Surgical Adjuvant Therapy for Lung Cancer

Symposium on Adjuvant Treatment of Cancer

Surgical Adjuvant Therapy for Lung Cancer

E. Carmack Holmes, M.D.*

Lung cancer is the number one killer among cancers in the United States. An estimated 110,000 patients will have succumbed to this disease during the year 1981. Although many advances have been made in the treatment of lung cancer in the areas of diagnosis and staging, only recently have improvements in therapy become available as adjunctive management. In recent years, with the advent of careful intraoperative staging, it has become clear that the five-year survival rate following resection of Stage I lung cancer is higher than was previously reported. Sixty to 70 per cent of patients with Stage I lung cancer will survive five years following surgery, and indeed, those with T 1 N 0 lesions can anticipate an 80 per cent five-year survival. 13' 26 These studies indicate the critical importance of careful intraoperative staging, including lymph node sampling, in order to determine accurately the TMN classification. If this is done, it is clear that patients with T 1 N 0 lesions do not require adjuvant therapy, and only the more advanced Stage I tumors will benefit from adjuvant therapy (T1 N 1 and T 2 N0 ). The more advanced resectable lesions (Stage II and Stage III tumors) have a poor survival following surgery, however, and systemic adjuvant therapy is desirable. Since the first site of recurrence following surgery is outside the thorax in 75 per cent of cases, it is clear that the major thrust in surgical therapy should be directed toward systemic therapy. For these reasons, immunotherapy and chemotherapy have been extensively investigated as adjuncts to surgery. Unfortunately, sophisticated immunotherapeutic agents have not become available, and the mechanism of action of immunotherapy is poorly understood. Therefore, the clinical trials using immunotherapy have not been based on a clear understanding of the immunologic relationship between the host and the tumor. Unfortunately, many of the immunotherapy trials have relied on historical controls rather than concomitant randomized controls and this presents additional problems. Chemotherapy has been evaluated extensively as an adjunct to surgery over the last 15 years. Unfortunately, through most of this period, the chemotherapy available for the treatment of lung cancer was not very effective, with response rates of only 15 to 20 per cent. It is therefore not surprising that many of these trials have been

*Professor of Surgery, Division of Oncology, UCLA School of Medicine, Los Angeles, California

Surgical Clinics of North America-Vol. 61, No. 6, December 1981

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negative. However, the advent of combination chemotherapy for bronchogenic carcinoma has resulted in response rates considerably higher (30 to 40 per cent), and surgical adjuvant trials using these combination chemotherapeutic agents are promising.•· 10

SURGICAL ADJUVANT CHEMOTHERAPY Surgical adjuvant chemotherapy has been extensively investigated by the VA Group. 7 • 22 Most of these studies involved single chemotherapeutic agents such as cyclophosphamide (Cytoxan), nitrogen mustard, methotrexate, and hexamethylenamine. Since the response rates to single chemotherapeutic agents have varied between 10 and 20 per cent, it is not surprising that the clinical trials evaluating these agents have been negative. Indeed, in several trials, the group receiving the agent did worse than the group treated with surgery alone. However, more recently, combination chemotherapy regimens have been developed. These combination regimens include various combinations of adriamycin, Cytoxan, vincristine, cis-platinum, and CCNU. With these combined regimens, response rates have been significantly improved, with rates as high as 40 per cent having been reported. 4 · 10· 2 ' It is therefore appropriate that these new and more effective combination chemotherapy regimens be evaluated in a surgical adjuvant setting. Although no trials evaluating these combination chemotherapeutic agents have been completed, preliminary trials are encouraging. 17 Takita has investigated combination chemotherapy given preoperatively and has found that in some patients with advanced lung cancer the lesion can be converted to a resectable mass by the preoperative administration of chemotherapy. 24 Although these studies are preliminary, they are very encouraging. Obviously, one of the more exciting areas in the treatment of lung cancer is the potential use of combination chemotherapy in association with surgery, either in the preoperative period or in the postoperative period, or at both times.

SURGICAL ADJUVANT IMMUNOTHERAPY As indicated earlier in this article, most of the clinical trials using immunotherapy that have been reported to date have been empirical, and in many studies, the appropriate controls have not been employed. However, a number of studies have been performed. Most of these studies have involved the use of bacillus Calmette-Guerin (BCG) as an immunotherapeutic agent administered following surgical resection. BCG is capable of nonspecifically stimulating the immune response in animals; however, there is no evidence that BCG is capable of correcting immunosuppression. BCG has been evaluated in the treatment of lung cancer by three different routes, intradermal, intrapleural, and intralesional (Table 1). Intradermal BCG as an adjunct to surgery has been used in several studies. In the study reported by Perlin, patients were treated with intradermal BCG alone, BCG given intradermally with a tumor cell vaccine, or no further treatment following resection. 18 BCG did result in a significant prolongation of the disease-free interval in patients with Stage I lung cancer, but there was no advantage with the addition of the tumor cell vaccine. Pouillart gave patients BCG intradermally following surgery or no further treatment. 19 Patients with Stage I disease appeared to have a

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Table 1.

Trials Evaluating BCG as Immunotherapy for Lung Cancer AUTHOR

Perlin 18 Pouillart 19 Edwards5 Roscoe 20

McKneally 15 Lowe 11 Wright"7 LCSCt 12 Holmes8

BCG ROUTE*

ID BCG + TCV vs. ID BCG vs. control ID BCG vs. control ID BCG vs. control ID BCG vs. control IP BCC + INH vs. INH alone IP BCC + INH vs. INH placebo IP BCG vs. IP BCC + levamisole vs. control IP BCG + INH vs. INH placebo IL BCG

*ID = intradermal; IP = intrapleural; IL = intralesional; TCV = tumor cell vaccine; INH = isoniazid. tLung Cancer Study Croup

prolongation in survival; however, this prolongation was quite modest. In another study, one dose of BCG was given intradermally 10 days following resection, and these patients were compared with historical controls. Although there was a slight difference in favor of the BCG-treated group, this difference was not statistically significant. 5 Roscoe also evaluated intradermal BCG in patients undergoing resection for lung cancer and found no difference in the control group and the group receiving BCG!0 These studies are difficult to interpret because the patients were not accurately staged intraoperatively and were not, therefore, stratified for the presence or absence of positive hilar and mediastinal nodes. This lack of careful intraoperative staging and the frequent use of historical controls makes the interpretation of these studies very difficult. However, the results do suggest an affect of intradermal BCG, but this effect is very modest and is not sufficiently potent to make an appreciable impact on survival. BCG has also been evaluated by the intrapleural route. In these studies, BCG is given intrapleurally postoperatively by way of the chest tubes. The first of these studies was performed by McKneally and his associates. 15 They randomized 169 patients to receive intrapleural BCG plus isoniazid or isoniazid alone. At three years, there was a 62 per cent recurrence rate in the control group and a 33 per cent recurrence rate in the group treated with BCG only among patients with Stage I resected disease. There was no benefit in patients with Stage II and Stage III disease. A second study in Britain also randomized patients to receive intrapleural BCG and no further treatment. The control patients did not receive isoniazid but isoniazid placebo. Unfortunately, the patients in this study were not stratified for histologic type or stage of the disease prior to randomization and the duration of follow-up is short. However, these investigators have found no difference in survival when all the patients were considered and no difference in survival in patients with Stage I disease. 11 A third study by Wright and associates randomized patients postoperatively to receive BCG and levamisole, BCG alone, or no further treatment. Seventythree per cent of the patients in the group given BCG alone are alive at the end of three years, as compared with 54 per cent of the placebo group. 27 Finally, the Lung Cancer Study Group in the United States has recently completed a study in which patients were randomized to receive intrapleural BCG plus isoniazid or isoniazid placebo. At a median follow-up of 18 months, there is no difference in survival between the two groups. 12 Therefore, it appears that the initial enthusiasm for the

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use of intrapleural BCG as a postoperative surgical adjunct in lung cancer cannot be substantiated. Perhaps other routes of BCG, such as intralesional administration, may demonstrate a more impressive therapeutic effect. Studies in animal models as well as experiences with BCG immunotherapy in humans have indicated that the most effective way to induce tumor immunity with BCG is by direct intratumor injection. Intralesional BCG is capable of establishing potent systemic tumor immunity in animal models and induces regression of cutaneous malignant tumors in humans. To date, the experience has indicated that endobronchial tumors can be injected safely with BCG and this technique can control hemoptysis and cause regression of the tumor. 9 The use of BCG preoperatively, by the direct intralesional route in patients with lung cancer followed by resection two weeks after injection, is currently undergoing clinical trials. 14 This form of BCG immunotherapy has considerable promise, since it is the most effective way to administer immunotherapy in animal models and results in an intense lymphocyte infiltration into the tumor. The role of BCG immunotherapy as an adjunct to surgical resection certainly remains unclear. It appears that the intradermal route and the intrapleural route do not engender sufficient antitumor effects· to have a measurable impact on survival. Whether or not intralesional BCG will result in an improvement over these other routes remains to be seen. Specific immunotherapy involves the use of tumor cells containing tumor-associated antigens or fractions of tumor cells in various degrees of purification. The use of specific immunotherapy has not been extensively evaluated because of the difficulty in purification and identification of tumor antigens. A few studies have been performed that are promising, but there have been considerable difficulties in interpreting these studies because of the lack of adequate controls and proper stratification of the patients. 23• 25 Another agent that has been evaluated as a surgical adjuvant to pulmonary resection is levamisole. Levamisole has been widely used as an anthelmintic agent in animals and humans, and it is believed that levamisole is a potent immunopotentiating agent or an antianergic agent. Two prospective randomized studies have been performed evaluating this agent in patients with lung cancer. In these studies, levamisole was given to the patient preoperatively, then continued postoperatively. 1' 2 In the first study, levamisole did have a beneficial effect in patients who weighed less than 70 kg, leading the investigators to speculate that an inadequate dose of levamisole had been employed in the study for patients who weighed more than 70 kg. It was recommended, therefore, that levamisole be administered in a dose of at least 2.5 mg per kg. The second study, in which the dose was adjusted to 2.5 mg per kg, showed no superiority of levamisole over the control group. The precise role of levamisole in the treatment of lung cancer, therefore, remains controversial and unclear. Levamisole does appear to be effective in combination with chemotherapy in other solid tumors, and the immunorestorative properties of levamisole make it an attractive agent for the treatment of lung cancer, since these patients are quite immunosuppressed. However, at the current time, the value of levamisole as a surgical adjunct in the treatment of lung cancer is very much open to question.

SUMMARY Many patients with lung cancer have disease disseminated beyond the thorax at the time of presentation. In patients with resectable disease, the first site of

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recurrence following surgery is frequently outside of the thorax. Therefore, the major problem in lung cancer is control of distant metastatic disease rather than failure to control local disease. For these reasons, adjuvant therapy has been directed primarily toward the microscopic systemic disease. Immunotherapy has shown some promise as a systemic agent in lung cancer, but it is clear from the early trials that the effect of immunotherapy is marginal. Newer types of immunotherapy are being developed, and at the present time, intralesional BCG immunotherapy holds considerable promise. However, the ultimate success of immunotherapy will rely on the development of better immunotherapeutic agents and a better knowledge of the immunologic relationship between the host and the tumor. Studies evaluating chemotherapy as a systemic adjuvant to surgery have not been promising in the past. However, new combination chemotherapeutic regimens that have a response rate of 40 per cent in advanced disease and that have acceptable toxicity offer considerable promise in the area of adjuvant therapy. Certainly adjuvant chemotherapy has been successful in sarcomas, germ cell tumors of the testes, Wilms' tumors, and breast cancer, as well as other solid tumors, and it is reasonable to anticipate that effective combination chemotherapy will be developed that will be useful as a surgical adjuvant in lung cancer. Several trials are currently in progress evaluating preoperative chemotherapy in advanced resectable disease and also postoperative adjuvant therapy following total resection. These studies are now in progress and the preliminary results are encouraging, but the definitive statement cannot yet be made.

REFERENCES l. Amerey, W. K.: A placebo-controlled levamisole study in resectable lung cancer. In Terry, W. D., and

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Windhorst, D. (eds.): Immunotherapy of Cancer-Present Status of Trials in Man. New York, Raven Press, 1978. Anthony, H. M., Mearns, A. J., Mason, M. K., et al.: Levamisole in surgery of bronchial carcinoma patients-increase in deaths from cardiorespiratory failure. Thorax, 34:4-12, 1979. Bast, R. C., Zbar, B., Borsos, T., et al.: BCG in cancer. N. Engl. J. Med., 290:13-20, 1974. Eagan, R. T., Engle, J. M., and Frytak, S.: Platinum base polychemotherapy versus dianhydrogalactitol in advanced non-small cell lung cancer. Cancer Treat. Rep., 61:1339, 1977. Edwards, F. R., and Whitwell, F.: Use of BCG as an immunostimulant in the surgical treatment of carcinoma of the lung-a five year follow-up report. Thorax, 33:250-252, 1978. Hanna, M. G., Jr.: Immunological aspects of BCG mediated regression of established tumors and metastases in guinea pigs. Semin. Oncol., 1:319--335, 1974. Higgins, G. A.: Use of chemotherapy as an adjunct to surgery from bronchogenic carcinoma. Cancer, 30:1383, 1972. Holmes, E. C.: Immunotherapy of solid tumors. SuRe. CLIN. NoRTH AM., 59:371--380, 1979. Holmes, E. C., Ramming, K. P., Bein, M. E., et al.: Intralesional BCG immunotherapy of pulmonary tumors. J. Thorac. Cardiovasc. Surg., 77:362--368, 1979. Livingston, R. B.: Combination chemotherapy of bronchogenic carcinoma-non-oat cell. Cancer Treat. Rev., 4:153, 1977. Lowe, J., Shore, D. F., lies, P. B., et al.: Intrapleural BCG in operative lung cancer. Lancet, 1:11-14, 1980. Lung Cancer Study Group: Surgical adjuvant intrapleural BCG treatment for Stage I, non-small cell lung cancer. J. Thorac. Cardiovasc. Surg., in press. Martini, N., and Beattie, E. J.: Results of surgical treatment in Stage I lung cancer. J. Thorac. Cardiovasc. Surg., 74:499--504, 1977. Matthay, R. A., Mahler, D. A., Mitchel, M. S., et al.: Intratumoral BCG immunotherapy prior to surgery fur lung cancer. In Rosenberg, S. (ed.): Immunotherapy of Cancer-Present Status of Trials in Man. New York, Raven Press, 1980. McKneally, M. F., Maver, M., Lininger, L., et al.: Four year follow-up of the Albany experience with intrapleural BCG in lung cancer. J. Thorac. Cardiovasc. Surg., 81:45-492, 1981. Nathanson, L.: Use of BCG in treatment of human neoplasms-a review. Semin. Oncol., 1:337--350, 1974. National Lung Cancer Study Group: Surgical adjuvant immunotherapy in non-oat cell carcinoma. In Rosenburg, S. (ed.): Immunotherapy of Cancer-Present Status ofTrials in Man. New York, Raven Press, 1980.

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18. Perlin, E., Weise, J. L., Heim, W., et al.: Immunotherapy of carcinoma of the lung with BCG and allogeneic tumor cells. In Crispen, R. G. (ed.): Neoplasm Immunity: Solid Tumor Therapy. Proceedings of Chicago Symposium. Philadelphia, Franklin Institute Press, 1977. 19. Pouillart, P., Mathe, G., Palangie, T., eta!.: Trials of BCG immunotherapy in the treatment of resectable squamous cell carcinoma of the bronchus (Stage I and II). Cancer Immunol. Immunother. I:27l-273, 1976. 20. Roscoe, P., Pearce, S., Ludgate, S., et a!.: A control trial of BCG immunotherapy in bronchogenic carcinoma treated by surgical resection. Cancer Immunol. Immunother., 3:115--118, 1977. 21. Sarna, G. T., Holmes, E. C., and Petrovich, Z.: Lung cancer. In Haskell, C. (ed.): Cancer Treatment. Philadelphia, W. B. Saunders Co., 1980. 22. Shields, T. W.: Adjuvant cancer chemotherapy after resection of carcinoma of the lung. Cancer, 40:2057, 1977. 23. Stewart, T. H. M., Hollingshead, A., Harris, J., eta!.: Survival study of specific active immunotherapy in lung cancer. In Terry, W. D., and Windhorst, D. (eds.): Immunotherapy of Cancer-Present Status of Trials in Man. New York, Raven Press, 1978. 24. Takita, H., Hollingshead, A. C., Rizzo, D. J., eta!.: Treatment of inoperable lung carcinoma: A combined modality approach. Ann. Thorac. Surg., 28:363-368, 1979. 25. Takita, H., Takaada, M., Minowada, J., eta!. Adjuvant immunotherapy of Stage III lung cancer. In Terry, W. D., and Windhorst, D. (eds.): Immunotherapy of Cancer-Present Status of Trials in Man. New York, Raven Press, 1978. 26. Williams, D. E., Pairolero, P. C., Davis, C. S., et al.: Survival of patients surgically treated for Stage I lung cancer. J. Thorac. Cardiovasc. Surg., 82:70--16, 1981. 27. Wright, P. W., Hill, L. D., Peterson, A. V., eta!.: Host response to purified protein derivative of tuberculin predicts outcome in patients receiving intrapleural BCG and levamisole for resectable non-small cell lung cancer. Proc. Am. Assoc. Cancer Res., 21:230, 1980. Division of Oncology UCLA School of Medicine Los Angeles, California 90024