Transitioning to Neoadjuvant Therapy for Resectable Non-Small Cell Lung Cancer: Trends and Surgical Outcomes in a Regionalized Pulmonary Oncology Network.

BACKGROUND: Several regulatory agencies have approved the use of the neoadjuvant chemo-immunotherapy for resectable stage II and III of non-small cell lung cancer (NSCLC) and numerous trials investigating novel agents are underway. However, significant concerns exist around the feasibility and safety of offering curative surgery to patients treated within such pathways. The goal in this study was to evaluate the impact of a transition towards a large-scale neoadjuvant therapy program for NSCLC. METHODS: Medical charts of patients with clinical stage II and III NSCLC who underwent resection from January 2015 to December 2020 were reviewed. The primary outcome was perioperative complication rate between neoadjuvant-treated versus upfront surgery patients. Multivariable logistic regression estimated occurrence of postoperative complications and overall survival was assessed as an exploratory secondary outcome by Kaplan-Meier and Cox-regression analyses. RESULTS: Of the 428 patients included, 106 (24.8%) received neoadjuvant therapy and 322 (75.2%) upfront surgery. Frequency of minor and major postoperative complications was similar between groups (P = .22). Occurrence in postoperative complication was similar in both cohort (aOR = 1.31, 95% CI 0.73-2.34). Neoadjuvant therapy administration increased from 10% to 45% with a rise in targeted and immuno-therapies over time, accompanied by a reduced rate of preoperative radiation therapy use. 1-, 2-, and 5-year overall survival was higher in neoadjuvant therapy compared to upfront surgery patients (Log-Rank P = .017). CONCLUSIONS: No significant differences in perioperative outcomes and survival were observed in resectable NSCLC patients treated by neoadjuvant therapy versus upfront surgery. Transition to neoadjuvant therapy among resectable NSCLC patients is safe and feasible from a surgical perspective.

Accuracy of Cytologic vs Histologic Specimens for Assessment of Programmed Cell Death Ligand-1 Expression in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Programmed cell death ligand-1 (PD-L1) expression on tumor cells, evaluated by immunohistochemistry, guides the use of immunotherapy in advanced non-small cell lung cancer (NSCLC). RESEARCH QUESTION: What is the sensitivity and specificity of PD-L1 testing performed in cytologic vs paired histologic specimens in patients with NSCLC? STUDY DESIGN AND METHODS: The MEDLINE, Embase, Web of Science, and Cochrane Library databases were searched through June 1, 2021. The primary outcome was pooled sensitivity and specificity of PD-L1 testing performed on cytologic specimens compared with the reference standard of histologic specimens, analyzed at the PD-L1 expression cutoffs (tumor proportion score) ≥ 1% and ≥ 50%. Pooled sensitivity and specificity, and associated 95% CIs, were estimated using bivariate generalized linear mixed models. RESULTS: Twenty-six articles were included, encompassing a total of 1,064 pairs of histology specimens and cytology cell blocks, and 267 pairs of histology specimens and direct smears. Among these, 946 paired specimens were acquired without interval treatment between the collection of histology and cytology samples. The pooled sensitivity and specificity of cytology specimens compared with paired histology specimens at the PD-L1 expression cutoff ≥ 1% were 0.84 (95% CI, 0.77-0.89) and 0.88 (95% CI, 0.82-0.93), respectively, whereas the pooled sensitivity and specificity at cutoff ≥ 50% were 0.78 (95% CI, 0.69-0.86) and 0.94 (95% CI, 0.91-0.96), respectively. When only paired specimens acquired without interval treatment were considered, the pooled sensitivity and specificity of cytology specimens at PD-L1 expression cutoff ≥ 1% were 0.84 (95% CI, 0.76-0.90) and 0.89 (95% CI, 0.82-0.94), respectively, whereas the pooled sensitivity and specificity at cutoff ≥ 50% were 0.80 (95% CI, 0.71-0.89) and 0.94 (95% CI, 0.91-0.96), respectively. INTERPRETATION: Cytologic specimens provide an accurate assessment of PD-L1 expression in most patients with NSCLC, at both ≥ 1% and ≥ 50% cutoffs, when compared with histologic specimens. TRIAL REGISTRATION: PROSPERO; No.: CRD42020153279; URL: https://www.crd.york.ac.uk/prospero/.

Neoadjuvant Prehabilitation Therapy for Locally Advanced Non-Small-Cell Lung Cancer: Optimizing Outcomes Throughout the Trajectory of Care.

BACKGROUND: Prehabilitation is well established for improving outcomes in cancer surgery. Combining prehabilitation with neoadjuvant treatments may provide an opportunity to rapidly initiate cancer-directed therapy while improving functional status in preparation for local consolidation. In this proof-of-concept study, we analyzed non-small-cell lung cancer patients who underwent simultaneous prehabilitation and neoadjuvant therapy. PATIENTS AND METHODS: We retrospectively analyzed all patients who underwent neoadjuvant treatment for non-small-cell lung cancer followed by curative intent surgery between 2015 and 2021. Patients who were screened for the prehabilitation program were identified. The screening included assessment of physical performance, nutritional status, and signs of anxiety and depression. RESULTS: We identified a total of 141 patients who underwent neoadjuvant therapy. Twenty patients were screened to undergo a prehabilitation program. Four patients did not complete the exercise program (1 surgical intervention too soon, 1 drop-out after the first session, and 2 patients were deemed fit without intervention). The postoperative median length of stay was 2 days (range 1-18). Patients improved their 6-minute-walk test despite undergoing neoadjuvant treatment by a mean of 33 meters (± 50, P = .1). Self-reported functional status (DASI) showed significant improvement by a mean of 10 points (± 11, P = .03), and HADS-anxiety-score was significantly reduced after the prehabilitation program by a mean of 1.5 points (± 1, P = .005). CONCLUSION: Neoadjuvant prehabilitation therapy is feasible and associated with encouraging results. The performance of all measures remains a logistic challenge. With multimodal strategies for lung cancer treatment becoming key to optimal outcomes, neoadjuvant prehabilitation therapy is a concept worthy of prospective multi-center evaluation.

Real-World Outcomes of Patients With Advanced Non-small Cell Lung Cancer Treated With Anti-PD1 Therapy on the Basis of PD-L1 Results in EBUS-TBNA vs Histological Specimens.

BACKGROUND: Programmed death-ligand 1 (PD-L1) testing is feasible in most specimens acquired using endobronchial ultrasound-guided needle aspiration (EBUS-TBNA). RESEARCH QUESTION: Are the outcomes of patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI) on the basis of PD-L1 expression in EBUS-TBNA samples significantly different from those of patients who are treated on the basis of PD-L1 expression in histological samples? STUDY DESIGN AND METHODS: Patients treated with pembrolizumab or nivolumab between June 2016 and 2019 were included. Patient characteristics, PD-L1 expression, line of treatment, response (Response Evaluation Criteria in Solid Tumors [RECIST] criteria), and vital status (May 14, 2020) were recorded. Progression-free survival (PFS) and overall survival (OS) were assessed, and hazard ratios (HR) estimated. RESULTS: A total of 145 patients were treated with pembrolizumab or nivolumab on the basis of PD-L1 expression in EBUS-TBNA (31.7%) or histological (68.3%) samples. Most had metastatic disease, with a predominance of adenocarcinomas (64.1%). First-line pembrolizumab was administered to 61 patients with tumor proportion score ≥50% in EBUS-TBNA (n = 16) or histology samples (n = 45). Median OS and PFS of patients who received first-line pembrolizumab on the basis of PD-L1 results in EBUS-TBNA vs histology samples were not significantly different (OS 25.8 months vs not reached, respectively; HR, 0.82 [95% CI, 0.34-1.95], P = .651). Similarly, the median OS and PFS of patients who received subsequent lines of treatment on the basis of PD-L1 results in EBUS-TBNA vs histological samples were not significantly different (including after adjustment for PD-L1 expression). INTERPRETATION: These findings suggest that PD-L1 results in EBUS-TBNA samples can guide ICI therapy, with treatment outcomes being comparable to those of patients in whom PD-L1 expression was assessed in histological specimens.

Bronchoscopic tissue yield for advanced molecular testing: are we getting enough?

The treatment of advanced lung cancer has become increasingly personalized over the past decade as a result of the improved understanding of tumor molecular biology and anti-tumor immunity. An adequate tumor sample is central to targetable mutation analysis, and immunologic profiling. The majority of lung cancer patients currently present at an advanced disease stage, so that diagnosis and staging are largely based on small biopsy and cytology specimens. Flexible bronchoscopy techniques play a prominent role in the acquisition of these diagnostic specimens. This narrative review summarizes the available evidence with regards to the role of various conventional and advanced flexible bronchoscopy techniques in acquiring sufficient tissue for mutation analysis and programmed death-ligand 1 (PD-L1) testing.

Programmed Death Ligand 1 Testing of Endobronchial Ultrasound-guided Transbronchial Needle Aspiration Samples Acquired For the Diagnosis and Staging of Non-Small Cell Lung Cancer.

RATIONALE: Immunotherapy has become an integral part of management in patients with advanced non-small cell lung cancer (NSCLC). Programmed death ligand 1 (PD-L1) expression in at least 50% of tumor cells on histologic samples has been correlated with improved efficacy of the immune checkpoint inhibitor pembrolizumab. A limited number of studies have examined the suitability of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) specimens for assessment of PD-L1 status. OBJECTIVE: We sought to examine the feasibility and results of PD-L1 testing performed on EBUS-TBNA samples acquired for the diagnosis and staging of NSCLC. MATERIALS AND METHODS: Patients were identified from a prospectively maintained pathology database. Baseline characteristics were tabulated. Hematoxylin and eosin slides were reviewed to categorize cellularity between <100, 100 to 500, and >500 viable tumor cells. Samples were tested using Dako's PD-L1 IHC 22C3 pharmDx kit, with a minimum of 100 viable tumor cells. For patients in whom additional tissue samples were available, the results of PD-L1 testing were compared. RESULTS: PD-L1 testing was attempted on 120 EBUS-TBNA samples. The most common NSCLC subtype was adenocarcinoma (78%). Seventy-six specimens (63%) had a cellularity >500 tumor cells. Among 110 of 120 (92%) patients with an adequate endobronchial ultrasound (EBUS) sample, 53 of 110 (48.2%) had high PD-L1 expression, defined as a Tumor Proportion Score ≥50%. EBUS PD-L1 results were concordant with an available histologic sample in 14 of 18 patients (78%), with no false-negative results. CONCLUSION: PD-L1 testing was feasible in the majority of EBUS-TBNA samples acquired for the diagnosis and staging of NSCLC. Comparison of EBUS results with histologic samples revealed moderate concordance, with no false-negative results.

Impact of rapid investigation clinic on timeliness of lung cancer diagnosis and treatment.

BACKGROUND: Guidelines recommend timely evaluation of patients with suspected lung cancer. We evaluated the impact of a Rapid Investigation Clinic (RIC) on timeliness of lung cancer diagnosis and treatment between February 2010 and December 2011. METHODS: Investigation within the RIC was conducted by a pulmonologist and a nurse clinician. Controls were patients with lung cancer, investigated outside the RIC at the same institution during the same time period. The primary outcome was time between first contact with a local physician for suspected lung cancer (T0) and first treatment. Factors associated with the delay from T0 to first treatment were examined using multivariate analysis. Completeness of lung cancer staging according to guidelines was assessed. RESULTS: A total of 195 patients were investigated within the RIC vs. 132 patients outside the RIC. The median delay between T0 and first treatment was 65 days (interquartile range [IQR] 46-92 days) in the RIC and 78 days (IQR 49-119 days) in the non-RIC patients (p ≤ 0.01). Time from T0 to pathological diagnosis was shorter in the RIC (median 26 days; IQR 14-42 days) vs. non-RIC patients (median 40 days; IQR 16-68 days). In multivariate analysis, investigation in the RIC was associated with a reduction in time to first treatment of 24 days (95% confidence interval [CI] 12-35 days) when adjusted for relevant confounders. Guideline-concordant investigation occurred more frequently in RIC patients, based on the quality indicators examined. CONCLUSIONS: A Rapid Investigation Clinic reduces delays to lung cancer diagnosis and treatment, and impacts quality of care.

Long-term Outcomes of Induction Carboplatin and Gemcitabine Followed by Concurrent Radiotherapy With Low-dose Paclitaxel and Gemcitabine for Stage III Non-small-cell Lung Cancer.

BACKGROUND: Standard treatment for unresectable stage III non-small-cell lung cancer (NSCLC) is concurrent chemo-radiation (CRT). A regimen of induction carboplatin and gemcitabine followed by CRT was developed at the McGill University Health Centre to prevent delays in treatment initiation. We report the long-term outcomes with this regimen based on a pooled analysis of both protocol patients from a phase II study and nonprotocol patients. METHODS AND MATERIALS: Outcomes and toxicity data were retrieved for 142 patients with stage III NSCLC: 43 patients treated on protocol between January 2003 and November 2004, and 101 patients treated off-protocol between December 2004 and August 2013. Patients received 2 cycles of carboplatin with an area under the curve of 5 intravenously (IV) on day 1 and gemcitabine 1000 mg/m2 IV on days 1 and 8 every 3 weeks, followed on day 50 by CRT, 60 Gy/30 over 6 weeks, concomitantly with 2 cycles of paclitaxel 50 mg/m2 IV and gemcitabine 100 mg/m2 IV on days 1 and 8 every 3 weeks. RESULTS: The median overall survival was 23.2 months. With a median follow-up of 23.8 months, the 3-, 4-, and 5-year overall survival was 38%, 30%, and 26%, respectively. The median and 5-year progression-free survival rates were 12.5 months and 25%, respectively. Rates of grade ≥ 3 hematologic, esophageal, and respiratory toxicity were 20%, 10%, and 10%, respectively. Forty-eight patients received further lines of chemotherapy. CONCLUSION: The present analysis affirms the favorable toxicity profile of this novel induction chemotherapy, without apparent compromise in clinical outcomes, when compared with regimens using immediate concurrent CRT.

Optimizing tissue sampling for the diagnosis, subtyping, and molecular analysis of lung cancer.

Lung cancer has entered the era of personalized therapy with histologic subclassification and the presence of molecular biomarkers becoming increasingly important in therapeutic algorithms. At the same time, biopsy specimens are becoming increasingly smaller as diagnostic algorithms seek to establish diagnosis and stage with the least invasive techniques. Here, we review techniques used in the diagnosis of lung cancer including bronchoscopy, ultrasound-guided bronchoscopy, transthoracic needle biopsy, and thoracoscopy. In addition to discussing indications and complications, we focus our discussion on diagnostic yields and the feasibility of testing for molecular biomarkers such as epidermal growth factor receptor and anaplastic lymphoma kinase, emphasizing the importance of a sufficient tumor biopsy.

Phase II multicenter trial with carboplatin and gemcitabine induction chemotherapy followed by radiotherapy concomitantly with low-dose paclitaxel and gemcitabine for stage IIIA and IIIB non-small cell lung cancer.

INTRODUCTION: The optimal combination of concomitant radiotherapy (RT) and chemotherapy in stage III unresectable non-small cell lung cancer (NSCLC) remains unclear. The role of induction chemotherapy with carboplatin/gemcitabine regimen has not been established in stage III NSCLC. METHODS: Forty-two stage III NSCLC patients, 41 assessable, with a median age of 60 years and good performance status, entered this trial between January 2003 and November 2004. They received carboplatin area under the curve 5 on day 1 and gemcitabine 1000 mg/m2 on days 1 + 8 every 3 weeks for two cycles, followed on day 50 by RT 60 Gy, concomitantly with paclitaxel 50 mg/m2 and gemcitabine 100 mg/m2 on days 1 + 8 every 3 weeks for two cycles. RESULTS: After induction, the partial response (PR) was 73.1% and stable disease was 24.4%. Disease progressed in one patient. After RT and paclitaxel/gemcitabine, 22% achieved a complete response and 73% a PR, and 5% had disease progression. The median survival was 25 months, the 1-year survival rate was 73.2%, and the 2-year survival rate was 50.5%. During concomitant RT and chemotherapy, grade 3 neutropenia, thrombocytopenia, and anemia occurred in eight, three, and three patients, respectively, and grade 4 neutropenia and thrombocytopenia in one patient each. One patient developed an esophageal fistula and died shortly after, which was considered a grade 5 toxicity; one patient developed grade 4 interstitial pneumonitis, and three patients developed grade 3 esophagitis. CONCLUSION: This regimen appears to be effective and was well tolerated. Further studies using this approach are warranted in patients with stage III NSCLC.

Sequential therapy with Vinorelbine followed by Gemcitabine in patients with metastatic non small cell lung cancer (NSCLC), performance status (PS) 2, or elderly with comorbidities--a multicenter phase II trial.

BACKGROUND: High risk patients with metastatic non small cell lung cancer (NSCLC) including patients with performance status (PS) 2 or elderly with comorbidities do poorly on combination chemotherapy regimens. We evaluated a sequential treatment with Vinorelbine followed by Gemcitabine to determine its effect on survival and the toxicity in this patient population. METHODS: Forty-two evaluable patients, median age 75, 21 patients with PS 2 and 21 patients with PS 0 or 1, 37 patients with stage IV and five patients with stage III B NSCLC entered the trial. They received Vinorelbine 30 mg/m2, i.v., on days 1+8 every 3 weeks followed by Gemcitabine 1000 mg/m2, i.v., on days 1+8 every 3 weeks, each for two cycles for stable disease or one cycle after best response. Then stable patients continued until progressive disease on Vinorelbine or Gemcitabine according to the patient's preference. RESULTS: A total of 126 cycles of Vinorelbine were administered to 42 patients, median of three cycles per patient and 74 cycles of Gemcitabine, median of 1.0 cycle per patient. Sixteen patients (38%) achieved PR, 11 patients on Vinorelbine, 5 patients on Gemcitabine; 12 patients (26%) had stable disease, 7 patients on Vinorelbine, 5 patients on Gemcitabine. Of 24 patients with progressive disease on Vinorelbine, 3 patients (12.5%) responded to Gemcitabine. Median time-to-first progression was 3.5 months, median survival was 8 months, 1-year survival was 12 patients (28.5%). No grade 3 or 4 toxicities were reported. CONCLUSION: This sequential treatment offers excellent palliative treatment with minimal toxicity for high-risk patients with metastatic NSCLC.

Weekly paclitaxel and gemcitabine chemotherapy for metastatic non-small cell lung carcinoma (NSCLC): a dose-optimizing phase II trial.

BACKGROUND: The current dose-optimizing Phase II study evaluated the effect of weekly paclitaxel and gemcitabine on the response rate and survival of patients with non-small cell lung carcinoma (NSCLC) using dose modifications that permitted optimal treatment intensity. METHODS: Forty-five patients (40 with TNM Stage IV and 5 with TNM Stage IIIB NSCLC) were treated with gemcitabine at 1000 mg/m(2) via a 30-minute intravenous (i.v.) infusion and with paclitaxel at 100 mg/m(2) via a 60-minute i.v. infusion. The first 3 patients received chemotherapy on Days 1, 8, and 15 every 4 weeks; the next 42 patients, participating in the Phase II trial, received chemotherapy on Days 1 and 8 every 3 weeks. RESULTS: The 3 patients who received paclitaxel and gemcitabine on Days 1, 8, and 15 every 4 weeks tolerated the treatment poorly. One patient died suddenly after Day 15 treatment during the first cycle, and the other 2 patients discontinued the treatment because of unacceptable toxicity before the third cycle of chemotherapy. The next 42 patients, 40 of whom were evaluable, entered this trial between May 2000 and April 2001. They received paclitaxel at 100 mg/m(2) i.v. followed by gemcitabine at 1000 mg/m(2) i.v. on Days 1 and 8 every 3 weeks. Two patients (5%) achieved complete response, 20 (50%) achieved partial response, and 8 (20%) had stable disease. Median survival (MS) was 9.8 months; and 1-year survival was 35%. The 32 patients with performance status (PS) 0 or 1 had an MS of 11 months; the 8 patients with PS 2 had an MS of 3 months. Toxicity (especially hematologic toxicity, neuropathy, and alopecia) was minimal. CONCLUSION: A weekly paclitaxel and gemcitabine regimen that incorporated the authors' dose modifications resulted in good efficacy with minimal toxicity.