With a median age at diagnosis of 70, lung cancer remains a significant public health challenge for older Americans. Surgery is a key component in treating most patients with non-metastatic lung cancer. These patients experience postoperative pain, fatigue, loss of respiratory capacity, and decreased physical function. Data on quality of life (QOL) in older adults undergoing lung cancer surgery is limited, and few interventions are designed to target the needs of older adults and their family caregivers (FCGs). The primary aim of this comparative effectiveness trial is to determine whether telephone-based physical activity coaching before and after surgery will be more beneficial than physical activity self-monitoring alone for older adults and their FCGs. In this multicenter comparative effectiveness trial, 382 older adults (≥ 65 years) with lung cancer and their FCGs will be recruited before surgery and randomized to either telephone-based physical activity coaching or physical activity self-monitoring alone. Participants allocated to the telephone-based coaching comparator will receive five telephone sessions with coaches (1 pre and 4 post surgery), an intervention resource manual, and a wristband pedometer. Participants in the self-monitoring only arm will receive American Society of Clinical Oncology (ASCO) physical activity information and wristband pedometers. All participants will be assessed at before surgery (baseline), at discharge, and at days 30, 60, and 180 post-discharge. The primary endpoint is the 6-minute walk test (6MWT) at 30 days post-discharge. Geriatric assessment, lower extremity function, self-reported physical function, self-efficacy, and QOL will also be assessed. The trial will determine whether this telephone-based physical activity coaching approach can enhance postoperative functional capacity and QOL outcomes for older adults with lung cancer and their FCGs. Trial results will provide critical findings to inform models of postoperative care for older adults with cancer and their FCGs. ClinicalTrials.gov Identifier: NCT06196008.

The treatment landscape for operative resection of Stage IV non-small cell lung cancer (NSCLC) is rapidly expanding, with recent evidence demonstrating feasibility and efficacy of pulmonary resection as a component of local consolidative therapy (LCT) in oligometastatic disease. However, the operative details and technical complexity of surgical resection following targeted therapy in Stage IV disease have not been explored, particularly in a population of patients including oligo- as well as polymetastatic disease. Thus, we aimed to characterize the intraoperative nuances of pulmonary resection in this cohort.

Approximately 95% of patients who have an initial response to ALK-TKIs exhibit an incomplete response, resulting in residual disease that may enable emergence of acquired resistance. Minimizing or eliminating residual disease with local consolidative therapy (LCT) may delay development of resistance and improve clinical outcomes.

Surgery serves a key role in curative therapy for early-stage non-small cell lung cancer (NSCLC), and operative decision-making is heavily dictated by clinical stage. Multiple patient- and disease-specific factors can influence stage assignment in the therapy-naïve patient. As such, discordant clinical and pathological staging may occur, and clinical overstaging may indicate risk of worse outcomes for patients with features that are not otherwise captured in our staging paradigm. Thus, we sought to evaluate the impact of clinical overstaging on overall survival (OS) in patients with pathologic stage I NSCLC who underwent upfront surgery. A single-center database was queried for patients who underwent resection of pathologic stage I NSCLC 1998–2021 in the absence of neoadjuvant therapy. Clinicopathologic, circulomic, and operative details were collected. Patients were grouped by clinical-to-pathologic stage concordance to evaluate impact of clinical overstaging on outcomes. Kaplan-Meier and multivariable analyses were performed to assess impact on OS. 2318 patients met inclusion criteria, among whom 151 (6.5%) were clinically overstaged. Slightly over half were women (1355, 58.4%), most were smokers (1649, 71.0%), and median age was 67.0 years (interquartile range [IQR]: 60.1–73.3). In clinically overstaged patients, clinical tumor (T) and nodal (N) statuses were significantly discordant from pathologic T and N status (p < 0.001 for both). Moreover, clinically overstaged patients had shorter median OS (115.4 months) than those with stage-concordance (156.7 months, p < 0.001). After controlling for confounders, we found that clinically overstaged patients experienced greater mortality (hazard ratio 1.34, CI 1.04–1.73). Clinical overstaging of patients with pathologic stage I NSCLC was associated with worse survival compared concordant staging. This finding may be attributable nto patient and disease factors that prompted assignment of higher clinical stage, and further investigation is needed to better elucidate and ameliorate such factors. Moreover, heightened postoperative cancer surveillance may be indicated for patients found to be clinically overstaged.

BACKGROUND:Despite the importance of tumor-infiltrating T lymphocytes (TILs) in cancer biology, the relationship between TIL phenotypes and their prognostic relevance for localized non-small-cell lung cancer (NSCLC) has not been well established.PATIENTS AND METHODS:Fresh tumor and normal adjacent tissue was prospectively collected from 150 patients with localized NSCLC. Tissue was comprehensively characterized by high-dimensional flow cytometry of TILs integrated with immunogenomic data from multiplex immunofluorescence, T-cell receptor sequencing, exome sequencing, RNA sequencing, targeted proteomics, and clinicopathologic features.RESULTS:While neither the magnitude of TIL infiltration nor specific TIL subsets were significantly prognostic alone, the integration of high-dimensional flow cytometry data identified two major immunotypes (IM1 and IM2) that were predictive of recurrence-free survival independent of clinical characteristics. IM2 was associated with poor prognosis and characterized by the presence of proliferating TILs expressing cluster of differentiation 103, programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing protein 3, and inducible T-cell costimulator. Conversely, IM1 was associated with good prognosis and differentiated by an abundance of CD8+ T cells expressing cytolytic enzymes, CD4+ T cells lacking the expression of inhibitory receptors, and increased levels of B-cell infiltrates and tertiary lymphoid structures. While increased B-cell infiltration was associated with good prognosis, the best prognosis was observed in patients with tumors exhibiting high levels of both B cells and T cells. These findings were validated in patient tumors from The Cancer Genome Atlas.CONCLUSIONS:Our study suggests that although the number of infiltrating T cells is not associated with patient survival, the nature of the infiltrating T cells, resolved in distinct TIL immunotypes, is prognostically relevant in NSCLC and may inform therapeutic approaches to clinical care.

Local consolidative therapy (LCT) following systemic therapy for selected patients with oligometastatic non-small cell lung cancer (NSCLC) is an evolving treatment strategy. We sought to identify predictive genomic markers for overall survival (OS) and progression free survival (PFS) in patients presenting with synchronous oligometastatic NSCLC at diagnosis.

Management of oligometastatic non-small cell lung cancer (NSCLC) has rapidly evolved in recent years, with heightened emphasis on the benefits derived from local consolidative therapy (LCT). Pulmonary resection has been established as an important component of LCT, previously shown by our group to be both feasible and associated with long-term survival; however, technical aspects of such surgical procedures have not been well characterized. We sought to review the technical complexity of operations performed within a large cohort of patients with oligometastatic NSCLC.

Purpose: Local consolidative therapy (LCT) for oligometastatic non-small cell lung cancer (NSCLC) is an evolving treatment paradigm. We investigated whether the biologically effective dose (BED) of consolidative radiation therapy (RT) to the primary tumor predicted for improved local control, progression-free survival (PFS), and overall survival (OS) among NSCLC patients presenting with oligometastatic disease. Materials and methods: Patients presenting to a single institution (2000-2017) with stage IV NSCLC, <= 3 synchronous metastatic lesions at diagnosis, and treated with RT to the primary tumor were identified. Univariate and multivariable Cox proportional-hazards regression modeling were performed to identify factors associated with local recurrence-free survival (LRFS), PFS, and OS. Results: One hundred twenty-four patients were identified meeting our inclusion criteria. With a median follow-up of 55.1 months, median PFS and OS for the entire cohort were 11.0 months and 25.3 months, respectively. The median BED (alpha/beta = 10) of RT to the primary tumor was 74.3 Gy. On univariate analysis, increased BED to the primary tumor predicted for improved PFS (p < 0.001) and LRFS (p = 0.01), with a median PFS of 8.5 vs 12.8 months and median LRFS of 23.4 vs 58.4 months between patients treated with BED < 75 Gy and >= 75 Gy, respectively. Increased BED to the primary tumor was also associated with significantly improved OS (p = 0.02); patients treated with a BED of <75 Gy demonstrated a median OS of 22.9 months vs 27.5 months if treated with BED >= 75 Gy. On multivariable analysis, primary site BED remained a significant predictor of OS (p = 0.02) and PFS (p = 0.002). Conclusions: We found that delivery of >75 Gy BED RT regimens to the primary lesion in patients with synchronous oligometastatic NSCLC is associated with improved local control, PFS, and OS. These data support results of recent prospective trials and other ongoing prospective efforts to characterize therapeutic benefits associated with this management strategy. (C) 2021 Elsevier B.V. All rights reserved.

BACKGROUND:Long-term survival outcomes of trimodal therapy (TMT; chemoradiation plus surgery) and bimodal therapy (BMT; chemoradiation) have seldom been analysed. In a selective-surgery paradigm, the benefit of TMT in patients with a complete clinical response is controversial. Factors associated with survival in patients with a clinical complete response to chemoradiation were evaluated.METHODS:Patients with stage II-III oesophageal squamous cell carcinoma treated with TMT or BMT from 2002 to 2017 were evaluated. The BMT group consisted of patients who were otherwise eligible for surgery but underwent chemoradiation alone followed by observation. This group included patients who later had salvage oesophagectomy. Survival was evaluated and compared between TMT and BMT groups. Elastic net regularization was performed to select co-variables for Cox multivariable survival analysis in patients with a clinical complete response.RESULTS:Of 143 patients, 60 (41.9 per cent) underwent TMT and 83 (58.0 per cent) BMT. Patients who underwent TMT had longer median overall survival than those who had BMT (77 versus 33 months; P = 0.019). For patients with a clinical complete response, TMT achieved longer median overall survival than BMT (123 versus 55 months; P = 0.04). BMT had a high locoregional recurrence rate (48 versus 6 per cent; P < 0.001); 26 of 29 patients with locoregional recurrence in the BMT groupunderwent salvage resection. Cox multivariable analysis demonstrated that upper-mid oesophageal tumour location (hazard ratio (HR) 2.04; P = 0.024) and tumour length (HR 1.18; P = 0.046) were associated with worse survival. Although TMT was not associated with survival, it was a predictor of reduced recurrence (HR 0.28; P = 0.028). The maximum standardized uptake value after chemoradiation also predicted recurrence (HR 1.33; P < 0.001).CONCLUSION:In patients who achieve a clinical complete response, TMT reduces locoregional recurrence but may not prolong survival. The differences in survival outcomes may be due to patient selection; therefore, a selective-surgery strategy in oesophageal squamous cell carcinoma is a reasonable approach.

As our knowledge of and the corresponding body of literature in the area of pulmonary metastatic disease continue to grow, so does our understanding in terms of identifying the best patients to undergo aggressive local therapy. We are honored to read the letter from Williams and colleagues1 regarding our recent findings demonstrating that location within the colon is yet another factor contributing to patient prognosis.2 We absolutely agree with the authors that biology is king, and understanding the relevant prognostic indicators for pulmonary metastasectomy in colorectal cancer can help us guide patients who may be very heterogenous in terms of overall risk profiles.

Historically, treatment for non-small cell lung cancer (NSCLC) has been stage-dependent, with surgery typically considered the standard of care for stage I disease and a potential component of multi-modality care for stages II-III. By contrast, for stage IV disease, therapy aimed at prolongation of life has included systemic treatments, including chemotherapy, and, in recent years, targeted agents and immunotherapy. For metastatic disease, surgery has previously had a fairly limited role. However, oligometastatic disease may offer a potential opportunity for more aggressive local options. The distinct tumor biology and limited disease burden may be associated with improved outcomes.1 The landmark oligometastatic trial published by Gomez in 20162 aimed to assess the effect of local consolidative therapy (LCT) on progression-free survival (PFS) of patients with 3 or fewer metastases who received standard first-line chemotherapy, and patients were randomized to LCT vs maintenance treatment. LCT improved PFS and time to development of new metastatic lesions. Moreover, comprehensive LCT (cLCT) was also shown to improve overall survival (OS).3 A subsequent review from our institution of 194 patients, including those both on and off the oligometastatic clinical trial, aimed to identify those patients who would derive greatest benefit from LCT.4 This study revealed that cLCT was associated with improved OS, with median survival of 29 months for cLCT compared to 23 months for those with subcomprehensive LCT or no LCT. Moreover, lower intrathoracic stage, non-squamous histology, and absence of bone metastases were all associated with improved OS after cLCT, theoretically identifying those patients most likely to benefit from aggressive local therapy—which can consist of surgery or radiation. In terms of surgery itself, we next aimed to evaluate the outcomes of operative pulmonary resection as LCT in oligometastatic disease,5 using radiotherapy as a benchmark comparator. Evaluating patients with 3 or fewer synchronous metastases and received LCT to all sites, we analyzed survival and progression. Surgery to the primary tumor was performed in 28% after a median of 3.7 months. 90-day post-treatment mortality after surgery was 0%, and, after a median follow-up of 57 months, median OS after surgery was greater than 55 months. Median OS for radiation in this group was 23 months. Thus, it was concluded that surgery should remain a component of LCT for operable oligometastatic NSCLC patients, and it should be considered in randomized trial for patients with metastatic disease. While surgery has demonstrated survival benefits in the oligometastatic population, the potential complexity of these procedures cannot be overstated. In our institutional experience, thoracotomies have been required in more than 4/5 of operations, and adhesions and hilar fibrosis have been common. Events such as need for proximal pulmonary arterial control and unplanned changes in extent of operation are not infrequent, and the majority of cases have been reported as more difficult than usual. Thus, proper patient selection for surgery is imperative, as is preparation for the types of resources potentially needed for these cases. Despite surgical complexity, ability to achieve negative margins and to safely manage the patients perioperatively has been reassuring. Given the success of surgery as a component of LCT, surgery has become an important part of ongoing clinical trials evaluating LCT after novel agents for metastatic NSCLC. The LONESTAR trial6 aims to evaluate the benefits of LCT after immunotherapy, in that patients receive 12 weeeks of ipilumimab and nivolumab, after which those individuals with non-progressive disease are randomized to LCT + continued immunotherapy vs continued immunotherapy alone. While radiation is required to at least one disease site, surgery to the primary site of disease is emphasized whenever possible. Similar to the LONESTAR trial, the NORTHSTAR trial is investigating the role of LCT after tyrosine-kinase inhibitor therapy for patients with EGFR-mutant metastatic NSCLC. Patients who have non-progressive disease after 6-12 weeks of osimertinib are randomized to LCT vs continued targeted therapy, again, offering surgery whenever feasible to the primary site of disease.7 More recently, the BRIGHTSTAR trial was initiated, evaluating the role of LCT after 8 weeks of brigatinib for patients with metastatic ALK-mutated NSCLC, with the primary endpoints of safety and feasibility and secondary endpoints of PFS, OS, and time to progression.8 A number of patients have already undergone surgery on each of these trials, with promising perioperative outcomes. Despite the potential for innovation and expanded surgical indications, consideration must be given to the safety and potential technical challenges in such cases. We must consider issues related to fibrosis, adhesions, and sclerotic lymph nodes, as well as our limitations in identifying those patients with residual disease vs complete response. Surgery as LCT for oligometastatic NSCLC represents an exciting frontier for thoracic surgery, as a potential opportunity to help patients with advanced disease. Implications for training and resource allocation remain ever pertinent, and surgery needs to be considered as a potential therapeutic component in novel clinical trials in even advanced disease. References: 1. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995 Jan;13(1):8-10. 2. Gomez DR et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016 Dec;17(12):1672-1682. 3. Gomez DR et al. 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. J Clin Oncol. 2019 Jun 20;37(18):1558-1565. 4. Mitchell KG et al. Improved Overall Survival With Comprehensive Local Consolidative Therapy in Synchronous Oligometastatic Non-Small-Cell Lung Cancer. Clin Lung Cancer. 2020 Jan;21(1):37-46.e7. 5. Mitchell KG et al. Pulmonary resection is associated with long-term survival and should remain a therapeutic option in oligometastatic lung cancer. J Thorac Cardiovasc Surg. 2020 Mar 25:S0022-5223(20)30633-4. 6. Phase III Trial of (LCT) After Nivolumab and Ipilimumab, https://clinicaltrials.gov/ct2/show/NCT03391869 7. Elamin YY et al. Randomized phase II trial of osimertinib with or without local consolidation therapy (LCT) for patients with EGFR-mutant metastatic NSCLC (NORTHSTAR). Annals of Oncology (2018)29 (suppl_8):viii493-viii547. 8. Elamin Y et al. BRIGHTSTAR: A pilot trial of local consolidative therapy (LCT) with brigatinib in tyrosine kinase inhibitor (TKI)-naïve ALK-rearranged advanced NSCLC.Journal of Clinical Oncology 2020 38:15_suppl, 9624-9624 Surgery, OLIGOMETASTATIC, NSCLC

Abstract While preoperative tobacco cessation has been associated with decreased pulmonary complications in lung cancer patients in the postoperative period, this relationship has not been explored among patients undergoing esophagectomy in this era of increasingly prevalent tobacco cessation campaigns and enhanced recovery after surgery. Methods We reviewed ever-smokers who underwent esophagectomy at a single institution from January 2004 through June 2019 for esophageal cancer. Occurrence of Clavien-Dindo classification ≥3 major postoperative morbidity (MPM), including anastomotic leak, chylothorax, reoperation, organ dysfunction, respiratory failure, and ICU readmission was calculated. In an effort to evaluate an effect of smoking cessation on outcome, never-smokers were excluded from analyses. Multivariable logistic regression with backwards stepwise elimination was completed to determine the optimal cessation interval associated with reduction in MPM. Robust standard errors were used to account for clustering among surgeons. Results 725 patients met inclusion criteria, including 666 (92%) with adenocarcinoma and a smaller proportion with squamous cell carcinoma. Most patients were male (650, 90%), and the median age was 63 years (IQR 57–69). Records showed that 505 patients (60%) had quit >5 years prior to esophagectomy, and 82 (11%) were current smokers or had quit within the month preceding esophagectomy. MPM occurred in 213 (29%). After univariate regression, age, gender, pack-year history, operative duration, and FEV1 were included in a multivariable model. While age remained associated wtih MPM, preoperative tobacco cessation of any interval was not associated with outcomes. Conclusion Our previous publication showed increased complication risk for smokers undergoing esophagectomy compared to non-smokers. However, among ever-smokers, no specific interval of preoperative cessation demonstrated decreased MPM. In a setting of active tobacco cessation programs, patients who have not completely achieved abstinence may still be offered surgery with equivalent perioperative outcomes.