT) and surgery in marginally resectable non-small cell lung cancer (NSCLC) [abstract]. Proc Am Soc Clin Oncol1:143, 1982 Spain R, Anderson P, Speer J, et al: Improved survival with mitomycin-C, cis-platinum and continuous vinblastine infusion plus radiation therapy or surgery over RT alone for stage III limited, initially inoperable, non-small cell lung cancer [abstract]. In Proceedings of the IV World Conference on Lung Cancer, Toronto, Canada, 1985, p 33 Spain R, Cullen S, Kircher T, et al: Dexamethasone prophylaxis of lung toxicity induced by mitomycin-C, cis-platinum, and continuous vinblastine infusion in stage III nonsmall cell lung cancer [abstract]. In Proceedings of the IV World Conference on Lung Cancer, Toronto, Canada, 1985, p 109 Stanley K: Prognostic factors for survival in patients with inoperable lung cancer. JNCI 65:25-32, 1980 Strauss G, Sherman D, Schwartz J, et al: Combined modality therapy for regionally advanced stage III non-small cell carcinoma of the lung employing neoadjuvant chemotherapy, radiotherapy, and surgery [abstract]. Proc Am Soc Clin Oncol 5:172, 1986 Takita H, Regal AM, Antkowiak JG, et al: Chemotherapy followed by lung resection in inoperable non-small cell lung carcinomas due to locally far-advanced disease. Cancer 57:630-635, 11)86 Trybula M, Taylor SG IV, Bonomi P, et al: Preoperative simultaneous cisplatin/5fluorouracil and radiotherapy in clinical stage III, non-small cell bronchogenic carcinoma [abstract]. Proc Am Soc Clin Oncol 4:182, 1985 Weisenburger TH, Gail M, Holmes EC: Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. N Eng! J Med 315:1377-1381, 1986 Wheeler C, Ervin T, Come S, et al: Platinum, 5-FU and methotrexate: An active regimen in non-small cell lung cancer [abstract]. Proc Am Soc Clin Oncol 5:181, 1986 World Health Organization: HistolOgical typing of lung tumors. In Kreyberg L (ed): International Histologic Classification of Tumors, vol 1. Geneva, WHO, 1967, pp 1926 Yanagihara R, Riviera R, Kummet T: 5-Fluorouracil, cisplatin, etoposide, and vincristine chemotherapy in non-small cell lung cancer [abstract]. Proc Am Soc Clin Oncol 5:173, 1986

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