The results of the surgical treatment of stage I nonsmall

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1 Stage I Non-Small Cell Lung Cancer: A Pragmatic Approach to Prognosis After Complete Resection Pascal Thomas, MD, FECTS, Christophe Doddoli, MD, Xavier Thirion, MD, Olivier Ghez, MD, Marie-José Payan-Defais, MD, Roger Giudicelli, MD, and Pierre Fuentes, MD Departments of Thoracic Surgery and Lung Transplantation, Medical Information and Biostatistics, and Pathology, Ste Marguerite Hospital, University Méditerranée (Aix-Marseille II), School of Medicine, Marseille, France; and UPRES EA, IFR Jean Roche, Marseille, France The results of the surgical treatment of stage I nonsmall cell lung cancer (NSCLC) are disappointing. Although surgical resection is considered the standard of care because of the presumed local nature of the disease at that stage, as many as 30% of patients having undergone a complete resection experience recurrence, generally in distant organs, testifying to the presence of occult micrometastatic disease [1]. Although various histologic prognosticators have been investigated, such as the tumor size or the presence of blood vessel invasion, they are not yet fully incorporated into the TNM classification [2]. From a surgical point of view, the extent of the adequate lung resection continues to be debated in the literature. Wedge resection is associated with an increased risk for local recurrence when compared with lobectomy [3] but appears to be a viable compromise for patients with cardiopulmonary impairment when considering respective operative risks. At the opposite side of the surgical spectrum the place of pneumonectomy in those patients seldom has been addressed specifically. Indeed, tumor invasion crossing the oblique fissure may be removed either by pneumonectomy or lobectomy with partial resection of the invaded lobe. In the same Accepted for publication Nov 28, Address reprint requests to Dr Thomas, Department of Thoracic Surgery and Lung Transplantation, Ste Marguerite Hospital CHU Sud, 270 Bd Ste Marguerite, Marseille Cedex 9, France; pathomas@ap-hm.fr. Background. Long-term results of the surgical treatment of stage I non-small cell lung cancer (NSCLC) are disappointing. Methods. Univariate and multivariate analyses were conducted on 515 consecutive lung resections for stage I NSCLC performed from 1990 to 1999 and identified by reviewing a database into which data were entered prospectively. Tumors were staged as stages IA (n 147) and IB (n 348) according to the 1997 UICC (Union Internationale Contre le Cancer) ptnm classification. Results. Operative mortality rates were 6.2%, 5.3%, 2.3%, and 0% for pneumonectomy, bilobectomy, lobectomy, and lesser resections, respectively. Overall survival rate was 61.1% (55.8% to 66.5%) at 5 years. Univariate analysis identified three significant adverse prognosticators: arteriosclerosis as comorbidity, pathologic T2 status, and blood vessel invasion. Male sex (p 0.056) and performance of pneumonectomy (p 0.057) were at the threshold of statistical significance. At multivariate analysis, three independent prognosticators entered the model: arteriosclerosis, blood vessels invasion, and performance of pneumonectomy. Conclusions. Long-term survival of patients with completely resected stage I NSCLC was adversely influenced in a relatively balanced way by factors related to the clinical status of the patient, to the tumor, and to the treatment. (Ann Thorac Surg 2002;73: ) 2002 by The Society of Thoracic Surgeons manner the alternative surgical option for tumors located at the vicinity of the lobar hilum may be a bronchoplastic or angioplastic lobectomy. Besides, the impact on prognosis of the use of new surgical approaches such as video-assisted minithoracotomy when compared with open thoracotomy has not been fully evaluated to date. Finally, this group of patients with a relatively favorable oncologic prognosis appears to be the best suited sample to study the impact of other clinical factors such as age, sex, comorbidities, or history of another extrapulmonary primary malignancy. We aimed to add information on all these topics by a retrospective analysis of a group of 511 consecutive patients who underwent resection of stage I NSCLC during the last decade in a single institution. Material and Methods The medical records of all patients who underwent lung resection for a pathologic stage I non-small cell lung cancer as defined by the new International Classification System [2] were reviewed for the 10-year period ranging from January 1990 to December Patient charts were identified by screening of a database into which data were entered prospectively for any patient undergoing surgery for lung malignancy at our department. Patients who received chemotherapy or radiotherapy preoperatively were not included in this review. There were 511 patients, 430 men and 81 women, 2002 by The Society of Thoracic Surgeons /02/$22.00 Published by Elsevier Science Inc PII S (01)

2 1066 THOMAS ET AL Ann Thorac Surg STAGE I NON-SMALL CELL LUNG CANCER 2002;73: whose ages ranged from 31 to 86 years (mean 63 10). These 511 patients underwent 515 lung resections; 4 patients were operated on twice because they developed a resectable metachronous stage I NSCLC during the study period. Besides, for 14 patients of the present series (2.7%) the tumor was already a second primary lung cancer. A history of another primary extrapulmonary malignancy was noted in 63 patients (12.3%). The median delay between the two malignancies was 46 months, whereas the range extended from 6 months to 15 years. Most of them were squamous cell carcinoma of the head and neck (n 22). Four patients had had a lymphoma. Other locations were bladder (n 11), prostate (n 6), uterus (n 5), colon and rectum (n 4), kidney (n 4), esophagus (n 3), skin (n 3), and miscellaneous (n 7). Six patients experienced multiple neoplasms before the diagnosis and the treatment of their lung cancer. Ninety-two patients (18%) had arteriosclerosis involving the coronary arteries (n 44), the cerebral arteries (n 16), or both (n 3), or the limb arteries (n 29). Locoregional lung cancer staging was made with computed tomographic (CT) scan and fiberoptic bronchoscopy. Abdominal ultrasound and CT scan of adrenal glands was obtained routinely, whereas brain CT scan (n 147) and nuclear bone scan (n 122) were performed selectively in patients presenting with symptoms. Mediastinoscopy was performed in 26 patients in whom chest CT scan identified enlarged lymph nodes (short axis more than 1 cm). Functional evaluation routinely included spirometry, blood gas analysis at rest, carbon monoxide diffusion capacity, and 6-minute walk test. Split perfusion nuclear scan was done in patients with an impaired pulmonary reserve (estimated postresection forced expiratory volume in 1 second [FEV 1 ] of less than 1 L). The cardiovascular status of each patient was determined by looking at suspicious symptoms, history of cardiovascular disease, and electrocardiographic abnormalities. Those patients, as well as patients who received previously any kind of cardiovascular surgery or transluminal angioplasty underwent exercise stress testing or thallium imaging and then cardiac catheterization when appropriate. Other patients underwent routine echocardiography to assess ventricular function and to detect wall-motion abnormalities or pulmonary hypertension either when they were older than 70 years or when the foreseen resection was a pneumonectomy. All patients were operated on by or under the supervision of three staff surgeons (P.T., R.G., P.F.). The surgical approach was a posterolateral thoracotomy in 295 patients, a muscle-sparing lateral thoracotomy in 109, and a sternotomy in 1 patient who required the combined resection of contralateral giant bullae. A videoassisted minithoracotomy as previously described [5] was used in 110 patients. Lung resections consisted of wedge resections or segmentectomies (n 25), lobectomies (n 390), bilobectomies (n 19), and pneumonectomies (n 81), including completion pneumonectomies in 6 cases. Lung conservation techniques were applied in 30 patients to avoid a pneumonectomy and to spare functional lung parenchyma: lobectomy with reconstruction of the pulmonary artery (n 3), bronchial sleeve lobectomy with (n 3) or without reconstruction of the pulmonary artery (n 6), lobectomy (n 16), or segmentectomy (n 2) with partial resection of the invaded lobe for tumors crossing the posterior portion of the oblique fissure. Complete R0 cancer resection was achieved in all patients. Routine hilar and mediastinal lymph node dissection was performed in all cases and included the resection of all nodes in stations 10 and 11 and at least the sampling of the following node stations: 7 and 9 in all cases, 2R and 4R in right-sided resections, 4L, 5, and 6 in left-sided resections. Pathology disclosed an adenocarcinoma in 216 cases, a squamous cell carcinoma in 215, a large cell carcinoma in 72, a neuroendocrine carcinoma in 6, and a composite tumor in which squamous and glandular or neuroendocrine components were mixed in 6. There were 147 stage IA tumors and 348 stage IB tumors according to the UICC ptnm classification of 1997 [2]. Interlobar space invasion was classified as T2. The tumor size ranged from 0.5 cm to 13 cm (mean 4 2 cm). Peritumoral lymphatic (n 16) and blood vessel (n 32) invasion, or both (n 2), by tumor emboli was routinely evaluated by hematoxylin and eosin stains on surgical specimens. Survival data were updated for September 2000 by contact with the patient or the referring physician. For patients lost to medical follow-up missing data were obtained by consulting the City Hall registry. Survival was estimated using the product limit method of Kaplan- Meier from the date of the operation and included the operative mortality as well as any cancer-related and unrelated death. Frequencies were compared with the - 2 test when appropriate. Means are given as the standard deviation. Survival rates are presented with their 95% confidence intervals within parentheses. Differences between survival curves have been assessed by the log-rank test. A univariate analysis was performed and a likelihood ratio test was used to identify the significant prognosticators. Proportional hazards regression (Cox model) was used to incorporate in the same model any explanatory variables with a p value of less than Forward stepwise procedure and likelihood ratio tests were used to select the variables with the greatest prognostic value (p 0.05). This statistical analysis was performed by using the SPSS version 10.0 software package (SPSS Inc, Chicago, IL). Results Mortality There were 15 postoperative deaths (2.9%). The operative mortality rates were 6.2%, 5.3%, and 2.3% for pneumonectomy (n 5), bilobectomy (n 1), and lobectomy (n 9), respectively. Mortality was nil after left pneumonectomy whereas it was 11.9% after right pneumonectomy. Mortality was nil after wedge resection or segmentectomy. Among the 30 patients in whom a parenchymasparing technique was performed to avoid a pneumonectomy, 1 (3.3%) died during the postoperative period.

3 Ann Thorac Surg THOMAS ET AL 2002;73: STAGE I NON-SMALL CELL LUNG CANCER 1067 Table 1. Relationship Between Categorical Variables and Survival of Patients With Surgically Resected Pathologic Stage I Non-Small Cell Lung Cancer Variable Number of Observations (n 515) 95% CI 5 Years Lower Upper 2 p Value Sex Male % 53.0% 64.7% Female % 63.1% 86.0% Arteriosclerosis Yes % 33.6% 59.0% No % 58.3% 70.1% History of other cancers Yes % 47.6% 76.4% No % 55.0% 66.5% Tumor location Right % 52.9% 67.5% Left % 54.4% 70.1% Operation Pneumonectomy 81 53% 38.6% 67.3% Other resections % 57% 68.4% Approach Open % 56.8% 68.7% VATS % 51.4% 74.4% Histology SCC % 53.2% 69.1% Other % 54.9% 69.1% pt status T % 65.2% 83.3% T % 49.1% 62.0% Blood vessel invasion Yes % 35.4% 73.6% No % 56.4% 67.4% Lymph vessel invasion Yes % 17.1% 84.6% No % 56.2% 67.0% SCC squamous cell carcinoma; VATS video-assisted thoracic surgery. Survival Survival information was obtained in all but 9 patients (98.2%). At completion of the study, 337 patients were alive, 165 were dead, and 9 were lost to follow-up. The median follow-up for the survivors was 35 months (mean 44 33). Their clinical status was as follows: alive and well (67.1%), alive with disease (14.6%), alive with another cancer (2.7%), and unknown (15.8%). The median survival for the patients who died was 22 months (mean 32 26). The cause of death was related to the operation in 9% of the cases, to the lung cancer in 40.1%, and to another cancer in 4.8%. Cancer-unrelated deaths accounted for 12% of all deaths. The cause of death could not be clearly attributable to their cancer in 34.1% of the patients despite the review of their death certificates. No family members were available and contact with their referring physician was not informative. Their median survival was 28 months (mean 32 23), and their demographic and clinical characteristics were not significantly different from those of other patients who died from a documented cause. Among the 117 patients who experienced recurrence of their lung cancer, 89 (76%) developed distant metastases and 28 (24%) developed a locoregional recurrence as the first site of recurrence. Estimated overall survival rates were 61.1% (55.8 to 66.5) and 44.2% (36.9 to 51.5) at 5 and 10 years, respectively. A significant difference of 5-year survival rates was found between stage IB and stage IA patients (p 0.047). The survival rates of stage I lung cancer patients with reference to various discrete variables are shown in Table 1. Univariate analysis identified three of them as significant for a poor prognosis: arteriosclerosis as comorbidity, pathologic T2 status, and blood vessels invasion. Male sex (p 0.056) and performance of pneumonectomy (p 0.057) were at the threshold of the statistical significance, while two continuous variables were close to being significant: age per year (p 0.081) and tumor size per cm (p 0.068). When considered as categorical variables, no significant differences could be identified by comparing 5-year survival rates at different thresholds: tumor size less than 1 cm (68.7% [42.9% to 94.6%]) versus ranging between 1 and 3 cm (66.1% [58.5% to 73.8%]),

4 1068 THOMAS ET AL Ann Thorac Surg STAGE I NON-SMALL CELL LUNG CANCER 2002;73: Table 2. Results of Multivariate Analyses of Prognostic Factors in Surgically Resected Pathologic Stage I Non-Small Cell Lung Cancer Variables p Value Odds Ratio 95% Confidence Interval Lower Upper Arteriosclerosis (y/n) Pneumonectomy (y/n) Blood vessel invasion (y/n) y/n yes/no. tumor size ranging between 3 and 6 cm (57.4% [49% to 65.9%]) versus larger than 6 cm (58.1% [40% to 76.2%]), patients younger than 70 years (63.8% [57.9% to 69.8%]) versus patients older than 70 years (54.3% [42.9% to 65.7%]; p 0.15). History of other cancers, location of the tumor, use of video-assisted techniques, histology, and lymphatic vessels invasion had no prognostic relevance. At multivariate analysis (Table 2) three independent prognostic factors entered the model: one clinical variable (arteriosclerosis), one pathologic variable (blood vessels invasion), and one therapeutic variable (performance of pneumonectomy). The clinical status of the patients who survived the operation did not differ significantly when comparing patients having undergone pneumonectomy with other patients: proportions of patients who experienced cancer recurrence were 26.3% and 27.1%, respectively (p 0.88). Besides, respective proportions of patients with an unknown clinical status at the date of last follow-up or death were 27.6% and 21.5% (p 0.23). For patients in whom a parenchyma-sparing technique was performed to avoid a pneumonectomy, survival at 5 years was 69.5% (51.5% to 87.5%) and this rate was not statistically different from that of patients treated with pneumonectomy 53% (38.6% to 67.3%; Fig 1). For patients who underwent lesser resections than lobectomy, 5-year survival also did not differ (64.8% [40.4% to 89.3%] versus 63.1% [57.1% to Fig 1. Survival curves of stage I lung cancer patients having received pneumonectomy or lung conservative techniques to avoid pneumonectomy. (NS not significant.) 69.1%]; not significant). The incidence of local recurrences was 12% after wedge resection or segmentectomy and 5.8% after standard lobectomy (p 0.21). Comment Mortality rates observed in this series are in line with internationally reported data for lung cancer operations [5]. Although lobectomy is generally possible for stage I disease, the portion of patients undergoing pneumonectomy varies from 6% [6 8] to 20% [9 11] in recent reports and was about 15% in our experience. Of concern is the fact that the mortality rates considered on a 30-day basis remain between 5% and 10% after a conventional pneumonectomy. As illustrated by our results, mortality for right-sided procedures is about 10% to 12% while rates for left-sided procedures range from 1% to 3.5% [5]. To improve postoperative pulmonary reserve, we have employed parenchyma-sparing resections in unfit patients with poor pulmonary function, ie, bronchial and bronchovascular sleeve lobectomy for central lung tumors and lobectomy with partial atypical resection of the invaded lobe for peripheral tumors crossing the fissure. The associated in-hospital mortality was then twice as low, whereas long-term results compared advantageously with those of pneumonectomy. This favorable risk/benefit ratio pleads clearly in favor of parenchymasparing operations even if we agree that this retrospective review could not identify the portion of the patients having received pneumonectomy who would have been also candidates for lesser resections. Indeed, in our experience, performance of a pneumonectomy affected long-term survival even when the incidence of recurrent disease was similar to that observed after other types of resections. Therefore we intuitively postulate that cardiopulmonary impairment due to pneumonectomy did not only alter the quality of life but also led to fatal consequences in some instances, thus affecting long-term survival. This issue remains controversial. Ferguson and Karrison [8] have shown recently that survival was worse after pneumonectomy. After adjusting for age, T and N status, and FEV 1, they found that survival did not differ significantly from that for other resections and concluded that pneumonectomy does not have an important prognostic impact. However, their material included a very small number of patients with stage I disease who had undergone pneumonectomy, thus precluding any firm conclusion on its prognostic influence in patients with early stage disease. Despite the absence of randomized trials a host of literature now supports the use of extended sleeve resection techniques to treat centrally located tumors, even in patients with adequate pulmonary reserve [12 14]. Surprisingly, the prognostic relevance of invasion beyond the interlobar pleura has seldom been documented. In the experience of Okada and associates [15], the survival of patients with involvement of the interlobar pleura was significantly worse than that of patients with T1 or T2 disease, and was similar to that of patients with T3 disease. In contrast, Miura and colleagues [16] reported

5 Ann Thorac Surg THOMAS ET AL 2002;73: STAGE I NON-SMALL CELL LUNG CANCER 1069 no difference between the outcome of patients with invasion beyond interlobar pleura who undergo lobectomy with a partial resection of the invaded lobe and the outcome of patients with visceral pleural invasion who undergo standard lobectomy. Given the high risk of right pneumonectomy, this type of conservative surgery ought to be attempted more particularly for right-sided lung resections whenever a complete resection is feasible. Wedge resection or segmentectomy made by open thoracotomy or video-assisted techniques appeared to be a viable compromise for surgical treatment of stage I NSCLC for patients with cardiopulmonary impairment. We observed an increased risk for local recurrence, however, although not statistically significant. These findings sustain the contention that lobectomy remains the surgical treatment of choice for patients with stage I non-small cell lung cancer who have adequate physiologic reserve and are in line with those of the randomized trial from the Lung Cancer Study Group [3]. Male sex was identified at univariate analysis as a possibly adverse prognosticator, similar to findings of a previous study reporting the protective effect linked to female sex in early stage carcinoma (stage I and II) while absent in more advanced stage carcinoma [17]. However, gender was not identified as an independent prognosticator when more powerful covariates were incorporated in the Cox model. Age was found close to being significant but we failed to identify any significant threshold value for this variable. Indeed, the biological behavior of bronchogenic carcinoma does not differ significantly between younger and older patients [18]. Furthermore, the older the patient, the higher is the pressure to select candidates fit for surgery, thus skewing the prognostic impact of that variable. The presence of major comorbid conditions probably reflects better the physiologic age than does the chronologic age. Among patients with comorbid conditions that one would expect intuitively to adversely influence longterm survival, the presence of arteriosclerosis at the time of the diagnosis and treatment of the lung cancer appeared to affect survival. Potentially lethal locations of arteriosclerosis are those involving the coronary and brain arteries. We incorporated in the study group patients with an apparently isolated vascular disease of the inferior limbs because arteriosclerosis is a potentially multifocal disease by definition. The common link to these two conditions is tobacco addiction. Indeed, the majority of patients with resectable lung carcinoma have smoking habits before surgery and the correlation between smoking and postoperative complications is well known. The prognostic influence observed in our patient population was not explained by an increased early mortality, however, and skewed down the whole survival curve as illustrated by Figure 2. A similar finding has been reported by Fujisawa and coworkers [19] who demonstrated significant correlations between overall survival and age and pack-years of smoking. These findings suggest that quit-smoking programs should be integrated into cancer treatment regimens on a routine basis and are consistent with the claim by Westeel and colleagues [20] that intensive follow-up might improve Fig 2. Survival curves of stage I lung cancer patients according to the presence or absence of arteriosclerosis. survival through better management of tobacco-related comorbidities. In contrast, we did not observe any adverse prognostic effect when resection of stage I lung cancer followed previous treatments of extrathoracic malignancies. Otherwise said, the tendency for a new primary tumor to develop was not associated with an amplified tendency to develop distant metastases. In those patients also, the tissue diagnosis of a lung mass may be misleading because it may respond either to a primary lung cancer or to a solitary metastasis. This is particularly true when the lung tumor proves to be an adenocarcinoma because most extrathoracic neoplasms are adenocarcinomas. Our policy was to consider and to manage the lung tumor as a primary cancer whenever the previous malignancy was proven to be in locoregional remission. Our survival data in this patient population are in accordance with those of Massard and associates [21] and reflect an adequate selection process. Tumor size by itself had some prognostic relevance, particularly when we compared tumors smaller than 3 cm and tumors bigger than 3 cm according to the threshold retained by the TNM classification to define T1 and T2 tumors. Inside each subcategory, however, no prognostic influence could be attributed to this variable, according to Yanagi and associates [22]. Conversely, blood vessel invasion was present in about 7% of our cases and was recognized as an independent predictive factor of poor outcome in this group of patients without lymph node involvement. This pathologic finding has been extensively studied in the literature on the basis of multivariate regression analysis, especially for stage I tumors, but surprisingly has not yet been incorporated in the ptnm classification [6, 23 25]. An individual databased meta-analysis has suggested a 13% reduction in the risk of death and an absolute benefit of 5% at 5 years with adjuvant cisplatin-containing chemotherapy in patients with resected NSCLC [26]. However, there is very little evidence that the addition of adjuvant chemotherapy may reduce the distant metastasis rates and prolong the survival after adequate resection of stage I NSCLC

6 1070 THOMAS ET AL Ann Thorac Surg STAGE I NON-SMALL CELL LUNG CANCER 2002;73: Table 3. Survival of Patients With Surgically Resected Pathologic Stage I Non-Small Cell Lung Cancer: Data From the Literature First Author [27]. Blood vessel invasion may be regarded as the first step toward a minimal hematogenous tumor cell dissemination and hence provides a rationale for selective application of any effective systemic adjuvant treatment in completely resected stage I NSCLC. The prognosis of our patients with stage I NSCLC was in line with internationally published data (Table 3). It was adversely affected in a relatively balanced way by one factor related to clinical status of the patient (presence of arteriosclerosis), one factor related to the treatment (performance of pneumonectomy), and one factor related to the tumor (blood vessel invasion). 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