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REVIEW ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 73-81
 

Is pneumonectomy a justified procedure in patients with persistent N2 nonsmall cell lung cancer disease following induction therapy


Department of Thoracic Surgery, University College London Hospital, NHS Foundation Trust, London, UK

Date of Web Publication1-Dec-2017

Correspondence Address:
Dr. S Mitsos
Department of Thoracic Surgery, University College London Hospital, NHS Foundation Trust, London
UK
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_209_17

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 » Abstract 

Optimal management and the role of surgery in multimodality treatment for N2 disease nonsmall cell lung cancer (NSCLC) are controversial. In this review, we focus on the possible role of pneumonectomy as a justified procedure in patients with persistent N2 disease following induction therapy. We have conducted an OVID PubMedbased search including manuscripts published in English for relevant studies. The interpretation of these trials highlights the lack of clarity and consistency in our management and leaves areas of controversy. There are no Level 1 data to support either performing or not performing pneumonectomy in this setting. The majority of the literature reviewed stresses the high risk of mortality and morbidity following pneumonectomy as a part of a trimodality approach to Stage IIIA/N2 NSCLC disease. However, selected highvolume institutions do follow this strategy with the level of risk seemingly justifying it for a highly selected group of patients, and this approach to Stage III/N2 NSCLC can be offered safely with acceptable mortality. Patient selection, response rate to induction therapy, and R0 resection are crucial for survival in experienced centers.


Keywords: Induction therapy, lung cancer surgery, neoadjuvant therapy, outcomes, persistent N2 disease, pneumonectomy


How to cite this article:
Mitsos S, Petko M, Patrini D, Hayward M, Scarci M, Lawrence D, Panagiotopoulos N. Is pneumonectomy a justified procedure in patients with persistent N2 nonsmall cell lung cancer disease following induction therapy. Indian J Cancer 2017;54:73-81

How to cite this URL:
Mitsos S, Petko M, Patrini D, Hayward M, Scarci M, Lawrence D, Panagiotopoulos N. Is pneumonectomy a justified procedure in patients with persistent N2 nonsmall cell lung cancer disease following induction therapy. Indian J Cancer [serial online] 2017 [cited 2020 Mar 29];54:73-81. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/73/219567



 » Introduction Top


Lung cancer is the leading cause of cancer death for both men and women. More than 75% of the cases the disease are diagnosed in advanced stages.[1] Approximately 30% of patients who are newly diagnosed with nonsmall cell lung cancer (NSCLC) are classified as N2 Stage IIIA on the basis of metastasis to the mediastinal lymph nodes (MLNs). N2-IIIA NSCLC involves potential heterogeneity in MLN involvement, which could influence the decision regarding which treatment plan among various options is chosen. Choice of treatment plan differed according to the extent of mediastinal involvement.[2] Different therapeutic strategies that include surgery, chemotherapy, radiotherapy, or some combination of these modalities have been offered to patients with Stage IIIA NSCLC. The selection of an optimal treatment modality for those patients has been a major controversial issue in thoracic oncology. Adequate decision for treatment of persistent N2 disease after induction therapy raises major ethical issues, especially if pneumonectomy is required. On the one hand, can we exclude those patients from having an operation that might produce long-term survival? On the other hand, is it reasonable to subject a patient to a high-risk procedure when long-term prognosis is poor? There is some consensus about the indication for multimodality therapy in most patients with locally advanced NSCLC; however, there is no clear agreement about which therapy should be applied to patients with N2 disease.

The objectives of this systematic review were to determine if pneumonectomy is a justified procedure in patients with persistent N2 disease following induction therapy. We conducted a comprehensive literature search using the OVID PubMed interface with results limited to English language articles from 2005 to 2016 combining the following key words: (pneumonectomy) AND (persistent N2 disease) OR (ypN2) AND (induction therapy) OR (neoadjuvant therapy). A manual search was used to follow up references. In those studies presented at scientific meetings, the discussion was reviewed when available.


 » Main Text Top


Five hundred and fifteen papers were returned using a reported search. From these fifteen papers were identified as providing best evidence, reflecting different outlooks on the question. The authors, journal, date and country of publication, patient group studied, relevant outcomes, and results of these papers are shown in [Table 1].
Table 1: The characteristics of all included trials

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Veeramachaneni et al.[3] attempted to determine practice patterns of North American thoracic surgeons dealing with Stage IIIA/N2 NSCLC patients. They invited 2539 active surgeons who expressed interest in general thoracic surgery on the cardiothoracic surgery network in a web-based survey to evaluate four clinical vignettes of patients with single station N2 disease. One of the vignettes is a focus of a patient with macroscopic N2 disease requiring right pneumonectomy. None of the respondents opted for surgery only. Nearly 4% of respondents offered pneumonectomy followed by adjuvant therapy and 22% opted for definite chemoradiation. The remaining 74% opted for induction therapy: 12% would subsequently operate regardless of N2 down staging - 7% would attempt lobectomy if it was technically feasible versus 5% who would proceed with right pneumonectomy; 62% would operate only after downstaging of N2 disease - 30% would proceed to right pneumonectomy versus 32% who would attempt a lesser resection. This was a hypothetical scenario, extrapolating from individual assessments of patients' age, performance status, beliefs, etc., as well as implications of the setting, in which particular thoracic surgeon worked. It confirmed a lack of consensus for the optimal strategy and there might be even more heterogeneity in “real-world” practice. Significantly, 62% versus 12% of surgeons required a downstaging of N2 disease to offer a right pneumonectomy. Half of the respondents would consider a lesser resection if technically feasible, though there are little data supporting a decision not to resect previously involved tissue.

Kim et al.[4] reviewed original articles available on PubMed from 1990 to 2010 describing pneumonectomy after neoadjuvant therapy. Overall, 30- and 90-day mortality was 7% and 12%, respectively. The difference is more pronounced when laterality is correlated: for right pneumonectomy, 11% and 20% versus 5% and 9% for left pneumonectomy, respectively. The authors argue that the impact of extensive surgery following neoadjuvant chemo- and/or radiotherapy is better reflected in a horizon of 90 days in comparison with the traditional 30-day period of observed morbidity and mortality. If radiotherapy was the sole mode of induction, such a difference was not observed. The authors conclude that the data clearly demonstrate a strong correlation between pneumonectomy mortality and center volume, as well as surgeon specialization; hence patients should be selected very carefully for pneumonectomy following an induction therapy and such an approach should be used primarily in centers with sufficient experience and documented low mortality for (right) pneumonectomy postinduction therapy.

Weder et al.[5] reported on 827 patients who underwent neoadjuvant therapy for locally advanced NSCLC. Patients with an objective response or at least stable disease after induction therapy were selected for surgery – 176 patients required a pneumonectomy. R0 resection was documented in 92% of patients. 90-day mortality was 3%. Age, extent of resection, and side of pneumonectomy did not influence outcome. Median survival was 23 months, 5-year survival was 38%; 5-year survival among completely sterilized patients was 56%, but the difference was not statistically significant. The authors conclude that pneumonectomy can be performed safely following induction therapy for locally advanced Stage IIIA/B cancer by an experienced team of surgeons and anesthetist/intensivist in a high volume center – they refer to the selection of favorable patterns of mediastinal disease and response to induction therapy. They argue that only complete resection has a positive impact on survival – incomplete resection is comparable to radical radiotherapy.

Gudbjartsson et al.[6] reported his experience with 130 patients after pneumonectomy for NSCLC. Thirty-five patients had clinically fewer than two station N2 involvement, and these patients underwent induction chemotherapy (all patients) and/or chemoradiotherapy (27/35 patients) followed by surgery. The remaining 95 patients proceeded directly to surgery. Right-sided pneumonectomy was significantly associated with increased risk of bronchopleural fistula (BPF). There was no significant difference in survival of the two groups, with respective 1- and 5-year survival of 74% and 46% in neoadjuvant/surgery group versus 72% and 34% in surgery first group (P > 0.21). This study reported very low early postoperative death rates (1/130; 0.8%), no further deaths at 90 days and 5-year survival of 46% in the neoadjuvant/surgery group. The authors conclude that pneumonectomy may be justified in selected groups of patients even following induction therapy. Right pneumonectomy is, however, a risk factor for (nonfatal) BPF.

Tanaka et al.[7] presented perioperative and long-term results of 37 patients following pneumonectomy as a part of trimodality approach to pN1 (18 patients) and pN2 (19 patients; 7 bulky N2 and 10 multistation N2) disease NSCLC. There was zero 30-day mortality. Twenty-three patients (62%) received adjuvant therapy. Five-year survival was 34.3% in pN1 and 28% in pN2. The authors conclude that in selected patients, a pneumonectomy can be a treatment option for locally advanced NSCLC even after induction therapy and add that survival between pN1 versus pN2 and between single station N2 versus multistation N2 and right versus left pneumonectomy was not significantly different. This is a report from a community hospital in the authors' own words; zero perioperative mortality is a remarkable achievement. The five early deaths from distant metastatic disease raise a question if those seven bulky and ten multistation N2 patients were among these affected. The authors acknowledge the need to define selection criteria and exclude high-risk patients.

Mansour et al.[8] presented an experience with 153 patients with cN2 following pneumonectomy. Group 1 is 28 patients with persistent N2 disease after induction chemotherapy; Group 2 is 32 patients with N0/1 after induction chemotherapy, and Group 3 is 93 patients who proceed to pneumonectomy immediately, and pN2 status was documented radiologically. There were no statistically significant differences between the groups in terms of short-term mortality and morbidity though there was a tendency to higher 30-day mortality among non-downstaged patients (Group 1-10.7%). Five-year survival was 32.2%, 34.8%, and 12.4% in Group 1, 2, and 3, respectively. The authors conclude that induction therapy, persistence of N2 disease, and the side of pneumonectomy had no statistically significant negative influence both on short- or long-term outcome; long-term outcome of patients following neoadjuvant therapy was superior to that of patients having surgery initially followed by adjuvant therapy. The authors speculate that the extent/completeness of lymph node resection plays an important part in long-term survival. This extent cannot be determined by imaging, neither on computed tomography (40% of enlarged MLN are benign) nor on positron emission tomography (PET) (20%–25% false positive). They argue that radical MLN resection complementing R0 lung resection may achieve an acceptable long-term result even without downstaging following induction therapy.

Kim et al.[9] evaluated their experience with pneumonectomy for locally advanced NSCLC after concurrent chemoradiation between 1983 and 2007, excluding those with progressive disease. One hundred and twenty-nine patients underwent pneumonectomy - 86 of those had cN2 and 43 had central disease. Thirty-two patients were downstaged to N1/0; the remaining 54 pneumonectomies were performed in ypN2 patients. Nineteen patients (14.7%) died within 90 days (right: 13/65 patients - 20% vs. left: 6/64 patients - 9%). Overall 5-year survival was 32% versus 34% for right and left pneumonectomy, respectively. Five-year survival of patients with pN0 was 42% versus 28% for N2 and 26% for N1 (approaching statistical significance: P <0.0988 and P < 0.0568, respectively). The authors comment that even without complete primary tumor sterilization, their results confirm the notion that MLN downstaging, in particular, ypN0 status carries a survival benefit. Notably, among 54 patients with confirmed ypN2 disease, there were 7/34 patients - 21% alive after 5 years following right pneumonectomy and 6/20 patients – 30% alive after left pneumonectomy. Development of acute respiratory distress syndrome (ARDS) or BPF was the only factor of adverse 5-year survival in multivariate analysis. The authors conclude that in view of higher perioperative mortality and inferior 5-year survival, right-sided pneumonectomy should not be offered to the subset of patients with positive N2 involvement after induction therapy, though they remark that an optimal patient as defined by a clinician, could warrant such a procedure.

Shah et al.[10] reported on 324 patients after surgical resection for Stage IIIA NSCLC. Pneumonectomy was performed in 55 patients: 42% had N2 disease and 20% underwent induction therapy. Median survival was 16.5 months; 5-year actuarial survival was 29% for all pneumonectomy patients and 36% versus 20% for N0/1 and N2 patients, respectively. Risk factors for adverse survival in multivariable analysis were age >60 years, preoperative renal failure, and induction therapy. Patients undergoing pneumonectomy had similar 5-year survival to matched lobectomy patients, 29% versus 41%, respectively. Survival of patients with N2 versus non-N2 disease was not significantly different. The authors point out that the majority of patients with N2 involvement had microscopic disease detected postresection despite negative imaging and invasive staging/restaging and acknowledge that the study was underpowered to find the difference in survival based on N2 status. Despite that the authors do not favor performing pneumonectomy after induction therapy in patients with N2 positive Stage IIIA disease.

Aggarwal et al.[11] analyzed the outcome of 249 patients with Stage IIIA NSCLC (96.5%N2) treated by definite chemoradiotherapy (103 patients) versus induction chemoradiotherapy followed by lobectomy (105 patients) versus induction chemoradiotherapy followed by pneumonectomy (41 patients). Follow-up was completed for 71% of patients. 30-day mortality was 2.9% in the lobectomy group and 11.3% in the pneumonectomy group. Survival outcomes were better in the surgical group; the difference reached statistical significance in the lobectomy group (39 vs. 22 months), not in the pneumonectomy group (28 vs. 22 months). The authors conclude that in the absence of a clear survival benefit for patients requiring pneumonectomy after induction chemoradiation and with high mortality rates outside of experienced centers, pneumonectomy should not be considered a part of clinical practice in a trimodality setting.

Bueno et al.[12] retrospectively reviewed the medical records of 103 patients with pN2 NSCLC who underwent induction therapy followed by lung resection. This is one of few studies with 100% pathological staging including cases with multiple N2 nodes. All patients were followed up until death (85 patients/82%) or to a median of 60.9 months. Median survival among 18 living patients was 60.9 months. Twenty-nine ypNO patients had a 5-year survival of 35.8% and median survival of 21.3 months. It was significantly worse for 25 ypN1 and 74 ypN2 patients: 5-year survival 9% and median survival 15.9 months. The 5-year and median survivals of patients who underwent lobectomy - 27% and 21 months, respectively, were significantly better than those who underwent pneumonectomy- 6% and 16.6 months. Multivariable analysis showed two significant independent factors associated with improved cancer-free survival: ypN0 status and non-adenocarcinoma histology. The authors hypothesize that ypN0 status is a marker of eradication of systemic disease. Pneumonectomy was a factor in poor outcome only on univariate analysis - the authors hypothesize that these usually larger or centrally located tumors requiring pneumonectomy are more apt to have blood-borne metastases and are more difficult to resect completely. The authors point out that 11 out of 13 survivors beyond the 60 months mark after surgery had a viable tumor upon resection (ypN2) and hypothesized that surgical resection is necessary for local control.

Paul et al.[13] retrospectively reviewed prospectively collected data on 136 patients who underwent lung resection after induction chemotherapy or chemoradiation with clinically staged N2 disease deemed resectable at presentation between 1990 and 2010. R0 resection was achieved in 131 patients (96.3%). There was a single in-hospital death in the pneumonectomy group. Median survival in the entire cohort was 31.8 months. Five-year overall survival was 33.4%. It was better in a group of 61 patients with complete or partial response - 43.8% versus 25.2% among the remaining 75 patients with minimal response/stable disease. Looking at the MLN response, patients with pathologic downstaging to ypN0/1 had a significantly better 5-year survival of 45% versus 20% of patients with persistent ypN2. Single versus multilevel N2 disease did not affect survival significantly. Survival was significantly better among patients treated by lobectomy 36% versus 22% for patients treated by pneumonectomy. Further, patients treated with lobectomy after being downstaged to ypN0/1 enjoyed 5-year survival of 48% versus 27% after pneumonectomy. There was, however, no statistical difference in 5-year survival between patients with residual N2 disease treated with lobectomy versus pneumonectomy: 21% versus 19%, respectively. The authors point out that despite low in-hospital mortality, pneumonectomy was associated with both worse overall and disease-free survival relative to lobectomy, regardless of downstaging. This finding, in the author's opinion, suggests that the notion that survival after pneumonectomy may be improved if in-hospital mortality is reduced may be incorrect. Further, the poor outcomes after pneumonectomy are also not likely to be averted if a sleeve lobectomy is performed instead – patients undergoing pneumonectomy have a higher tumor burden as represented by a larger primary tumor and bulkier nodal disease. The authors conclude that the case against surgical resection in the face of persistent nodal metastases is not conclusive and requires further evaluation. They argue that the decision to proceed with lung resection should be an individual determination based on age, performance status, comorbidities, possibility of achieving R0 resection, and last but not least by the availability of viable treatment alternatives and the patient's wishes.

Steger et al.[14] presented a retrospective single-center study of 146 patients with NSCLC Stage III (cN2 52 patients) managed by a trimodality approach consisting of induction chemoradiation followed by surgery. Overall 30-day mortality was 2.7% and 90-day mortality was 7.5%; 0% and 7.3% in lobectomy group and 5.1% and 7.7% in pneumonectomy group. In univariate analysis, a pneumonectomy, right-sided pneumonectomy, and initial T- and N-stage were not risk factors for survival. Significant factors for survival were ypT- and ypN-stages. Steger et al. concluded that response rate to induction therapy cannot be predicted precisely, it ranges from progression to complete response, and the likelihood of R0 resection can only be estimated after induction therapy by experienced thoracic surgeons. Therefore, precociously denying surgery or neoadjuvant approach, even in cases of possible pneumonectomy may not be the best choice as long as the neoadjuvant protocol is similar to full dose radiochemotherapy.

To further examine this philosophy, in 2012, Steger et al.[15] reported an experience with 83 patients with pN2/3 NSCLC accepted for trimodality therapy. Thirty-five patients were found to have persistent mediastinal involvement - thirty ypN2 and five ypN3. There were two hospital deaths (2.4%). The performed procedure (pneumonectomy vs. bi-/lobectomy) was not a significant negative indicator for survival. ypT-stage was shown to have a prognostic value. Both uni- and multivariate testing has shown that persistent, but resectable N2/3 disease after induction therapy is a significant risk factor for survival (mean survival ypN0/1 70 months vs. ypN2/3 32 months; P < 0.001). The authors argue that these results, however, do not differ greatly from resectable Stage III NSCLC managed by definite chemoradiation. Such cohorts by definition do include both nonresponders and responders to induction therapy, and the authors question the outcome of a nonsurgical strategy for established nonresponders. The authors point out that median progression-free interval among 35 ypN2/3 patients is 17 months and 13 of these patients did not exhibit recurrence/progression during follow-up. The surgery does not address systemic disease; however, as a part of trimodality approach, it offers the exclusive advantage of resection of persistent N2 disease in cases of incomplete response.

Cerfolio et al.[16] reported the outcomes of 216 patients with advanced NSCLC (161 patients, 75% with N2 disease) enrolled in trimodality treatment between 1998 and 2008. Complete pathologic response was documented in 71 patients (33%). There were five early deaths (2.3%). On univariate analysis, forced expiratory volume in the first second <50%, diffusing capacity of the lung for carbon monoxide <60%, age >75 years, and smoking history were associated with morbidity/mortality and surgical procedure was not. The authors stress the selective nature of the cohort, in particular, a favorable pattern of N2 disease: single station, microscopic, PET negative, or surprise. Pneumonectomy is represented marginally (5%) thus reflecting the institutional policy of not offering radical surgery for persistent N2 disease confirmed on frozen section (exploratory thoracotomy 16%).


 » Conclusion Top


The role of surgery in multimodality treatment of N2 disease NSCLC is unclear despite a body of data from five randomized controlled phase III trials, multiple single-center phase II trials, and retrospective studies. Recent meta-analysis states that there is no area in the management of lung cancer where there are more evidence and less consensus.

The interpretation of these trials highlights the lack of clarity and consistency in our management and leaves areas of controversy. Inconsistencies are related but not limited to (1) staging: imaging versus histology; (2) characterization of N2 disease (single- versus multistation/zone), (3) optimal induction therapy: chemotherapeutic agents; radiotherapy dose/timing/fields, (4) downstaging: imaging versus histology, (5) surgery: timing and extent, and (6) adjuvant therapy and prophylactic cranial irradiation.

The majority of the literature reviewed stresses the high risk of mortality and morbidity following pneumonectomy as part of a trimodality approach to persistent N2 NSCLC disease. Pneumonectomy has been shown to have high rates of perioperative mortality, when performed for Stage III disease, particularly after induction therapy. With respect to pneumonectomy, side does matter under certain circumstances. Due to these results, many clinicians do not favor performing pneumonectomy after induction therapy in patients with N2 positive Stage IIIA disease.[17] On the other hand, alternative data have demonstrated that pneumonectomy can be performed safely in these patients with acceptable perioperative morbidity and mortality, as well as long-term survival.[5],[13],[14] There are, however, no level 1 data to support either performing or not performing pneumonectomy in this setting.

Selected high volume institutions do follow this strategy with the level of risk seemingly justifying it for a highly selected group of patients with a smaller size of primary tumor, single station/zone, nonbulky, nonfixed N2 disease among responders to induction therapy with favorable pulmonary and cardiac function/reserve. It is needed to evaluate each case separately considering experienced team of surgeons and anesthetist/intensivist in a high volume center, impact of other patient variables such as overall functional status, comorbid conditions, smoking status, and pulmonary function and collegial multidisciplinary decision-making. For each case, there might be different choices or preferences. During the past 3 decades, the use of surgery for the treatment of advanced NSCLC has evolved from primary therapy to its current role as an important component in multimodality management strategies. Pneumonectomy in the neoadjuvant trimodality approach to Stage III NSCLC can be done safely with acceptable mortality in patients with persistent N2 disease. The selection of patients, response rate to induction therapy, and quality of surgery (R0 resection, complete MLN resection) are crucial for survival in experienced centers, rather than the extent of resection. Prospectively collected data from multiple institutions are needed to validate this approach and that would include generating data on patient outcomes treated with definite chemoradiation who happen to be nonresponders and patients enrolled in trimodality treatment who for whatever reason did not proceed to surgery.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

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