The Value of Adjuvant Radiotherapy in Pulmonary and Chest Wall Resection for Bronchogenic Carcinoma

The Value of Adjuvant Radiotherapy in Pulmonary and Chest Wall Resection for Bronchogenic Carcinoma G. A. Patterson, M.D., R. Ilves, M.D., R. J. Ginsberg, M.D., J. D. Cooper, M.D., T. R. J. Todd, M.D., and F. G. Pearson, M.D. ABSTRACT Thirty-five patients, 29 men and 6 women, underwent pulmonary and chest wall resection for treatment of bronchogenic cancer which had extended into the chest wall. Anterior chest wall resection was performed in 6 patients, lateral resection in 2, and posterior resection in 27. Marlex mesh was employed as a prosthetic material in 13 patients. Radiotherapy was given as part of the planned therapeutic regimen in 13 patients. Three patients (8.5%) died in the postoperative period. There were 21 late deaths. Eleven patients are alive 7 months to 12 years after resection. The overall actuarial survival, including operative mortality, is 38% at 5 years. Actuarial survival of the 13 irradiated patients is 56% at 2 and 5 years. We believe that bronchogenic carcinoma with chest wall involvement is not hopeless, and that resection of the lung and chest wall can be performed with an acceptable mortality rate. The chest wall is involved by direct tumor extension in approximately 2 to 8% of patients undergoing thoracotomy for bronchogenic cancer [l-31. Until the report by Coleman [4] in 1947 of 2 long-term survivors among 5 patients undergoing combined resection, it was generally believed that chest wall involvement with lung cancer indicated a uniformly dismal prognosis. Since then, a number of series have supported combined resection of chest wall and lung for such pulmonary tumors. The role of adjuvant radiotherapy, however, is controversial. In a small number of patients, surgeons at the Mayo Clinic considered radiotherapy to be of no value [2]. However, Mishina and coworkers [31 recently reported increased long- From the Thoracic Surgical Group, Toronto General Hospital, Toronto, Ontario, Canada. Presented at the Eighteenth Annual Meeting of The Society of Thoracic Surgeons, Jan 11-13, 1982, New Orleans, LA. Address reprint requests to Dr. Ilves, Toronto General Hospital, Eaton Wing N 10-230, Toronto M5G 1L7, Canada. term survival with adjuvant radiotherapy or radiotherapy combined with chemotherapy. The present study reviews our results with combined pulmonary and chest wall resection, and attempts to clarify the role of adjuvant radiotherapy. Patients and Methods Between September, 1969, and January, 1981, 35 patients underwent resection of the lung and chest wall for treatment of bronchogenic cancer, which had extended both grossly and microscopically into the chest wall. In all patients, the tumor had extended through the parietal pleura by microscopy and, in most, into the musculoskeletal chest wall as well. Patients with tumors extending through the mediastinum, pericardium, or diaphragm were excluded from this study. Patients with superior sulcus tumors were also excluded. Clinical Findings PATIENT POPULATION. There were 29 men and 6 women. The mean age was 64 years, with a range of 53 to 81 years. The most common symptom seen was chest pain, which was present in 26 patients (74%). All patients had clearly demonstrable lesions on chest roentgenograms. Special rib views and laminagrams were used in 20 patients and showed definitive evidence of chest wall invasion in 9. The CAT scan, which was used once, also defined invasion. OPERATIVE PROCEDURES. Twenty-six patients underwent a single lobectomy, 2 had a bilobectomy, 1 had a lobectomy with a wedge resection, 5 had a pneumonectomy, and 1, an isolated wedge resection (Table 1). The number of ribs involved in the resection is shown in Table 2. Three ribs were resected most frequently (18 patients). Anterior chest wall resection was performed in 6 patients, lateral resection, in 2 patients, and posterior resection, in 27 692 0003-4975/82/120692-06$01.25 @ 1982 by The Society of Thoracic Surgeons

693 Patterson et al: Adjuvant Radiotherapy after Pulmonary and Chest Wall Resection Table 1. Operative Procedures in 35 Patients Undergoing Pulmonary and Chest Wall Resection for Bronchogenic Carcinoma Procedure Lobectomy 26 Bilobectomy 2 Lobectomy + wedge resection 1 Pneumonectomy 5 Wedge resection 1 Total 35 No. of Patients Table 2. Number of Ribs Resected in Operations for Bronchogenic Carcinoma No. of Ribs No. of Patients 3 9 18 4 1 patients. In 29 resections, the pulmonary and chest wall specimens were removed en bloc. Resection was believed to be curative in 30 patients and palliative in 5 others, who had tumor involvement at the resection margins or the highest removed lymph node. Marlex mesh, the only prosthetic material used, was employed in a single layer in 8 patients and in a double layer in 5 patients. Pathological Findings The distribution of tumor cell types is shown in Table 3. The most frequently observed tumor was squamous cell carcinoma in 27 patients. By definition, these tumors are all classified as T3. Twenty-four patients had NO lesions, 6 patients had N1 lesions, and N2 disease was found in 5 patients. Adjunctive Therapy Radiotherapy was part of the planned therapeutic regimen in 13 patients. Five patients were irradiated preoperatively and 8, postoperatively. In 2 patients, radiation was utilized because of known residual chest wall Table 3. Cell Types and Staging of Tumors in Bronchogenic Carcinoma Seen in 35 Patients Characteristic Cell type Squamous cell 27 carcinoma Adenocarcinoma 5 Large cell carcinoma 1 Mixed cellularity 1 Unspecified 1 Total 35 Staging T3NO T3N1 T3N2 Total No. of Patients 24 6 5 35 involvement. In another 2 patients, radiation was added because of mediastinal node involvement, which was grossly removed. In the other 9 patients, there was no particular bias for adjuvant therapy other than the surgeon's preference. The dose of radiation ranged from 2,000 to 5,000 rads, averaging 3,464 rads. Twenty-two patients were not irradiated. Chemotherapy was not used as part of the initial therapy in any patient. Results Three patients died in the postoperative period, for an operative mortality of 8.5%. Respiratory failure was the major precipitating event in all deaths. A lobectomy was done in 2 of these patients, 1 of whom was reconstructed with single-layer Marlex mesh. The third patient had a pneumonectomy, also with single-layer Marlex reconstruction. Chest wall instability was not thought to contribute to the respiratory failure. Two of the patients who died also had extensive mediastinal dissection for N2 nodes. Eleven patients are alive seven months to 12 years postoperatively (follow-up as of August, 1981). The overall actuarial survival, including operative mortality, is 38%. Two patients are alive with known metastatic disease. No survivors have locally recurrent disease in the chest wall. All 21 late deaths occurred from dis-

694 The Annals of Thoracic Surgery Vol 34 No 6 December 1982 0 I 2 3 4 5 TIME SINCE SURGERY (YRS) Actuarial survival for chest wall resection. Radiated) (Combined) (Non-rodialedl seminated metastatic disease. There are no survivors among 5 patients with N2 disease. Only one of 6 patients with N1 disease is alive (at 2 years) with known metastatic disease. Of 22 patients not irradiated, only 4 remain alive (survival range, 2 to 8 years). One of these is the single N1 survivor. Actuarial survival is 36% at 2 years and 30% at 5 years (see Figure). Of 13 patients who received radiation, 7 are alive. This number includes 2 of 5 patients irradiated preoperatively and 5 of 8 patients irradiated postoperatively. Actuarial survival for irradiated patients is 56% at 2 years and 56% at 5 years. In the irradiated group, 2 patients had palliative, incomplete resections and N1 lesions; 2 other patients had N2 lesions. This leaves 9 irradiated patients with T3NO lesions and curative resections. Seven of the 9 (78%) are alive and free of disease. Of 14 patients who were not irradiated and who also had T3NO lesions and curative resections, only 3 (21%) are alive (Table 4). Local chest wall recurrence did not develop in any irradiated patient. Among the 22 patients who were not irradiated, 6 (27%) developed locally recurrent disease. Five patients had incomplete resections; 2 of these had postoperative irradiation. There were no survivors in this group, but local recurrence was seen in only 1 nonirradiated patient who also had hematogenous metastases. Atelectasis of a lung or lobe was the most frequent complication, occurring in 10 patients. Five of these patients had Marlex reconstructions. Respiratory failure, requiring mechanical ventilatory support for more than 24 hours, was seen in 6 patients. Two patients developed wound infections, and 2 others developed late postoperative empyema, necessitating removal of the Marlex mesh; 1 of these patients had developed a late bronchopleural fistula. Most of the patients were relieved of their chest wall pain, but 3 developed intractable postthoracotomy discomfort. In no patient was late chest wall instability a symptomatic problem. Comment Our experience confirms earlier reports of the value of surgical resection for carcinoma of the lung involving the chest wall. The actuarial survival for the patients in our series was 38% at 5 years. Previous studies have also stated that the general use of adjuvant radiotherapy preoperatively is of no value [5]. However, Paulson [6] has demonstrated the benefit of preoperative radiotherapy in patients with superior sulcus tumors. Some reports have agreed that preoperative radiotherapy is beneficial [7], while others have disagreed [S]. In tumors involving Table 4. Follow-up Results in Patients Having Curative Resections (Excluding Operative Mortality) Irradiated Patients Nonirradiated Patients Staging of Tumor No. of Survivors No. of Deaths No. of Survivors No. of Deaths T3NO 7 2 3 10 T3N1...... la 1 T3N2 0 1 0 2 Total 7 3 4 13 With known metastases. bexcluding 1 operative death.

695 Patterson et al: Adjuvant Radiotherapy after Pulmonary and Chest Wall Resection the nonapical chest wall, the role of adjuvant radiotherapy is unclear. Mishina and colleagues [3] suggest that adjuvant radiotherapy does improve survival, but the number of patients in their series was small, and in some patients adjuvant chemotherapy was also used. Geha and associates [2] believed that postoperative radiotherapy was of no benefit. In our series, there was an appreciable difference in 5-year actuarial survival between the nonirradiated and irradiated groups: 30% and 56%, respectively. This difference is even more marked when comparing curative resections for T3NO disease. In the irradiated group, the 5-year actuarial survival was 69%, including one operative death. It should be stressed that the two groups were similar in all respects, and that adjuvant radiotherapy was used according to the surgeon's preference. There was no statistically significant difference in actuarial survival during the 5-year postoperative period between the irradiated and nonirradiated groups (p = 0.1). This could be because of the small number of observations involved. Radiotherapy seems to diminish the incidence of local recurrence. Among 12 irradiated operative survivors in our series, none developed chest wall recurrence. In contrast, among 20 nonirradiated operative survivors, 6 developed locally recurrent disease. As is generally recognized, nodal involvement portends an unfavorable prognosis. Geha and ass6'ciates [21 reported only 1 fiveyear survivor among 5 patients undergoing combined pulmonary and chest wall resection. Mishina and colleagues [31 also reported 1 five-year survivor among 10 patients with nodal involvement. These figures are somewhat lower than those generally reported for lung cancer [9]. However, they are consistent with our analysis. Only 1 of 6 patients with N1 disease is alive two years after operation, and none of 4 patients with N2 disease is alive. There are several statements in the literature that our study does not support. Jamieson and co-workers [lo] state that operative mortality and morbidity are lower with pneumonectomy than with lobectomy in this group. Lavenson and Serfas [ll] have even suggested that pneumonectomy should be the procedure of choice when a combined resection is required. Our results are not consistent with these views. The operative mortality for pneumonectomy was 1 in 5 patients (20%), and there were no survivors among the patients who underwent pneumonectomy. This finding is in agreement with others [2, 31, and reflects either a larger tumor or more extensive nodal involvement. It has also been stated that en bloc resection is mandatory [2]. Our figures suggest this is not the case. Of 6 patients undergoing discontinuous resection, 3 are alive. In such patients, the adherence of the lung to the chest wall must not be overly solid or extensive; however, 2 of these survivors did have microscopic invasion of the intercostal muscle. Mishina and associates [3] correlate the depth of chest wall invasion with the prognosis. The majority of patients undergoing chest wall resection do not require a prosthetic chest wall support. However, large resections, especially those in an anterior or lateral position outside the range of scapular cover, should be stabilized by means of a prosthesis. Many materials have been used successfully [lo, 12, 131. Ramsey and Cliffton 1121 reported a decrease in paradoxical motion, pneumonia, and scapular fixation in the thorax among their patients who received a prosthesis after chest wall and pulmonary resection. In our patients, Marlex mesh made no difference in the rate of atelectasis. The only two wound infections occurred in the absence of a prosthesis. Prosthetic materials are clearly of use in large defects. Our preference is to use Marlex mesh, as its pliability and ease of handling give it technical advantages. When the mesh is used in a double thickness with its fibers placed at 90" and under tension, almost complete resistance to stretching is obtained. Larger defects can be managed by using a "sandwich" composed of Marlex and methylmethacrylate, as described by McCormack and associates [13]. Our 8.5% operative mortality is consistent with that reported previously for these resections: 4% by Geha and colleagues [2], 9% by Grillo and associates [l], 15% by Ramsey and Cliffton [121, and 16% by Jamieson and associates [lo]. Respiratory failure was the major precipitating event in all our early deaths.

696 The Annals of Thoracic Surgery Vol 34 No 6 December 1982 1. 2. 3. 4. 5. 6. Our conclusions from this study are: 11. Lavenson GS, Serfas LS: Advantage - of pneumonectomy in massive excision of the chest wall. Am J Surg 115:558, 1968 12. Ramsey HE, Cliffton EE: Chest wall resection for Chest wall involvement by bronchogenic carcinoma does not imply a hopeless prognosis. Resection of the lung and chest wall can be done with acceptable mortality and morbidity. Large portions of the chest wall can be resected using autogenous tissue or prosthetic material for reconstruction. There is no difference in survival between en bloc resection and discontinuous resection. Nodal status is a strong prognostic indicator. The use of adjuvant radiotherapy is favorable for long-term survival and lack of local recurrence. References 1. Grillo HD, Greenberg JJ, Wilkins EW: Resection of bronchogenic carcinoma involving the thoracic wall. J Thorac Cardiovasc Surg 51:417, 1966 2. Geha AS, Bernatz PE, Woolner LB: Bronchogenic carcinoma involving the thoracic wall: surgical treatment and prognostic significance. J Thorac Cardiovasc Surg 54:394, 1967 3. Mishina H, Suemash K, Yoneyama T, et al: Surgical pathology and prognosis of the combined resection of chest wall and lung in lung cancer. Jap J Clin Oncol8:161, 1978 4. Coleman FP: Primary carcinoma of the lung with invasion of the ribs: pneumonectomy and simultaneous block resection of the chest wall. Ann Surg 126:156, 1947 5. A Collaborative Study: Reoperative irradiation of cancer of the lung: final report of a therapeutic trial. Cancer 36:914, 1975 6. Paulson DL: Carcinomas in the superior pulmonary sulcus. J Thorac Cardiovasc Surg 70:1095, 1975 7. Attar S, Miller JE, Sattersfield J, et al: Pancoast s tumor: irradiation or surgery? Ann Thorac Surg 28:578, 1979 8. Kirsh MM, Dickerman R, Fayos J, et al: The value of chest wall resection in the treatment of superior sulcus tumors of the lung. Ann Thorac Surg 15:339, 1973 9. Wilkins EW, Scannell JA, Craver JG: Four decades of experience with resections for bronchogenic carcinoma at the Massachusetts General Hospital. J Thorac Cardiovasc Surg 76:364,1978 10. Jamieson MPG, Walbaum PR, McCormack RJM: Surgical management of bronchial carcinoma invading the chest wall. Thorax 34:612, 1979 primary carcinoma of the lung. Ann Surg 167:342, 1968 13. McCormack P, Bains MS, Beattie EJ Jr, Martini N: New trends in skeletal reconstruction after resection of chest wall tumors. Ann Thorac Surg 31:45, 1981 Discussion DR. NAEL MARTINI (New York, NY): I have had the privilege of reviewing the manuscripts of Dr. Piehler and colleagues and Dr. Patterson and associates. The points of agreement seem to be that chest wall involvement does not necessarily imply an incurable situation, that complete resection is possible in some patients and that long-term survival is obtainable, particularly if the regional nodes are not involved. Histology does not seem to influence survival except in oat cell carcinoma. Despite the peripheral location of the tumors, epidermoid carcinoma seems to be the predominant histology observed in this group of patients. We agree that superior sulcus tumors do better and should be analyzed separately for survival. The paper of Dr. Piehler and his co-workers clearly addresses a purer group of patients since it excludes those having incomplete resections. En bloc resection, the recommended technique, is preferred but cannot always be done. The goal must be complete excision of all diseased tissue, with the assurance of microscopically clear margins of resection. Local recurrence and survival are influenced by the completeness of the resection. Even microscopic residual disease at the margins, so frequently a problem when extension to the spine is also present, adversely affects the survival. It is still unclear what the role of radiation should be in this group of patients. Although more local recurrence was observed by Dr. Patterson and his colleagues in patients who did not receive external radiation, no patient has apparently died because of local recurrence; all of the patients who have died have had disseminated disease. We observed no impact on survival with the use of preoperative or postoperative radiation therapy, particularly in patients with complete resection and no lymphatic metastasis. In the recent past, we irradiated 5 patients who had microscopic disease at the margins of resection despite complete excision of the entire gross tumor. None of these patients had lymphatic metastases, but all 5 have subsequently died. Three had massive local recurrences, despite irradiation. Moreover, involvement of the regional lymph nodes clearly poses a major prognostic risk, since only an occasional patient with N1 or N2 disease lives 3 or more years.

697 Patterson et al: Adjuvant Radiotherapy after Pulmonary and Chest Wall Resection There seems to be a particular tendency on the part of both studies to confine skeletal reconstruction to autologous tissue. We have converted to the routine use of Marlex mesh for skeletal reconstruction in nearly all our patients. The mesh is easy to apply and readily available, and it rarely causes infection that might warrant its removal. Finally, it is unclear from both studies how many patients had histological invasion of only the parietal pleura. In our experience, patients with only parietal pleural involvement do better than patients with pleural as well as skeletal and bone disease. We believe that the extent of tumor involvement and the completeness of the resection are the main determinants of survival in this group of patients. DR. MARCUS L. DILLON (Lexington, KY): We have been studying the effect of randomized postoperative radiation in our stage I and I1 cancer patients. The local recurrence rate has been very good in irradiated patients. However, the distant metastatic rate in these patients is 25% which is high compared with the local recurrence rate of 2%. The opposite is true in the nonirradiated patients. Although nothing is proved statistically because the number of patients is too small, we believe that irradiation may immunosuppress these patients, so that they tend to break out with distant metastases. Have you observed this phenomenon? DR. SALEM M. SAYEGH (New Orleans, LA): If irradiation is of value in these patients, would Dr. Patterson and his associates prefer preoperative irradiation, since the radiation affects only the lobe that is to be removed? With postoperative irradiation, the radiation affects the remaining lobes, and postoperative or radiation pneumonitis may result. DR. ALLEN J. TOGUT (Brockton, MA): Is there any experience with preoperative chemotherapy in these chest wall lesions? DR. RAYMOND DIETER (Glen Ellyn, IL): I would like to ask Dr. Patterson if he has any opinion as to why the cell type of the tumors did not make any difference in the results. DR. PATTERSON: We would like to thank Dr. Martini for his comments. I think everyone recognizes his group as a leader in the field of chest wall resection for cancer. Since most of our resections were posterior and seemed to be adequately covered by the scapula, we did not use Marlex mesh as often as Dr. Martini s group does. Regarding his points about locally recurring disease and survival, all of the patients who developed locally recurring disease in our group subsequently developed disseminated disease and died. None of the survivors have locally recurrent disease. Concerning Dr. Dillon s comments, we are not certain where his radiation site was. The only mediastinal radiation given in our series was to those patients who had N2 lesions. In response to Dr. Sayegh, I think we would irradiate a patient preoperatively if we knew for certain that the chest wall was involved, but I think in many instances one is not certain whether there is chest wall involvement prior to the thoracotomy. Dr. Togut, we did not use chemotherapy in any of our patients as part of their initial management. Needless to say, however, many of these patients who developed subsequent disseminated disease did undergo a course of chemotherapy. Dr. Dieter, we did not look at the influence of cell type in this series because of the preponderance of squamous cell tumors with the scattered appearance of a few other types. We very much appreciated listening to the report of Dr. Piehler and his colleagues, and I think that their statement of the purpose of their paper is essentially the same as ours. However, we also feel strongly that radiotherapy is of benefit.