Completion pneumonectomy: a valuable option for lung cancer recurrence or new primaries

Completion pneumonectomy: a valuable option for lung cancer recurrence or new primaries Background: The preoperative selection of patients with lung cancer recurrence remains a major clinical challenge. Several aspects of this kind of surgery are still insufficiently evidence-based, with only a few series with more than 50 patients. Methods: A retrospective study on 29 patients who underwent a completion pneumonectomy for postoperative lung cancer recurrence or new primary was done in the period between October 2004 and December 2015. Inclusion criteria include complete (R0) first and second resections, histologically proven recurrent or new malignancy, complete pathohistological report after both operations, and exact data about the treatment outcome at the time of the last contact with patients or their families. Results: There were 25 (86.2%) males and 4 (13.8%) females (M:F 6.2:1). In 13/29 patients, the interval between the first and second operations was less than 2 years, while in the remaining 16 patients, it was longer than 2 years. Concerning theoperativestage distribution, stageIwasmorefrequentafter thefirst operation(44.8vs. 22%), whilestageIII was dominant after the second operation (40.7 vs. 10.3%). The same tumor histology after the first and second operations existed in 24 (82.8%) patients. Adjuvant treatment was given to 53.6% of patients after the first and to 45.5% of patients after the second operation. The overall 5-year survival was 30%, median survival being 35 ± 16.9 months (1.896, 68.104 95% CI). A median survival of patients in post-surgery stage I after re-do surgery was better in comparison with that in higher stages (35 ± 22.6 vs.17.2 ± 15.1 vs. 21 ± 6.7 months, p > 0.05). Patients with the same tumor type at both operations lived significantly longer (median survival 48 ± 21.5 vs. 7.7 ± 1.9 months) than patients with different tumor histology after the second operation. Patients under 60 years (42.9%) lived longer than patients older than 60 years (median survival 69 ± 4.5 vs. 17.2 ± 14.3 months). The Cox regression analysis revealed only the disease stage at first operation and the same/different tumor histology as significant prognostic factors. One patient died from cardiac insufficiency caused by bronchopleural fistula (3.4% operative mortality). Operative morbidity was 34.4%. Conclusion: Completion pneumonectomy may be a reasonable option for postoperative lung cancer recurrence or new primaries only in carefully selected patients, in whom the potential oncological benefits overweigh the surgical risk. * Correspondence: profsubotic@gmail.com Clinic for Thoracic Surgery, Clinical Center of Serbia, 26, Koste Todorovica, Belgrade 11000, Serbia School of Medicine, University of Belgrade, Belgrade, Serbia Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Subotic et al. World Journal of Surgical Oncology (2018) 16:98 Page 2 of 9 Background bronchoscopy transcarinal or transtracheal Postoperative tumor recurrence, occurring in 30–77% of needle-biopsy). Re-mediastinoscopy was not a part of patients, is the main cause of a poor long-term survival mediastinal re-staging in this group of patients. Upfront after lung cancer surgery, still remaining less than 50% surgery was offered only to biopsy-negative patients. [1]. Surgery, in the form of a completion pneumonec- Biopsy-positive patients underwent a chemotherapy tomy, is possible in up to 4% of patients with (2-3 cycles) and in case of response to treatment or in loco-regional recurrence or new primaries [2]. the absence of the disease progression, re-do surgery Loco-regional recurrence, occurring in 4.6–24% of pa- was offered. Current study inclusion criteria include tients after complete resection [3], remains a major chal- complete (R0) second resection, histopathologically lenge from the standpoint of optimal diagnostic and proven recurrent or new malignancy, detailed postsurgi- therapeutic approach. The most frequent surgical option cal histopathological report, and exact data about the in these patients is a completion pneumonectomy, treatment outcome at the time of the last contact with meaning removal of the remaining lung after the first re- patients or their families. section, usually after lobectomy or bilobectomy, less fre- Exclusion criteria include (1) patients with otherwise quently after a sublobar resection. Other therapeutic resectable tumors, but whose general condition was too options are definitive chemotherapy and radiation ther- poor for major surgery and subsequent adjuvant therapy; apy, either alone or combined [4, 5]. (2) unclear local disease spread in terms of complete re- Patient selection for this kind of surgery is still insuffi- section; surgery was indicated only if the risk of explora- ciently evidence-based. There are only a few series with tive thoracotomy was practically zero, because of a high more than 50 patients, focused more to the appropriateness probability of lung expansion problems and related com- of this operation from the standpoint of a high operative plications; on the other hand, involvement of the peri- risk than from the standpoint of the oncological benefit. cardium and intrapericardial part of the pulmonary vein The aim of the study is to assess the treatment out- and/or artery (without extension to the myocardium), as come after completion pneumonectomy for postopera- well as involvement of the proximal part of the main tive lung cancer recurrence or new primary by analyzing bronchus (if a sleeve pneumonectomy is still possible) data from two high-volume surgical centers. and diaphragm, were not arguments for rejection from surgery; only direct invasion of the myocardium, trachea, Methods esophagus, aorta, circumferential invasion of the super- The analysis represents the two-institutional experience ior vena cava and spinal involvement were absolute con- with 29 patients who underwent a completion pneu- traindications for surgery; (3) predicted-postoperative monectomy for postoperative lung cancer recurrence or FEV < 30% in patients with COPD or restrictive ventila- new primary in the period between October 2004 and tory disorders; and (4) oxygen consumption during effort December 2015. Inclusion criteria for completion pneu- < 10 ml/kg in patients with increased overall cardiorespi- monectomy include potentially curative (R0) first resec- ratory risk (previous coronary artery stenting or bypass tion for primary NSCLC, histologically proven recurrent surgery, serious cardiac rhythm disorders, with or with- or new malignancy and/or CT aspect of malignancy at out associated COPD). the ipsilateral hilar or parenchymal level, no distant me- The preoperative lung function and risk assessment tastases, and no multilevel N2 disease. In most of the before the second operation followed the ESTS/ERS cri- patients, the indication for completion pneumonectomy teria for fitness for surgery [6]. All patients underwent was established preoperatively. Only in patients with the calculation of the predicted-postoperative FEV be- sublobar resection, this decision was determined during fore the second operation by using a perfusion lung scin- the operation, because of the anticipated lack of radical- tigraphy. Having in mind a re-do surgery, only patients ity or reexpansion problems. In patients with left-sided with ppoFEV ≥ 35% were included. Diffusion was mea- (upper or lower) lobectomy as the first operation, com- sured in all patients irrespectively of the lung function pletion pneumonectomy was the only possible option, after the first surgery. Only patients with DLco ≥ 50% at because an additional generous wedge resection would rest were included. Patients with moderate COPD and have been associated with major reexpansion problems. patients with any type of cardiac co-morbidity, irrespec- In the present series, there were no patients with a mid- tively of the lung function results, underwent exercise dle lobe recurrence with a favorable local situation in testing with determination of the oxygen consumption − 1 − 1 terms of oncological radicality, in whom it would be (VO ). The VO value ≥15 ml kg min was set up as 2 2 possible to avoid completion pneumonectomy. cut-off value for re-do surgery. All patients were in- The mediastinal re-staging was based on cluded in the program of preoperative therapy according high-resolution CT and PET. Patients with PET-positive to institutional protocol. Pulmonary physiotherapy N2 disease underwent a bronchoscopic (EBUS or rigid (bronchodilator aerosols in 0.9% NaCl solution, during Subotic et al. World Journal of Surgical Oncology (2018) 16:98 Page 3 of 9 10 min through jet nebulisers) was performed in three by the diaphragm muscle. In patients undergoing a right daily sessions, 5 days a week with the duration according pneumonectomy after the radiation treatment, pericardial to need. In COPD patients, in addition to physiotherapy, fat pad was the first choice, followed by omentum flap intravenous bronchodilator therapy (theophylline deriva- (two patients). tives 12.5 or 25 mg twice a day) combined with The quantitative variables are presented as means Berodual, Spiriva, or Symbicort (in case of the need for (standard deviation) or medians (ranges), depending on faster lung function recovery) was administered as well. data distribution. Statistical significance was calculated Hyposaturation in the arterial blood at rest was a contra- using the log rank test. All p values less than 0.05 was indication for surgery. considered significant. Survival (including operative The re-staging of the mediastinum was based on mortality) was calculated by the Kaplan–Meier method. high-resolution CT and PET. Mediastinoscopy was not Survival analysis included disease stage after the first done for mediastinal re-staging in the analyzed group. In and second operations, depending on T and N factors, all patients, preoperative bronchoscopy was done at least tumor histology, age, and interval between the two oper- 7 days before the scheduled surgery, in case additional bi- ations. Cox regression model was used to assess the in- opsies and histopathological analyses from the site of the fluence of particular risk factors to study endpoints. anticipated bronchial cut were necessary. The final selec- There were 25 (86%) males and 4 (14%) females tion was more restrictive than for the first operation, (M/F 6.2:1). The age of the patients (mean, range) was mostly in relation to the patients’ age and general 60.2 ± 7.6 (49–76) years. In 13/29 patients, the interval be- condition. tween the first and second operations was less than 2 years, Modified Martini-Melamed criteria [7] were used to and in the remaining 16 patients, it was longer than differentiate recurrent from new primaries: if the tumor 2 years. In five patients, the tumor histology after the sec- of the same histology was located at the bronchial stump ond operation was different from the tumor type at the level or within the parenchyma, close to the margins of first operation, and in all of them, the interval between the previous resections, it was classified as a local recur- two operations was longer than 30 months, thus classify- rence, even after more than 2 years after the first oper- ing them as clearly, new primaries. So, 24 patients had ation. Disease stage was determined by using the actual, loco-regional relapse. seventh edition of TNM classification for lung cancer. The policy for lymphadenectomy during the lung resec- Results tion in all lung cancer patients comprised systematic Group description lymphadenectomy from the supreme mediastinal level Right- and left-sided operations were equally distributed down to the pulmonary ligament level. All the fatty tissues (15/14), in a similar way as upper and lower lobectomies were removed together with the lymph nodes from the as the first operations, in 10 (34%) and 11 (38%) pa- paratracheal, pretracheal, retrocaval, aortico-pulmonary, tients, respectively and tumor histology, with squamous subcarinal (including N3 nodes), and paraesophageal re- cell and adenocarcinoma existing in 14 (48%) patients gion. The minimal quality requirement was at least four each. Sublobar resections were initially done in 17% of different mediastinal nodal groups removed, in addition to patients, while a middle lobectomy was the first oper- those removed en block with the specimen. ation in 3 (10%) patients. The structure of the analyzed In 19 patients, the bronchial suture was performed group is presented on Table 1. manually, cartilage-to-cartilage, membranous-to-membranous, In patients with loco-regional recurrence, tumor re- by using a continuous PDS 2-0 with 1-3 single, reinfor- lapse at the hilar level existed in 19/24 (79.1%) pa- cing PDS 3-0 stitches. In 10 patients, the main bron- tients. Of these, endobronchial tumor growth or chus was stapled by a bronchial TA stapler. In all stenosis by extrabronchial compression, as confirmed patients with right-sided pneumonectomy after induc- by bronchoscopy, existed in 13 patients. In the tion chemotherapy, the bronchial stump was routinely remaining patients, the recurrence occurred at the protected by the pericardial fat pad or, when poor-quality, parenchymal level. Table 1 Structure of the analyzed group Postoperative T Postoperative N Postoperative disease stage Adj.Th T1 T2 T3 T4 N0 N1 N2 I II IIIA n % n % n % n % n % n % n % n % n % n %% IOP 10 34.4 16 55.1 2 6.9 1 3.4 15 51.7 13 44.8 1 3.4 13 44.8 13 44.8 3 10.3 53.6 IIOP 7 24.1 8 27.5 8 27.5 4 20.9 11 37.9 10 34.5 6 20.6 6 20.6 10 34.4 11 37.9 45.5 IOP first operation, IIOP second operation, Adj. Th adjuvant therapy Subotic et al. World Journal of Surgical Oncology (2018) 16:98 Page 4 of 9 Concerning the operative stage distribution, the stage The disease-free interval in patients operated in stage I I was more frequent after the first operation (45 vs. was longer in comparison with patients operated in stages 22%), whilst the stage III was dominant after the second II and III—42(30.5–53.4) vs. 20 (14.1–25.8) months, re- operation (40.7 vs. 10.3%). The same tumor histology spectively (χ =0,813; p =0,367). after the first and second operations in existed in 24 Survival of patients depending on disease stage after (83%) patients, while it was different in five (17%) pa- the completion pneumonectomy is presented in Fig. 1b tients. Adjuvant treatment was given to 53.6% of pa- and Table 2. Despite a better median survival of patients tients after the first and to 45.5% of patients after the in stage I (compared with stages II and III—35 ± 22.6 second operation. vs. 17.2 ± 15.1 vs. 21 ± 6.71 months), this survival differ- In no patients, the lung function after the first oper- ence did not reach the level of statistical significance. ation was within normal ranges. Purely restrictive venti- There was no significant survival difference depending on latory disorders existed in 8 (27.7%) of patients and the length of interval between the first and second opera- mixed disorders in 7 (24.1%) patients, while in the tions (median survival 55 ± 12.4 vs. 17.2 ± 1.5 months), remaining 14(48.2%) patients, light and light to moder- with the cut-off interval set up at 31 months, based on ate COPD was equally distributed. Combined COPD median interval (Table 2). and cardiac comorbidity existed in 11 (37.9%) patients There was no significant survival difference between pa- (cardiac rhythm disorders and myocardiopathy in 7 and tients with squamous and adenocarcinoma (Table 3, 4 patients, respectively). Diabetes mellitus existed in 6 Fig. 2a). Patients with the same tumor type at both opera- (20.6%) patients. tions lived significantly longer (median survival 48 ± 21.5 vs. 7.7 ± 2 months) than patients with different tumor hist- Survival ology after the second operation (Table 3,Fig. 2b). The overall survival is presented in Fig. 1a. The 3- and The median survival of patients with stages I, II, and 5-year survival was 53 and 30%, respectively. Median sur- III at first operation was 18 (95% CI 14.8–21.2) vs. 55 vival was 35 ± 16.9 months (1.9, 68.1 95% CI). A separate (95% CI 41.8–68.2) vs. 7 months (95% CI 0.43–13.5), re- analysis including only patients with a loco-regional re- spectively Table 4,Fig. 3). This survival difference was not lapse demonstrated that a median survival was 48 months statistically significant (χ =4.38; p = 0.11). However, (5.8–90.1 CI 95%), while 3- and 5-year survival were 59 because of a small number of patients in stage III at first and 33%, respectively. The disease-free interval for the en- operation, a separate comparison between stages I and II tire group was 30 (12.4–47.6) months. revealed a significant survival difference (χ =5.6, p = 0.01). Fig. 1 Survival after completion pneumonectomy. a Overall. b Depending of disease stage of the second operation. Blue, stage I; green, stage II; gray, stage III Subotic et al. World Journal of Surgical Oncology (2018) 16:98 Page 5 of 9 Table 2 Survival (in months) depending on disease stage and interval between the operations Op stage Median SE 95% CI Mean SE 95% CI I 35.0 22.65 0.00 79.4 64.03 24.41 16.18 111.88 II 17.20 15.17 0.00 46.93 39.97 11.84 16.75 63.19 III 21.0 6.76 7.74 34.25 27.75 6.30 15.38 40.11 Survival according to interval between the two operations < 30 months 55.0 12.42 30.65 79.34 57.85 15.85 26.79 88.92 > 30 months 17.20 1.57 14.11 20.28 43.68 18.09 8.22 79.14 < 30 months, interval between the two operations shorter than 30 months; > 30 months, the same interval longer than 30 months Survival depending on T and N factors at first operation is one patient with pleural empyema without broncho- presented on Fig. 4 and Table 4. Survival of patients with pleural fistula and another one with postoperative pneu- T2 tumors was significantly better than survival of patients monia of the remaining lung. In this patient, pneumonia with T1 tumors (χ = 11.1; p = 0.004) (Fig. 4a). Similarly, the resolved after 7 days of parenteral antibiotic therapy. median survival of patients with N0 lesions was inferior to The heart arrhythmia requiring medical treatment oc- survival of patients with N1 lesions 17.2 (13.9–20.4) vs. curred in four (14%) patients. Bronchopleural fistula 55 months (41.5–68.4), respectively. This survival occurred in two patients: the first one was a patient aged difference was statistically significant (χ =4.3; p = 0.04) > 65 years with generalized disease that was unrecognized (Fig. 4b). Age of the patients was associated with significant at the time of surgery and this patient died within the first survival difference in a way that patients under 60 years 30 postoperative days; the other one was a younger patient (42.9%) lived longer than patients older than 60 years operated after previous chemotherapy, in whom extra- (median survival 69 ± 4.5 vs. 17.2 ± 14.3). pleural lung liberation and excessive peribronchial dissec- tion were done. The fistula occurred despite the bronchial Prognostic factors stump protection by the pericardial fat pad. In this patient, The Cox regression analysis included age, disease and the subsequent empyema was put under control by initial nodal stage at first operation, tumor histology (same vs. chest tube aspiration followed by repeated thoracenteses different), and interval between the two operations. Only after the chest tube removal. disease stage at first operation (HR = 3.44, 95% CI, df = 1, The 90-day mortality did not differ from the 30-day sig. = 0.06) and same/different tumor histology (HR = 7.85, mortality, as checked and confirmed during regular out- 95% CI, df = 1, sig. = 0.005) were identified as significant patient controls according to widely accepted schedule. prognostic factors. Discussion Operative mortality and morbidity Survival One patient died from cardiac insufficiency caused by The 30% overall 5-year survival of patients in the current bronchopleural fistula, thus constituting 3.44% 30-day study fits within the range of reported survival rates. Ac- operative mortality. Postoperative complications were cording to data from 10 studies published before 2007 registered in 10 (34.5%) patients. Postoperative bleeding [2, 8–16], each including more than 30 operated pa- (successfully solved by rethoracotomy) and broncho- tients, 5-year survival was under 30% in four studies, be- pleural fistula occurred in two (7%) patients each. One tween 30 and 40% in additional three studies, while it of two patients with bronchopleural fistula was the only was over 40% in three studies (44, 44.5, and 57%). In a one who died within 30 days postoperatively. There was multicentric study on 165 patients, published in 2012, the 5-year survival was 48.9 and 23.9%, for squamous cell and adenocarcinoma, respectively [17]. The reason Table 3 Survival (in months) depending of tumor histology for better long-term survival of patients in the present Tumor type Median SE 95% CI Mean SE 95% CI study, compared with studies with survival rates under Squamous 23.20 21.21 0.00 64.78 48.38 17.01 15.03 81.72 25%, is the higher proportion of stage III patients in Adeno Ca 35.0 14.86 5.86 64.13 51.99 17.74 17.20 86.77 these studies (66 vs. 40.7% in the present study). PH1 = PH2 48.0 21.5 5.85 90.14 55.61 12.90 30.32 80.90 Stage-related survival in the analyzed group confirmed PH1 ≠ PH2 7.7 1.98 3.80 11.59 7.72 1.46 4.84 10.59 the significance of the disease stage, whose influence re- PH1 = PH2, tumor histology was the same after both operations; PH1 ≠ PH2, mains inconsistent throughout the literature. In the tumor histology after the second operation was different vs. histology after the present study, despite a better survival in the stage I, the first operation PH1 pathohistology at first operation, PH2 pathohistology at second operation survival difference was not statistically significant, like in Subotic et al. World Journal of Surgical Oncology (2018) 16:98 Page 6 of 9 Fig. 2 Survival depending of tumor histology. a Squamous cell carcinoma vs. adenocarcinoma; b same vs. different tumor type the aforementioned study of Guggino et al. (67.5 vs. [9]. Such an inconsistence in the reported data is prob- 33.3% for stages I and II, respectively) [2]. Unlike that, in ably due to different criteria for cancer recurrences and the study of Chataigner et al. [18], survival of patients new primaries. with stage I and II disease was significantly better than Although some data suggest a poor prognosis of recur- in patients with stage III disease (56 vs. 17%; p = 0.02). rent adenocarcinoma vs. squamous cell carcinoma, like Our finding of significant survival difference between in the aforementioned multicentric study [17], there is recurrent and second primary tumors should be taken not enough evidence for this factor to be taken into ac- with caution, because of the small number (17.25%) of count as essential for preoperative patient selection. In patients with clear criteria for second primaries. Such a the present study, survival difference depending on finding is not in line with literature data, varying be- tumor type was not significant. In the present study, tween no survival difference (38 vs. 41%) [18], through slightly better (44.6 vs. 29.2%) [2] to significantly better survival for second primaries, with only 10% of the pa- tients with a recurrent carcinoma surviving 21 months [16]. Some other results confirm the same survival trend Table 4 Survival (in months) according to stage, T and N factors of the first operation Op stage Median SE 95% CI Mean SE 95% CI I 18.0 1.62 14.82 21.18 21.48 3.34 14.92 28.04 II 55.0 6.73 41.8 68.19 67.67 19.44 29.56 105.78 III 7.00 3.34 0.43 13.56 47.63 42.7 0.00 131.3 T1a + T1b 17.20 1.64 14.33 20.0 29.66 8.45 13.1 46.22 T2a + T2b 48.0 19.83 9.11 86.88 65.52 16.25 33.65 97.38 T3 + T4 7.0 0.00 –– 5.63 1.57 2.54 8.72 N0 17.20 1.66 13.94 20.45 20.55 3.27 14.20 26.89 Fig. 3 Survival depending of diseases stage of the first operation N1 + N2 55.0 11.74. 31.98 78.01 71.31 18.06 35.92 106.71 Subotic et al. World Journal of Surgical Oncology (2018) 16:98 Page 7 of 9 Fig. 4 Survival depending of T (a) and N (b) factors at first operation despite a certain trend in favor of interval between the Adjuvant therapy two operations shorter than 31 months (mean survival In the present study, adjuvant treatment was given to 57.8 ± 15.8 vs. 43.6 ± 18.1 months), this survival differ- 53.6% of patients after the first operation and to 45.5% of ence was not significant. In one of the few studies deal- patients after the second operation. In fact, one important ing with this factor, longer interval was associated with point in the preoperative selection was the likelihood that better survival, but again without statistical significance the patient will be fit for subsequent adjuvant treatment. (35.4 vs. 54.6% 5-year survival for intervals < 2 and > Based on the promising results of five largest adjuvant 2 years, respectively) [2]. Unclear prognostic significance chemotherapy trials with a confirmed survival benefit at of this factor additionally complicates the preoperative 5years [21–23], in terms of recurrence prevention, it still selection. remains to be confirmed whether such a treatment would As the influence of the disease stage and other rele- be also appropriate in patients with visceral pleural, intra- vant factors at the time of initial surgery are not suffi- vascular, and lymphatic invasion, irrespectively of nodal ciently addressed in the literature, this aspect was stage, both after the initial and re-do surgery. separately analyzed in the present study. Our data sug- gest that, if patients with a stage I get the lung cancer Operative morbidity and mortality recurrence, they will do worse than those with recur- The 3.4% mortality and 34.5% complication rates in the renceafter thestage II diseaseatfirst surgery. This present study are strongly in favor of the appropriateness finding is less surprising having in mind that the of this type of surgery, provided the patient selection is 10–15% reported incidence of local recurrence in adequate. The main concern related to this operation early-stage lung cancer [19]. In addition, a high recur- has traditionally been the alleged high complication rate. rence rate was reported in patients with stage I after However, based on ~ 12% reported operative mortality complete resection (25–50%) [20]. However, based on and < 40% operative morbidity in the last 15 years, in the analyzed data, an appropriate explanation for the the majority of series, it is clear that these complication obtained stage-related survival could not be given. The rates are comparable with those after standard pneu- size of the analyzed series is quite limited, although it monectomy [24]. The 6.9% bronchopleural fistulas in is also debatable whether the greater series would the present study falls within the range of the reported give some additional answers or clarifications. Includ- rates, being 7–13.3% in the majority of the series. Des- ing some of biochemical tumor markers into the ana- pite a sufficient number of surgical series, the reported lysis could possibly be of benefit for future studies of data are of limited value in terms of operative risk pre- this problem. diction. Even in the biggest series, either no significant Subotic et al. World Journal of Surgical Oncology (2018) 16:98 Page 8 of 9 factors of complications were identified or factors were Authors’ contributions DS contributed to the manuscript concept, surgery, literature retrieve, and found as significant only by univariate analysis, like for writing. LM took part in the surgery, patient data collection, and manuscript example, predicted-postoperative (ppo) FEV < 50% [17]. drafting and writing. DM collected the patient data and drafted the manuscript. Our experience, supporting many other reports [25–27], IS drafted the manuscript and did the statistics. LM and JH collected the data and drafted the manuscript. All the authors have read and approved the is strongly in favor of bronchial stump protection, espe- manuscript. cially for right-sided operations. In the present series, pericardial fat, diaphragm, and omental flaps were used Ethics approval and consent to participate According to the current legislation, such type of approval is not routinely whenever possible. We also want to point out the risk of obtained for retrospective type of studies. If necessary, it can be obtained intraoperative death, reaching 5.3%, with the main and submitted during the review process. causes of death being injury of the great vessels of the Competing interests heart, usually due to major pleural or pericardial adhe- The authors declare that they have no competing interests. sions as a consequence of the first surgery [28]. Our pol- icy to avoid such incidents, as previously reported by Publisher’sNote others, was the early opening of the pericardium, rather Springer Nature remains neutral with regard to jurisdictional claims in published than dissection around shortened vessels surrounded by maps and institutional affiliations. thickened peribronchial and perivascular tissue. Author details Clinic for Thoracic Surgery, Clinical Center of Serbia, 26, Koste Todorovica, Study limitations Belgrade 11000, Serbia. School of Medicine, University of Belgrade, Belgrade, Serbia. Department of Thoracic Surgery, Hospital Clinic, Barcelona University, The major limitation of the current study is the small Barcelona, Spain. Institute for Medical Statistics, School of Medicine, number of included patients, determined by strict selec- 5 University of Belgrade, Belgrade, Serbia. Department of Thoracic Surgery, tion criteria for this kind of surgery. The patient number Hospital Sagrat Cor, Barcelona University, Barcelona, Spain. was additionally restricted by the need to include Received: 9 February 2018 Accepted: 9 May 2018 well-matched groups from two institutions. Another limitation is survival analysis after two opera- References tions in different settings. By using the date of either the 1. Subotic D, Van Schil P, Grigoriu B. Optimizing treatment for postoperative initial or re-do surgery as “time zero,” some pitfalls will lung cancer recurrence. Eur Respir J. 2016;47:374–8. appear. As we recently discussed this problem, in the 2. 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Ann Thorac Surg. 1995;59:196–200. 29. Chansky K, Subotic D, Foster NR, Blum T. Survival analyses in lung cancer. J Thorac Dis. 2016 Nov;8(11):3457–63. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png World Journal of Surgical Oncology Springer Journals

Completion pneumonectomy: a valuable option for lung cancer recurrence or new primaries

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Medicine & Public Health; Surgical Oncology
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Abstract

Background: The preoperative selection of patients with lung cancer recurrence remains a major clinical challenge. Several aspects of this kind of surgery are still insufficiently evidence-based, with only a few series with more than 50 patients. Methods: A retrospective study on 29 patients who underwent a completion pneumonectomy for postoperative lung cancer recurrence or new primary was done in the period between October 2004 and December 2015. Inclusion criteria include complete (R0) first and second resections, histologically proven recurrent or new malignancy, complete pathohistological report after both operations, and exact data about the treatment outcome at the time of the last contact with patients or their families. Results: There were 25 (86.2%) males and 4 (13.8%) females (M:F 6.2:1). In 13/29 patients, the interval between the first and second operations was less than 2 years, while in the remaining 16 patients, it was longer than 2 years. Concerning theoperativestage distribution, stageIwasmorefrequentafter thefirst operation(44.8vs. 22%), whilestageIII was dominant after the second operation (40.7 vs. 10.3%). The same tumor histology after the first and second operations existed in 24 (82.8%) patients. Adjuvant treatment was given to 53.6% of patients after the first and to 45.5% of patients after the second operation. The overall 5-year survival was 30%, median survival being 35 ± 16.9 months (1.896, 68.104 95% CI). A median survival of patients in post-surgery stage I after re-do surgery was better in comparison with that in higher stages (35 ± 22.6 vs.17.2 ± 15.1 vs. 21 ± 6.7 months, p > 0.05). Patients with the same tumor type at both operations lived significantly longer (median survival 48 ± 21.5 vs. 7.7 ± 1.9 months) than patients with different tumor histology after the second operation. Patients under 60 years (42.9%) lived longer than patients older than 60 years (median survival 69 ± 4.5 vs. 17.2 ± 14.3 months). The Cox regression analysis revealed only the disease stage at first operation and the same/different tumor histology as significant prognostic factors. One patient died from cardiac insufficiency caused by bronchopleural fistula (3.4% operative mortality). Operative morbidity was 34.4%. Conclusion: Completion pneumonectomy may be a reasonable option for postoperative lung cancer recurrence or new primaries only in carefully selected patients, in whom the potential oncological benefits overweigh the surgical risk. * Correspondence: profsubotic@gmail.com Clinic for Thoracic Surgery, Clinical Center of Serbia, 26, Koste Todorovica, Belgrade 11000, Serbia School of Medicine, University of Belgrade, Belgrade, Serbia Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Subotic et al. World Journal of Surgical Oncology (2018) 16:98 Page 2 of 9 Background bronchoscopy transcarinal or transtracheal Postoperative tumor recurrence, occurring in 30–77% of needle-biopsy). Re-mediastinoscopy was not a part of patients, is the main cause of a poor long-term survival mediastinal re-staging in this group of patients. Upfront after lung cancer surgery, still remaining less than 50% surgery was offered only to biopsy-negative patients. [1]. Surgery, in the form of a completion pneumonec- Biopsy-positive patients underwent a chemotherapy tomy, is possible in up to 4% of patients with (2-3 cycles) and in case of response to treatment or in loco-regional recurrence or new primaries [2]. the absence of the disease progression, re-do surgery Loco-regional recurrence, occurring in 4.6–24% of pa- was offered. Current study inclusion criteria include tients after complete resection [3], remains a major chal- complete (R0) second resection, histopathologically lenge from the standpoint of optimal diagnostic and proven recurrent or new malignancy, detailed postsurgi- therapeutic approach. The most frequent surgical option cal histopathological report, and exact data about the in these patients is a completion pneumonectomy, treatment outcome at the time of the last contact with meaning removal of the remaining lung after the first re- patients or their families. section, usually after lobectomy or bilobectomy, less fre- Exclusion criteria include (1) patients with otherwise quently after a sublobar resection. Other therapeutic resectable tumors, but whose general condition was too options are definitive chemotherapy and radiation ther- poor for major surgery and subsequent adjuvant therapy; apy, either alone or combined [4, 5]. (2) unclear local disease spread in terms of complete re- Patient selection for this kind of surgery is still insuffi- section; surgery was indicated only if the risk of explora- ciently evidence-based. There are only a few series with tive thoracotomy was practically zero, because of a high more than 50 patients, focused more to the appropriateness probability of lung expansion problems and related com- of this operation from the standpoint of a high operative plications; on the other hand, involvement of the peri- risk than from the standpoint of the oncological benefit. cardium and intrapericardial part of the pulmonary vein The aim of the study is to assess the treatment out- and/or artery (without extension to the myocardium), as come after completion pneumonectomy for postopera- well as involvement of the proximal part of the main tive lung cancer recurrence or new primary by analyzing bronchus (if a sleeve pneumonectomy is still possible) data from two high-volume surgical centers. and diaphragm, were not arguments for rejection from surgery; only direct invasion of the myocardium, trachea, Methods esophagus, aorta, circumferential invasion of the super- The analysis represents the two-institutional experience ior vena cava and spinal involvement were absolute con- with 29 patients who underwent a completion pneu- traindications for surgery; (3) predicted-postoperative monectomy for postoperative lung cancer recurrence or FEV < 30% in patients with COPD or restrictive ventila- new primary in the period between October 2004 and tory disorders; and (4) oxygen consumption during effort December 2015. Inclusion criteria for completion pneu- < 10 ml/kg in patients with increased overall cardiorespi- monectomy include potentially curative (R0) first resec- ratory risk (previous coronary artery stenting or bypass tion for primary NSCLC, histologically proven recurrent surgery, serious cardiac rhythm disorders, with or with- or new malignancy and/or CT aspect of malignancy at out associated COPD). the ipsilateral hilar or parenchymal level, no distant me- The preoperative lung function and risk assessment tastases, and no multilevel N2 disease. In most of the before the second operation followed the ESTS/ERS cri- patients, the indication for completion pneumonectomy teria for fitness for surgery [6]. All patients underwent was established preoperatively. Only in patients with the calculation of the predicted-postoperative FEV be- sublobar resection, this decision was determined during fore the second operation by using a perfusion lung scin- the operation, because of the anticipated lack of radical- tigraphy. Having in mind a re-do surgery, only patients ity or reexpansion problems. In patients with left-sided with ppoFEV ≥ 35% were included. Diffusion was mea- (upper or lower) lobectomy as the first operation, com- sured in all patients irrespectively of the lung function pletion pneumonectomy was the only possible option, after the first surgery. Only patients with DLco ≥ 50% at because an additional generous wedge resection would rest were included. Patients with moderate COPD and have been associated with major reexpansion problems. patients with any type of cardiac co-morbidity, irrespec- In the present series, there were no patients with a mid- tively of the lung function results, underwent exercise dle lobe recurrence with a favorable local situation in testing with determination of the oxygen consumption − 1 − 1 terms of oncological radicality, in whom it would be (VO ). The VO value ≥15 ml kg min was set up as 2 2 possible to avoid completion pneumonectomy. cut-off value for re-do surgery. All patients were in- The mediastinal re-staging was based on cluded in the program of preoperative therapy according high-resolution CT and PET. Patients with PET-positive to institutional protocol. Pulmonary physiotherapy N2 disease underwent a bronchoscopic (EBUS or rigid (bronchodilator aerosols in 0.9% NaCl solution, during Subotic et al. World Journal of Surgical Oncology (2018) 16:98 Page 3 of 9 10 min through jet nebulisers) was performed in three by the diaphragm muscle. In patients undergoing a right daily sessions, 5 days a week with the duration according pneumonectomy after the radiation treatment, pericardial to need. In COPD patients, in addition to physiotherapy, fat pad was the first choice, followed by omentum flap intravenous bronchodilator therapy (theophylline deriva- (two patients). tives 12.5 or 25 mg twice a day) combined with The quantitative variables are presented as means Berodual, Spiriva, or Symbicort (in case of the need for (standard deviation) or medians (ranges), depending on faster lung function recovery) was administered as well. data distribution. Statistical significance was calculated Hyposaturation in the arterial blood at rest was a contra- using the log rank test. All p values less than 0.05 was indication for surgery. considered significant. Survival (including operative The re-staging of the mediastinum was based on mortality) was calculated by the Kaplan–Meier method. high-resolution CT and PET. Mediastinoscopy was not Survival analysis included disease stage after the first done for mediastinal re-staging in the analyzed group. In and second operations, depending on T and N factors, all patients, preoperative bronchoscopy was done at least tumor histology, age, and interval between the two oper- 7 days before the scheduled surgery, in case additional bi- ations. Cox regression model was used to assess the in- opsies and histopathological analyses from the site of the fluence of particular risk factors to study endpoints. anticipated bronchial cut were necessary. The final selec- There were 25 (86%) males and 4 (14%) females tion was more restrictive than for the first operation, (M/F 6.2:1). The age of the patients (mean, range) was mostly in relation to the patients’ age and general 60.2 ± 7.6 (49–76) years. In 13/29 patients, the interval be- condition. tween the first and second operations was less than 2 years, Modified Martini-Melamed criteria [7] were used to and in the remaining 16 patients, it was longer than differentiate recurrent from new primaries: if the tumor 2 years. In five patients, the tumor histology after the sec- of the same histology was located at the bronchial stump ond operation was different from the tumor type at the level or within the parenchyma, close to the margins of first operation, and in all of them, the interval between the previous resections, it was classified as a local recur- two operations was longer than 30 months, thus classify- rence, even after more than 2 years after the first oper- ing them as clearly, new primaries. So, 24 patients had ation. Disease stage was determined by using the actual, loco-regional relapse. seventh edition of TNM classification for lung cancer. The policy for lymphadenectomy during the lung resec- Results tion in all lung cancer patients comprised systematic Group description lymphadenectomy from the supreme mediastinal level Right- and left-sided operations were equally distributed down to the pulmonary ligament level. All the fatty tissues (15/14), in a similar way as upper and lower lobectomies were removed together with the lymph nodes from the as the first operations, in 10 (34%) and 11 (38%) pa- paratracheal, pretracheal, retrocaval, aortico-pulmonary, tients, respectively and tumor histology, with squamous subcarinal (including N3 nodes), and paraesophageal re- cell and adenocarcinoma existing in 14 (48%) patients gion. The minimal quality requirement was at least four each. Sublobar resections were initially done in 17% of different mediastinal nodal groups removed, in addition to patients, while a middle lobectomy was the first oper- those removed en block with the specimen. ation in 3 (10%) patients. The structure of the analyzed In 19 patients, the bronchial suture was performed group is presented on Table 1. manually, cartilage-to-cartilage, membranous-to-membranous, In patients with loco-regional recurrence, tumor re- by using a continuous PDS 2-0 with 1-3 single, reinfor- lapse at the hilar level existed in 19/24 (79.1%) pa- cing PDS 3-0 stitches. In 10 patients, the main bron- tients. Of these, endobronchial tumor growth or chus was stapled by a bronchial TA stapler. In all stenosis by extrabronchial compression, as confirmed patients with right-sided pneumonectomy after induc- by bronchoscopy, existed in 13 patients. In the tion chemotherapy, the bronchial stump was routinely remaining patients, the recurrence occurred at the protected by the pericardial fat pad or, when poor-quality, parenchymal level. Table 1 Structure of the analyzed group Postoperative T Postoperative N Postoperative disease stage Adj.Th T1 T2 T3 T4 N0 N1 N2 I II IIIA n % n % n % n % n % n % n % n % n % n %% IOP 10 34.4 16 55.1 2 6.9 1 3.4 15 51.7 13 44.8 1 3.4 13 44.8 13 44.8 3 10.3 53.6 IIOP 7 24.1 8 27.5 8 27.5 4 20.9 11 37.9 10 34.5 6 20.6 6 20.6 10 34.4 11 37.9 45.5 IOP first operation, IIOP second operation, Adj. Th adjuvant therapy Subotic et al. World Journal of Surgical Oncology (2018) 16:98 Page 4 of 9 Concerning the operative stage distribution, the stage The disease-free interval in patients operated in stage I I was more frequent after the first operation (45 vs. was longer in comparison with patients operated in stages 22%), whilst the stage III was dominant after the second II and III—42(30.5–53.4) vs. 20 (14.1–25.8) months, re- operation (40.7 vs. 10.3%). The same tumor histology spectively (χ =0,813; p =0,367). after the first and second operations in existed in 24 Survival of patients depending on disease stage after (83%) patients, while it was different in five (17%) pa- the completion pneumonectomy is presented in Fig. 1b tients. Adjuvant treatment was given to 53.6% of pa- and Table 2. Despite a better median survival of patients tients after the first and to 45.5% of patients after the in stage I (compared with stages II and III—35 ± 22.6 second operation. vs. 17.2 ± 15.1 vs. 21 ± 6.71 months), this survival differ- In no patients, the lung function after the first oper- ence did not reach the level of statistical significance. ation was within normal ranges. Purely restrictive venti- There was no significant survival difference depending on latory disorders existed in 8 (27.7%) of patients and the length of interval between the first and second opera- mixed disorders in 7 (24.1%) patients, while in the tions (median survival 55 ± 12.4 vs. 17.2 ± 1.5 months), remaining 14(48.2%) patients, light and light to moder- with the cut-off interval set up at 31 months, based on ate COPD was equally distributed. Combined COPD median interval (Table 2). and cardiac comorbidity existed in 11 (37.9%) patients There was no significant survival difference between pa- (cardiac rhythm disorders and myocardiopathy in 7 and tients with squamous and adenocarcinoma (Table 3, 4 patients, respectively). Diabetes mellitus existed in 6 Fig. 2a). Patients with the same tumor type at both opera- (20.6%) patients. tions lived significantly longer (median survival 48 ± 21.5 vs. 7.7 ± 2 months) than patients with different tumor hist- Survival ology after the second operation (Table 3,Fig. 2b). The overall survival is presented in Fig. 1a. The 3- and The median survival of patients with stages I, II, and 5-year survival was 53 and 30%, respectively. Median sur- III at first operation was 18 (95% CI 14.8–21.2) vs. 55 vival was 35 ± 16.9 months (1.9, 68.1 95% CI). A separate (95% CI 41.8–68.2) vs. 7 months (95% CI 0.43–13.5), re- analysis including only patients with a loco-regional re- spectively Table 4,Fig. 3). This survival difference was not lapse demonstrated that a median survival was 48 months statistically significant (χ =4.38; p = 0.11). However, (5.8–90.1 CI 95%), while 3- and 5-year survival were 59 because of a small number of patients in stage III at first and 33%, respectively. The disease-free interval for the en- operation, a separate comparison between stages I and II tire group was 30 (12.4–47.6) months. revealed a significant survival difference (χ =5.6, p = 0.01). Fig. 1 Survival after completion pneumonectomy. a Overall. b Depending of disease stage of the second operation. Blue, stage I; green, stage II; gray, stage III Subotic et al. World Journal of Surgical Oncology (2018) 16:98 Page 5 of 9 Table 2 Survival (in months) depending on disease stage and interval between the operations Op stage Median SE 95% CI Mean SE 95% CI I 35.0 22.65 0.00 79.4 64.03 24.41 16.18 111.88 II 17.20 15.17 0.00 46.93 39.97 11.84 16.75 63.19 III 21.0 6.76 7.74 34.25 27.75 6.30 15.38 40.11 Survival according to interval between the two operations < 30 months 55.0 12.42 30.65 79.34 57.85 15.85 26.79 88.92 > 30 months 17.20 1.57 14.11 20.28 43.68 18.09 8.22 79.14 < 30 months, interval between the two operations shorter than 30 months; > 30 months, the same interval longer than 30 months Survival depending on T and N factors at first operation is one patient with pleural empyema without broncho- presented on Fig. 4 and Table 4. Survival of patients with pleural fistula and another one with postoperative pneu- T2 tumors was significantly better than survival of patients monia of the remaining lung. In this patient, pneumonia with T1 tumors (χ = 11.1; p = 0.004) (Fig. 4a). Similarly, the resolved after 7 days of parenteral antibiotic therapy. median survival of patients with N0 lesions was inferior to The heart arrhythmia requiring medical treatment oc- survival of patients with N1 lesions 17.2 (13.9–20.4) vs. curred in four (14%) patients. Bronchopleural fistula 55 months (41.5–68.4), respectively. This survival occurred in two patients: the first one was a patient aged difference was statistically significant (χ =4.3; p = 0.04) > 65 years with generalized disease that was unrecognized (Fig. 4b). Age of the patients was associated with significant at the time of surgery and this patient died within the first survival difference in a way that patients under 60 years 30 postoperative days; the other one was a younger patient (42.9%) lived longer than patients older than 60 years operated after previous chemotherapy, in whom extra- (median survival 69 ± 4.5 vs. 17.2 ± 14.3). pleural lung liberation and excessive peribronchial dissec- tion were done. The fistula occurred despite the bronchial Prognostic factors stump protection by the pericardial fat pad. In this patient, The Cox regression analysis included age, disease and the subsequent empyema was put under control by initial nodal stage at first operation, tumor histology (same vs. chest tube aspiration followed by repeated thoracenteses different), and interval between the two operations. Only after the chest tube removal. disease stage at first operation (HR = 3.44, 95% CI, df = 1, The 90-day mortality did not differ from the 30-day sig. = 0.06) and same/different tumor histology (HR = 7.85, mortality, as checked and confirmed during regular out- 95% CI, df = 1, sig. = 0.005) were identified as significant patient controls according to widely accepted schedule. prognostic factors. Discussion Operative mortality and morbidity Survival One patient died from cardiac insufficiency caused by The 30% overall 5-year survival of patients in the current bronchopleural fistula, thus constituting 3.44% 30-day study fits within the range of reported survival rates. Ac- operative mortality. Postoperative complications were cording to data from 10 studies published before 2007 registered in 10 (34.5%) patients. Postoperative bleeding [2, 8–16], each including more than 30 operated pa- (successfully solved by rethoracotomy) and broncho- tients, 5-year survival was under 30% in four studies, be- pleural fistula occurred in two (7%) patients each. One tween 30 and 40% in additional three studies, while it of two patients with bronchopleural fistula was the only was over 40% in three studies (44, 44.5, and 57%). In a one who died within 30 days postoperatively. There was multicentric study on 165 patients, published in 2012, the 5-year survival was 48.9 and 23.9%, for squamous cell and adenocarcinoma, respectively [17]. The reason Table 3 Survival (in months) depending of tumor histology for better long-term survival of patients in the present Tumor type Median SE 95% CI Mean SE 95% CI study, compared with studies with survival rates under Squamous 23.20 21.21 0.00 64.78 48.38 17.01 15.03 81.72 25%, is the higher proportion of stage III patients in Adeno Ca 35.0 14.86 5.86 64.13 51.99 17.74 17.20 86.77 these studies (66 vs. 40.7% in the present study). PH1 = PH2 48.0 21.5 5.85 90.14 55.61 12.90 30.32 80.90 Stage-related survival in the analyzed group confirmed PH1 ≠ PH2 7.7 1.98 3.80 11.59 7.72 1.46 4.84 10.59 the significance of the disease stage, whose influence re- PH1 = PH2, tumor histology was the same after both operations; PH1 ≠ PH2, mains inconsistent throughout the literature. In the tumor histology after the second operation was different vs. histology after the present study, despite a better survival in the stage I, the first operation PH1 pathohistology at first operation, PH2 pathohistology at second operation survival difference was not statistically significant, like in Subotic et al. World Journal of Surgical Oncology (2018) 16:98 Page 6 of 9 Fig. 2 Survival depending of tumor histology. a Squamous cell carcinoma vs. adenocarcinoma; b same vs. different tumor type the aforementioned study of Guggino et al. (67.5 vs. [9]. Such an inconsistence in the reported data is prob- 33.3% for stages I and II, respectively) [2]. Unlike that, in ably due to different criteria for cancer recurrences and the study of Chataigner et al. [18], survival of patients new primaries. with stage I and II disease was significantly better than Although some data suggest a poor prognosis of recur- in patients with stage III disease (56 vs. 17%; p = 0.02). rent adenocarcinoma vs. squamous cell carcinoma, like Our finding of significant survival difference between in the aforementioned multicentric study [17], there is recurrent and second primary tumors should be taken not enough evidence for this factor to be taken into ac- with caution, because of the small number (17.25%) of count as essential for preoperative patient selection. In patients with clear criteria for second primaries. Such a the present study, survival difference depending on finding is not in line with literature data, varying be- tumor type was not significant. In the present study, tween no survival difference (38 vs. 41%) [18], through slightly better (44.6 vs. 29.2%) [2] to significantly better survival for second primaries, with only 10% of the pa- tients with a recurrent carcinoma surviving 21 months [16]. Some other results confirm the same survival trend Table 4 Survival (in months) according to stage, T and N factors of the first operation Op stage Median SE 95% CI Mean SE 95% CI I 18.0 1.62 14.82 21.18 21.48 3.34 14.92 28.04 II 55.0 6.73 41.8 68.19 67.67 19.44 29.56 105.78 III 7.00 3.34 0.43 13.56 47.63 42.7 0.00 131.3 T1a + T1b 17.20 1.64 14.33 20.0 29.66 8.45 13.1 46.22 T2a + T2b 48.0 19.83 9.11 86.88 65.52 16.25 33.65 97.38 T3 + T4 7.0 0.00 –– 5.63 1.57 2.54 8.72 N0 17.20 1.66 13.94 20.45 20.55 3.27 14.20 26.89 Fig. 3 Survival depending of diseases stage of the first operation N1 + N2 55.0 11.74. 31.98 78.01 71.31 18.06 35.92 106.71 Subotic et al. World Journal of Surgical Oncology (2018) 16:98 Page 7 of 9 Fig. 4 Survival depending of T (a) and N (b) factors at first operation despite a certain trend in favor of interval between the Adjuvant therapy two operations shorter than 31 months (mean survival In the present study, adjuvant treatment was given to 57.8 ± 15.8 vs. 43.6 ± 18.1 months), this survival differ- 53.6% of patients after the first operation and to 45.5% of ence was not significant. In one of the few studies deal- patients after the second operation. In fact, one important ing with this factor, longer interval was associated with point in the preoperative selection was the likelihood that better survival, but again without statistical significance the patient will be fit for subsequent adjuvant treatment. (35.4 vs. 54.6% 5-year survival for intervals < 2 and > Based on the promising results of five largest adjuvant 2 years, respectively) [2]. Unclear prognostic significance chemotherapy trials with a confirmed survival benefit at of this factor additionally complicates the preoperative 5years [21–23], in terms of recurrence prevention, it still selection. remains to be confirmed whether such a treatment would As the influence of the disease stage and other rele- be also appropriate in patients with visceral pleural, intra- vant factors at the time of initial surgery are not suffi- vascular, and lymphatic invasion, irrespectively of nodal ciently addressed in the literature, this aspect was stage, both after the initial and re-do surgery. separately analyzed in the present study. Our data sug- gest that, if patients with a stage I get the lung cancer Operative morbidity and mortality recurrence, they will do worse than those with recur- The 3.4% mortality and 34.5% complication rates in the renceafter thestage II diseaseatfirst surgery. This present study are strongly in favor of the appropriateness finding is less surprising having in mind that the of this type of surgery, provided the patient selection is 10–15% reported incidence of local recurrence in adequate. The main concern related to this operation early-stage lung cancer [19]. In addition, a high recur- has traditionally been the alleged high complication rate. rence rate was reported in patients with stage I after However, based on ~ 12% reported operative mortality complete resection (25–50%) [20]. However, based on and < 40% operative morbidity in the last 15 years, in the analyzed data, an appropriate explanation for the the majority of series, it is clear that these complication obtained stage-related survival could not be given. The rates are comparable with those after standard pneu- size of the analyzed series is quite limited, although it monectomy [24]. The 6.9% bronchopleural fistulas in is also debatable whether the greater series would the present study falls within the range of the reported give some additional answers or clarifications. Includ- rates, being 7–13.3% in the majority of the series. Des- ing some of biochemical tumor markers into the ana- pite a sufficient number of surgical series, the reported lysis could possibly be of benefit for future studies of data are of limited value in terms of operative risk pre- this problem. diction. Even in the biggest series, either no significant Subotic et al. World Journal of Surgical Oncology (2018) 16:98 Page 8 of 9 factors of complications were identified or factors were Authors’ contributions DS contributed to the manuscript concept, surgery, literature retrieve, and found as significant only by univariate analysis, like for writing. LM took part in the surgery, patient data collection, and manuscript example, predicted-postoperative (ppo) FEV < 50% [17]. drafting and writing. DM collected the patient data and drafted the manuscript. Our experience, supporting many other reports [25–27], IS drafted the manuscript and did the statistics. LM and JH collected the data and drafted the manuscript. All the authors have read and approved the is strongly in favor of bronchial stump protection, espe- manuscript. cially for right-sided operations. In the present series, pericardial fat, diaphragm, and omental flaps were used Ethics approval and consent to participate According to the current legislation, such type of approval is not routinely whenever possible. We also want to point out the risk of obtained for retrospective type of studies. If necessary, it can be obtained intraoperative death, reaching 5.3%, with the main and submitted during the review process. causes of death being injury of the great vessels of the Competing interests heart, usually due to major pleural or pericardial adhe- The authors declare that they have no competing interests. sions as a consequence of the first surgery [28]. Our pol- icy to avoid such incidents, as previously reported by Publisher’sNote others, was the early opening of the pericardium, rather Springer Nature remains neutral with regard to jurisdictional claims in published than dissection around shortened vessels surrounded by maps and institutional affiliations. thickened peribronchial and perivascular tissue. Author details Clinic for Thoracic Surgery, Clinical Center of Serbia, 26, Koste Todorovica, Study limitations Belgrade 11000, Serbia. School of Medicine, University of Belgrade, Belgrade, Serbia. Department of Thoracic Surgery, Hospital Clinic, Barcelona University, The major limitation of the current study is the small Barcelona, Spain. Institute for Medical Statistics, School of Medicine, number of included patients, determined by strict selec- 5 University of Belgrade, Belgrade, Serbia. Department of Thoracic Surgery, tion criteria for this kind of surgery. The patient number Hospital Sagrat Cor, Barcelona University, Barcelona, Spain. was additionally restricted by the need to include Received: 9 February 2018 Accepted: 9 May 2018 well-matched groups from two institutions. Another limitation is survival analysis after two opera- References tions in different settings. By using the date of either the 1. Subotic D, Van Schil P, Grigoriu B. Optimizing treatment for postoperative initial or re-do surgery as “time zero,” some pitfalls will lung cancer recurrence. Eur Respir J. 2016;47:374–8. appear. As we recently discussed this problem, in the 2. 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World Journal of Surgical OncologySpringer Journals

Published: May 28, 2018

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