Summary Background Results from a previous phase 3 study suggested that prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolongs overall survival compared ...with no prophylactic cranial irradiation in patients with extensive-disease small-cell lung cancer. However, because of the absence of brain imaging before enrolment and variations in chemotherapeutic regimens and irradiation doses, concerns have been raised about these findings. We did a phase 3 trial to reassess the efficacy of prophylactic cranial irradiation in the treatment of extensive-disease small-cell lung cancer. Methods We did this randomised, open-label, phase 3 study at 47 institutions in Japan. Patients with extensive-disease small-cell lung cancer who had any response to platinum-based doublet chemotherapy and no brain metastases on MRI were randomly assigned (1:1) to receive prophylactic cranial irradiation (25 Gy in ten daily fractions of 2·5 Gy) or observation. All patients were required to have brain MRI at 3-month intervals up to 12 months and at 18 and 24 months after enrolment. Randomisation was done by computer-generated allocation sequence, with age as a stratification factor and minimisation by institution, Eastern Cooperative Oncology Group performance status, and response to initial chemotherapy. The primary endpoint was overall survival, analysed in the intention-to-treat population. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000001755, and is closed to new participants. Findings Between April 3, 2009, and July 17, 2013, 224 patients were enrolled and randomly assigned (113 to prophylactic cranial irradiation and 111 to observation). In the planned interim analysis on June 18, 2013, of the first 163 enrolled patients, Bayesian predictive probability of prophylactic cranial irradiation being superior to observation was 0·011%, resulting in early termination of the study because of futility. In the final analysis, median overall survival was 11·6 months (95% CI 9·5–13·3) in the prophylactic cranial irradiation group and 13·7 months (10·2–16·4) in the observation group (hazard ratio 1·27, 95% CI 0·96–1·68; p=0·094). The most frequent grade 3 or worse adverse events at 3 months were anorexia (six 6% of 106 in the prophylactic cranial irradiation group vs two 2% of 111 in the observation group), malaise (three 3% vs one <1%), and muscle weakness in a lower limb (one <1% vs six 5%). No treatment-related deaths occurred in either group. Interpretation In this Japanese trial, prophylactic cranial irradiation did not result in longer overall survival compared with observation in patients with extensive-disease small-cell lung cancer. Prophylactic cranial irradiation is therefore not essential for patients with extensive-disease small-cell lung cancer with any response to initial chemotherapy and a confirmed absence of brain metastases when patients receive periodic MRI examination during follow-up. Funding The Ministry of Health, Labour and Welfare of Japan.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Pembrolizumab plus pemetrexed‐platinum significantly improved overall survival (OS) and progression‐free survival (PFS) with manageable safety compared with placebo plus pemetrexed‐platinum in ...patients with previously untreated metastatic nonsquamous non–small‐cell lung cancer (NSCLC) without EGFR/ALK alterations in the global, randomized, double‐blind, phase 3 KEYNOTE‐189 study. We present results of Japanese patients enrolled in the KEYNOTE‐189 global and Japan extension studies. Patients were randomized 2:1 to intravenous pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for up to 35 cycles. All patients received pemetrexed 500 mg/m2 plus the investigator’s choice of cisplatin or carboplatin Q3W for four cycles, followed by maintenance pemetrexed 500 mg/m2 Q3W (all intravenous). Co–primary endpoints were OS and PFS. Forty Japanese patients enrolled (pembrolizumab, n = 25; placebo, n = 15). At data cutoff (20 May 2019; median time from randomization to data cutoff, 18.5 range, 14.7‒38.2 months), the median OS was not reached in the pembrolizumab plus pemetrexed‐platinum arm; the median OS was 25.9 (95% confidence interval CI, 11.9‒29.0) months in the placebo plus pemetrexed‐platinum arm (hazard ratio HR .29; 95% CI, .07‒1.15). The median (95% CI) PFS was 16.5 (8.8‒21.1) compared with 7.1 (4.7‒21.4) months (HR, .62; 95% CI, .27‒1.42), respectively. There were no grade 5 adverse events (AE). Grade 3/4 AE occurred in 72% vs 60% of patients in the pembrolizumab vs placebo arms; 40% vs 20% had immune‐mediated AE, and 4% vs 0% had infusion reactions. Efficacy and safety outcomes were similar to those from the global study and support first‐line therapy with pembrolizumab plus pemetrexed‐platinum in Japanese patients with nonsquamous NSCLC without EGFR/ALK alterations.
In conclusion, consistent with the global KEYNOTE‐189 study, pembrolizumab in combination with pemetrexed and platinum improved OS, PFS, ORR, and PFS2 compared with placebo plus pemetrexed‐platinum and demonstrated a manageable safety profile in Japanese patients with previously untreated metastatic nonsquamous NSCLC. The results from this study confirm the role of pembrolizumab plus pemetrexed‐platinum as a first‐line standard‐of‐care therapy for Japanese patients with metastatic nonsquamous NSCLC.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Introduction
Endobronchial ultrasound (EBUS) bronchoscopes have been used mainly through the airway for EBUS-guided transbronchial needle aspiration (EBUS-TBNA); however, they can also be used ...through the esophagus. The esophageal approach, endoscopic ultrasound with bronchoscope-guided fine needle aspiration (EUS-B-FNA), has gradually become popular, as it can evaluate lesions that cannot be accessed through the airway.
Purpose
This study aimed to evaluate the value of adding EUS-B-FNA to EBUS-TBNA performed by pulmonologists for intrathoracic lesions in the clinical setting.
Methods
Between March 2009 and March 2020, all patients who underwent EUS-B-FNA and EBUS-TBNA for diagnostic purposes were included and retrospectively analyzed at a single institution.
Results
A total of 1794 procedures using an EBUS bronchoscope including, EBUS-TBNA, EUS-B-FNA, and the combination of EBUS-TBNA and EUS-B-FNA for evaluating intrathoracic lesions, were performed. We finally analyzed 276 patients who underwent EUS-B-FNA for diagnostic purposes. EUS-B-FNA provided diagnostic materials from only EBUS-TBNA-inaccessible lesions in 26 patients and in 18 patients whose conditions were inappropriate for bronchoscopy (e.g., respiratory failure, airway stenosis, etc.). EUS-B-FNA provided diagnostic results in four patients with non-diagnostic EBUS-TBNA results. EUS-B-FNA was preferable to EBUS-TBNA in 4.4% (48 of 1091) of patients; therefore, adding EUS-B-FNA to EBUS-TBNA increased the diagnostic yield from 72.6% (1043 of 1437) to 75.9% (1091 of 1437).
Conclusion
Pulmonologists are able to enhance diagnostic yields by acquiring the EUS-B-FNA technique.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To evaluate the efficacy of pemetrexed plus cisplatin versus vinorelbine plus cisplatin as postoperative adjuvant chemotherapy in patients with pathologic stage II-IIIA nonsquamous non-small-cell ...lung cancer (NSCLC).
We performed a randomized, open-label, phase III study at 50 institutions within 7 clinical study groups in Japan. Patients with completely resected pathologic stage II-IIIA (TNM 7th edition) nonsquamous NSCLC were randomly assigned to receive either pemetrexed (500 mg/m
, day 1) plus cisplatin (75 mg/m
, day 1) or vinorelbine (25 mg/m
, days 1 and 8) plus cisplatin (80 mg/m
, day 1) with stratification by sex, age, pathologic stage,
mutation, and institution. These treatments were planned to be given every 3 weeks for 4 cycles. The primary end point was recurrence-free survival in the modified intent-to-treat population, excluding ineligible patients.
Between March 2012 and August 2016, 804 patients were enrolled (402 assigned to vinorelbine plus cisplatin and 402 assigned to pemetrexed plus cisplatin). Of 784 eligible patients, 410 (52%) had stage IIIA disease and 192 (24%) had
-sensitive mutations. At a median follow-up of 45.2 months, median recurrence-free survival was 37.3 months for vinorelbine plus cisplatin and 38.9 months for pemetrexed plus cisplatin, with a hazard ratio of 0.98 (95% CI, 0.81 to 1.20; 1-sided
= .474). Grade 3-4 toxicities reported more frequently for vinorelbine plus cisplatin than for pemetrexed plus cisplatin were febrile neutropenia (11.6%
0.3%, respectively), neutropenia (81.1%
22.7%, respectively), and anemia (9.3%
2.8%, respectively). One treatment-related death occurred in each arm.
Although this study failed to show the superiority of pemetrexed plus cisplatin for patients with resected nonsquamous NSCLC, this regimen showed a better tolerability as adjuvant chemotherapy.
Background and Objective
Ultrathin bronchoscopy aids in the diagnosis of peripheral pulmonary lesions. However, both the working channel and the specimens are small. A 1.1‐mm ultrathin cryoprobe that ...can enter the working channel of the ultrathin bronchoscope is now available, which may overcome the limitations of small specimen size. The aim of this study was to evaluate the feasibility, efficacy and safety of ultrathin bronchoscopic cryobiopsy using an ultrathin cryoprobe for diagnosing peripheral pulmonary lesions.
Methods
Patients with peripheral pulmonary lesions ≤30 mm in diameter were prospectively enrolled in the study. All patients underwent forceps biopsy followed by cryobiopsy using a 3.0‐mm ultrathin bronchoscope under radial probe endobronchial ultrasound guidance, virtual bronchoscopic navigation and fluoroscopic guidance. The primary endpoint was the feasibility of cryobiopsy.
Results
In total, 50 patients with peripheral pulmonary lesions were enrolled in the study; the median longest diameter on computed tomography was 17.9 mm. Cryobiopsy was performed successfully in 49 patients (98%). Forceps biopsy, cryobiopsy and the combination of these two methods provided a specific diagnosis in 54% (27/50), 62% (31/50) and 74% (37/50) of patients, respectively. The median size of specimens obtained via cryobiopsy was significantly larger than the median size obtained via forceps biopsy (7.0 vs. 1.3 mm2, respectively, p < 0.001). Mild bleeding during cryobiopsy occurred in 47 patients (94%). No moderate/severe bleeding or pneumothorax occurred.
Conclusion
Ultrathin bronchoscopic cryobiopsy is feasible, effective and sufficiently safe for the diagnosis of peripheral pulmonary lesions.
To date, no prospective study has evaluated the use of a 1.1‐mm ultrathin cryoprobe in combination with ultrathin bronchoscopy. Ultrathin bronchoscopic cryobiopsy was successfully performed in most of our patients without any significant complications, which enhanced the overall diagnostic yield when combined with forceps biopsy.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background Silicone stenting has been widely used to palliate respiratory symptoms in patients suffering from airway stenosis. Although many types and shapes of stents have been developed, there is ...no ideal stent for stenosis around the carina between the bronchus to the right upper lobe and the bronchus intermedius (primary right carina). The purpose of this study was to evaluate the feasibility, efficacy, and safety of a new silicone stent designed for treating airway stenosis around the primary right carina. Methods We recruited 16 patients with suspected stenosis around the primary right carina. Ten of the patients met the inclusion criteria for inserting the study stent. All stenting procedures were performed with a rigid and flexible bronchoscope under general anesthesia. Results The study stent could be mounted successfully on the primary right carina in all 10 patients. Five patients underwent stenting using only the new stent, and the other five underwent stenting with it on the primary right carina and a silicone Y stent on the main carina. The dyspnea index improved in eight of the 10 patients, including one who was mechanically ventilated. Early complications developed in three patients (temporary pneumonia in two and retention of secretions in one), and late complications occurred in two patients (granuloma formation in one and hemoptysis in one). Conclusions Stent placement with the new silicone stent designed to fit on the primary right carina is feasible, effective, and acceptably safe. Trial registry UMIN-Clinical Trials Registry; No.: UMIN000001776; URL: www.umin.ac.jp/ctr
Objective The role of combined endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) with a single ...bronchoscope is poorly understood. The purpose of the present study was to elucidate the roles of EBUS-TBNA and EUS-FNA with a single bronchoscope in the preoperative hilar and mediastinal staging of non–small cell lung cancer (NSCLC). Methods A total of 150 patients with potentially resectable known or suspected NSCLC were enrolled in our prospective study. EBUS-TBNA was performed, followed by EUS-FNA, with an EBUS bronchoscope for N2 and N3 nodes ≥5 mm in the shortest diameter on ultrasound images, in a single session. Results EBUS-TBNA was performed for 257 lymph nodes and EUS-FNA for 176 lymph nodes. Of the 150 patients, 146 had a final diagnosis of NSCLC. Of these 146 patients, 33 (23%) had N2 and/or N3 nodal metastases. The sensitivity of EBUS-TBNA, EUS-FNA, and the combined approach per patient was 52%, 45%, and 73%, respectively (EBUS-TBNA vs the combined approach, P = .016, McNemar's test). The corresponding negative predictive value was 88%, 86%, and 93%. Two patients (1%) developed severe cough from EBUS-TBNA. Conclusions The combined endoscopic approach with EBUS-TBNA and EUS-FNA is a safe and accurate method for preoperative hilar and mediastinal staging of NSCLC, with better results than with each technique by itself.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective Endobronchial ultrasound–guided transbronchial needle aspiration (EBUS-TBNA) has been reported to be an accurate and safe method to confirm a pathologic diagnosis of sarcoidosis. However, ...only a few retrospective or small prospective studies have been published on EBUS-TBNA versus transbronchial lung biopsy (TBLB), which has been the standard method for making a pathologic diagnosis of sarcoidosis so far. The aim of this study was to compare the diagnostic yield of EBUS-TBNA and TBLB through a flexible bronchoscope in patients with stage I and II sarcoidosis. Methods A total of 62 patients with suspected stage I and II sarcoidosis were included in this prospective study. EBUS-TBNA was performed (2 lymph nodes, 2 needle passes for each lymph node), followed by TBLB (5 biopsy specimens from multiple lung segments) in the same setting. The final diagnosis of sarcoidosis was based on clinicoradiologic compatibility and pathologic findings. Results Of the 62 patients enrolled, 54 were given a final diagnosis of sarcoidosis. The diagnostic yield of EBUS-TBNA and TBLB for sarcoidois by showing noncaseating epithelioid cell granuloma was 94% (stage I, 97%; stage II, 88%) and 37% (stage I, 31%; stage II, 50%), respectively. The difference was statistically significant ( P < .001). One case of pneumothorax and 3 cases of moderate bleeding (7%) resulted from TBLB, and 1 case of severe cough (2%) from EBUS-TBNA. Conclusions The diagnostic yield of EBUS-TBNA for stage I and II sarcoidosis is higher than for TBLB.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Identification of patients with drug-resistant pathogens at initial diagnosis is essential for treatment of pneumonia.
To elucidate clinical features of community-acquired pneumonia (CAP) and ...healthcare-associated pneumonia (HCAP), and to clarify risk factors for drug-resistant pathogens in patients with CAP and HCAP.
A prospective observational study was conducted in hospitalized patients with pneumonia at 10 institutions in Japan. Pathogens identified as not susceptible to ceftriaxone, ampicillin-sulbactam, macrolides, and respiratory fluoroquinolones were defined as CAP drug-resistant pathogens (CAP-DRPs).
In total, 1,413 patients (887 CAP and 526 HCAP) were analyzed. CAP-DRPs were more frequently found in patients with HCAP (26.6%) than in patients with CAP (8.6%). Independent risk factors for CAP-DRPs were almost identical in patients with CAP and HCAP. These included prior hospitalization (adjusted odds ratio AOR, 2.06; 95% confidence interval CI, 1.23-3.43), immunosuppression (AOR, 2.31; 95% CI, 1.05-5.11), previous antibiotic use (AOR, 2.45; 95% CI, 1.51-3.98), use of gastric acid-suppressive agents (AOR, 2.22; 95% CI, 1.39-3.57), tube feeding (AOR, 2.43; 95% CI, 1.18-5.00), and nonambulatory status (AOR, 2.45; 95% CI, 1.40-4.30) in the combined patients with CAP and HCAP. The area under the receiver operating characteristic curve for counting the number of risk factors was 0.79 (95% CI, 0.74-0.84).
The clinical profile of HCAP was different from that of CAP. However, physicians can predict drug resistance in patients with either CAP or HCAP by taking account of the cumulative number of the risk factors. Clinical trial registered with https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000004001&language=E ; number UMIN000003306.
This phase I study aimed to determine tolerability and preliminary efficacy of single‐agent alpelisib (BYL719) in Japanese patients with advanced solid malignancies. The primary objective of the ...study was to estimate the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of oral alpelisib in patients with advanced solid tumors who had progressed despite standard therapy. The expansion part included patients with PIK3CA mutation/amplification; safety, preliminary efficacy, pharmacokinetic (PK)/pharmacodynamic profile, and food effect on the PK profile of alpelisib at the MTD/RP2D were determined. Oral alpelisib was given as a single agent on a continuous 28‐day treatment cycle once daily. Overall, 33 patients received alpelisib. Dose‐limiting toxicities were observed in 2 patients in the escalation part (at 400 mg/day) and 1 patient in the expansion part (at 350 mg/day). The RP2D of alpelisib was determined as 350 mg/day based on overall safety profile in the dose escalation part and previous data from a Western population; the MTD was not determined. The most common all‐grade treatment‐suspected adverse events were hyperglycemia and maculopapular rash (48.5% each) and diarrhea (45.5%). The PK of alpelisib in the Japanese population was similar to that reported in the Western population. The overall response rate, disease control rate, and median progression‐free survival at 350 mg/day were 3%, 57.6%, and 3.4 months, respectively. Alpelisib as single agent showed a favorable safety profile and encouraging preliminary efficacy in Japanese patients with advanced solid tumors.
This phase I study showed that alpelisib, an α‐specific PI3K inhibitor, as a single agent showed a favorable safety profile and encouraging preliminary efficacy in Japanese patients with advanced solid tumors.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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