Clinical benefit of platinum doublet combination therapy in older adults with advanced non-small cell lung cancer: A prospective multicenter study by the National Hospital Organization in Japan.

BACKGROUND: Previous trials suggest that older adults with non-small cell lung cancer (NSCLC) derive benefit from platinum doublet combination therapy, but its superiority is controversial. Although geriatric assessment variables are used to assess the individual risk of severe toxicity and clinical outcomes in older patients, the standard first-line treatment is still debated. Therefore, we aimed to identify the risk factors for clinical outcomes in older patients with NSCLC. METHODS: Patients aged ≥75 years with advanced NSCLC treated at any of 24 National Hospital Organization institutions completed a pre-first-line chemotherapy assessment, including patient characteristics, treatment variables, laboratory test values, and geriatric assessment variables. We evaluated whether these variables were the risk factors for progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 148 patients with advanced NSCLC were treated with combination therapy (n = 90) or monotherapy (n = 58). Median PFS was 5.3 months and OS was 13.6 months. We identified that hypoalbuminemia (hazard ratio [HR] 2.570, 95% confidence interval [CI]: 1.117-5.913, p = 0.0264) was a risk factor for PFS and monotherapy (HR 1.590, 95% CI: 1.070-2.361, p = 0.0217), lactate dehydrogenase (HR 3.682, 95% CI: 1.013-13.39, p = 0.0478), and high C-reactive protein (HR 2.038, 95% CI: 1.141-3.642, p = 0.0161) were risk factors for OS. The median OS was significantly longer in patients treated with combination therapy than in those who received monotherapy (16.5 months vs. 10.3 months; HR 0.684, 95% CI: 0.470-0.995, p = 0.0453). DISCUSSION: Platinum doublet combination therapy may be beneficial in older patients with NSCLC. Identification of risk factors will assist in the development of a personalized treatment strategy.

Real-world data on the efficacy and safety of immune-checkpoint inhibitors in elderly patients with non-small cell lung cancer.

PURPOSE: Immune-checkpoint inhibitors (ICIs) are effective against advanced non-small cell lung cancer (NSCLC). However, whether the efficacy and safety of ICI treatment in elderly patients are similar to those in younger patients is unclear. This study was designed to address this question. METHODS: We enrolled patients who received ICI monotherapy in Japan between December 2015 and December 2017; those ≥75 years of age comprised the elderly group. We compared the efficacy and safety of ICI monotherapy in elderly patients with those in younger patients and explored prognostic factors in elderly patients. RESULTS: We enrolled 676 patients; 137 (20.3%) were assigned to the elderly group. The median age of the elderly and younger groups was 78 (range, 75-85) and 66 (range, 34-74) years. The median progression-free survival (4.8 months vs. 3.3 months, p = 0.1589) and median overall survival (12.3 months vs. 13.0 months, p = 0.5587) were similar between the elderly and younger groups. Multivariate analysis revealed that a significantly better OS in the elderly group was associated with better responses to first- or second-line ICI treatment (p = 0.011) and more immune-related adverse events (irAEs) (p = 0.02). IrAEs that led to ICI discontinuation occurred in 34 of 137 patients (24.8%) in the elderly group, and their survival was significantly higher than that in those who did not have irAEs. CONCLUSION: ICI is also effective in elderly NSCLC patients, and treatment discontinuation due to irAEs may be a good prognostic marker.

Predicting systemic therapy toxicity in older adult patients with advanced non-small cell lung cancer: A prospective multicenter study of National Hospital Organization in Japan.

INTRODUCTION: Previous studies have developed risk stratification schemas to assess systemic therapy toxicity. However, it is controversial which geriatric assessment variables should be used to assess the individual risk of severe treatment-associated toxicity in older adult patients. MATERIALS AND METHODS: Patients aged ≥70 years with advanced non-small cell lung cancer (NSCLC) treated at 24 National Hospital Organization institutions completed a pre-first-line systemic therapy assessment, including patient characteristics, treatment variables, laboratory test values, and geriatric assessment variables. Patients were followed through one cycle of systemic therapy to assess grade 3 (severe) to grade 5 (death) adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: In total, 348 advanced NSCLC patients with a median age of 76 years (range, 70 to 95 years) joined this prospective study. Severe adverse events ≥grade 3 occurred in 136 patients (39.1%). Predictors of hematologic toxicity were treatment variables, body mass index, body weight loss, and limitation in daily living due to dementia. These predictors provided the predictive model of hematologic toxicity ≥grade 3; 0 point (22.2%), 1 point (33.8%), 2 points (59.6%), ≥3 points (73.3%). Sex, daily living independence level, and lactate dehydrogenase levels were associated with non-hematologic toxicity ≥grade 3 in multivariate analysis. A scoring system using these predictors distinguished the risk levels of non-hematologic toxicity ≥grade 3; 0 point (6.6%), 1 point (12.2%), 2 points (39.0%), 3 points (75.0%). DISCUSSION: A stratification using individual extracted risk factors may be useful to predict the vulnerability to systemic therapy in older adult NSCLC patients.

First-line osimertinib in elderly patients with epidermal growth factor receptor-mutated advanced non-small cell lung cancer: a retrospective multicenter study (HOT2002).

Osimertinib is a standard of care therapy for previously untreated epidermal growth factor receptor mutation-positive non-small cell lung cancer. However, limited data exist regarding the efficacy and safety of osimertinib as a first-line therapy for elderly patients aged 75 years or older. To assess the potential clinical benefits of osimertinib in this population, this retrospective multi-institutional observational study included 132 patients with non-small cell lung cancer (age ≥ 75 years), who received osimertinib as first-line treatment. The proportion of patients with 1-year progression-free survival was 65.8% (95% confidence interval 57.1-73.5). The median progression-free survival was 19.4 (95% confidence interval 15.9-23.9) months. The median overall survival was not reached (95% confidence interval 24.6-not reached). The frequency of pneumonitis was 17.4%, with a grade 3 or higher rate of 9.1%. More than two-thirds of treatment discontinuations due to pneumonitis occurred within 3 months of starting osimertinib, and the prognosis of patients with pneumonitis was unsatisfactory. Osimertinib is one of the effective first-line therapeutic options for patients aged 75 years or older; however, special caution should be exercised due to the potential development of pneumonitis.

Prognostic factors in patients with advanced non-small cell lung cancer after long-term Anti-PD-1 therapy (HOT1902).

OBJECTIVES: Limited information is available on the appropriate treatment duration of immune checkpoint inhibitors (ICIs). We aimed to identify candidates who would benefit from ICI discontinuation after one year of treatment for metastatic non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This retrospective multi-institutional observational study examined medical records of all consecutive patients with advanced or recurrent NSCLC, who started ICI monotherapy at 15 institutions in Japan between December 2015 and December 2017. Patients who received initial ICI therapy for >1 year without progressive disease were defined as the long-term treatment (LT) group; others were defined as the non-long-term treatment (NLT) group. Primary outcomes included the prognostic factors in the LT group, whereas secondary outcomes included efficacy of ICI rechallenge, safety, and survival outcomes in the overall population. RESULTS: In total, 676 patients were enrolled, and 114 (16.9 %) were assigned to the LT group. The median time interval from the start of initial ICI administration to data cutoff was 34.3 months (range, 24.1-47.8); thus, all surviving patients were followed-up for at least 2 years from the start of initial ICI. Median progression-free survival (PFS) was longer in the LT than in the NLT group (33.6 months vs. 2.7 months; p < 0.001). On multivariate analysis, significantly better PFS was associated with smoking (hazard ratio [HR]=0.36, p = 0.04), and complete response (CR; HR=uncomputable, p < 0.001) in the LT group. Thirty-seven patients (5.5 %) received ICI rechallenge, including 10 in the LT group. Among patients receiving rechallenge treatment, the median PFS was 2.2 months, with no difference between the LT and NLT groups. CONCLUSIONS: In the LT group, smoking and achieving CR were significantly associated with better PFS. Since rechallenge treatment was not effective, careful consideration is required for discontinuing ICI. However, these prognostic factors are helpful in considering candidates for ICI discontinuation. TRIAL REGISTRATION: UMIN ID, UMIN000041403.

A randomized phase II trial of cisplatin plus gemcitabine versus carboplatin plus gemcitabine in patients with completely resected non-small cell lung cancer: Hokkaido Lung Cancer Clinical Study Group Trial (HOT0703).

PURPOSE: This study evaluated the efficacy and safety of platinum plus gemcitabine (P/G) combinations as postoperative adjuvant chemotherapies for non-small cell lung cancer. METHODS: Patients with postoperative stage IB-IIIA non-small cell lung cancer were randomly assigned to receive either cisplatin plus gemcitabine (GP arm) or carboplatin plus gemcitabine (GC arm) every 3 weeks for four cycles. The primary endpoint was 2-year disease-free survival (DFS). Secondary endpoints were safety, feasibility, overall survival (OS), and biomarker analyses. RESULTS: A total of 102 patients were randomized (stage IB, 22%; II, 36%; IIIA, 42%; histology: 74% adenocarcinoma). Of the 51 patients in each arm, 37 (73%) completed 4 cycles. During follow-up (median 5.8 years; range 0.1-9.7 years), estimated DFS and OS rates at 2 years were 59.6% and 86.3% with GP and 68.0% and 86.3% with GC, respectively. No significant difference in DFS was noted between arms (P = 0.163), although 3-, 4-, and 5-year DFS rates were higher with GC. Hematological toxic effects were comparable and non-hematological toxic effects were infrequent. DFS was significantly higher in the excision repair cross-complementation group 1 (ERCC1)-low group than in the ERCC1-high group for the GP arm (P = 0.045). CONCLUSION: Both P/G combination regimens were feasible and well-tolerated, and thus may represent valid options for postoperative adjuvant treatment of non-small cell lung cancer. Although no significant differences in DFS were evident between regimens, the present data favor the adoption of GC for further evaluation. CLINICAL TRIAL REGISTRATION: UMIN-CTR ( https://www.umin.ac.jp/ctr/ ) identifier: UMIN000000913.

Gefitinib Plus Bevacizumab vs. Gefitinib Alone for EGFR Mutant Non-squamous Non-small Cell Lung Cancer.

BACKGROUND/AIM: A phase II trial was conducted to assess the efficacy and safety of gefitinib plus bevacizumab for EGFR mutation-positive non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomly assigned to receive either gefitinib at 250 mg/day alone or with bevacizumab at 15 mg/kg every 3 weeks. RESULTS: Ten patients were allocated to the gefitinib group (group A) and 6 to the gefitinib plus bevacizumab group (group B). Median survival time (80%CI) for progression-free survival (PFS) was 15.1 months for group A, and 5.4 months for group B. Overall survival probability at 1 year (95%CI) was 0.750 for group A, and 0.667 for group B. The response rate was 44 % for group A and 50 % for group B. Adverse events occurred at a similar frequency in both groups. CONCLUSION: PFS was shorter in group B than group A, and therefore there was no basis to proceed to a phase III trial.

Virtual bronchoscopic navigation without X-ray fluoroscopy to diagnose peripheral pulmonary lesions: a randomized trial.

BACKGROUND: Transbronchial biopsy for peripheral pulmonary lesions is generally performed under X-ray fluoroscopy. Virtual bronchoscopic navigation (VBN) is a method in which virtual images of the bronchial route to the lesion are produced based on CT images obtained before VBN, and the bronchoscope is guided using these virtual images, improving the diagnostic yield of peripheral pulmonary lesions. VBN has the possibility of eliminating the need for X-ray fluoroscopy in the bronchoscopic diagnosis of peripheral lesions. To determine whether VBN can be a substitute for X-ray fluoroscopy, a randomized multicenter trial (non-inferiority trial) was performed in VBN and X-ray fluoroscopy (XRF) -assisted groups. METHODS: The non-inferiority margin in the VBN-assisted group compared with the XRF-assisted group was set at 15%. The subjects consisted of 140 patients with peripheral pulmonary lesions with a mean diameter > 3 cm. In the VBN-assisted group, the bronchoscope was guided to the lesion using a VBN system without X-ray fluoroscopy. In the XRF-assisted group, the same bronchoscope was guided to the lesion under X-ray fluoroscopy. Subsequently, in both groups, the lesion was visualized using endobronchial ultrasonography with a guide sheath (EBUS/GS), and biopsy was performed. In this serial procedure, X-ray fluoroscopy was not used in the VBNA group. RESULTS: The subjects of analysis consisted of 129 patients. The diagnostic yield was 76.9% (50/65) in the VBN-assisted group and 85.9% (55/64) in the XRF-assisted group. The difference in the diagnostic yield between the two groups was -9.0% (95% confidence interval: -22.3% ~ 4.3%). The non-inferiority of the VBN-assisted group could not be confirmed. The rate of visualizing lesions by EBUS was 95.4% (62/65) in the VBN-assisted group and 96.9% (62/64) in the XRF-assisted group, being high in both groups. CONCLUSIONS: On EBUS/GS, a bronchoscope and biopsy instruments may be guided to the lesions using VBN without X-ray fluoroscopy, but X-ray fluoroscopy is necessary to improve the accuracy of sample collection from lesions. During transbronchial biopsy for peripheral pulmonary lesions, VBN cannot be a substitute for X-ray fluoroscopy. TRIAL REGISTRATION: UMIN-CTR (UMIN000001710); registered 16 February 2009.

Usefulness of Endobronchial Ultrasonography With a Guide Sheath and Virtual Bronchoscopic Navigation for Ground-Glass Opacity Lesions.

BACKGROUND: Endobronchial ultrasonography with guide sheath (EBUS-GS) could be useful for diagnosing ground-glass opacity (GGO) predominant-type lesions in the peripheral lung. Furthermore, several studies have reported that transbronchial biopsy using EBUS-GS and virtual bronchoscopic navigation (VBN) was safe and effective for diagnosing small peripheral lung lesions. Our objectives were to diagnose solitary peripheral GGO predominant-type lesions by transbronchial biopsy using EBUS-GS and VBN under radiographic fluoroscopic guidance, and to evaluate the clinical factors associated with diagnostic yield. METHODS: The medical records of 169 patients with GGO predominant-type lesions who underwent transbronchial biopsy using EBUS-GS and VBN under radiographic fluoroscopic guidance were retrospectively reviewed. RESULTS: Endobronchial ultrasonography images could be obtained for 156 (92%) of 169 GGO predominant-type lesions, and 116 (69%) were successfully diagnosed by this method (20 of 31 pure GGO lesions [65%]; 96 of 138 mixed GGO predominant-type lesions [70%]). The mean size of diagnosed lesions was significantly larger than that of nondiagnosed lesions (22 mm versus 18 mm, p < 0.01). Regarding diagnostic yield based on computed tomography sign, cases with presence of a bronchus leading directly to a lesion had significantly higher diagnostic yield than the other lesions (p < 0.01). CONCLUSIONS: The addition of VBN to EBUS-GS could be useful in clinical practice for diagnosing GGO predominant-type lesions in the peripheral lung.

Endobronchial ultrasonography with a guide sheath for pure or mixed ground-glass opacity lesions.

BACKGROUND: Ground-glass opacity (GGO) lesions are difficult to diagnose by transbronchial biopsy (TBB). OBJECTIVES: We attempted to diagnose solitary peripheral GGO predominant-type lesions by TBB using endobronchial ultrasonography with a guide sheath (EBUS-GS) under X-ray fluoroscopic guidance, and to evaluate several factors associated with diagnostic yield. METHODS: The medical records of 67 patients with GGO predominant-type lesions who underwent TBB using EBUS-GS under X-ray fluoroscopic guidance were retrospectively reviewed. RESULTS: Of the 67 lesions, 38 (57%) were successfully diagnosed by EBUS-GS (5/11 pure GGO lesions and 33/56 mixed GGO lesions). The diagnosable lesions were significantly larger than the nondiagnosable lesions (24 vs. 17 mm, respectively; p < 0.01). Regarding the diagnostic yield by signs on computed tomography, the lesions with a bronchus leading directly to a lesion had a significantly higher diagnostic yield than the others (p < 0.05). When GGO lesions were confirmed under X-ray fluoroscopic guidance, the diagnostic yield was 79% (vs. 40% in lesions not visible on X-ray fluoroscopy; p < 0.05). CONCLUSIONS: EBUS-GS is a useful and valuable diagnostic modality, even for GGO predominant-type lesions located at the lung periphery.

Cyclooxygenase-2 inhibitors for non-small-cell lung cancer: A phase II trial and literature review.

Several preclinical and clinical studies have demonstrated that cyclooxygenase-2 (COX-2) inhibitors are efficient for the treatment of non-small-cell lung cancer (NSCLC). However, two recent phase III clinical trials using COX-2 inhibitors in combination with platinum-based chemotherapy failed to demonstrate a survival benefit. Thus, validation and discussion regarding the usefulness of COX-2 inhibitors for patients with NSCLC are required. We conducted a prospective trial using COX-2 inhibitors for the treatment of 50 NSCLC patients accrued between April, 2005 and July, 2006. Patients with untreated advanced NSCLC received oral meloxicam (150 mg daily), carboplatin (area under the curve = 5 mg/ml × min on day 1) and docetaxel (60 mg/m2 on day 1) every 3 weeks. The primary endpoint was response rate. The response and disease control rates were 36.0 and 76.0%, respectively. The time-to-progression (TTP) and overall survival (OS) were 5.7 months [95% confidence interval (CI): 4.6-6.7] and 13.7 months (95% CI: 11.4-15.9), respectively. The 1-year survival ratio was 56.0%. Grade 3 neuropathy was observed in only 1 patient. We performed tumor immunohistochemistry for COX-2 and p27 and investigated the correlation between their expression and clinical outcome. COX-2 expression in the tumor tended to correlate with a higher response rate (50.0% in the high- and 18.2% in the low-COX-2 group; P=0.092). Based on our results and previous reports, various trial designs, such as the prospective use of COX-2 inhibitors only for patients with COX-2-positive NSCLC, including the exploratory analysis of biomarkers associated with the COX-2 pathway, may be worth further consideration.

Phase II study of gefitinib readministration in patients with advanced non-small cell lung cancer and previous response to gefitinib.

OBJECTIVE: Salvage treatment for acquired resistance to gefitinib has yet to be developed. We conducted the first prospective phase II study of gefitinib readministration in previous gefitinib responders. METHODS: Gefitinib (250 mg/day) was readministered to patients with advanced/metastatic non-small cell lung cancer who had achieved objective response to initial gefitinib and subsequently received cytotoxic chemotherapy after disease progression with initial gefitinib. The primary endpoint was the objective response rate with gefitinib readministration. Secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), quality of life, and toxicity. Changes in lung cancer-related symptoms were evaluated using the seven-item lung cancer subscale of the questionnaire. RESULTS: Sixteen patients were enrolled between February 2005 and January 2008. Most had received ≥3 regimens of chemotherapy. Response and disease-control rates for all patients were 0 and 44%. Median PFS and OS were 2.5 and 14.7 months, respectively. Four of 7 patients with stable disease experienced a long duration (≥6 months) of disease control without severe toxicity. Symptom improvement was observed in 2 of 12 patients (17%) for whom quality of life was evaluable. CONCLUSION: Gefitinib represents a useful therapeutic option for selected previous gefitinib responders.

Diagnostic value of endobronchial ultrasonography with a guide sheath for peripheral pulmonary lesions without X-ray fluoroscopy.

STUDY OBJECTIVES: We evaluated the feasibility and efficacy of transbronchial biopsy (TBB) and bronchial brushing by endobronchial ultrasonography (EBUS) with a guide sheath (GS) as a guide for diagnosing peripheral pulmonary lesions (PPLs) without radiographic fluoroscopy. PATIENTS: One hundred twenty-one patients with 123 PPLs (mean diameter, 31.0 mm) whose bronchoscopic findings were normal. METHODS: An EBUS-GS was inserted and advanced to the PPL without fluoroscopy. Once we obtained the EBUS image, the probe was withdrawn and the GS was left in place. TBB and/or bronchial brushing were performed via the GS. When an EBUS image could not be obtained, we changed to the bronchoscopic examination under fluoroscopy. RESULTS: Seventy-six of 123 PPLs (61.8%) were diagnosed by EBUS-GS guidance without fluoroscopy. The diagnostic yield for PPLs > 20 mm in diameter (75.6%) was significantly higher than that for those

Clinical benefit of readministration of gefitinib for initial gefitinib-responders with non-small cell lung cancer.

BACKGROUND: Gefitinib, an oral agent of epidermal growth factor receptor tyrosine kinase inhibitor, has a certain efficacy against non-small cell lung cancer (NSCLC). Several predictive factors of gefitinib sensitivity have been well described. However, few studies have investigated the clinical features of gefitinib-responders. In the present study, we analyzed the response and disease progression of primary and metastatic lesions to gefitinib in responders and the results of gefitinib readministration following temporary cessation of gefitinib upon progression of initial gefitinib treatment and other treatments. METHOD: We retrospectively evaluated the clinical courses of 27 NSCLC patients who received gefitinib and achieved either a complete or partial response. RESULTS: The best-response rate and disease-control rate against the initial chemotherapy for the gefitinib-responders were 27.3% and 77.3%, respectively. Favorable efficacy was observed in the primary lesion and metastases to the lung, liver and brain, while there was no obvious effect on bone metastasis. The primary lesion and intrapulmonary metastasis were the sites of major recurrence. Median progression-free survival was 13.8 months, median duration of gefitinib treatment was 17.0 months and median overall survival was 29.2 months. Some of the patients who experienced disease progression after responding to gefitinib were again sensitive to readministration of gefitinib following temporary cessation of gefitinib and other treatments. CONCLUSION: Patients may still be expected to have prolonged survival if they once responded to gefitinib and then underwent various subsequent treatments followed by readministration of gefitinib. These findings might provide valuable information for the management of gefitinib-responders.

Phase II study of carboplatin and weekly paclitaxel in advanced non-small cell lung cancer.

BACKGROUND: The optimal schedule of taxane administration has been an area of active interest in several clinical trials. PATIENTS AND METHODS: To evaluate the efficacy and toxicity of carboplatin and weekly paclitaxel combination chemotherapy, a phase II study was conducted for chemo-naïve, advanced non-small cell lung cancer (NSCLC) patients. Patients received paclitaxel 100 mg/m2 on days 1, 8 and 15, and carboplatin with the target dose of area under the curve of 6 on day 1 every 28 days. RESULTS: Forty patients were enrolled. Overall response rate and survival at one year by intent-to-treat analyses was 35% and 57.5%, respectively. The median survival time was 12.2 months. Twenty-two patients (56%) had grade 3 or greater neutropenia. Grade 3 sensory and motor neuropathy were seen in one patient (3%). CONCLUSION: Carboplatin and weekly paclitaxel combination chemotherapy is an active and feasible regimen for patients with advanced NSCLC.

Pulmonary blastoma within bronchioloalveolar cell carcinoma.

Pulmonary blastoma is a rare tumour of the lung composed of epithelial and mesenchymal elements that morphologically resemble the embryonal structure of the lung. The authors report a 79-year-old man who was diagnosed with a pulmonary blastoma within bronchioloalveolar cell carcinoma. Macroscopic, histopathological and immunohistochemical findings suggested that the pulmonary blastoma was closely associated with the bronchioloalveolar cell carcinoma.

Increased neutrophils in bronchoalveolar lavage fluids from a patient with pulmonary edema associated with pheochromocytoma.

Pulmonary edema, both cardiogenic and noncardiogenic, has been reported as a manifestation of pheochromocytoma. We report a patient with pheochromocytoma complicated by acute pulmonary edema that appeared clinically noncardiogenic. The patient had an uncomplicated course and rapid resolution of pulmonary edema. Bronchoalveolar lavage fluids (BALF) showed a marked accumulation of neutrophils, suggesting involvement of neutrophil-mediated lung injury in noncardiogenic pulmonary edema associated with a pheochromocytoma.