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Neoadjuvant therapy has been theorized to increase complexity of non–small cell lung cancer resections; however, specific factors that contribute to intraoperative challenges after induction therapy have not been well described. We aimed to characterize the effect of nodal involvement and nodal treatment response on surgical complexity after neoadjuvant therapy.
Methods
We identified patients treated with neoadjuvant therapy followed by anatomic lung resection for cN + non–small cell lung cancer between 2010 and 2020. Patients were categorized according to clinical N1 versus N2 disease. To evaluate the effect of nodal response to therapy, thoracic radiologists measured clinically suspected and pathologically involved lymph nodes before and after induction therapy. Operative reports were reviewed to identify technical challenges specifically related to nodal disease. Categorical outcomes were compared using Fisher exact test.
Results
One hundred twenty-four patients met inclusion criteria, among whom 107 (86.3%) were treated with neoadjuvant chemotherapy, whereas chemoradiation (n = 8) and targeted therapy (n = 9) were less common. In cases with N1 disease, 8/38 (21.0%) required proximal pulmonary arterial control, whereas this was necessary in only 2/88 (2.3%) of N2 cases (P = .001). Likewise, sleeve resection and arterioplasty were needed more frequently during resection of N1 disease (7/38, 18.4%) versus N2 disease (0/88, P < .001). Increased nodal response to therapy was associated with greater likelihood of requiring change in vascular approach (P = .011).
Conclusions
After induction therapy, N1 disease was associated with greater need for complex surgical maneuvers than N2 disease. Likewise, substantial treatment response was associated with increased intraoperative technical challenges. Recognizing such factors enables surgical teams to engage in appropriate operative planning to ensure patient safety.
When undertaking lung resection after induction therapy, radiographic extent of nodal response to therapy and hilar nodal involvement indicate greater likelihood of needing advanced techniques.
Neoadjuvant therapy before surgical resection of non–small cell lung cancer has been well recognized as being associated with greater case complexity. We have identified specific clinical predictors of objective measures of technical complexity. Adequate preparation will allow for the safe completion of these technically challenging cases.
Non–small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths in men and women in the United States and worldwide.
In recent years, substantial developments have been made in the realm of pharmacologic targets for this disease. Nonetheless, while the agents and regimens available for NSCLC rapidly evolve, surgery continues to serve as an integral component of multimodal care for patients with lung cancer. Resection after induction therapy has been a long-time standard of care for patients with locally advanced disease, and new indications are on the horizon for neoadjuvant therapy in earlier-stage resectable disease. Induction treatment in the setting of stage IB disease is currently being evaluated in a number of ongoing clinical trials.
Even among patients with oligometastatic stage IV NSCLC, the role for local consolidative surgery after systemic therapy has been associated with clear survival benefits.
Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non–small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study.
As a result, surgeons are operating on patients with advanced disease who might have historically been offered systemic therapy only.
Surgical indications for NSCLC patients pretreated with systemic therapy are expanding throughout all stages of the disease spectrum. As such, previous investigators have evaluated pathologic end points, survival benefits, and care plan adherence in association with the receipt of neoadjuvant therapy, through a number of important recent clinical trials.
Surgical outcomes from the phase 3 CheckMate 816 trial: nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC).
However, limited data exist regarding the objective effect of neoadjuvant treatment on operative challenges such as blood loss, operative time, and surgical approach.
Feasibility and surgical outcomes of video-assisted thoracoscopic pulmonary resection in patients with advanced-stage lung cancer after neoadjuvant chemoradiotherapy.
Moreover, there is a definite paucity in the literature pertaining to objective measures of technical complexity in this setting, as well as the extent to which response to neoadjuvant therapy might contribute to increasing operative challenges.
There are a number of factors recognized to contribute to the technical complexity of anatomic lung resection, including but not limited to central tumor location, large tumor size, reoperative procedures necessitating adhesiolysis, preoperative radiation obliterating the surgical planes, and tumor involvement of adjacent structures such as the superior vena cava or vertebrae. Well trained surgeons might be equipped with the skills needed to navigate these challenging scenarios, but adequate operative planning is pivotal to performing such procedures safely and ensuring that all necessary personnel and resources are readily available when challenges arise. At this time, little is known regarding potential radiographic or clinical findings that might be likely to be correlated with more complex operative cases, nor is there even clear consensus in terms of defining those elements that might constitute a complex case.
The use of radiologic studies to predict intraoperative complexity has not been rigorously evaluated. Moreover, without concrete, objective measures, inter-rater reliability of interpreting such scans can be particularly suboptimal. This issue was exemplified by previous investigators who showed that the use of chest imaging to merely predict extent of surgical resection was subjectively dependent on the experience of the person reading the scan.
With regard to using preoperative data to predict surgical complexity, clear, objective measures are clearly in need. A limited list of vague findings on preoperative imaging and bronchoscopy have been associated with the intraprocedural presence of adherent lymph nodes
—although data associating these findings with intraoperative events are lacking.
In this study, we aimed to evaluate the effect of nodal response to preoperative therapy on intraoperative complexity of anatomic lung resections performed for NSCLC. We hypothesized that extent of nodal reduction would correlate with intraoperative challenges. Thus, we aimed to assess the relationships between nodal involvement and nodal reduction on subsequent objective, measurable intraoperative events related to surgical complexity.
Methods
Study Population
Before retrieval of data, a waiver of informed consent was obtained from our institutional review board (2020-0929; approved October 5, 2020). A prospectively maintained institutional database was queried to identify patients treated with neoadjuvant therapy followed by anatomic surgical resection for node-positive NSCLC between January 2010 and May 2020. To be included in the study, patients were required to have cross-sectional chest imaging (computed tomography [CT] and/or positron emission tomography [PET]/CT) available for review from pretreatment and preoperative time points. Patients were excluded from primary analyses if they did not have histologic confirmation of nodal involvement, if the treatment was for recurrent disease, or if they were treated with a regimen not currently approved for standard of care neoadjuvant therapy. A comparison cohort was identified consisting of patients who underwent upfront surgical resection for cN1 pN1 disease during the same time period.
Radiologic Evaluations
PET and/or CT scan(s) were reviewed for each patient before the initiation of neoadjuvant therapy and also after completion of neoadjuvant treatment. Targeted lymph nodes to be measured were selected on the basis of Response Evaluation Criteria in Solid Tumors 1.1 criteria,
and short axis diameter was measured on pre- and post-treatment imaging studies. Additionally, all nodes proven to be positive for malignancy on the basis of pathologic assessment were identified and measured. Lymph nodes were defined as pathologically positive on the basis of pretreatment biopsy and/or surgical pathology. Among patients for whom CT scans were obtained without contrast, accurate objective measurement of hilar lymph nodes was limited. In these cases, the largest pretreatment lymph node station was evaluated for nodal reduction. Imaging studies were reviewed by 2 experienced dedicated thoracic diagnostic radiologists (C.S. and M.G.).
Operative Complexity
Operative reports were reviewed for the presence or absence of the following criteria: lymph nodes described as matted/sticky/hard, lymph nodes unable to be removed from the pulmonary artery (PA), lymph node adherence to the PA resulting in tear, lymph nodes forcing a change in approach to vascular dissection, proximal and/or intrapericardial PA control required because of nodal adherence, change in extent of resection because of lymph nodal adherence to structures, and pulmonary arterioplasty or sleeve resection related to nodal adherence. Cases in which PA reconstruction was required because of central tumor involvement were not counted. A change in approach to vasculature was defined as a dissection beginning with the artery first and the surgeon switching to vein first approach or vice versa because of encountering difficulty related to nodal adherence. These criteria were selected in advance of chart review on the basis of input from 9 experienced thoracic oncologic surgeons as being representative of potential technical findings encountered and maneuvers performed in response to challenging nodal dissections. Operative approach was left to surgeon discretion.
Statistical Analyses
Continuous variables are presented as median and interquartile range (IQR) and categorical variables are expressed as frequency and percentage. Differences between groups were analyzed using the Mann–Whitney U test for continuous data and Pearson χ2 or Fisher exact test for categorical data as appropriate. On the basis of the findings from these preliminary analyses, as well as important clinicopathologic data determined a priori, multivariable linear regression models were created to evaluate the relationship between variables associated with increased risk of surgical complexity and surgical outcome variables. Models were checked for violation of collinearity. All analyses were performed using R, version 4.0.2 (R Foundation for Statistical Computing).
Results
The database query identified 180 patients treated for N + NSCLC, of whom 124 met inclusion criteria and were therefore included in analyses (Figure 1). Patients were fairly evenly distributed between sexes (63 female, 51%), and most presented with clinical stage IIIA disease (75, 60%), adenocarcinoma (79, 64%), and a history of current or previous cigarette smoking (102, 82%; Table1). Of 124 surgical procedures performed, 107 (86.3%) were initiated via thoracotomy approach, with 2 of 17 (11.8%) minimally invasive cases converted to open. Of the 17 cases begun via minimally invasive technique, 9 were attempted video-assisted thoracoscopic surgery with 2 converted nonemergently to open and 8 were begun and completed via robotic-assisted thoracoscopic surgery. Three-quarters of the resections were performed as lobectomies (n = 95; 76.6%). The remaining procedures consisted of 9 bilobectomies (7.3%), 14 pneumonectomies (11.3%) 1 segmentectomy (0.8%) and 6 sleeve lobectomies (4.8%). The median percent short axis reduction in lymph node size was 26.6% (interquartile range [IQR], 9.3%-40%), and thus a cutoff value of 30% was chosen for subsequent analyses of nodal reduction by rounding to the nearest 10th.
Effect of Nodal Stage on Need for Advanced Operative Maneuvers
We first compared the frequencies of need for advanced technical maneuvers between those patients with cN1 disease versus those with cN2 to 3 disease. Importantly, we found that patients with cN1 disease were reliably more likely to require a change in approach to the vascular dissection because of adherent lymph nodes (21.1% vs 7.0%; P = .035), with more cases necessitating proximal PA control (21.1% vs 2.3%; P = .001) and even intrapericardial PA control (P = .03) to safely perform the vascular dissection. Furthermore, all cases necessitating arterioplasty or arterial sleeve because of adherent lymph nodes occurred in cases performed for patients with cN1 disease (Table 2). A subgroup analysis in which we compared complexity of cases performed in patients with N1 and N2 nodal stations involved versus those with skip N2 disease is shown in Table E1.
Table 2Clinical nodal status and intraoperative challenges
Effect of Nodal Response to Therapy on Need for Advanced Operative Maneuvers
We next examined the effect of response to therapy, as indicated by percent short axis reduction after neoadjuvant therapy, on the frequency of challenging intraoperative nodal findings requiring advanced maneuvers. We found that >30% short axis nodal reduction was associated with the node that could not be removed from the PA (15.8% vs 3.0%; P = .023) as well as an increased likelihood of requiring a change in approach to the vasculature (19.9% vs 4.5%; P = .011; Table 3).
Table 3Clinical nodal reduction and intraoperative challenges
Forty (32.3%) patients had histologically confirmed hilar nodal (levels 10-11) involvement. Among these individuals, 34/40 (85.0%) were evaluated for hilar nodal response to therapy (6 patients with hilar nodal disease underwent cross-sectional imaging without intravascular contrast, limiting the measurement of hilar nodal stations). In this subset of the entire cohort, 6 of 18 (33.3%) patients with nodal reduction >30% required a change in approach to vasculature whereas 2 of 16 (12.5%) with lesser response required a change in approach (Table 4). Although this trend might indicate a signal that merits further investigation, the P value was greater than .05 here. Of the 40 patients with histologically confirmed hilar nodal involvement, 13 had nodal involvement on pretreatment biopsy and subsequently had nodal complete response on surgical pathology. Five of 13 (38.5%) required arterioplasty because of lymph node adherence to the PA, 5/13 (38.5%) required proximal PA control, and in 5/13 (38.5%) the nodal adherence necessitated a change in response to the vasculature.
Table 4Extent of hilar nodal reduction among pathologically involved, radiographically measurable hilar nodes and intraoperative challenges
For the purpose of our primary analyses described previously, we excluded patients who received therapeutic agents outside of currently approved, standard of care therapy. However, because of the potential likelihood for future expansion of our pharmacological armamentarium, as well as the great utility of developing a foundation for elucidating the intraoperative findings after receipt of such agents, we conducted additional exploratory analyses of this cohort of individuals. When analyses were performed in this subset of patients (n = 21), our findings were similarly upheld. Specifically, we found that in resections performed in patients with either cN1 disease or nodal reduction >30% (n = 14), 7 (50%) included descriptions of lymph nodes that could not be removed from the PA, 6 (42.9%) required arterioplasty related to nodal findings, and 2 (14.2%) necessitated sleeve resection because of adherent nodes. When we reviewed cases without these risk factors in this cohort (n = 7), 2 (28%) described nodes that could not be removed from the PA, 2 (28%) required a change in vascular approach, and 0 cases required sleeve or arterioplasty (Table E2). Although these findings were not found to have a P value less than .05, likely because of a small patient population, they are clinically important differences.
Perioperative Outcomes
All 124 cases were completed safely, with a median estimated blood loss (EBL) of 200 (IQR, 150-302.5) mL and procedure duration of 194 (IQR, 149-236) minutes. The median length of stay was 5 (IQR, 3-6) days. In total, 15 (11.2%) patients experienced a complication that would be classified as Clavien–Dindo grade 3 or greater, including 2 patients (1.5%) who died during the index hospitalization. The causes of death were related to pneumonia and myocardial infarction. The most common complication was atrial fibrillation requiring medical management in 15 patients (12.1%), followed by discharge with home oxygen (n = 11; 8.9%) and discharge with chest tube (n = 10; 8.1%; Table 5). Neither cN nor reduction >30% was predictive of increased EBL (Table E3) or length of procedure (Table E4). However, when analyzing cN2 to 3 versus cN1 independently, we found that the association was negatively correlated with EBL (estimate, −112; SE, 56.5; P = .050), indicating that patients with cN1 disease are more likely to have increased EBL.
Comparison With the Cohort That Underwent Upfront Resection
The database query identified 41 patients with cN1 pN1 disease managed with upfront surgery. Compared with patients who underwent neoadjuvant therapy followed by surgical resection for cN1 disease, those treated with primary resection were less likely to require proximal PA control (4.9% vs 21%; P = .043), intrapericardial PA control (0 vs 10.5%; P = .049), or arterioplasty/sleeve because of adherent lymph node (0 vs 18.4%; P = .004; Table E5).
Discussion
In this study, we found that cN1 disease as well as nodal response to therapy as indicated by percent of short axis reduction were associated with increased complexity of subsequent anatomic lung resection. Our criterion-centered evaluations of technical complexity are novel, distinctly different from previous studies that relied on subjective assessments to evaluate operative difficulty,
and serve as a foundation for future studies that might use surgical complexity as an end point of interest. By defining operative complexity using objective measures, we aim to create a mechanism for reporting difficulty that conveys not only that a case was challenging, but what the source of difficulty was and how it was managed. Further, we have shown that cN1 involvement as well as significant nodal response to therapy are both associated with increased likelihood of requiring advanced maneuvers to complete the vascular dissections. Both of these variables are concrete values that are known before the surgical procedure and might allow for anticipation of difficulties while enabling adequate planning to ensure safe outcomes (Video 1).
In recent work published by Takeda and colleagues,
the authors reported that lymph node size >8 mm detected on CT scan and dark pigmentation on bronchoscopy could be used to stratify patients according to risk of PA-adherent nodes. Further, Li and Wang
reported that interference by lymph nodes was the most common reason for conversion from minimally invasive lung resection to open thoracotomy. In our study, we have corroborated these findings and further addressed the same problem using a more specific, objective approach to predicting intraoperative markers of case complexity. We have successfully shown that nodal response to therapy and location of involved nodal stations are important predictors of intraoperative challenges. Unlike previous studies, we did not find that this nodal adherence was associated with increased conversion to open thoracotomy, although it is important to note that most of the postinduction cases in this series were initiated via open approaches. The current study focused on the hypothesis of nodal reduction in size, because we were aimed to characterize the specific effect of this sclerotic response on surgical complexity, and, as such, we have not delved into other clinical measures of tumor response, such as reduction of fluorodeoxyglucose avidity on PET imaging, Response Evaluation Criteria in Solid Tumors criteria, or others. Although those other measures might be of interest in predicting pathologic response, they were not related to our central hypothesis of nodal sclerosis affecting technical components of the operation. Moreover, in addition to identifying risk factors for case complexity, this study is one of the first to thoroughly outline intraoperative aspects of case complexity. Building on previous investigations that have described potential intraoperative features of challenging cases,
this study has produced a comprehensive list of intraoperative findings for measuring complexity of dissection. These features might be used in future evaluations of surgical complexity, particularly in the growing body of clinical trials aimed to assess pathologic end points after neoadjuvant therapy.
There is a shifting paradigm in the management of NSCLC, in that treatments previously shown to be effective in the adjuvant setting are now being evaluated in the neoadjuvant setting and among patients with earlier stages of disease. Concurrently, the established role of surgical resection in the management of oligometastatic disease has expanded the patient population for whom surgery might play a role in multimodal therapy. As a result of these changes, the patients we are encountering in the operating room are different than those we managed surgically as recently as 5 years ago. Previous authors have described increased complexity associated with the receipt of neoadjuvant therapy.
Two centres experience of lung cancer resection in patients with advanced non-small cell lung cancer upon treatment with immune checkpoint inhibitors: safety and clinical outcomes.
However, it is important to note that in this study as well as the previous studies out of our institution, these procedures can be performed safely.
Because these cases were all completed safely and with reasonable morbidity, the question might arise as to the relevance of surgical complexity. It should be clearly recognized that this series represents an institutional series at a large, urban, academic cancer center, with a group of 9 dedicated thoracic surgical oncologists, well supported by dedicated thoracic anesthesiologists, thoracic nursing and scrub teams, and ample resources to conduct high-level complex operations. However, at a national level, nearly 1 in 10 anatomic lung resections for lung cancer are performed by individuals without training in cardiothoracic surgery, with an estimated 1500 cases being performed by general surgeons over a recent 4-year period.
yet we must recognize the ongoing receipt of NSCLC surgical care in a variety of environments, by surgeons with training in general surgery, cardiovascular surgery, and thoracic oncology. Although the complication rate in our cohort is appropriate for the procedures performed,
it should be noted that this was achieved at a high-volume institution, and even still, in 4 cases, a second thoracic surgeon was required to assist in the operating room because of complexity of the cases. Moreover, it is imperative to recognize that surgeon skill alone does not result in case success; rather, it is the combined efforts of a well prepared team including anesthesia, nursing, blood bank, sterile supplies, and more. Appropriate rooms and equipment must be available, adequate time must be allocated, and accurate expectations must be presented during the informed consent process. All of these elements are necessary to promote safe outcomes after these surgical resections.
An additional important consideration raised by the evolving surgical cohort is the need to expose trainees to more technically challenging operative cases. It might be more common for faculty surgeons to take over during more challenging cases, and, at times, this is necessary to promote a safe environment for the patient. However, it must be recognized that every operating room encounter might serve as a valuable educational tool for a trainee, and appropriate preoperative planning discussions and debriefing are key components to such educational experiences. Using these tools, even portions of the resection performed by the attending surgeon might effectively demonstrate how to manage friable tissue, incomplete planes, and, very importantly, how to work collaboratively on a team to ensure safe patient outcomes. Additionally, with an increasing level of operative of surgical complexity, the value of simulation and practice outside of the operating room cannot be overstated.
Although to our knowledge, this is the first report to show that clinical nodal staging and response to therapy may be correlated with increased risk of operative complexity, there are some inherent limitations. First, this was a retrospective analysis that relied on review of operative reports, and, thus, the validity of the analyses required detailed description of the procedure by the provider. Fortunately, all 124 patients included in the analysis had operative reports that provided detailed description of the dissection of the hilum, and any questions of findings were reviewed by a second surgeon-investigator. Additionally, the number of patients included in the analysis, as well as the infrequency of operative complexities limited the power and types of feasible analyses that could be performed. Our aim was to show trends in correlation, and the sample size was sufficient to show a meaningful relationship between clinical findings and operative complexity. Furthermore, a comparison was made between patients who underwent upfront resection versus those who received neoadjuvant therapy and there are likely variables not accounted for in the analysis that might contribute to different operative findings in these 2 populations. Because in this study we used data collected from a single quaternary academic center where, in our practice, we undertake advanced procedures in sometimes very aggressive disease, there might be limitations regarding the generalizability of our findings. It will be important moving forward to evaluate predictors of operative complexity in a variety of settings.
Conclusions
In this study, we have shown that cN1 disease and nodal reduction in short axis diameter of ≥30% are associated with increased complexity of anatomic lung resection because of nodal adherence to the PA. By enabling providers to use these clinical variables to anticipate a more complex procedure, these findings will allow for improved preoperative planning and acquisition of appropriate resources to ensure a safe procedure. It is our hope that these clinical variables, as well as those previously known to contribute to complexity (central tumor location, neoadjuvant therapy, reoperation, tumor size, involvement of vital structures), will be disclosed in future clinical studies so as to allow providers to understand potential source(s) of operative complexity and to anticipate strategies and resources needed for safe and successful management (Figure 2).
The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non–small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study.
Surgical outcomes from the phase 3 CheckMate 816 trial: nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC).
Feasibility and surgical outcomes of video-assisted thoracoscopic pulmonary resection in patients with advanced-stage lung cancer after neoadjuvant chemoradiotherapy.
Two centres experience of lung cancer resection in patients with advanced non-small cell lung cancer upon treatment with immune checkpoint inhibitors: safety and clinical outcomes.
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