Treatment of Inoperable Lung Carcinoma: A Combined Modality Approach

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1 Treatment of Inoperable ung Carcinoma: A Combined Modality Approach Hiroshi Takita, M.D., Ariel C. Hollinshead, h.d., Donna J. Rizzo, R.N., Christine M. Kramer, M.S., Tah Y. Chen, M.D., Joginder N. Bhayana, M.D., and Francis Edgerton, B.S. ABSTRACT Twenty-four patients with inoperable lung carcinoma other than of the small cell type who received cis diamminedichloro platinum (III-based combination chemotherapy were further treated with all available treatment modalities: radiation therapy, lung resection, chemotherapy, and immunotherapy. There were 2 operative deaths, and 2 patients died and 8 months postoperatively of cardiac causes. ostmortem examination on these 4 patients revealed no evidence of residual tumor. The remaining 20 patients are alive 7 to 33 months fram the onset of chemotherapy and 4 to 27 months following lung resection. These results, although preliminary, are encouraging, and further study is in progress. In spite of recent progress, the only curative therapy for lung carcinoma that is not of the small cell variety remains lung resection [lo]. Since 17, various cis diamminedichloro platinum () (DD)-based combination chemotherapies have been given as primary treatment of inoperable lung carcinomas not of the small cell type, and response rates of 18.2 to 5.7% have been observed. The responders were further treated with a combination of all available treatment modalities: operation, chemotherapy, radiation therapy, and immunotherapy. Our experience is summarized in this report. From the Department of Thoracic Surgery, Roswell ark Memorial Institute, Buffalo, the Department of Medicine, George Washington University, Washington, DC, and the Surgical Service, Veterans Administration Hospital, Buffalo, NY. Supported in part by National Cancer Institute Research Contract N01-CB resented at the Fifteenth Annual Meeting of The Society of Thoracic Surgeons, Jan 15-17, 17, hoenix, AZ. Address reprint requests to Dr. Takita, Department of Thoracic Surgery, Roswell ark Memorial Institute, Elm St, Buffalo, NY Material and Methods One hundred twenty-eight patients with inoperable lung carcinoma other than of the small cell type were treated with cis diamminedichloro platinum () (DD)-based combination chemotherapy regimens. Regimen A consisted of DD, adriamycin (ADM), Cytoxan (cyclophosphamide) (CTX), and vincristine (VCT)[2, 121; Regimen B1, DD, ADM, and VCT [El; Regimen B2, DD, 1-(2 chloroethy1)-3- (cyclohexyl-1-nitrosourea) (CCNU), and VCT [12]; Regimen B3, DD, CTX, and VCT [121; Regimen C, DD, ADM, CTX, CCNU, and VCT [12, 131; and Regimen D, DD, ADM, CTX, CCNU, VCT, and methotrexate. Regimen A gave a response rate (more than 50% regression of the lesion) of 20.4% (10 of 4 patients), and in 3 patients the lesion became resectable. Regimen B1 gave a response rate of 27.3% (3 of ll), and 2 patients became resectable. Regimen B2 gave a response rate of 18.8% (3 of 1) and 2 patients became resectable. Regimen 83 gave a response rate of 18.2% (2 of ll), but none became resectable. Regimen C gave a response rate of 5.7% (23 of 35), and 12 patients became resectable. Regimen D gave a response rate of 33.3% (2 of ), and 2 patients became resectable. In 2 patients following Regimen C, the lesion remained static and the general condition of the patients appeared improved while on chemotherapy. In another patient also following Regimen C, the disease progressed while the patient was being treated with chemotherapy, but subsequent radiation therapy reduced the size of the tumor considerably. These 3 patients also had radical lung resection. Thus, a total of 24 patients originally considered to be inoperable, following chemotherapy, underwent lung resection. The age of these 24 patients ranged from 43 to years (median, 57.5 years), and all but by Hiroshi Takita

2 34 The Annals of Thoracic Surgery Vol 28 No 4 October 17 were men. Ten patients had squamous cell carcinoma, 7 had adenocarcinoma, 3 had bronchioalveolar carcinoma, 3 had large cell carcinoma, and 1 had mixed adenosquamous cell carcinoma. Six patients had undergone previous exploratory thoracotomy, and the lesion was found to be unresectable prior to chemotherapy. One patient had Stage I1 squamous cell carcinoma and was originally thought unable to survive a right pneumonectomy because of poor pulmonary function with a maximum breathing capacity of 25% (42.3 liters per minute) [4]. After 2 courses of chemotherapy, the tumor size decreased and the more conservative lung resection became possible. The patient subsequently had a right upper lobectomy. The other 23 patients had Stage I disease [l]. In 13 the disease was limited to the hemithorax, and in 10, it was disseminated. One patient with brain metastasis received a course of radiation therapy followed by excision of a metastasis by a craniotomy before lung resection was done. Two patients with apparent solitary bone metastasis received additional localized radiation therapy to the area before lung resection. The patients received 2 to 12 courses (median, 3 courses) of chemotherapy preopera- tively at 4- to -week intervals in a 2- to 1- month period (median, 3 months). reoperative reevaluation studies included complete blood count, blood chemistries, bone scan, tomograms of the chest, pulmonary function, bronchoscopy, and liver scan. ung resection was advised to the patients when all evidence of the disease became apparently resectable. To recover from the side-effects of chemotherapy, the patients had a waiting period before thoracotomy of at least 3 weeks after the administration of the last treatment. The aim of thoracotomy was to remove all visible evidence of tumor by lung resection, lymph node dissection, and resection of structures invaded by the tumor. ostoperatively, the patients received 3 additional doses of chemotherapy alternating with immunotherapy consisting of lung tumorassociated antigen and complete Freund s adjuvant [ 1. Results obectomy was done in patients (Tables 1,2). In 2 additional patients, lobectomy was combined with chest wall resection. One patient underwent a middle lobectomy, bilateral mediastinal node dissection, and excision of Table 1. Therapy and Survival Data for atients with Squamous Cell Carcinoma From From atient Chemo- ung ung Radical No. TNM therapv Resection Status Resection rocedures Deadc Dead atnm system for cancer staging: T = primary tumors; N = regional lymph nodes; M = distant metastasis. OGrossly incomplete resection. At postmortem examination, no evidence of tumor. I = pneumonectomy; = lobectomy. b IJb

3 35 Takita et al: Inoperable ung Carcinoma Table 2. Therapy and Survival Data for atients with Other Cell Types of Cancer From atient Chemo- ung ung R ad ica 1 No. TNM" Cell Type therapy Resection Status Resection rocedures Adeno 2 27 I' arge Ad-Squ From Br-A h Br-A arge h arge Adeno 14 " Adeno 8 Dead" Adeno Adeno 10 7 h Adeno Br-A Adeno 4 0 Dead" - atnm system for cancer staging: T = primary tumors; N = regional lymph nodes; M = distant metastasis. bgrossly incomplete resection. 'At postmortem examination, no evidence of tumor. "Bilateral lung lesions removed by median sternotomy. Adeno = adenocarcinoma; = pneumonectomy; arge = large cell; Ad-Squ = mixed adenosquamous; Br A1 = bronchioalveolar; = lobectomy. metastatic neck nodes. One patient with a tumor of the superior sulcus underwent upper lobectomy and a thorough cauterization of the involved chest wall. Ten patients had a pneumonectomy with mediastinal node dissection. Some also had intrapericardial ligation of the pulmonary vessels. In 1 patient, partial resection of the superior vena cava was done. In 5 patients, the resection was grossly incomplete. One patient with bronchioalveolar carcinoma underwent local excision of bilateral multiple lung tumor foci by a median sternotomy. There were 2 postoperative deaths: 1 patient died of cardiac arrest from an undetermined cause in the recovery room and another of pneumonia. Three patients required tracheostomy because of pulmonary infection and respiratory failure. One patient had hemiplegia due to a cerebrovascular accident in the immediate postoperative period; but at the time of writing she was able to walk. There were 2 deaths and 8 months postoperatively: 1 patient died of acute coronary artery occlusion and the other, of right heart failure. ostmortem examination was done on all 4 patients, and there was no evidence of residual tumor. The remaining 20 patients are alive 7 to 33 months from the onset of chemotherapy and 4 to 27 months following lung resection. Of these 20 patients, 5 are alive with evidence of disease 4, 7, 8,, and 27 months postoperatively. Eleven patients are receiving postoperative chemoimmunotherapy, and patients have completed the full course of the treatment. Two illustrative case reports follow. atient 1 A 52-year-old man had a left thoracotomy in April, 177. The operative report describes "a tumor cm. in diameter invading the wall of the descending thoracic aorta over a 5- cm. length. The mass was invading the pericardium and the left atrium. In addition to that, it was extensively adherent to the esophageal muscle" (Fig 1A). The patient was referred to Roswell ark

4 3 The Annals of Thoracic Surgery Vol 28 No 4 October 17 A Fig 1. (A) ateral chest roentgenogram showing a large lesion in the lower lobe. (B) After 2 courses of chemotherapy, the lower lobe lesion is no longer visualized. Memorial Institute in May, 177. Two courses of chemotherapy with DD, ADM, and VCT were given, and the lesion was no longer visible on chest roentgenogram (Fig lb).' On July 13, 177, a repeat left thoracotomy and pneumonectomy were done. The tumor this time measured 2 cm in diameter and was adherent to the pericardium, but free from the aorta, esophagus, and atrium. ostoperatively, the patient received 3 more doses of the same chemotherapy and tumor vaccine. He is doing well without recurrence (Table 2, atient 2). atient 2 A 53-year-old man was found to have bilateral lung lesions following hemoptysis (Fig 2A). Bronchoscopy revealed a lesion of the superior segment of the right lower lobe, and blood at the orifice of the left upper lobe. Cytological findings from right bronchial washings were positive for squamous cell carcinoma (Table 1, atient 2). The patient received 3 courses of chemotherapy with DD, ADM, CTX, CCNU, and VCT. B Repeat bronchoscopy, chest roentgenogram, and tomogram showed complete disappearance of the right lung lesion (Fig 2B). On February 27, 178, the patient underwent a left upper lobectomy for squamous cell carcinoma. ostoperatively, he received 3 more doses of chemotherapy alternately with tumor vaccine. At present, the patient is doing well without recurrence. Comment The more conventional therapy for inoperable lung carcinoma not of the small cell type is radiation therapy. However, there has been no report proving significant superiority in survival of patients who received radiation therapy compared with the control group in a randomized study [3, 71. Moreover, preoperative radiation therapy did not improve resectability or postoperative survival compared with the control group [1. Chemotherapy for treatment of lung carcinoma other than of the small cell type is still aimed at "temporary reduction in tumor size, symptomatic improvement and prolongation of survival" [81. For the past three years, we have chosen chemotherapy rather than radiation therapy as the primary mode of treatment for patients with inoperable lung carcinoma that is

5 37 Takita et al: Inoperable ung Carcinoma A Fig 2. (A) Chest roentgenogram showing lesions of the left upper lobe and right lower lobe. (B) After 3 courses of chemotherapy, the right lower lobe lesion is not visible. not of the small cell variety because radiation therapy does not seem to prolong the survival and subsequent chemotherapy appears less effective in patients who have been exposed to previous radiafion therapy. Since starting clinical trials with DD-based combination chemotherapy, we have begun to observe occasional responses of good quality. In some of the patients, the lesion becomes apparently operable. Since the only known curative therapy is lung resection, those patients with chemotherapy response underwent lung resection whenever possible. Following lung resection, the patients were given 3 more doses of the same chemotherapy, alternately with 3 doses of tumor vaccine. The tumor vaccine consists of allogeneic pooled lung tumorassociated antigen mixed with complete Freund s adjuvant and is injected intradermally []. This tumor vaccine has been reported to be effective in improving survival in patients with Stage I and Stage I1 lung carcinomas in a randomized study [ll]. The question can be raised that if effective chemotherapy is continued instead of lung re- B section, will the tumor eventually disappear. There is increasing evidence that a neoplasm consists of a heterogenous cell population [5, 141. It is our opinion that presently available chemotherapeutic agents are not effective enough to destroy all the neoplastic cells and, that, eventually, the surviving resistant tumor cells will proliferate and cause chemotherapy failure. Therefore, it is logical to remove all tumors from the body whenever feasible. As evidence, we observed that chemotherapy is more effective against metastatic lesions; and the metastatic lesions are histologically more poorly differentiated compared with the primary lesion. Our results, although preliminary, are encouraging, and further study is in progress. References American Joint Committee for Cancer Staging and End Results Reporting: A clinical staging system for carcinoma of the lung. Chicago, 173 Bjornsson S, Takita H, Kuberka N, et al: Combination chemotherapy plus methanol extracted residue of bacillus Calmette-Guerin or Corynebacterium parvum in stage I lung cancer. Cancer Treat Rep 2:505, 178 Brashear RE: Should asymptomatic patients with inoperable bronchogenic carcinoma receive immediate radiotherapy? No. Am Rev Respir Dis 7:4, 178 Didolkar MS, Moore RH, Takita H: Evaluation of

6 38 The Annals of Thoracic Surgery Vol 28 No 4 October 17 the risk in pulmonary resection for bronchogenic carcinoma. Am J Surg 127:700, Fidler ZJ: Tumor heterogeneity and the biology of cancer invasion and metastasis. Cancer Res 38:251, 178. Hollinshead AC, Stewart THM, Herberman RB: Delayed hypersensitivity reaction to soluble membrane antigens of human malignant lung cells. J Nat Cancer Inst 52:327, Roswit B, iberson S, Ohanian M, et al: Survival with inoperable lung cancer. NY State J Med 7:50, Selawry 0s: The role of chemotherapy in the treatment of lung cancer. Semin Oncol 1:25, 174. Shields TW: reoperative radiation therapy in the treatment of bronchial carcinoma. Cancer 30:1388, Shields TW, Ritts RE Jr: Bronchial carcinoma. Springfield, I, Thomas, 174, pp Stewart THM, Hollinshead AC, Harris JE, et al: Specific active immunotherapy in lung cancer: a survival study. Can J Surg 20:370, Takita H, Hollinshead AC, Bjomsson S: Chemotherapy, surgery and immunotherapy of inoperable lung cancer. ASCO roceedings 1:31, Takita H, Marabella C, Edgerton F, et al: cis diamminedichloro platinum (), adriamycin, cyclophosphamide, CCNU and vincristine (ACCO), in non-small cell lung carcinoma: A preliminary report. Cancer Treat Rep 3:2, Zubrod CG: Selective toxicity of anticancer drugs (presidential address). Cancer Res 38:4377, 178 Discussion DR. EDWARD J. BEATTIE, JR. (New York, NY): I read Dr. Takita s paper with great interest and was most impressed to see that 24 of 128 patients clinically in Stage 1 responded objectively to the chemotherapy protocol. I was also pleased to see that the TNM system of staging was used. I believe strongly that the TNM system for staging lung cancer should be mandatory for papers presented at meetings such as this and in published papers. I have one query. Six of 24 patients were staged as N- (dash). Since these patients underwent a thoracotomy, what does the N- mean? In the series, operative survivors were staged as MO and as M1. I believe it is helpful that survival statistics be grouped by the stage of disease. Our experience is that there is a significant difference between MO and M1. The Japanese lung staging system groups M1 as Stage IV, rather than combining it with MO as Stage 1, as do the Americans. Few patients in the M1 group are long-term survivors whereas there are a considerable number of N2 MO survivors. Twenty of the present patients survived up to 17 months, with a median survival rate of 8.5 months, although 5 were alive with disease. This is a significant improvement. I would like to see the figures expressed in a survival curve. At Memorial Hospital, 80 patients with lung cancer with gross mediastinal disease had a median survival rate of only months with conventional and external radiotherapy, and 5% were dead at 12 months. With the addition of internal radiation therapy at Memorial Hospital for these patients, 85% were alive at months and there was an approximate survival rate of 30% at two years. The present data strongly suggest that with effective chemotherapy and operation (and I believe with the addition of internal radiation therapy), we may change strikingly the survival time for patients with Stage I lung cancer. DR. TAKITA: In answer to Dr. Beattie s question, I deleted the classification of N- (dash) for some patients because I was not sure at the beginning of treatment whether the patient had lymph node metastases or not. Many of the patients did not undergo mediastinoscopy. I think we know that radiation therapy does not appear to prolong survival in patients with lung cancer, except those with ancoast s tumor or very localized tumors. On the other hand, the results of chemotherapy are still unknown, and I am interested in using it as the primary treatment until results can be compared with those of irradiation.