Synchronous non-small cell lung cancers

Synchronous Rodney

F. Pommier,

Non-Small

MD, John T. Vetto, MD, Judy T. Lee, Katherine

INTRODUCTION: The few series of synchronous lung cancers have included small cell and carcinoid tumors. We wished to determine the prognosis for patients with synchronous non-small cell lung cancer (NSCLC). METHODS: A database of 3034 lung cancer patients was reviewed for synchronous NSCLC. Survival was determined by Kaplan-Meier method and compared by log-rank analysis. RESULTS: There were 27 patients (0.8%). Fourteen were completely resected (CR) and had a 5year survival rate of 45% The 5-year survival rate for patients whose highest stage tumor was stage I or II was 38%, versus 0% for patients whose highest tumor stage of Ill (P = 0.01). The 5-year survival rate for patients with two stage I tumors was 41% versus 0% for patients with 2 stage III tumors (P = 0.03). The &year survival rate for patients treated with wedge resections was similar to that for patients treated with lobectomies or pneumonectomy (L/P). CONCLUSIONS: We conclude that the prognosis for patients with synchronous NSCLC may not be dismal if both tumors are resectable and stage I or II. Wedge resections are an alternative for those who cannot tolerate L/P. Am J Surg. 1996;171:521-524

L

ung cancer is the most common cause of cancer deaths among men and women in the United States. Particularly problematic are the rare patients who present with synchronous lung cancers. The reported incidence of synchronous lung cancers is l-2% of all lung cancer cases.le4 Whether these patients can be successfully treated and which patients should be selected for surgical treatment remain largely unresolved issues. There are very few series reporting synchronous lung cancers,‘-4 and they often report dismal 5-year survival rates of 0%5 to 6%.’ These results seetn to suggest that surgical treatment may be futile. However, we believe that previous series of synchronous lung cancers have the following flaws: (1) every series has included small cell lung cancers, which have a markedly poorer prognosis; (2) some series have mcluded bronchial

From the Section of Surgical Oncology, Division of General Surgery, Oregon Health Sciences University, Portland, Oregon. Requests for reprints should be addressed to Rodney F. Pommier, MD, Assistant Professor of Surgery, Section of Surgical Oncology, l223A, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97201. Presented at the 62nd Annual Meeting of the North Pacific Surgical Association, Victoria, British Columbia, November 9-l 1, 1995.

0 1996 by Excerpta All rights reserved.

Medica,

Inc.

Cell Lung

Cancers

M. Johnston,

PorHand, Oregon

carcinoid tumors, which have a good prognosis; (3) some series have mcluded patients with two bronchoalveolar card cinemas, which may represent cases of solitary lung cancer with aerogenous metastases; and (4) with the exception of the series by Ferguson et al,’ the survival rates have been for all patients grouped together. Accordingly, WC believe that the true prognosis for patients with synchronous non-small cell lung cancer (NSCLC) remains undetermined. Therefore, WC:report the present series in an effort to determine the true prognosis for patients with synchronous NSCLC and tc’ determine prognostic criteria for selection of patients for surgical treatment. METHODS The lung cancer databases of the Oregon Health Sciences University and the Portland Veterans Affairs Medical Center (n = 3,034 patients between January 1, 1974and Sep+ tember 30, 1994) were reviewed for cases of synchronous lung cancers. Cases of synchronous lung cancers were further screened for inclusion in this series using modifications of criteria established by other authors.2-4 The criteria were: ( 1) total physical separation of lesions within the lung was required; (2) patients with two distinct tumors of different histologies were included: (3) patients with two tumors of the same histology had to have the second tumor present in a different segment, lobe, or lung and no distant metastatic disease at initial staging. The latter required a negative bone scan, a negative radioisotope brain scan or computerized tomography (CT) brain scan, negative ultrasonography or CT scan of the liver, and a negative CT scan of the adrenals. This criterion is based on the belief that lung cancers metastasize most commonly to bone, brain, liver, and adrenal glands, but rarely to lung; ((4) patients with two bronchoalveolar tumors were excluded because of the possibility of aerogenous metastases; and (5) patients in whom either tumor was small cell carcinoma or bronchial carcinoid were excluded. Tumor staging was performed according to ehe international TNM (Tumor, Nodes, Metastases) classification of lung cancer6 b ase d on data obtained from imaging techniques, bronchoscopy, invasive diagnostic techniques (mediastinoscopy, mediastinal lymph node biopsies), and operative findings. Follow-up data were obtai.ned on all patients. Survival rates were calculated by the method of Kaplan and Meier’ and compared by log-rank analysis. RESULTS Patient Characteristics Using the above criteria, 27 patients with synchronous NSCLC were identified. There were 26 males amd 1 female. The average age was 63 years and the age range was 17 to 78 years. 0002-961 O/96/$1 PII SOOO2-9610(96~00019-0

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Figure 1. Overall NSCLC.

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Treatment Resection was attempted in 20 of the 27 patients. Fourteen patients had complete surgical resection, and 6 did not. Among the I4 patients who had complete resections, 4 patients had two lobectomies, 4 patients had pneumonectomies, 3 patients had both tumors excised by a single lobectomy, 2 patients had a lobectomy for one tumor and a wedge resection for the second tumor, and 1 patient had two wedge resections. Two patients who had complete resection of their disease received adjuvant mediastinal radiation therapy for histologically positive N2 (mediastinai) lymph nodes. There were no operative deaths. Of the 6 patients who were explored but did not have complete surgical resections, 4 patients had only 1 tumor resected. Two patients were explored but left completely unresected. Seven patients were deemed not to be surgical candidates. This was because of the clinically unresectable disease in 4 patients and because of inadequate pulmonary function or poor medical condition in 3 patients. These 7 patients and the 6 patients who did not have complete surgical resections received palliative treatment in most cases. This included radiation therapy in 6 patients, laser ablation therapy plus radiation therapy in 1 patient, and chemotherapy in 6 patients. AMERICAN

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Tumor Staging Staging combinations for the synchronous tumors among the 27 patients were as follows: two stage I tumors in 12 patients; one stage 11 tumor and one stage 1 tumor in 3 patients; two stage II tumors in 2 patients; one stage IIIA tumor and one stage I tumor in 5 patients; two stage IIIA tumors in 2 patients; one stage IIIB tumor and one stage II tumor in 1 patient; two stage IIIB tumors in 2 patients.

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Tumor Histologies Fifteen patients had two tumors of the same histology; there were squamous cell carcinomas in 12 patients, adenocarcinomas in 2 patients, and adenosquamous carcinomas in 1 patient. In the remaining 12 patients, 7 had one squamous cell carcinoma and one adenocarcinoma; 2 patients had one adenocarcinoma and one bronchoalveolar carcinoma; 1 patient had one squamous cell carcinoma and one bronchoalveolar carcinoma; 1 patient had one squamous cell carcinoma and one large cell carcinoma; and 1 patient had one large cell carcinoma and one bronchoalveolar carcinoma.

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Figure 2. Survival grouped according est stage tumor is tumor is stage IIIA

curves for patients with synchronous NSCLC to their highest stage tumor. Stage I, II = highstage I or stage II; Stage Ill = highest stage or stage IIIB.

Survival The survival curve for all 27 patients is shown in Figure 1. The 5-year survival rate was 24% (mean survival, 15 months). Twenty-two patients have died. Six patients died of other causes and all other deaths were due to lung cancer. The 5-year survival rate for patients with two tumors of the same histology was 33% (mean survival, 10 months) versus 17% (mean survival, 5 months) for tumors of different histology. This difference was not statistically significant (p = 0.95). The survival curves for patients grouped according to their highest stage tumor is shown in Figure 2. The 5-year survival rate for patients whose highest stage tumor is stage I or II was 38% (mean survival, 15 months). There were no 5-year survivors among the patients whose highest stage tumor is stage III (mean survival, 9 months). This difference was statistically significant (P = 0.01). The survival curves for patients grouped according to the stage of the first tumor and the stage of the second tumor are as expected. The 5-year survival rate for patients with two stage I tumors was 41% (mean survival, 15 months). The S-year survival rate for patients with on.e stage I tumor and one stage II tumor was 0% (mean survival, 5 months). The 5-year survival rate for patients with two stage II tumors was 50% (mean survival, 10 months). The 5-year survival rate for patients any stage III tumors was 0% (mean survival, 3 months). The difference in survival rates between patients with two stage 1 tumors and patients any stage III tumors was statistically significant (P = 0.03). The survival curves for patients whose tumors were or were not completely resected are shown in Figure 3. The 5-year survival rate for patients whose tumors were completely resected was 45 ‘0/ ( mean survival, I5 months) versus 0% (mean survival, 3 months) for patients with incomplete resection. This difference was statistically significant (I’ = 0.007 ) . The survival curves for patients grouped according to the treatment received are shown in Figure 4. ‘The 5-year survival rate for patients who had both tumors treated by formal lung resection (lobectomy, bilobectom.y, pneumonectomy) was 48% (median survival, 10 months). The survival rate for patients treated by resections involving wedge resections (one lobectomy and one wedge resection or two wedge resections) was 50% at 50 months of follow-up (meMAY

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Figure 3. Survival curves for patients with synchronous NSCLC grouped according to whether or not both tumors were resected completely. Comp Resect = complete resection; Incomp. Resect = incomplete resection.

dian survival, 19 months). The 5-year survival rate for patients treated by any other modality was 0% (median survival, 4 months). There was no significant difference in survival rates between patients treated by formal lung resection and those treated by wedge resections (P = 0.95). The difference in survival rates between patients who had both tumors treated by formal lung resections and those treated by any other modality was statistically significant {P

= 0.007). DISCUSSION In the majority of lung cancer patients, the entire respie ratory epithelium has been exposed to the same carcinogens (eg, tobacco, asbestos), putting the entire respiratory epithelium at risk for carcinogenesis. Indeed, this concept of a “field change” in an epithelium has become accepted as playing a role in the development of multiple tumors in the lung cancers have been resame organ.sz9 Metachronous ported to occur in up to 10% of patients who survive more than 3 years after resection of their first tumor,‘**” emphasizing the need for long-term follow-up of resected lung cancer patients. Very few series report synchronous lung cancers, but the reported incidence is approximately l-Z% of all lung cancer cases. ‘-’ In our series, the incidence was 0.8%. The few series that have reported synchronous lung cancers have mostly reported a very dismal prognosis for their patients. Carey et al’ reported a 5-year survival rate of only 6%, while Deschamps et al’ reported a 5-year survival rate of 15.7%. These reports suggest that operative treatment may be futile. Other series offer a better prognosis, including the series by Martini et al’ with a 5year survival rate of 23%, and a series by Rosengart et al4 with a 5-year survival rate of 44%. These series have reported survival rates for all patients grouped together, without providing survival rates for patients based on the stages of the tumors or other prognostic indicators. Only the series by Ferguson et al5 reported survival rates based on the stages of the synchronous tumors. However, in their series only 11 of 26 patients were believed to have had “definite” synchronous lung cancers, while 15 of 26 had “possible” synchronous lung cancers. Surprisingly, there were no 5-year survivors among their patients with two stage I tumors. THE AMERICAN

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MONTH Figure 4. Survival curves for patients with synchronous NSCL: plotted as a function of the treatment received. Botll tumors formally resected-both tumors resected by lobectomy, bilobectomy, or pneumonectomy; one or both tumors wedge resected-one tumor resected by lobectomy and one by wedge resection or both tumors resected by wedge resection; Other-any other treatment (only one tumor surgically resected, radiation therapy, laser ablation, and radiation, chemotherapy, or combinations thereof).

We believe that previous series of synchronous lung cancers have not permitted the prognosis for synchronous NSCLC, the type of lung cancer most amenable to successful surgical treatment, to be determined. Specifically, previous series’ -5 have included patients with small cell car, cinema, which has a poorer prognosis than non-small cell lung cancer. In addition, some series’-’ also included patients with bronchial carcinoid tumors, which have an extremely good prognosis. Some series’ have included patients with synchronous bronchoalveolar carcinomas, which may represent solitary lung cancers with aerogenous metastases rather than true cases of synchronous lung cancers. In order to produce a “pure” series of !synchronous NSCLCs, we used the accepted criteria for ,synchronous lung cancers, but excluded patients with small cell carcinomas, bronchial carcinoid tumors, or more than one bronchoalveolar carcinoma. Furthermore, to guard against the error of including patients with lung metastases from solitary lung cancer, we also adopted the criterion that patients with two lung tumors of the same histology have no bone, brain, liver, or adrenal metastases. The overall 5-year survival rate for patients with synchronous NSCLC was 24%. Comparisons between this overall survival rate and the overall survival rates reported in other series are of limited value because of the considerably different inclusion and exclusion criteria used for the present series. Regardless, it is notable that this 24% overall survival rate is considerably higher than the dismally poor 5-year survival rate of 6% reported by Carey et al’ and the 15.7% fate reported by Deschamps et al,’ and would indicate that surgical therapy for patients with synchronous NSCLC may not be futile in selected cases. On the contrary, patients who are treated surgically have a considerably better prognosis. The 5-year survival rate for patients who had complete surgical resection of both tumors was 45%, compared with 0% for patients witlh incomplete resection. Plotting survival rates as a function of tumor stage in patients with two lung cancers is impossible using a system designed for staging solitary lung tumors. Accordingly, we JOURNAL

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plotted survival as a function of the tumor with the highest stage. This revealed a clear dichotomy in survival rates; patients whose highest stage tumor is stage 1 or 11 had a 5-year survival rate of 38%, while there were no 5-year survivors among patients whose highest stage tumor was stage III. Thus, the stages of each lesion should be considered in treatment planning. Patients with two stage I tumors have a 41% 5-year survival rate. This is markedly higher than the O”/o j-year survival rate reported by Ferguson et al’ for patients with two stage 1 tumors. This difference may be due to the inclusion in their series of poor prognosis patients. Paradoxically, there were a few 5-year survivors in their series among patients whose highest stage tumor was stage II or stage III, which may also be a reflection of their inclusion and exclusion criteria. In the present series, there were no 5year survivors among patients with one stage I tumor and one stage II tumor, while 50% of the patients with two stage II tumors were alive at 24 months of follow-up. The small numbers of patients involved in these twu groups (n = 3 for the former group, n = 2 for the latter) makes it difficult to draw any meaningful conclusions from these two survival curves. However, given the data in the survival curves in Figure 2, it seems reasonable to attempt complete surgical resections in patients with either one stage I tumor and one stage II tumor or in patients with 2 stage II tumors. In the present series, there were no 5-year survivors among patients with stage 111 tumors (either IIIA or IIIB). Thus, WC would agree with previous series that surgical resection in these patients would probably be futile. Many patients with stage III tumors are stage IilA becatlse of the presence of clinical mediastinal nodal disease (N2 disease). This is a stage of NSCLC for which surgical resection has generally not been helpful. However, recenr improvements in resectability and survival rates have been reported by the group at Memorial Sloan-Kettering Cancer Center utilizing preoperative (“neoadjuvant”) chemotherapy.” These encouraging results have prompted other protocol trials, such as Southwest Oncology Group (SWOG) trials number 9252 and 9416, in which such patients are treated with preoperative chemotherapy and/or radiation therapy and then surgical resection. Unfortunately, patients with synchronous tumors will not be eligible for enrollment in such protocols because of the presence of a second tumor. Patients with lung cancer often lack adequate pulmonary reserve to permit formal curative tesections of solitary lung carcinomas, and this factor is even more limiting in patients with two lung carcinomas. Rarely, both lesions may he resected by a single lobectomy, but often a bilobectomy or pneumonectomy is required to formally resect both lesions. Wedge resections offer an alternative for resection of either one or both tumors. In the present series, patients who underwent a formal lung resection had an excellent j-year survival rate of 48%. Although only three patients had wedge resections, they appeared to have an equivalent 50% survival rate at 50 months of follow-up. Whde more data are needed, wedge resections may be an acceptable alternative for patients with resectable disease who are unable to tolerate formal lung resection of both tumors. We believe that formal lung resection should be performed whenever 524

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possible. Rosengart et al4 have stated that wedge resections and segmentectomies may compromise survbval rates by 515% compared to formal lung resections. Carey et al’ reported that patients with synchronous lung carcinomas with the same histology have a significantly bet. ter prognosis than patients with synchronous lung cancers of different histologies. This finding was not confirmed by either the series reported by Deschamps et al,’ or by our series. In our series, patients with synchronous tumors of the same histology had a 5year survival rate of 33% versus 17% for patients with tumors of different histologies. We believe that the difference reported by Carey et al” can be explained by the inclusion in their series of patients with small cell carcinoma. Patients with small cell carcinomas were all included in the group of patients with different histologies, as no patients were unfortunate enough to have two small cell carcinomas. CONCLUSlONS Based on the results of this study, we conclude that candidates for surgical treatment of synchronous NSCLC may result in long-term survival for patients in whom both tumors are stage I1 or less, and in whom complete resection of both tumors (either by formal lung resection, wedge resection, or a combination thereof) can be accomplished. The histologies of the NSCLC s are irrelevant to treatment decisions. We further conclude that, because of their pour prognosis and poor outcome with all treatment modalitie,i, patients with synchronous NSCLCs in which either or both tumors are stage III should receive palliative, rather than surgical, treatment. Exceptions would include patients who are eligible for clinical studies of preoperative (“neoadjuvant”) therapy. REFERENCES primary lung cancer. J Thuruc Cmdiovasc Surg. 1990;99:769-778. 2. Carey FA, Donnelly SC, Walker WS, et al. Synchronous primxy lung cancers: prevalence in surgical material and ,clmical implica, ttons. Thorax. 1993;48:344-346. 3. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardlouasc kg. 1975;60:606-612. 4. Rosengart TK, Martini N, Ghosn P, Burt M. Multqle primary lung carcinomas; prognosis and treatment. Ann Thorac Surg 1991:52:773-779. 5. Ferguson MK, DeMeester TR, DesLduriers J, et al. Diagnosis and management of synchronous lung cancers. ] Thorax Cardiovasc Surfi. 1985;89:378-385. 6. Mountain CF. A new international staging system for lung cancer. Chest. 1986;S9:225S-233s. 7. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am StLlt Alsuc. 1958;53:457-481. 6. Kakizoe T, Matumoto K, Nishio Y, et al. Si@icance of carcinoma in situ and dysplasia in association wirh bladder cancer. J Ural. 1985;133:395-398. 9. Rauer WC, McGavron MH. Carcinoma in situ and evaluation of eptthehal changes m laryngn-pharyngeal biopsies. JAMA. 1972;221:72-75. 10. Van Bodegom PC, Wagcnaar SS, Corrin B, et al. Second pnmary lung cancer: importance of long term follow up. Thtrmx. 1989;44:788-79. 11, Martini N, Kris MG, Flehinger BJ, et al. Prc-operative chemotherapy of stage IIIA (N2) non-small cell lung cancer: the Memorial Sloan-Kettering Cancer Center experience with 136 patients. Ann Thorax Surgery. 1993;55:1365-1374. MAY

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