Best first-line therapy for people with advanced non-small cell lung cancer, performance status 2 without a targetable mutation or with an unknown mutation status.

BACKGROUND: Most people who are newly diagnosed with non-small cell lung cancer (NSCLC) have advanced disease. For these people, survival is determined by various patient- and tumor-related factors, of which the performance status (PS) is the most important prognostic factor. People with PS 0 or 1 are usually treated with systemic therapies, whereas people with PS 3 or 4 most often receive supportive care. However, treatment for people with PS 2 without a targetable mutation remains unclear. Historically, people with a PS 2 cancer are frequently excluded from (important) clinical trials because of poorer outcomes and increased toxicity. We aim to address this knowledge gap, as this group of people represents a significant proportion (20% to 30%) of the total population with newly diagnosed lung cancer. OBJECTIVES: To identify the best first-line therapy for advanced lung cancer in people with performance status 2 without a targetable mutation or with an unknown mutation status. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 17 June 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared different chemotherapy (with or without angiogenesis inhibitor) or immunotherapy regimens, specifically designed for people with PS 2 only or studies including a subgroup of these people. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. overall survival (OS), 2. health-related quality of life (HRQoL), and 3. toxicity/adverse events. Our secondary outcomes were 4. tumor response rate, 5. progression-free survival, and 6. survival rates at six and 12 months' treatment. We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We included 22 trials in this review and identified one ongoing trial. Twenty studies compared chemotherapy with different regimens, of which 11 compared non-platinum therapy (monotherapy or doublet) versus platinum doublet. We found no studies comparing best supportive care with chemotherapy and only two abstracts analyzing chemotherapy versus immunotherapy. We found that platinum doublet therapy showed superior OS compared to non-platinum therapy (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.57 to 0.78; 7 trials, 697 participants; moderate-certainty evidence). There were no differences in six-month survival rates (risk ratio [RR] 1.00, 95% CI 0.72 to 1.41; 6 trials, 632 participants; moderate-certainty evidence), whereas 12-month survival rates were improved for treatment with platinum doublet therapy (RR 0.92, 95% CI 0.87 to 0.97; 11 trials, 1567 participants; moderate-certainty evidence). PFS and tumor response rate were also better for people treated with platinum doublet therapy, with moderate-certainty evidence (PFS: HR 0.57, 95% CI 0.42 to 0.77; 5 trials, 487 participants; tumor response rate: RR 2.25, 95% CI 1.67 to 3.05; 9 trials, 964 participants). When analyzing toxicity rates, we found that platinum doublet therapy increased grade 3 to 5 hematologic toxicities, all with low-certainty evidence (anemia: RR 1.98, 95% CI 1.00 to 3.92; neutropenia: RR 2.75, 95% CI 1.30 to 5.82; thrombocytopenia: RR 3.96, 95% CI 1.73 to 9.06; all 8 trials, 935 participants). Only four trials reported HRQoL data; however, the methodology was different per trial and we were unable to perform a meta-analysis. Although evidence is limited, there were no differences in 12-month survival rates or tumor response rates between carboplatin and cisplatin regimens. With an indirect comparison, carboplatin seemed to have better 12-month survival rates than cisplatin compared to non-platinum therapy. The assessment of the efficacy of immunotherapy in people with PS 2 was limited. There might be a place for single-agent immunotherapy, but the data provided by the included studies did not encourage the use of double-agent immunotherapy. AUTHORS' CONCLUSIONS: This review showed that as a first-line treatment for people with PS 2 with advanced NSCLC, platinum doublet therapy seems to be preferred over non-platinum therapy, with a higher response rate, PFS, and OS. Although the risk for grade 3 to 5 hematologic toxicity is higher, these events are often relatively mild and easy to treat. Since trials using checkpoint inhibitors in people with PS 2 are scarce, we identified an important knowledge gap regarding their role in people with advanced NSCLC and PS 2.

Sarcoidosis presenting with glazy mucoid sputum and dyspnea: a case report.

BACKGROUND: Patients with pulmonary sarcoidosis commonly present with a dry cough; a productive cough suggests a complicating airway infection or an alternative diagnosis such as tuberculosis or bronchiectasis. CASE PRESENTATION: A 36-year-old European (Frisian) woman recently diagnosed with pulmonary sarcoidosis presented with debilitating exertional dyspnea and cough productive of glazy mucoid sputum. Several different attempts including video-assisted thoracoscopic biopsies failed to reach a second or alternative diagnosis including an infectious, autoimmune or collagen-vascular condition. She responded to steroids but with poor tolerance to this treatment, which could not be tapered. After she was started on anti-tumor necrosis factor alpha (TNF-α) therapy with infliximab, 200 mg at three-monthly intervals, she has been fine for well over a decade. CONCLUSIONS: In this patient with sarcoidosis who had a productive cough accompanied by fever, an extensive workup and prolonged follow-up, an alternative or second diagnosis could be ruled out; we therefore conclude that this highly unusual presentation is part of the clinical spectrum of sarcoidosis.

Endosonography for lung cancer staging: predictors for false-negative outcomes.

OBJECTIVES: Non-small cell lung cancer (NSCLC) guidelines recommend endosonography (endobronchial [EBUS] and/or transesophageal ultrasound [EUS]) as the initial step for mediastinal tissue staging. Identifying predictors for false negative results could help establish which patients should undergo confirmatory surgical staging. MATERIALS AND METHODS: 775 NSCLC patients staged negative by EBUS, EUS or combined EUS/EBUS were retrospectively analyzed. Predictors of false-negative outcomes were identified by logistic regression analysis. RESULTS AND CONCLUSION: Three predictors for false-negative outcomes were identified: central location of the lung tumor (OR 3.7/4.5/3.6 for EBUS, EUS and EUS/EBUS respectively, p<0.05), nodal enlargement on CT (OR 3.2/2.5/4.9 for EBUS, EUS and EUS/EBUS respectively, p<0.05) and FDG-avidity of N2/N3 lymph node stations on PET (OR 4.2/4.0/7.5 for EBUS, EUS and EUS/EBUS respectively, p<0.05). One subgroup (peripheral lung tumor, nodal enlargement on CT without FDG-avidity for N2/N3) had a low predicted probability (7.8%) for false-negative EUS. For combined EUS/EBUS, two subgroups were identified: peripheral located tumor with nodal enlargement on CT but without FDG-avidity for N2/N3 (predicted probability 4.7%) and centrally located tumor without affected lymph nodes on CT or PET (predicted probability 3.4%). In conclusion, for specific well-defined subsets of NSCLC patients the low predicted probability of metastasis after negative endosonography might justify omitting confirmatory surgical staging.

Endosonography for the diagnosis of malignant lymphoma presenting with mediastinal lymphadenopathy.

BACKGROUND: Endosonography combined with fine needle aspiration (FNA) is a minimally invasive technique for intrathoracic mediastinal nodal sampling. The value of endosonography with FNA for the diagnosis of malignant mediastinal lymphoma is under debate. In this study, the sensitivity and negative predictive value of endosonography for the assessment of primary versus recurrent malignant lymphoma were assessed. METHODS: Forty-nine patients with suspected primary (n=32) or recurrent (n=17) lymphoma were retrospectively analyzed. They presented with mediastinal nodal enlargement and underwent endosonography for diagnostic purposes between 2001 and 2011. The final diagnosis was based on surgical biopsy, conclusive cell block analysis, or longstanding clinical and radiologic follow-up. RESULTS: In 33 patients, a final diagnosis of lymphoma was established; in 16 patients (33%) alternative diagnoses (eg, small cell lung cancer, sarcoidosis) were found. Sensitivity and negative predictive value of endosonography in diagnosing primary versus recurrent mediastinal lymphoma were 55% and 57% versus 88% and 90%, respectively. No complications occurred during these procedures. CONCLUSIONS: On the basis of these data, we conclude that endosonography is a minimally invasive, safe, and sensitive method for the assessment of recurrent mediastinal malignant lymphoma or alternative diagnoses but has limitations in assessing a primary lymphoma diagnosis.

Implementation of endoscopic ultrasound for lung cancer staging.

BACKGROUND: EUS-guided FNA is currently advocated in lung cancer staging guidelines as an alternative for surgical staging to prove mediastinal metastases. To date, training requirements for chest physicians to obtain competency in EUS for lung cancer staging are unknown. OBJECTIVE: To test a training and implementation strategy for EUS for the diagnosis and staging of lung cancer. DESIGN: Prospective national multicenter implementation trial. Nine (chest) physicians from 5 hospitals participated in a dedicated EUS educational program (investigation of 50 patients) for the diagnosis and staging of lung cancer. EUS outcomes of trainees were compared with those of the training center. SETTING: Four general hospitals, the national cancer center (implementation centers), and a tertiary referral center (expert center). PATIENTS: This study involved 551 consecutive patients with (suspected) lung cancer, all candidates for surgical staging, who underwent EUS in 1 of the 5 implementation centers (n = 346) or the single expert center (n = 205). Surgical-pathological staging was the reference standard in case no mediastinal metastases were found. RESULTS: EUS had a sensitivity of 83% versus 82% and accuracy of 89% versus 88% for mediastinal nodal staging (implementation center vs expert center). Surgery was spared because of EUS findings in 51% versus 54% of patients. A single complication occurred in each group. LIMITATION: Surgical-pathological verification of mediastinal nodes was not available in all patients staged negative at EUS. CONCLUSION: Chest physicians who participate in a dedicated training and implementation program for EUS in lung cancer staging can obtain results similar to those of experts for mediastinal nodal staging.