Site of Recurrence in Patients. of the Lung Resected for Cure. with Stages I and I1 Carcinoma

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1 Site of Recurrence in Patients with Stages I and I1 Carcinoma of the Lung Resected for Cure Steven C. Immerman, M.D., Robert M. Vanecko, M.D., Willard A. Fry, M.D., Louis R. Head, M.D., and Thomas W. Shields, M.D. ABSTRACT Ninety-nine patients with Stage I or 11 lung carcinoma that was other than the small cell type and who survived for more than 30 days after a "curative" resection were followed for five years or until death if it occurred prior to the five-year anniversary. Recurrent disease developed in 44 patients. Clinical data and data from postmortem examination were reviewed in these 44 patients in an attempt to classify each recurrence as either initially local or distant metastatic disease. The site of the first documented recurrence was local in 18 patients and distant metastases in 26. When the patients with recurrence were separated into TNM categories, it was apparent that in those patients without lymph node metastases demonstrated in the resected specimen (NO), the initial recurrence tended to be a distant metastases, whereas in those with such involvement (Nl), the initial occurrence was more often local. In light of these data, selection of appropriate initial adjuvant therapeutic modalities may be different for each type of patient. Surgical resection is the therapy of choice in patients with Stage I or Stage I1 carcinoma of the lung that is other than the small cell type. These stages include those patients whose disease may be categorized pathologically as T1 NO, T1 N1, T2 NO, and T2 N1. All patients in these two stages are assumed to have no distant metastasis (MO). However, despite the apparent removal of all local disease, local recurrence or distant metastases will develop within five years in a large number of such patients. In order to determine the incidence and the initial From the Department of Surgery, Northwestern University Medical School, Chicago, IL. Presented at the Seventeenth Annual Meeting of The Society of Thoracic Surgeons, Jan 26-28,1981, Los Angeles, CA. Address reprint requests to Dr. Shields, Department of Surgery, Northwestern University Medical School, 303 E Chicago Ave, Chicago, IL site of recurrence in Stage I and Stage I1 patients, we reviewed the records of a series of patients whose disease was classified as T1 NO, T2 NO, T1 N1, or T2 N1, who had undergone curative resection (no microscopic proof of residual disease remaining in the ipsilateral hemithorax), and who were eligible for fiveyear survival. It is believed that the evaluation of this information may make it possible to better determine the most appropriate initial adjuvant therapeutic modality for each TN category in these Stage I and Stage I1 groups. Material and Methods The hospital charts, office records, and postmortem reports for all patients with pathological Stage I or Stage I1 carcinoma of the lung that was not of the small cell type and that was resected for cure from 1967 through 1975 were reviewed. Three of the teaching hospitals of Northwestern University Medical School were involved in this review: Northwestern Memorial Hospital, Veterans Administration Lakeside Medical Center, and Evanston Hospital. One hundred twenty-two patients in these two categories who had undergone resection were found. Three died within 30 days of the operation, and 20 were lost to follow-up; these 23 patients were excluded from the study. Complete data were obtained on the other 99 patients. All were followed for five years or until death if it occurred before the fifth year anniversary. The presence or absence of tumor at the time of death or at the fifth anniversary of each patient was determined. In addition, specific attention was paid to the initial site of recurrence. Local recurrence was defined as any recurrent disease within the ipsilateral hemithorax, ipsilateral supraclavicular lymph nodes, or mediastinum. All other sites of recurrence were considered distant metastases by The Society of Thoracic Surgeons

2 24 The Annals of Thoracic Surgery Vol 32 No 1 July 1981 Only biopsy-proved recurrence or histologically confirmed postmortem findings were considered in these determinations. Results There were 72 men and 27 women. Each patient was assigned a specific TN category from review of the pathological report of the resected specimen. Thirty-nine patients were judged to have T1 NO disease (a lesion no greater than 3 cm in size at or distal to a lobar bronchus and no visceral pleural involvement; all lymph node groups free from metastatic disease). Thirtyeight patients had T2 NO disease (a lesion greater than 3 cm in size at least 2 cm distal to the tracheal carina, or a tumor of any size with visceral pleural involvement; no metastatic involvement of any lymph node group). There were 4 patients with T1 N1 disease and 18 with T2 N1 disease (similar T1 or T2 designations, but with metastatic disease in either the lobar or hilar lymph nodes; mediastinal nodes free from disease). The last two categories were combined since the prognosis has been shown to be similar in both groups [l, 21. The histological diagnosis was squamous cell carcinoma in 43 patients, adenocarcinoma in 34, and undifferentiated large cell carcinoma in 17. Five patients were classified as having mixed adenosquamous cell carcinoma. Forty-nine patients were alive at the fifth year anniversary, a 49% five-year survival. Four of these patients had documented recurrent disease prior to this fifth anniversary. Thus, the overall five-year disease-free survival was 45%. In the patients with T1 NO disease, the five-year disease-free survival was 64%; in those with T2 NO disease, it was 45%; and in those patients in the combined group of T1 N1 and T2 N1, it was 14% (Table 1). Fifty patients had died before the fifth anniversary, 10 of them without clinical or postmortem evidence of recurrent carcinoma. Forty patients died with recurrent disease either biopsy-proved or demonstrated at postmortem examination. Thus of the 99 patients, 44 (44%) were treatment failures. The site of the first documented recurrence was a local recurrence in 18 patients and a distant metastasis in 26. Seven of these patients either manifested recurrence clinically or were discovered at postmortem examination to have both local recurrence and distant metastases. Distant metastases were recognized somewhat earlier than local recurrence, but not by a substantial period of time. In 55% of the patients, the recurrent disease was noted within the first year of operation and in 80% by the second anniversary. Of the 4 patients who were alive with recurrent disease at the fifth anniversary, recurrence in 1 developed during the second year and apparently was successfully treated by irradiation. In a second patient, the recurrent disease was noted in the fourth postoperative year; he remains alive with disease three years later. In the other 2 patients, the recurrent disease occurred in the first and fourth years; both died of the disease after the fifth year. In all 4 patients, the cell type was adenocarcinoma. When the patients with recurrent disease were separated into the Tl NO, T2 NO, and T1 N1 plus T2 N1 categories, either local or distant recurrence was observed in 11 of 39 patients (28O/0), 19 of 38 patients (50%), and 14 of 22 patients (64%), respectively. Initial local recurrence or distant metastasis was noted with equal frequency in the T1 NO patients. Initial distant Table 1, Survival Related to TNM Classification Patients Alive at 5 Years Patients Dead TNM No. of No No Status Patients Disease Disease Disease Disease T1 NO (64%) 9 3 T2 NO (45%) 17 2 T1 N1 + T2 N (14%) 14 5 Total 99 4 (4%) 45 (45%) 40 (40%) 10 (10%)

3 25 Immerman et al: Site of Recurrence in Stages I and I1 Carcinoma of the Lung Table 2. Site of First Recurrence Related to TNM Sfatus TNM No. of Local Distant Total Status Patients Recurrence Metastasis Recurrence T1 NO 39 5 (13%) 6 (15%) 11 (28%) T2 NO 38 4 (10.5%) 15 (39.5%) 19 (50%) T1 N1 + T2 N (41%) 5 (23%) 14 (64%) Total (18%) 26 (26%) 44 (44%) Table 3. Frequency of Recurrence Related to Cell Type Cell Type No. of No Patients Recurrence Recurrence Squamous (35%) 28 (65%) Adenocarcinoma (53%) 16 (47%) Large cell 17 7 (41%) 10 (59%) Mixed adeno- 5 4 (80%) 1(20%) squamous Total (44%) 55 (56%) metastases was evident four times more often than initial local recurrence in patients with T2 NO lesions. The patients with T1 N1 and T2 N1 lesions were found to have initial local recurrence twice as commonly as distant metastases (Table 2). In this series it was apparent that there was a tendency for the T1 N1 and T2 N1 lesions to recur locally and for the T2 NO lesions to manifest distant metastases. The 38 patients with T2 NO lesions had a 39.5% rate of distant recurrence and the 22 patients with either T1 N1 or T2 N1 lesions had a 41% rate of local recurrence. That the T2 NO lesions recur distantly and T1 N1 and T2 N1 lesions recur locally is significant at the p < level. When the patients were analyzed with respect to cell type, without regard to TN category, the patient with squamous cell carcinoma had the lowest rate of recurrence compared with the other two cell types (Table 3). However, cell type did not appear to have an influence on the initial site or time of recurrence. Comment The results of curative resection for carcinoma of the lung depend primarily on the stage of the disease at the time of operation. Although numerous factors relative to the patient and the disease are known to affect the prognosis, the size of the tumor and the presence or absence of lymph node metastases seem to be the more important factors [3-51. The specific cell type is of less consequence in tumors that are not of the small cell type [5]. Since surgical resection fails to cure all patients in whom the local disease has been excised, future improvement will be due to refinement of adjuvant therapeutic maneuvers. However, adjuvant therapy, except in isolated reports such as those of McKneally [6], Kirsh [7], and their associates, as well as others [8, 91, has not proved to be of great benefit in surgically treated patients with carcinoma of the lung [lo, 113. Nonetheless, if the site at which the tumor is most likely to recur in the various patient groups can be predicted, prophylactic adjuvant therapy may be used more accurately. Few data are available relative to the initial site of recurrence in successfully resected patients with Stage I or Stage I1 carcinoma of the lung. The autopsy data of Matthews and associates [12, 131 and of Rocmans' for patients dying within thirty days of operation are not too helpful except to note that in the presence of lymph node metastasis, recurrent or persistent disease in the hemithorax was more common than occult distant metastases. In a similar but smaller series, Mountain and Hermes [141 found initial distant metastasis to be more common than initial local recurrence in patients with either Stage I or Stage I1 disease. However, in our group of patients, the initial site of recurrence was more often a distant metastasis in patients without lymph node metastasis and a *Rocmans P: Personal communication, 1980.

4 26 The Annals of Thoracic Surgery Vol 32 No 1 July 1981 local recurrence in those with lymph node metastasis in the resected specimen. Evaluation of our results suggest that the primary adjuvant therapeutic modality for patients without lymph node metastases should be systemic adjuvant therapy; that is, either chemotherapy or immunotherapy. In the patients with tumor metastasis in either the lobar or hilar lymph nodes, the incidence of local recurrence is high and it seems reasonable that adjuvant therapy should be directed to local control. At present, radiation therapy would appear to be the therapeutic modality of choice for this latter group of patients. References 1. Shields TW, Keehn RJ: Postresection stage grouping in carcinoma of the lung. Surg Gynecol Obstet 145: , Shields TW, Humphrey EW, Easteridge CE, et al: Pathologic stage grouping of the patients with resected carcinoma of the lung. J Thorac Cardiovasc Surg 80: , Higgins GA, Shields TW, Keehn RJ: The solitary pulmonary nodule: ten-year follow-up of Veterans Administration-Armed Forced Cooperative Study. Arch Surg 110: , Soorae AS, Abbey-Smith R: Tumor size as a prognosis factor after resection of lung carcinoma. Thorax 32:19-25, Shields TW, Yee J, Conn JH, Robinette CD: Relationship of cell type and lymph node metastasis to survival after resection of bronchial carcinoma. Ann Thorac Surg 20: , McKneally MF, Maver CM, Alley RD, et al: Regional immunotherapy of lung cancer using intrapleural BCG: summary of a four year randomized study. In Muggia F, Rozencweig M (eds): Lung Cancer: Progress in Therapeutic Research. New York, Raven Press, Kirsh MM, Rotman H, Argenta L, et al: Carcinoma of the lung: results of treatment over ten years. Ann Thorac Surg 21: , Green N, Kurohara SS, George FW 111, Crews QE Jr: Postresection irradiation for primary lung cancer. Radiology 116:405, Martini N, Flehinger BJ, Saman MB, Beattie EJ Jr: Prospective study of 445 lung carcinomas with mediastinal lymph node metastases. J Thorac Cardiovasc Surg 80: , Higgins GA Jr, Shields TW: Experience of the Veterans Administration Surgical Adjuvant Group. In Muggia F, Rozencweig M (eds): Lung Cancer: Progress in Therapeutic Research. New York, Raven Press, , Shields TW: Preoperative radiation therapy in the treatment of bronchial carcinoma. Cancer 30~ , Matthews MJ, Kanhouwa S, Pickren J, Robinette D: Frequency of residual and metastatic tumor in patients undergoing curative surgical resection for lung cancer. Cancer Chemother Rep 4:63-67, Matthews MJ, Pickren J, Kanhouwa S: Who has occult metastases? Residual tumor in patients undergoing surgical resections for lung cancer. In Williams TE Jr, Wilson HE, Yohn DS (eds): Perspectives in Lung Cancer: Proceedings of the Frederick E. Jones Memorial Symposium in Thoracic Surgery, Columbus, OH, Karger, Basel, 1977, pp Mountain CR, Hermes KE: Management implications of surgical staging studies. In Muggia F, Rozencweig M (eds): Lung Cancer: Progress in Therapeutic Research, New York, Raven Press, 1979, pp Discussion DR. PETER c. PAIROLERO (Rochester, MN): I congratulate Dr. Immerman on this timely discussion of recurrent lung cancer. All of us who utilize the TNM classification appreciate these data, and hope that this system will eventually enable us to compare results more confidently. To better interpret Dr. Immerman s data, however, we need to know more about his patient population. For instance, how many patients with lung cancer did his group evaluate during the study? Did his 122 eligible patients include all patients with Stage I disease after surgical treatment? Perhaps Dr. Immerman also could elaborate further on which patients were ineligible. For instance, would a patient who is not likely to survive five years be considered ineligible? Finally, how does a 17% loss of follow-up information influence their data? Our experience with 350 patients with Stage I lung cancer after operation demonstrates a five-year survival of 71%. There has been recurrence in one-third of these patients, or 116. The rate of recurrence, however, varies with the different TN subgroups. The patients with T1 NO lesions have a 27% recurrence; those with T2 NO lesions, 37%; and those with T1 N1 lesions, 58%. Only the recurrence in the patients with T2 NO lesions differs from Dr. Immerman s study: they demonstrated a 53% recurrence. I ask Dr. Immerman to tell us to what extent mediastinal lymph nodes were actually biopsied in their patient population. If the nodes were not uniformly biopsied, it may be possible that some patients had an occult N2 lesion, which ultimately led to an increase in the recurrence rate. We utilize a different classification of recurrent lung cancer. In addition to regional occurrences and metastases, we include a third category of sub-

5 27 Immerman et al: Site of Recurrence in Stages I and I1 Carcinoma of the Lung sequent primary lung cancer. Approximately half of our recurrences are metastatic, one-fourth are regional, and one-fourth involve a new second primary lung cancer. If these recurrences are analyzed according to both their TN classification and their specific type, metastases continues to account for approximately half of the recurrences in each of the three subgroups of Stage I. We do not approach the one to four ratio of regional to metastatic recurrences that Dr. Immerman described in patients with T2 NO lesions, unless we group together second primary cancers and metastatic cancers. Dr. Immerman, what is your opinion regarding the possibility of a second primary lung cancer? Specifically, how should a patient with a resected squamous cell carcinoma of the right upper lobe who returns three years later with a solitary adenocarcinoma of the left lower lobe be classified? DR. ROBERT J. GINSBERG (Toronto, Ont, Canada): I congratulate Dr. Immerman on addressing the problem of the first site of recurrence, using the TNM classification of lung cancer. Only through such detailed staging will we be able to determine what types of adjuvant therapy may be indicated in the various stages of lung cancer following surgical treatment. The Lung Cancer Study Group of the National Institutes of Health has now evaluated 650 patients. We have mapped in detail the mediastinal nodes at thoracotomy prior to resection. In our group with NO lesions, we have found, like Dr. Immerman, that many had distant metastases. However, one-third of all first recurrences were seen in the brain, the commonest single site of first recurrence. Obviously the suggestion that adjuvant chemotherapy in this group of patients might be beneficial is negated by the fact that a third recur in a relatively chemotherapyresistant area-the brain. The other thing we have noted is that many of the patients suspected to have T2 N1 lesions really have T2 N2 lesions when lymph node mapping of the mediastinum is done. I m not sure this was done in Dr. Immerman s series. In our N1 and N2 groups, we have found that at least as many had recurrence distantly as locally. We have already identified 40 local recurrences and 48 distant recurrences. Therefore, radiotherapy alone might not play as big a part as one might think in preventing recurrent disease. In our experience more than half of the recurrences initially occur distantly, outside the field of radiotherapy treatment. DR. SHIELDS: I thank the discussants for their remarks. I always find it quite difficult to answer all their questions, especially since they have had several weeks to think about their questions while I have but two minutes to rebut them. There is no question that in this series a number of patients may well have been understaged. Most of the patients were done before the birth of the staging system. I think we are all well aware now that we should map the mediastinum and thereby stage our patients more appropriately. Nonetheless, I think it does show that even though the numbers are different, there is a similarity in the categories of recurrences. One of the differences that can occur in T2 NO lesions is the size of the lesion. If it is 3 to 5 cm, the patient has a reasonably good chance of survival. If it is 5 to 7 cm or larger, the patient has a much smaller chance of survival and such patients do have a high incidence of distant metastases. I think this may explain some of the difference between the Mayo group and our group with respect to the incidence of recurrence. Certainly, the patients with lymph nodes involved in the hilar and lobar area do not do well. Perhaps this is the group that should have received irradiation, and perhaps this will take care of the micrometastases left behind in the mediastinum. We purposely picked only the patients with Stage I and Stage I1 disease. Once you have a documented N2 lesion, the patient is in Stage I11 and we know that these patients without adjuvant therapy do very poorly. At the moment we have no good adjuvant for T1 NO lesions. These patients do pretty well without adjuvant therapy; only 28% have recurrent disease. This might well be the place for immunotherapy if we find the right modality to take care of the micrometastases that may be present. In the patients with a T2 NO lesion, certainly the chemotherapeutic regimens we have used to date have been inappropriate. We must be careful that when we do use one, it won t actually harm the patient. In line with the comment of Dr. Ginsberg, there is a high incidence of cerebral metastases in these patients. It is our impression that a fair number of these patients have adenocarcinoma originally classified as T1 NO and T2 NO. Perhaps prophylactic brain irradiation might be indicated in this specific group of patients, though we do not have data to support that at this time. Certainly we do not know what wholebrain irradiation would do to patients who survive over a prolonged period.