A review of 250 ten-year survivors after pneumonectomy for non-small-cell lung cancer

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1 European Journal of Cardio-Thoracic Surgery 45 (204) doi:0.093/ejcts/ezt494 Advance Access publication 6 October 203 ORIGINAL ARTICLE A review of 250 ten-year survivors after pneumonectomy for non-small-cell lung cancer Marc Riquet a, *, Pierre Mordant a, Ciprian Pricopi a, Antoine Legras a, Christophe Foucault a, Antoine Dujon b, Alex Arame a and Françoise Le Pimpec-Barthes a a b Department of General Thoracic Surgery, Georges Pompidou European Hospital, Descartes University, Paris, France Department of Thoracic Surgery, Cedar Surgical Centre, Bois Guillaume, France * Corresponding author. Department of General Thoracic Surgery, Georges Pompidou European Hospital, 20 rue Leblanc, Paris 7505, France. Tel: ; fax: ; marc.riquet@egp.aphp.fr (M. Riquet). Received 2 May 203; received in revised form 22 August 203; accepted 29 August 203 Abstract OBJECTIVES: During the last decades, pneumonectomy has been increasingly seen as a risky procedure, first reserved for tumours not amenable to lobectomy, and now discouraged even in advanced stages of non-small-cell lung cancer (NSCLC). Our purpose was to assess the long-term survival following pneumonectomy for NSCLC and its prognostic factors. METHODS: We set a retrospective study including every patient who underwent a pneumonectomy for NSCLC in 2 French centres from 98 to We then described the demographic and pathological characteristics of patients who survived >0 years, and studied the prognostic factors of long-term survival. RESULTS: During the study period, 466 pneumonectomies were performed for NSCLC, including 2 standard and 345 extended, and accounted for the overall population. Postoperative complications occurred in 396 patients (27%), including 93 deaths (6.3%). Five- and 0-year survival rates were 32 and 9%, respectively. Two-hundred and fifty patients survived >0 years after surgery, and accounted for the study group. The study group included a majority of males (n = 230, 92%), a mean age of 57 ± 9.2 years and a majority of clinical stage IIIA (n = 7, 46.8%). Induction, right-sided pneumonectomy, extended resection and adjuvant therapy were performed in 4 (6.4%), 09 (43.6%), 40 (6%) and 97 patients (38.8%), respectively. Histology revealed a majority of squamous cell carcinoma (n = 8, 72.4%), T2 tumours (n = 7, 36.8%) and N disease (n = 05, 42%). In multivariate analysis, factors associated with adverse outcomes included older age, advanced stage, extended resection, non-lethal postoperative complication, adenocarcinoma, lymphatic vessel microinvasion, N and N2 disease and R and R2 resection. CONCLUSIONS: During the last 30 years, pneumonectomy was effectively performed for advanced NSCLC, allowing a 0-year survival rate of 9%. Such results have not been reported with other non-surgical treatments and confirm that pneumonectomy is still an essential weapon in the armamentarium against lung cancer. Keywords: Non-small-cell lung cancer Pneumonectomy Long-term survival INTRODUCTION During the last decades, pneumonectomy has been increasingly seen as a risky procedure, first reserved for tumours not amenable to lobectomy, and now discouraged even in advanced stages of non-small-cell lung cancer (NSCLC). However, despite a commonly shared proficiency in sleeve resections, pneumonectomy may be unavoidable due to the extension of the primary tumour or related lymph nodes. Our purpose was to assess the long-term survival following pneumonectomy for NSCLC and its prognostic factors. We more particularly focused on patients who lived >0 years after the operation and could be considered cured. Presented at the 2st European Conference on General Thoracic Surgery, Birmingham, UK, May 203. METHODS Patients We set a retrospective study including every patient who underwent a pneumonectomy for NSCLC in Georges Pompidou European Hospital (Paris) and Cedar Surgery Centre (Bois Guillaume) from 98 to 2002, which permitted to have at least a 0-year follow-up. The data were prospectively entered since April 984. The preoperative workup included chest X-ray, bronchoscopy, computed tomography scan of the chest since 983, spirometry, lung perfusion scan and a thorough search for distant metastases. Mediastinoscopy was performed to exclude N3 disease and to confirm N2 involvement in the lung cancer patients included in various neoadjuvant treatment The Author 203. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

2 M. Riquet et al. / European Journal of Cardio-Thoracic Surgery 877 protocols depending on referring centres. N3 disease and distant metastases precluded surgery. Surgery All patients underwent pneumonectomy through a posterolateral thoracotomy. Completion pneumonectomies were excluded. Standard pneumonectomy was termed extensive pneumonectomy when the resection was extended to adjacent structures. We analysed the demographic and pathological characteristics of these patients. The criteria for considering lung tumours were those of the WHO classification [], and the staging system was the International Staging System for NSCLC recently modified [2]. Follow-up data The follow-up information was obtained from the hospital case records, from a questionnaire completed by the chest physician or general practitioner or from death certificates. The main outcome was overall survival, defined as the time interval between the date of operation and the date of death or the last follow-up visit for censored patients. The mean follow-up duration was 55.7 ± 64 months, 4.7 ± 53 months for the dead and 32 ± 73 months for the still alive patients. We first described the group of patients who survived >0 years after a pneumonectomy for NSCLC, then analysed their outcome and finally studied the prognostic factors of long-term survival. THORACIC Figure : Overall survival of the overall population (n = 466 (A)) and 0-year survivors (n = 250 (B)).

3 878 M. Riquet et al. / European Journal of Cardio-Thoracic Surgery Statistical analysis Continuous variables were described as mean ± standard deviation. Categorical variables were described as count and proportions. Actuarial survival curves were estimated by the Kaplan Meier method. Univariate analysis used the following variables: gender, age, type of surgical resection, histology, type of T and N involvement and perioperative treatments. Multivariate analysis was performed using the Cox proportional hazards model for overall survival analysis. All data analyses were conducted with a two-sided test: a P-value of < 0.05 was considered statistically significant. The statistical software used for the analysis was SEM (Anticancer Centre Jean Perrin, Clermont-Ferrand, France) [3]. Our Thoracic Surgery Society Ethic Committee (CERC-SFCTCV) approved this study and waived need for informed consent. RESULTS Overall population The overall population included 466 pneumonectomies for NSCLC. Among them, 2 (76.4%) were standard and 345 (23.6%) were extended. There were 307 males (89.2%), and the mean age was 60.9 ± 0. years. Postoperative complications occurred in 396 patients (27%), including 93 deaths (6.3%). Five- and 0-year survival rates were 32 and 9%, respectively (Fig. A). Study group All together, 250 patients (7.%) experienced 0-year survival after pneumonectomy for NSCLC. Patients main clinical characteristics are summarized in Table, surgical management in Table 2, histological features in Table 3, pathological TNM staging in Table 4 and pathological stage in Table 5. The group of 0-year survivors included a majority of males (n = 230, 92%), a mean age of 57 ± 9.2 years and a majority of clinical stage IIIA (n = 7, 46.8%). Induction and adjuvant therapy were performed in 4 (6.4%) and 97 patients (38.8%), respectively. Pneumonectomy was right-sided and extended in 09 (43.6%) and 40 patients (6%), respectively. Histology revealed a majority of squamous cell carcinoma (n = 8, 72.4%), T2 tumours (n = 7, 36.8%) and N disease (n = 05, 42%). Table : Patients clinical characteristics Demographics Male 230 (92%) Mean age 57 ± 9.2 Age >75 years 5 (2%) Past history Cancer 7 (6.8%) Cardiovascular 35 (4%) Hypertension 8 (3.2%) Vascular 7 (2.8%) Cardiac 20 (8%) Clinical stage Stage A 5 (2%) Stage IB 66 (26.4%) Stage IIA 6 (2.4%) Stage IIB 45 (8%) Stage IIIA 7 (46.8%) Stage IIIB 8 (3.2%) Stage IV 3 (.2%) Table 2: Surgical management Induction therapy 4 (6.4%) Surgery alone 2 (44.8%) Right side 09 (43.6%) Extended pneumonectomy 40 (6.0%) Adjuvant therapy 97 (38.8%) Complications* 4 (6.4%) *After exclusion of the 93 postoperative deaths. Table 3: Histology Squamous cell 8 (72.4%) Adenocarcinoma 45 (8%) Large cell 3 (5.2%) Adenosquamous 5 (2%) Others 3 (.2%) Not available 3 (.2%) Lymphatic vascular micro invasion 5 (2%) Blood vascular micro invasion 28 (.2%) Outcome The long-term survival curve of patients having survived 0 years and more is shown in Fig. B: their 5- and 20-year survival rates were 60.5 and 33.9%, respectively. The longest survivor survived 345 months. Considering 0-year survivors, 24 patients were still alive. Among them, three underwent surgery for malignant nodules on the remaining lung, whereas one patient underwent surgery for a brain metastasis and is alive at a 92-month follow-up. There was no mediastinal recurrence. Among the 26 deceased patients, the cause of death was cancer in 4 cases (lung n =3,othern = ), unrelated with cancer in 20 cases (myocardial infraction n = 2, pneumonia n = 2, stroke n =,othern = 5) and unavailable in 92 cases. Prognostic analysis The prognosis analysis is summarized in Table 6. In multivariate analysis after exclusion of postoperative mortality, factors associated with adverse long-term outcome included older age, advanced stage, extended resection, non-lethal postoperative complication, adenocarcinoma histology, lymphatic vessel micro invasion, N and N2 disease and R and R2 resection. Sex, induction treatment, side of pneumonectomy, blood vessel micro invasion and T status had no significant impact on long-term survival.

4 M. Riquet et al. / European Journal of Cardio-Thoracic Surgery 879 Table 4: Table 5: Comments pt and pn Tumour T0 7 (2.8%) Ta 23 (9.2%) Tb 35 (4.0%) T2a 86 (34.4%) T2b 3 (2.4%) T3 57 (22.8%) T4 (4.4%) Nodes N0 80 (32%) N 05 (42%) N2 65 (26%) N intralobar 35 (4%) N extralobar 70 (28%) N0N2 station 3 (5.2%) N0N2 2 stations 2 (0.8%) NN2 station 38 (5.2%) NN2 2 stations 2 (4.8%) pstaging Stage 0 7 (2.8%) Stage A 9 (7.6%) Stage IB 2 (8.4%) Stage IIA 74 (29.6%) Stage IIB 39 (5.6%) Stage IIIA 82 (32.8%) Stage IIIB 7 (2.8%) Stage IV (0.4%) Nowadays, pneumonectomy has a bad reputation. It carries a higher operative risk than limited resections and its impact on long-term survival after lung resection remains controversial [4 6]. However, this procedure may still be unavoidable because of anatomical or technical considerations [7]. Studying the long-term survival after pneumonectomy for NSCLC, we found that older age, advanced stage and extended or incomplete resections were associated with adverse survival, whereas laterality of pneumonectomy may have short-term morbidities but did not influence long-term survival. Furthermore, the long-term results reported here following pneumonectomy have not been reported following alternative treatments. Both patients who underwent pneumonectomy in 933 survived 30 and 29 years, respectively [7 9]. It is commonly said that when the results following a first procedure are unexpectedly good, it does not mean that the procedure itself is good. Five-year survival rates following pneumonectomy for NSCLC may be as high as 53% in Stage I [6, 0], 40% in Stage II [] and 29% in Stage III disease [2]. Overall 5-year survival including any stages may range from 2% [3] to 3% [4]. Longer survival has been reported, including a 7-year survival of 26% in Stage II [5], a 8-year survival of 20% (with 26 alive patients still at risk, 0 of them being stage pii) [] and a 0-year survival of 0% (0 patients still at risk, among them 7 with advanced stages) [3]. Deslauriers et al. [4] provided a survival curve demonstrating that out of 523 patients undergoing pneumonectomy for lung cancer, 62 and 47 patients were still at risk at 5 and 0 years, respectively, suggesting that this report of 250 ten-year survivors following pneumonectomy is the largest published to date. Factors influencing long-term survival are related to the patient s condition and tumour characteristics. The operative mortality is significantly higher in older patients [6]. However, despite Ramnath et al. [3] reporting that older patients were not associated with poorer survival, older age is generally an independent adverse predictor of survival [7], even in early stages [6, 5], as confirmed in our study. Male gender is also considered an independent predictor of adverse survival [6, 7], which was not demonstrated in our study. Thomas et al. [0] identified arteriosclerosis as significant adverse prognosticator in Stage I patients, as did Spaks and colleagues [5] in Stage II, and our study in the whole study group. We also observed that a history of prior malignancy was not frequent in long-term survivors, which was also reported to be a predictor of poor survival by Fernandez and colleagues [7]. In fact, all these factors of poorer prognosis are not specific to pneumonectomy and are also encountered in patients who undergo lesser resections. Interestingly, in the literature, survival analyses are never adjusted for non-lethal postoperative complications. However, after exclusion of postoperative mortality, we observed that the occurrence of non-lethal postoperative complications was an independent prognostic factor of adverse outcome, suggesting that post-pneumonectomy morbidity may reflect some patient fragility, and impact on long-term survival. Tumour-related prognostic factors included tumour stage, type of N involvement and the extent of pneumonectomy required. In most cases, the long-term results mostly reflect the stage of disease rather than the extent of the operation. In our experience, this relationship among extent of resection, tumour stage and long-term results has not changed over time, nor has it been modified according to the use of perioperative radiation or chemotherapy for patients with Stage III disease. Although the difference in survival has generally been slightly worse for patients requiring pneumonectomy, this difference has not been significant [6]. Ramnath et al. [3] reported that as expected, patients with Stage I disease survived longer than did patients with Stage II, III or IV disease. T status has been reported to be an independent prognostic factor among patients with Stage I [6, 0] and Stage II disease [5]. However, multivariate analysis revealed that in our experience, the extent of resection had a prognostic impact, but T status had not. Fernandez et al. reported that tumour-related predictors of poor survival were stage, and also grade and tumour size [7]. Blood vessel invasion may be a significant adverse prognosticator in Stage I patients [0], but did not show any prognostic impact in our study, whereas lymphatic vessel invasion did. Similarly, we observed that squamous cell carcinomas were more frequent than adenocarcinomas in long-term survivors. The type of N involvement is of tremendous importance. N2 disease has always been a significant predictor of worse outcomes when compared with N0 disease. However, in our study, 26% of the 0-year survivors following pneumonectomy had N2 involvement. Such long-term outcomes have not been reported in N2 disease with definitive chemoradiation [8, 9]. When reporting the results of the EORTC0894 trial in 2007, van Meerbeeck et al. [8] concluded that radiotherapy should be considered the preferred loco-regional treatment for N2 patients with pathologically proven stage IIIA-N2 NSCLC and a response to induction chemotherapy. However, the rates of incomplete resections and postoperative deaths reported in this trial were high, and the numbers THORACIC

5 880 M. Riquet et al. / European Journal of Cardio-Thoracic Surgery Table 6: mortality) Uni- and multivariate analyses of prognostic factors of long-term survival (n = 373 after exclusion of postoperative Variables Univariate Multivariate P-value Hazard ratio (HR) 95% confidence interval P-value Male vs female (considered as reference) Age >62 vs <62 (ref.) Clinical stage III IV vs I II (ref.) Induction ttt Right vs left side (ref.) Extended vs regular (ref.) Adjuvant treatment Postoperative complication Adenocarcinoma vs other histologies (ref.) Lymphatic vascular micro invasion Blood vascular micro invasion pt3 T4 vs pt T2 (ref.) pn vs pn0 (ref.) pn2 vs pn0 (ref.) Pathological stage III IV vs I II (ref.) R + R2 resection vs R0 (ref.) < <0.00 < < < < <0.00 < <0.00 <0.00 <0.00 < < < < < <0.00 ref.: the value of the variable considered a reference (HR = ) when calculating the HR in multivariate analysis. of patients at risk with and without progression were only 33 and 6 after 5 years, forbidding any definitive conclusion regarding the long-term efficacy of either management. Similarly, when Albain et al. [9] reported a randomized trial comparing concurrent chemoradiotherapy followed by resection with definitive concurrent chemoradiotherapy in pathologically proven stage IIIA-N2 NSCLC, no significant difference was found in overall survival between the two groups. However, the median follow-up for all patients was only 22.5 months. Furthermore, the trial was closed after inclusion of only 429 patients. As a result, there were only 6 and 45 patients alive with and without progression at 5 years, resulting in a lack of power and absence of data to infer long-term results and potential cure from NSCLC. This lack of long-term data is questionable, because the experience of randomized trials in thoracic oncology has recently confirmed that long-term results may be different from 5-year endpoints. The International Adjuvant Lung Cancer trial (IALT) showed that adjuvant chemotherapy following complete resection of NSCLC resulted in a significant increase in overall survival after a median follow-up of 4.6 years [20], but not after a median follow-up of 7.5 years [2]. The second publication has a less severe impact on clinical practice than the first one, despite the fact that most patients with advanced cancer would accept toxic treatment for even a % chance of cure but would be unwilling to accept the same treatment for a substantial increase in life expectancy without cure [22]. All together, these findings suggest that patients who do not know whether a treatment offers any possibility of cure may be compromised in their ability to make informed treatment decisions that are consonant with their preferences [23]. From our point of view, whether the goal of the multidisciplinary care is to seek a 5-year survival advantage of 5% or a chance to be cured of NSCLC should be discussed honestly with the patient, and constituted the basis of informed consent. If long-term survival can be obtained following pneumonectomy even in case of N2 disease, some questions are still to be answered regarding the prognostic impact of the side of resection, and the impact of pneumonectomy on quality of life (QOL). Simon et al. [] addressed the side of pneumonectomy as a possible factor for longterm prognosis, given its strong pronostic value on postoperative mortality. However, little has been reported in the medical literature. Ramnath et al. [3] reported that left tumour location was associated with a non-significant trend towards poorer survival. Fernandez et al. [7] observed that right pneumonectomy was associated with approximately twice the perioperative mortality as left pneumonectomy and that 3-year survival was not affected by laterality. In their prognostic analysis, right pneumonectomy was associated with worse long-term survival, but an assessment of the proportional hazards diagnostics showed that the assumption was violated. In fact, the side of pneumonectomy has no prognostic value and this is confirmed by other recentpublications[4, 24] and our study.

6 M. Riquet et al. / European Journal of Cardio-Thoracic Surgery 88 There remains much controversy surrounding pneumonectomy in terms of long-term detrimental impact on QOL. We have no data concerning the QOL of our patients. Many clinicians argue that patients who undergo pneumonectomy subsequently have a poor QOL, and therefore, surgeons should only select it as the last option [25]. Deslauriers et al. [4] reviewed 7 patients having a 5-year minimum follow-up. In general, patients were not severely handicapped by dyspnoea, and breathlessness was not a limiting factor for the performance of their daily activities. One hundred patients were further analysed: the loss of expiratory lung volumes was in the range of 5 30% and despite this loss, the mean postoperative forced expiratory volume in s (FEV) was still 58 ± 6% of predicted values. Most patients have relatively normal exercise tolerance (83 ± 7% of predicted values) assessed with the 6-min walk test, with only 9 of 9 patients having less than the expected normal values for men and women. In their study in which hyperinflation was quantified on posteroanterior chest radiography, more hyperinflation correlated with better FEV and thus has a beneficial effect on postoperative lung function. In about 40% of patients, the systolic pulmonary artery pressure was elevated mildly to moderately, but this elevation has no demonstrable effect on pulmonary function, blood gas values, cardiac output and exercise tolerance. The right ventricular index of myocardiac performance was normal. Bryant et al. [25] reviewed patients having a -year minimum follow-up following pneumonectomy. They studied physical and mental scores of QOL. The mean physical component score in their cohort was significantly lower than that of the average US population s score, whereas the mental QOL score was significantly higher. However, pneumonectomy reduced significantly a patient s physical score on the QOL survey, particularly in elderly patients. When they compared the patients who had a pneumonectomy for cancer (n = 97) with those who had a pneumonectomy for benign disease (n = 4), the mental score and physical score were both significantly higher in the patients who had the pneumonectomy performed for cancer. These results support the theory that patients who have cancer and undergo resection have higher mental scores, supporting pneumonectomy as an acceptable solution regarding long-term QOL. Conclusion Following pneumonectomy, 0-year survival rates of 9% may be obtained even with mediastinal lymph nodes metastases identified in one-third of the patients. 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Survival and quality of life at least year after pneumonectomy. J Thorac Cardiovasc Surg 202;44: THORACIC