Mesothelioma: Pleural, Version 1.2024.

Mesothelioma is a rare cancer that originates from the mesothelial surfaces of the pleura and other sites, and is estimated to occur in approximately 3,500 people in the United States annually. Pleural mesothelioma is the most common type and represents approximately 85% of these cases. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pleural mesothelioma. These NCCN Guidelines Insights highlight significant updates to the NCCN Guidelines for Mesothelioma: Pleural, including revised guidance on disease classification and systemic therapy options.

Phase 2 Trial of Nivolumab and Ramucirumab for Relapsed Mesothelioma: HCRN-LUN15-299.

Introduction: We hypothesized that ramucirumab could increase previously reported objective response rate (ORR) of 11% of single-agent nivolumab in the second-line therapy of unresectable mesothelioma. Methods: This was a cooperative group, single-arm, phase 2 trial enrolling patients with unresectable mesothelioma after progression on more than or equal to one pemetrexed-containing regimen. Ramucirumab and nivolumab were given intravenously every 14 days for up to 24 months. The primary end point was ORR; secondary end points were progression-free survival (PFS) rate at 24 weeks and overall survival (OS). Results: Between April 2018 and October 2021, 34 patients were recruited. Median age was 72 (range: 40-89) years, 12% were women, and 79% of tumors had epithelial histology. Median follow-up was 10.2 months (interquartile range 19.6 mo [4.3-23.8]). ORR was 22.6% (95% confidence interval [CI]: 9.6%-41.1%) in all population and 43% (95% CI: 10%-82%) in patients with nonepithelioid histology. Of all patients, 45.2% (95% CI: 27.3%-64.0%) had stable disease. PFS rate at 24 weeks was 32% (95% CI: 17%-51%). Median PFS was 4.2 months (95% CI: 1.9-6.4 mo). Median OS was 12.5 months (95% CI: 6.3-23.5 mo). There was no grade greater than or equal to four toxicity. Programmed death-ligand 1 expression in the tumor did not correlate with benefit from treatment. Activation of tumor-infiltrating lymphocytes in response to treatment was associated with a trend toward improvement in PFS. Conclusions: Nivolumab and ramucirumab combination was safe and generated PFS and OS rates and ORR that compare favorably with single-agent nivolumab in a similar patient population. The primary end point of 40% ORR was not reached. Further investigation of this regimen in mesothelioma with nonepithelioid histology may be warranted. Clinical Trial Information: NCT03502746.

Osimertinib vs. afatinib as first-line treatment for patients with metastatic non-small cell lung cancer with an EGFR exon 19 deletion or exon 21 L858R mutation.

Background: The optimal treatment sequencing for patients with metastatic epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) remains a subject of debate. In the United States, osimertinib is the preferred EGFR tyrosine kinase inhibitor (TKI) in the first-line setting. However, small retrospective studies suggest that alternative EGFR TKI sequencing strategies may produce similar outcomes. This study aimed to compare the outcomes of patients with metastatic NSCLC harboring an EGFR exon 19 deletion or exon 21 L858R mutation treated with osimertinib vs. afatinib as first-line therapy. Methods: This retrospective, single-institution study examined 86 patients with metastatic EGFR-mutant NSCLC treated with either afatinib (n=15) or osimertinib (n=71) in the first-line setting. The primary outcome was progression-free survival (PFS), and secondary endpoints included time on EGFR TKI, overall survival (OS), and the incidence of adverse events (AEs). Results: There was no difference in the PFS (median: 27.9 vs. 29.0 months, P=0.75), OS (P=0.18), and the median time on first-line EGFR TKI (23.9 vs. 15.2 months, P=0.10) between the afatinib and osimertinib groups, respectively. The number of AEs was also similar between the two treatment groups (P=0.17). Conclusions: In this real-world retrospective study, there were no differences in PFS or OS between patients treated with afatinib or osimertinib in the first-line setting. These findings should be further investigated in larger prospective studies.

Fatal Tracheoesophageal Puncture Leakage Associated With Lenvatinib.

Tracheoesophageal puncture (TEP) is a voice restorative option adopted by many head and neck cancer patients following laryngectomy. Though generally safe, TEP may develop leakage. Lenvatinib is a tyrosine kinase inhibitor (TKI) with anti-tumoral activity against head and neck malignancies.TKIs, including lenvatinib, have been associated with organ perforation or fistula formation. There remains a paucity of literature on the association between lenvatinib and TEP leakage. In this report, we described a patient with adenoid cystic carcinoma of the larynx who had a TEP. After approximately two weeks of treatment with lenvatinib, the patient developed a leakage of TEP. Despite several interventions, the patient died three months afterward due to a retropharyngeal abscess secondary to Fusobacterium nucleatum. To our knowledge, this is the first report of fatal lenvatinib-associated TEP leakage. Clinicians should be cognizant of a potentially rapid development of this complication when prescribing TKI for patients with TEP.

Mesothelioma: Peritoneal, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) focus on peritoneal mesothelioma (PeM). The NCCN Guidelines for PeM provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated PeM. The diagnosis of PeM may be delayed because PeM mimics other diseases and conditions and because the disease is so rare. The pathology section was recently updated to include new information about markers used to identify mesothelioma, which is difficult to diagnose. The term "malignant" is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.

A phase I/IB trial of binimetinib in combination with erlotinib in NSCLC harboring activating KRAS or EGFR mutations.

BACKGROUND: Activating mutations in EGFR or KRAS are highly prevalent in NSCLC, share activation of the MAPK pathway and may be amenable to combination therapy to prevent negative feedback activation. METHODS: In this phase 1/1B trial, we tested the combination of binimetinib and erlotinib in patients with advanced NSCLC with at least 1 prior line of treatment (unless with activating EGFR mutation which could be treatment-naïve). A subsequent phase 1B expansion accrued patients with either EGFR- or KRAS-mutation using the recommended phase 2 dose (RP2D) from Phase 1. The primary objective was to evaluate the safety of binimetinib plus erlotinib and establish the RP2D. RESULTS: 43 patients enrolled (dose-escalation = 23; expansion = 20). 17 harbored EGFR mutation and 22 had KRAS mutation. The RP2D was erlotinib 100 mg daily and binimetinib 15 mg BID × 5 days/week. Common AEs across all doses included diarrhea (69.8%), rash (44.2%), fatigue (32.6%), and nausea (32.6%), and were primarily grade 1/2. Among KRAS mutant patients, 1 (5%) had confirmed partial response and 8 (36%) achieved stable disease as best overall response. Among EGFR mutant patients, 9 were TKI-naïve with 8 (89%) having partial response, and 8 were TKI-pretreated with no partial responses and 1 (13%) stable disease as best overall response. CONCLUSIONS: Binimetinib plus erlotinib demonstrated a manageable safety profile and modest efficacy including one confirmed objective response in a KRAS mutant patient. While clinical utility of this specific combination was limited, these results support development of combinations using novel small molecule inhibitors of RAS, selective EGFR- and other MAPK pathway inhibitors, many of which have improved therapeutic indices. CLINICAL TRIAL REGISTRATION: NCT01859026.

NCCN Guidelines® Insights: Non-Small Cell Lung Cancer, Version 2.2023.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for management of disease in patients with NSCLC. These NCCN Guidelines Insights focus on neoadjuvant and adjuvant (also known as perioperative) systemic therapy options for eligible patients with resectable NSCLC.

Safety Monitoring Activity During EGFR or Anaplastic Lymphoma Kinase Inhibitor Therapy for Patients With Lung Cancer.

Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are highly effective for treatment of EGFR- or ALK-mutated lung cancer. Nevertheless, they are associated with several unique toxicities. Although the available US Food and Drug Administration (FDA)-approved drug label can provide guidance for safety monitoring, its integration into clinical practice has not been previously described. We studied the conduct of safety monitoring activity (SMA) at a large academic institution. On the basis of FDA-approved drug labels, two drug-specific SMAs were identified for osimertinib, crizotinib, alectinib, or lorlatinib. Electronic medical records of patients initiated on these drugs from 2017 to 2021 were retrospectively reviewed. Each course of treatment was evaluated for the occurrence of SMAs and the corresponding adverse events. Analyses included 130 treatment courses from 111 unique patients. For each SMA evaluated, the prevalence of SMA conduct ranged from 10.0% to 84.6%. The most frequently conducted SMA was ECG for lorlatinib therapy and the least was creatine phosphokinase analysis for alectinib. We observed none of the assessed SMAs being conducted in 41 treatment courses (31.5%). EGFR inhibitor predicted a higher likelihood of both SMAs being conducted than ALK inhibitors (P = .02). Serious, grade 3 or 4 adverse events were observed in 21 treatment courses (16.2%), including one grade 4 transaminitis related to alectinib. On the basis of our experience, the conduct of SMA was more challenging to implement for ALK inhibitor than for EGFR inhibitor. Clinicians should be vigilant and review the FDA-approved drug label before prescribing.

Iatrogenic Rupture of Saline Breast Implant Following Robotic-Assisted Lung Surgery.

Breast implants are prevalent in the United States. Patients with breast implants may be susceptible to iatrogenic implant rupture during cardiothoracic surgery. To our knowledge, however, this complication has never been described following robot-assisted thoracic surgery (RATS). We described a patient who developed a rupture of a saline breast implant after undergoing a robot-assisted left lower lobectomy. We hypothesized that a tear to the breast implant may have occurred either during the extraction of one of the surgical ports or during the forceful extraction of the resected specimen. This case highlights another potential complication of minimally invasive thoracic surgery. For patients with breast implants undergoing thoracic RATS, extra care should be made to the site of port placement and the avoidance of excessive force during surgery.

Smoking Cessation, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

Although the harmful effects of smoking after a cancer diagnosis have been clearly demonstrated, many patients continue to smoke cigarettes during treatment and beyond. The NCCN Guidelines for Smoking Cessation emphasize the importance of smoking cessation in all patients with cancer and seek to establish evidence-based recommendations tailored to the unique needs and concerns of patients with cancer. The recommendations contained herein describe interventions for cessation of all combustible tobacco products (eg, cigarettes, cigars, hookah), including smokeless tobacco products. However, recommendations are based on studies of cigarette smoking. The NCCN Smoking Cessation Panel recommends that treatment plans for all patients with cancer who smoke include the following 3 tenets that should be done concurrently: (1) evidence-based motivational strategies and behavior therapy (counseling), which can be brief; (2) evidence-based pharmacotherapy; and (3) close follow-up with retreatment as needed.

Impact of COVID-19 Pandemic on Frontline Pembrolizumab-Based Treatment for Advanced Lung Cancer.

BACKGROUND: Pembrolizumab monotherapy or pembrolizumab plus chemotherapy has become an important frontline treatment for advanced non-small cell lung cancer (NSCLC). To date, it remains unclear how the coronavirus disease 2019 (COVID-19) pandemic impacted the treatment outcome. METHODS: A quasi-experimental study was conducted based on a real-world database, comparing pandemic with pre-pandemic patient cohorts. The pandemic cohort consisted of patients who initiated treatment from March to July 2020, with follow-up through March 2021. The pre-pandemic cohort consisted of those initiating treatment between March and July 2019.The outcome was overall real-world survival. Multivariable Cox-proportional hazard models were constructed. RESULTS: Analyses included data from 2090 patients: 998 in the pandemic cohort and 1092 in the pre-pandemic cohort. Baseline characteristics were comparable, with 33% of patients having PD-L1 expression level ≥50% and 29% of patients receiving pembrolizumab monotherapy. Among those treated with pembrolizumab monotherapy (N = 613), there was a differential impact of the pandemic on survival by PD-L1 expression levels (p-interaction = 0.02). For those with PD-L1 level < 50%, survival was better in the pandemic cohort than the pre-pandemic cohort: hazard ratio (HR) 0.64 (95% CI: 0.43-0.97, p = 0.03). However, for those with PD-L1 level ≥ 50%, survival was not better in the pandemic cohort: HR 1.17 (95% CI: 0.85-1.61, p = 0.34). We found no statistically significant impact of the pandemic on survival among patients treated with pembrolizumab plus chemotherapy. CONCLUSIONS: The COVID-19 pandemic was associated with an increase in survival among patients with lower PD-L1 expression who were treated with pembrolizumab monotherapy. This finding suggests an increased efficacy of immunotherapy due to viral exposure in this population.

Amivantamab for Metastatic Lung Cancer With Paraneoplastic Disseminated Intravascular Coagulation: A Case Report.

Advanced cancers may be accompanied by paraneoplastic disseminated intravascular coagulation (DIC), resulting in thromboembolism or thrombocytopenia. Thrombocytopenia can limit the feasibility of myelosuppressive chemotherapy. Therefore, an alternative treatment option is needed. This report described a patient with metastatic pulmonary adenocarcinoma with EGFR exon 20 insertion and paraneoplastic DIC. Frontline chemotherapy failed to control the disease and worsened thrombocytopenia. However, treatment with amivantamab resulted in a rapid resolution of DIC and produced a partial tumor response. Based on our experience, for patients with EGFR exon 20 insertions with paraneoplastic DIC, amivantamab could be considered a preferred frontline treatment.

Dose-Limiting Pulmonary Toxicity in a Phase 1/2 Study of Radiation and Chemotherapy with Ipilimumab Followed by Nivolumab for Patients With Stage 3 Unresectable Non-Small Cell Lung Cancer.

PURPOSE: We hypothesized that concurrent ipilimumab with chemoradiationtherapy (chemoRT) followed by maintenance nivolumab would be safe for patients with unresectable stage III non-small cell lung cancer (NSCLC). We aimed to assess the safety (phase 1) and the 12-month progression-free survival (PFS) (phase 2) in a multi-institution prospective trial. METHODS AND MATERIALS: Eligible patients had unresectable stage III NSCLC. The treatment included platinum doublet chemotherapy with concurrent thoracic radiation therapy to 60 Gy in 30 fractions and ipilimumab (1 mg/kg) delivered during weeks 1 and 4. After chemoRT, maintenance nivolumab (480 mg) was given every 4 weeks for up to 12 cycles. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events, version 5.0. Survival analyses were performed with Kaplan Meier (KM) methods and log-rank tests. RESULTS: The trial was discontinued early after enrolling 19 patients without proceeding to the phase 2 component because of unacceptable toxicity. Sixteen patients (84%) had grade ≥3 (G3+) possible treatment-related toxicity, most commonly pulmonary AEs (n = 8, 42%). Fourteen patients (74%) discontinued study therapy early because of AEs (n = 12, 63%) or patient choice (n = 2, 11%). Eleven patients (58%) experienced G2+ pulmonary toxicity with median time to onset 4.1 months (95% CI 2.6-not reached [NR]), and 12-month freedom from G2+ pulmonary toxicity 37% (95% CI, 16-59). Five patients had G5 AEs, including 3 with G5 pulmonary AEs (1 respiratory failure with pneumonitis and pulmonary embolism, 1 pneumonia/chronic obstructive pulmonary disease exacerbation, 1 pulmonary fibrosis). Despite toxicities, the median PFS was 19.2 months (95% CI 6.1-NR) and the median overall survival was NR (95% CI 6.1-NR) with median follow-up of 30.1 months by the reverse KM method. CONCLUSIONS: Concurrent ipilimumab with chemoRT for unresectable stage III NSCLC is associated with pulmonary toxicity that may limit opportunities for improved outcomes. Future studies aiming to incorporate ipilimumab or other anti-CTLA4 therapies into management of unresectable stage III NSCLC should consider careful measures to minimize toxicity risk.

Association Between ALK Rearrangement and Ultra-Late Recurrence in Lung Cancer: Case Report and Pooled Analysis.

Ultra-late recurrence, defined as recurrence occurring 10 years or longer after curative treatment, is uncommon for non-small cell lung cancer (NSCLC). To date, factors associated with ultra-late recurrence remain unknown. We report a case with ultra-late recurrence and reviewed the literature published during 2010-2023. This is a case of a 66-year-old woman, with a significant smoking history and a previous history of lung adenocarcinoma, who underwent surgery for a brain metastasis detected on imaging. The pathology confirmed lung adenocarcinoma with an epidermal growth factor receptor (EGFR) exon 20 insertion, a finding consistent with the initial lung surgery a decade ago. With receiving intrathecal topotecan, the patient has maintained stable disease 10 months post-surgery. Given the rarity of ultra-late recurrence of NSCLC, we also conducted a pooled analysis with the outcome of interest being a time to recurrence. Data from this case report was analyzed along with previously published 26 cases of ultra-late recurrence. Multivariable analysis indicated that the only factor significantly predicting time to recurrence was anaplastic lymphoma kinase (ALK) rearrangement.

Prognostic Value of Positron Emission Tomography in Advanced Cholangiocarcinoma: A Single-Institution Study and Literature Review.

BACKGROUND:  Cholangiocarcinoma is an uncommon malignancy in Western countries. Previous studies from mostly Asian countries have suggested the prognostic value of 18F-fluorodeoxyglucose positron-emission tomography integrated with computerized tomography (PET/CT) for advanced cholangiocarcinoma. Here, we investigated the prognostic value of PET/CT at our institution. METHODS:  A retrospective cohort study based on medical record review was conducted for patients with advanced cholangiocarcinoma who underwent treatment from January 2009 to January 2019 at a large academic institution in the United States. The outcomes of interest were overall survival. Multivariable analyses were performed to characterize the relationship between survival and the highest maximum standardized uptake value (SUVmax) from baseline PET/CT scans. RESULTS:  Analyses included data from 61 patients. The median age was 68.9 years and 87% of patients were White. The median highest SUVmax was 8.7 (range: background value to 22.8). In a multivariable analytic model including SUVmax, patient demography, and baseline laboratory parameters, SUVmax was identified as one of the independent predictors of survival higher SUVmax significantly predicted worse survival, with hazard ratio 2.26 (95% CI: 1.07-4.75, p=0.03). White race, higher albumin level, younger age, and lower cancer antigen (CA) 19-9 levels were associated with a decreasing risk of death. CONCLUSION:  In this single-institution retrospective analysis, we found that baseline SUVmax was one of the significant prognostic factors for patients with advanced cholangiocarcinoma.

Impact of Robotic-Assisted Thoracic Surgery on the Completion of Adjuvant Chemotherapy Following Lung Cancer Resection.

Background Adjuvant chemotherapy can further improve treatment outcomes following the resection of non-small cell lung cancer (NSCLC). However, in practice, some patients are unable to tolerate all prescribed chemotherapy. One of the factors which may implicate adjuvant chemotherapy completion is a surgical technique. We investigated the impact of robotic-assisted thoracic surgery (RATS), a form of minimally invasive surgery, on chemotherapy completion. Methods We conducted a retrospective study of NSCLC patients who underwent adjuvant platinum-based chemotherapy at our institution during 2010-2020. The primary outcome of interest was chemotherapy completion, defined as receiving all 4 cycles of chemotherapy. We also performed an exploratory analysis to identify factors associated with chemotherapy completion. Results Analyses included 165 patients: 95 patients underwent traditional thoracotomy, and 70 patients underwent RATS. Baseline characteristics were comparable except for smaller tumor size and lower stage in the RATS group. Median operative time was longer in the RATS group than in the thoracotomy group: 198 vs. 139 minutes, p<0.001. Chemotherapy completion rates were not significantly different between groups: 74.3% vs. 75.8%, p=0.83, respectively. In addition, no significant difference was found in the incidences of postoperative complications between groups. In a propensity score matched analysis, there was also no difference in the chemotherapy completion rates between groups. Multivariable logistic regression analysis indicated that independent factors predicting completion of adjuvant chemotherapy were body mass index, postoperative complications, year of treatment, and T-stage. Conclusion In this large cohort of NSCLC patients who received adjuvant chemotherapy, no association was found between surgical technique and adjuvant chemotherapy completion.

Emerging Approaches to Complement Low-Dose Computerized Tomography for Lung Cancer Screening: A Narrative Review.

Lung cancer screening by low-dose computed tomography (LDCT) can save lives. Nevertheless, the test suffers from low accuracy. Improving its accuracy will reduce unnecessary invasive procedures and allow lung cancer treatment to be delivered sooner. This review describes the principles, advantages, and disadvantages of selected emerging modalities potentially useful to improve the accuracy of LDCT. A literature search was conducted using PubMed and Google scholar for relevant publications. We identified four key emerging approaches: radiomics, breath analysis, urine test, and blood test. Radiomics, which uses a computer program to extract various radiological features from radiographic images, holds the potential to improve the accuracy of LDCT. However, to date, there remains no adequately validated system. Breath analysis and urine tests represent a noninvasive and convenient means of screening by detecting substances such as volatile organic compounds associated with lung cancer. However, the results can be confounded by diets, medications, and concurrent medical conditions. Finally, a blood test to screen for protein biomarkers or methylation profiles such as Galleri® has high specificity. However, its sensitivity is low, especially for detecting early-stage lung cancer. Furthermore, the cost for mass public use can be significant. Based on our review, blood tests may have potential for future clinical utility. Its high specificity may be useful to rule in a suspicious lung nodule as malignant, so that other additional tests can be omitted. Data from a well-designed clinical trial will be needed to understand the clinical utility of this strategy.

Outcomes of Intraocular Metastasis From Lung Cancer in the Era of Targeted Therapy: A Systematic Review and Pooled Analysis.

INTRODUCTION: Metastasis to intraocular structures is a serious problem in lung cancer. Due to its rarity, however, limited information is available regarding the outcomes of treatment and prognosis. Literature often suggests a poor prognosis. We review current literature on the outcomes of systemic therapy and prognostic factors. METHODS: We conducted a systematic review of English literature published during 2009 to 2022 identified via Medline and Google Scholar search. Publications reporting on tumor response in the eyes or overall survival of patients with intraocular metastasis due to lung cancer were included. Pooled analysis of patients receiving systemic therapy was performed, utilizing individual-level patient data. RESULTS: A total of 79 publications contributed 92 patients into the analysis. Choroid was the most affected intraocular structure, in 82% of patients. Histology was small cell in 13% and non-small cell in 87%. Targeted therapy was utilized in 45% of patients. A pooled analysis demonstrated that the median overall survival was 27 months (95% CI: 21.8-32.2). Visual response among those with reported assessment showed that 92% of them had stable or improved vision while 8% experienced worsening of vision. Several factors including the year of treatment, age, targeted therapy, and radiation showed a significant association with survival. The strongest predictor of improved survival was the receipt of targeted therapy, with a hazard ratio of 0.31 (95% CI: 0.14-0.71), P = .005. CONCLUSIONS: For lung cancer patients with intraocular metastasis, systemic therapy can produce a favorable outcome. Particularly when a targeted therapy is feasible, long-term survival can be achieved.