Nintedanib plus chemotherapy for nonsmall cell lung cancer with idiopathic pulmonary fibrosis: a randomised phase 3 trial.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease implicated as an independent risk factor for lung cancer. However, optimal treatment for advanced lung cancer with IPF remains to be established. We performed a randomised phase 3 trial (J-SONIC) to assess the efficacy and safety of nintedanib plus chemotherapy (experimental arm) compared with chemotherapy alone (standard-of-care arm) for advanced nonsmall cell lung cancer (NSCLC) with IPF. METHODS: Chemotherapy-naïve advanced NSCLC patients with IPF were allocated to receive carboplatin (area under the curve of 6 on day 1) plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) (100 mg·m-2 on days 1, 8 and 15) every 3 weeks with or without nintedanib (150 mg twice daily, daily). The primary end-point was exacerbation-free survival (EFS). RESULTS: Between May 2017 and February 2020, 243 patients were enrolled. Median EFS was 14.6 months in the nintedanib plus chemotherapy group and 11.8 months in the chemotherapy group (hazard ratio (HR) 0.89, 90% CI 0.67-1.17; p=0.24), whereas median progression-free survival was 6.2 and 5.5 months, respectively (HR 0.68, 95% CI 0.50-0.92). Overall survival was improved by nintedanib in patients with nonsquamous histology (HR 0.61, 95% CI 0.40-0.93) and in those at GAP (gender-age-physiology) stage I (HR 0.61, 95% CI 0.38-0.98). Seven (2.9%) out of 240 patients experienced acute exacerbation during study treatment. CONCLUSIONS: The primary end-point of the study was not met. However, carboplatin plus nab-paclitaxel was found to be effective and tolerable in advanced NSCLC patients with IPF. Moreover, nintedanib in combination with such chemotherapy improved overall survival in patients with nonsquamous histology.

A phase II study of first-line afatinib for patients aged ≥75 years with EGFR mutation-positive advanced non-small cell lung cancer: North East Japan Study Group trial NEJ027.

BACKGROUND: Lung cancer is most common among older individuals. However, polypharmacy and comorbidities, which are also more common in older individuals, can limit treatment options. Previous studies suggest that afatinib can be used safely and effectively in elderly patients. This study investigated the anti-tumour activity and safety profile of first-line afatinib in previously-untreated elderly Japanese patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). METHODS: This was a single-arm, open-label, phase II study, performed in multiple centres in Japan. Previously untreated patients, aged ≥75 years, with EGFR mutation-positive (Del19 or L858R) advanced NSCLC were treated with afatinib 40 mg until disease progression or unacceptable toxicity. Adverse events (AEs) were managed with protocol-defined dose adjustments. The primary endpoint was objective response rate (ORR) by central review. RESULTS: In total, 38 patients received at least one dose of afatinib, and 37 were evaluable for response. Median age was 77.5 years (range 75-91), all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 60.5% had Del19-positive disease. Median follow-up was 838 days. ORR was 75.7% (2 complete responses and 26 partial responses). Median progression-free survival was 14.2 months (95% confidence interval [CI], 9.5-19.0). Median overall survival (OS) was 35.2 months (95% CI, 35.2-not reached); the 2-year OS rate was 78.3%. The most common grade 3/4 treatment-related AEs (TRAEs) were diarrhoea (28.9%), paronychia (23.7%), and rash/acne (15.8%). Dose reductions due to TRAEs were reported in 78.9% of patients, and eight (21.1%) patients discontinued afatinib due to TRAEs. No treatment-related deaths were reported. CONCLUSION: Although dose adjustments were relatively common in this small group of Japanese patients aged ≥75 years with EGFR mutation-positive NSCLC, discontinuation occurred much less frequently, and most patients were able to stay on treatment for well over a year. Further, afatinib was associated with high response rates and prolonged PFS and OS. TRIAL REGISTRATION: The trial is registered with Japan Registry of Clinical Trials (JRCT) as trial number 031180136 (date of initial registration: 19 February 2019), and the University Hospital Network (UMIN) as trial number 000017877 (date of initial registration: 11 June 2015).

Interstitial lung disease associated with nanoparticle albumin-bound paclitaxel treatment in patients with lung cancer.

BACKGROUND: Nanoparticle albumin-bound paclitaxel is indicated for the treatment of patients with lung cancer. It can induce interstitial lung disease, but the incidence of nanoparticle albumin-bound paclitaxel-associated interstitial lung disease in clinical practice has not been determined. We investigated the incidence of interstitial lung disease in patients with lung cancer who had received nanoparticle albumin-bound paclitaxel therapy at our institution. METHODS: We reviewed clinical data for patients with advanced lung cancer who received nanoparticle albumin-bound paclitaxel with or without carboplatin or bevacizumab therapy at the Nippon Medical School Main Hospital between April 2013 and September 2017. Interstitial lung disease was diagnosed based on clinical symptoms, radiographic findings and exclusion of other diseases. RESULTS: A total of 110 advanced lung cancer patients received nanoparticle albumin-bound paclitaxel, and nine of them (8.2%) developed interstitial lung disease. Of those who developed interstitial lung disease, eight were treated with corticosteroids and three received cyclophosphamide pulse therapy. High-resolution computed tomography images demonstrated diffuse alveolar damage pattern pneumonitis in seven patients and organized pneumonia pattern pneumonitis in two patients. Six of the patients with diffuse alveolar damage pattern pneumonitis died from respiratory failure. The two patients with organized pneumonia pattern pneumonitis recovered. The incidence of interstitial lung disease was 19.0% (8/42) among patients with preexisting interstitial pneumonia and 1.5% (1/68) among those without preexisting interstitial pneumonia. Six patients with preexisting interstitial pneumonia met the criteria for acute exacerbation of interstitial pneumonia (14.3%). CONCLUSION: Nanoparticle albumin-bound paclitaxel-associated interstitial lung disease was a severe and potentially fatal adverse event. We found it demonstrated diffuse alveolar damage or organized pneumonia pattern pneumonitis, and preexisting interstitial pneumonia was associated with higher rate of nanoparticle albumin-bound paclitaxel-associated interstitial lung disease.

Weekly paclitaxel in combination with carboplatin for advanced non-small-cell lung cancer complicated by idiopathic interstitial pneumonias: a single-arm phase II study.

BACKGROUND: Idiopathic interstitial pneumonias (IIPs) are associated with increased risk of lung cancer. In Japan, acute exaberation of IIPs induced by anticancer treatment is a critical issue. For this reason, there is limited available evidence regarding the optimal treatment approach for lung cancer patients complicated with IIPs. Our previous prospective pilot study demonstrated the safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced non-small-cell lung cancer (NSCLC) with IIPs. The current study was conducted to confirm the results of the same combination therapy used in a larger patient population. METHODS: Chemotherapy-naïve patients with advanced stage or post-operative recurrent NSCLC patients complicated by IIPs were enrolled. Patients received paclitaxel (100 mg/m2) on days 1, 8, and 15, and carboplatin (AUC 5.0) once every 4 weeks. RESULTS: Thirty-three of 35 enrolled patients were evaluable for analysis and received a median of four treatment cycles (range 1-6). Four patients (12.1%; 95% confidence interval 3.4-28.2%) had acute exacerbation (AEx)-related IIPs to the study treatment. However, no fatalities due to AEx were observed. The overall response was 69.7%. The median progression-free survival, median survival time, and 1-year survival were 6.3 months, 19.8 months, and 55.4%, respectively. CONCLUSIONS: The efficacy of carboplatin plus weekly paclitaxel treatment for advanced NSCLC patients with IIPs was comparable to that of conventional chemotherapy in advanced NSCLC patients without IIPs. Moreover, the primary endpoint was set to the frequency of treatment-related acute exacerbation, and the primary endpoint was met. These results suggest that patients with advanced NSCLC complicated by IIPs may benefit from this combination chemotherapy.

The Japanese Lung Cancer Society Guideline for non-small cell lung cancer, stage IV.

According to rapid development of chemotherapy in advanced non-small cell lung cancer (NSCLC), the Japan Lung Cancer Society has been updated its own guideline annually since 2010. In this latest version, all of the procedure was carried out in accordance with grading of recommendations assessment, development and evaluation (GRADE) system. It includes comprehensive literature search, systematic review, and determination of the recommendation by multidisciplinary expert panel which consisted of medical doctors, pharmacists, nurses, statisticians, and patients from patient advocacy group. Recently, we have had various types of chemotherapeutic drugs like kinase inhibitors or immune-checkpoint inhibitors. Thus, the guideline proposes to categorize patients into three entities: (1) driver oncogene-positive, (2) PD-L1 ≥ 50%, and (3) others. Based on this subgroup, 31 clinical questions were described. We believe that this attempt enables clinicians to choose appropriate treatment easier. Here, we report an English version of the Japan Lung Cancer Society Guidelines 2018 for NSCLC, stages IV.

Interstitial lung disease associated with amrubicin chemotherapy in patients with lung cancer: a single institutional study.

OBJECTIVE: Amrubicin, which is used as a chemotherapeutic agent for lung cancer, can induce interstitial lung disease. There is insufficient evidence on the incidence of amrubicin-associated interstitial lung disease under practical use settings. We therefore investigated the occurrence of interstitial lung disease in the patients with lung cancer who received amrubicin in our institution. METHODS: We reviewed the data of all patients with lung cancer who received amrubicin at the Nippon Medical School Hospital from March 2002 to April 2015. Interstitial lung disease was diagnosed based on clinical symptoms, radiographic findings and the exclusion of other diseases. RESULTS: We reviewed 92 consecutive patients with lung cancer. Amrubicin-associated interstitial lung disease occurred in 3 of the 92 patients (3.3%): 2 were definite interstitial lung disease and 1 was possible interstitial lung disease. The severity of interstitial lung disease was mild to moderate, and interstitial lung disease improved with or without corticosteroid therapy in all cases. The findings in a computed tomography image analysis showed preexisting pulmonary fibrosis (n = 13), including interstitial pneumonitis (n = 10) and radiation fibrosis (n = 3). No patients showed the presence of honeycomb lung. Among the 13 patients, 1 (7.7%) developed interstitial lung disease after amrubicin chemotherapy. CONCLUSION: Interstitial lung disease occurred in 3.3% of the patients in our study; this appeared to be less frequent than the rates in previous reports. Preexisting pulmonary fibrosis may be a risk factor for interstitial lung disease; however, no fatal cases were found among the patients with asymptomatic pulmonary fibrosis without honeycomb lung. It is thus considered to be necessary to carefully assess the possibility of preexisting pulmonary fibrosis and clarify the presence or absence of honeycomb lung before starting amrubicin chemotherapy.

MET FISH-positive status predicts short progression-free survival and overall survival after gefitinib treatment in lung adenocarcinoma with EGFR mutation.

BACKGROUND: Lung adenocarcinoma patients with EGFR gene mutations have shown a dramatic response to gefitinib. However, drug resistance eventually emerges which limits the mean duration of response. With that in view, we examined the correlations between MET gene status as assessed by fluorescence in situ hybridization (FISH) with overall survival (OS) and progression-free survival (PFS) in adenocarcinoma patients with EGFR gene mutations who had received gefitinib therapy. METHODS: We evaluated 35 lung cancer samples with EGFR mutation from adenocarcinoma patients who had received gefitinib. Gene copy numbers (GCNs) and amplification of MET gene before gefitinib therapy was examined by FISH. MET protein expression was also evaluated by immunohistochemistry (IHC). RESULTS: FISH assessment showed that of the 35 adenocarcinoma samples, 10 patients (29%) exhibited high polysomy (5 copies≦mean MET per cell) and 1 patient (3%) exhibited amplification (2≦MET gene (red)/CEP7q (green) per cell). IHC evaluation of MET protein expression could not confirm MET high polysomy status. The Eleven patients with MET FISH positivity had significantly shorter progression-free survival (PFS) and overall survival (OS) than the 24 patients who were MET FISH-negative (PFS: p = 0.001 and OS: p = 0.03). Median PFS and OS with MET FISH-positivity were 7.6 months and 16.8 months, respectively, whereas PFS and OS with MET FISH-negativity were 15.9 months and 33.0 months, respectively. Univariate analysis revealed that MET FISH-positivity was the most significant independent factor associated with a high risk of progression and death (hazard ratio, 3.83 (p = 0.0008) and 2.25 (p = 0.03), respectively). CONCLUSIONS: Using FISH analysis to detect high polysomy and amplification of MET gene may be useful in predicting shortened PFS and OS after Gefitinib treatment in lung adenocarcinoma. The correlation between MET gene status and clinical outcomes for EGFR-TKI should be further evaluated using large scale samples.

Randomized phase II trial comparing carboplatin plus weekly paclitaxel and docetaxel alone in elderly patients with advanced non-small cell lung cancer: north japan lung cancer group trial 0801.

BACKGROUND: Standard first-line chemotherapy for elderly non-small cell lung cancer (NSCLC) patients has been monotherapy with vinorelbine or gemcitabine. Docetaxel has also been considered as an alternative option for the elderly population in Japan. We have previously demonstrated the high efficacy of carboplatin plus weekly paclitaxel for elderly NSCLC patients. Consequently, we conducted a randomized phase II study to select the proper regimen for a future phase III trial. METHODS: Eligible patients were aged 70 years or older with newly diagnosed advanced NSCLC. Patients were randomly assigned either to a combination of carboplatin (area under the curve: 6 mg/mL per minute) with weekly paclitaxel (70 mg/m²) (CP regimen) or to single-agent docetaxel (60 mg/m²). The primary endpoint of this study was objective response rate. Secondary endpoints were progression-free survival, overall survival, and toxicity profile. RESULTS: Among 83 eligible patients (41 to CP, 42 to docetaxel), the objective response rates were 54% (95% confidence interval: 39%-69%) and 24% (95% confidence interval: 11%-37%) and median progression-free survival was 6.6 months and 3.5 months in the CP arm and the docetaxel arm, respectively. Severe neutropenia, febrile neutropenia, and nausea were significantly frequent in the docetaxel arm, whereas toxicities in the CP arm were generally moderate. One treatment-related death was observed in the docetaxel arm. CONCLUSION: The CP regimen achieved higher activity with less toxicity than single-agent docetaxel. Considering the results of this phase II trial and the IFCT-0501 trial, we have selected the CP regimen for a future phase III trial in elderly patients with advanced NSCLC.

Acute exacerbation predicting poor outcomes in idiopathic interstitial pneumonia and advanced lung cancer patients undergoing cytotoxic chemotherapy.

Effective treatment for advanced lung cancer and idiopathic interstitial pneumonia (IIP) remains an unmet medical need. The relationship between chemotherapy's effectiveness in advanced lung cancer and the risk of acute exacerbation of IIP is poorly investigated. There is limited evidence that patients who experience an acute exacerbation of IIPs during cytotoxic chemotherapy have poorer outcomes than those who do not. Among 1004 patients with advanced lung cancer and IIPs enrolled in our published multi-centre retrospective study from 110 Japanese institutions, 708 patients (male: female, 645:63; mean age, 70.4) received first-line chemotherapy. The occurrence of chemotherapy-triggered acute exacerbations of IIPs and overall survival (OS) were analysed. The OS between groups of patients with and without the occurrence of acute exacerbation was compared at four landmark time points (30, 60, 90, and 120 days), starting from the first-line chemotherapy, using the landmark method. The incidence of acute exacerbation in patients who received first-line chemotherapy with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) was more frequent in NSCLC patients than in SCLC (4.2% vs 12.6%; odds ratio [OR]: 3.316; 95% confidence interval [CI] 1.25-8.8). Median survival time was 9.9 months (95% CI 9.2-10.7). Patients who experienced acute exacerbation had significant worse survival outcomes than those who did not at various time points (30 days, hazard ratio [HR]: 5.191, 95% CI 2.889-9.328; 60 days, HR: 2.351, 95% CI 1.104-5.009; 90 days, HR: 2.416, 95% CI 1.232-4.739; and 120 days, HR: 2.521, 95% CI 1.357-4.681). Acute exacerbation during first-line chemotherapy can predict poor survival.Trial Registration number: UMIN000018227.

Clinicopathological Characteristics of Everolimus-Associated Interstitial Lung Disease: A Single-Center Consecutive Analysis.

BACKGROUND: Everolimus, a mammalian target of rapamycin inhibitor used as an antineoplastic drug, is associated with a remarkably high incidence of interstitial lung disease (ILD). The clinical and pathological characteristics of ILD caused by everolimus have not been thoroughly investigated; therefore, we aimed to elucidate the features of everolimus-associated ILD. METHODS: We retrospectively reviewed the medical records of patients who received everolimus for cancer treatment at our hospital. Patient backgrounds were compared between the ILD and non-ILD groups. Chest computed tomography (CT), changes in biomarkers, and lung histopathological features were analyzed for ILD cases. RESULTS: Sixty-six patients were reviewed, and ILD developed in 19. There were no differences in patient demographics between the ILD and non-ILD groups. The severity of ILD was grade 1 (G1) in 9 and grade 2 (G2) in 10 cases. Chest CT showed organizing pneumonia (OP) or a hypersensitive pneumonia pattern. The levels of lactate dehydrogenase, C-reactive protein, Krebs von den lungen-6, and surfactant protein-D (SP-D) at the onset of ILD were significantly higher than those at baseline. Analysis of G1 and G2 ILD subgroups showed a higher SP-D levels in the G2 subgroup. Five patients underwent lung biopsies; all specimens demonstrated alveolitis with lymphocytic infiltration and granulomatous lesions, and some had OP findings. CONCLUSIONS: Everolimus-associated ILD is mild and has a favorable prognosis. Patients with symptomatic ILD were more likely to have higher SP-D levels than those with asymptomatic ILD. Granulomatous lesions are an important pathological feature of everolimus-associated ILD.

Immunotherapy With Radiotherapy for Brain Metastases in Patients With NSCLC: NEJ060.

Introduction: Immune checkpoint inhibitor (ICI)-based treatment has become standard treatment for patients with advanced NSCLC. We aimed to determine the survival benefit of upfront radiotherapy for brain metastases (BMs) in patients with NSCLC who received ICI alone (ICI-alone) or with chemotherapy (ICI-chemo). Methods: This study included consecutive patients with NSCLC having BMs who received ICI alone or ICI-chemo at 50 institutes between February 2017 and September 2021. The presence of BMs was confirmed by imaging before treatment. Treatment outcomes were compared between patients who did and did not receive upfront radiotherapy for BMs. Potential confounding factors were adjusted between the groups through inverse probability treatment weighting (IPTW) analysis and overlap weighting (OW) analysis with propensity scores. Results: Patients were grouped as ICI-alone cohort, 224 patients (upfront-radiotherapy group, 135 patients; no-radiotherapy group, 89 patients) and ICI-chemo cohort, 367 patients (upfront-radiotherapy group, 212 patients; no-radiotherapy group, 155 patients). In the ICI-alone cohort, the overall survival of the upfront-radiotherapy group was significantly longer than that of the no-radiotherapy group (IPTW-adjusted hazards ratio [HR] = 0.45 [95% confidence interval [CI]: 0.29-0.72], OW-adjusted HR = 0.52 [95% CI: 0.35-0.77]). In contrast, in the ICI-chemo cohort, the OS of the upfront-radiotherapy group was not significantly different from that of the no-radiotherapy group (IPTW-adjusted HR = 1.02 [95% CI: 0.70-1.48], OW-adjusted HR = 0.93 [95% CI: 0.65-1.33]). Conclusions: Upfront radiotherapy for BMs was associated with longer overall survival in patients with NSCLC who received ICI alone; however, it did not exhibit survival benefits in the patients who received ICI-chemo.

Osimertinib plus local treatment for brain metastases versus osimertinib alone in patients with EGFR-Mutant Non-Small Cell Lung Cancer.

OBJECTIVES: Osimertinib is a standard treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and is highly effective for brain metastases (BMs). However, it is unclear whether local treatment (LT) for BMs prior to osimertinib administration improves survival in EGFR-mutant NSCLC. We aimed to reveal the survival benefit of upfront local treatment (LT) for BMs in patients treated with osimertinib. MATERIALS AND METHODS: This multicenter retrospective study included consecutive patients with EGFR mutation (19del or L858R)-positive NSCLC who had BMs before osimertinib initiation between August 2018 and October 2021. We compared overall survival (OS) and central nervous system progression-free survival (CNS-PFS) between patients who received upfront LT for BMs (the upfront LT group), and patients who received osimertinib only (the osimertinib-alone group). Inverse-probability treatment weighting (IPTW) analysis was performed to adjust for potential confounding factors. RESULTS: Of the 121 patients analyzed, 57 and 64 patients had 19del and L858R, respectively. Forty-five and 76 patients were included in the upfront LT group and the osimertinib-alone groups, respectively. IPTW-adjusted Kaplan-Meier curves showed that the OS of the upfront LT group was significantly longer than that of the osimertinib-alone group (median, 95 % confidence intervals [95 %CI]: Not reached [NR], NR-NR vs. 31.2, 21.7-33.2; p = 0.021). The hazard ratio (HR) for OS and CNS-PFS was 0.37 (95 %CI, 0.16-0.87) and 0.36 (95 %CI, 0.15-0.87), respectively. CONCLUSIONS: The OS and CNS-PFS of patients who received upfront LT for BMs followed by osimertinib were significantly longer than those of patients who received osimertinib alone. Upfront LT for BMs may be beneficial in patients with EGFR-mutant NSCLC treated with osimertinib.

Activity of EGFR-tyrosine kinase and ALK inhibitors for EML4-ALK-rearranged non-small-cell lung cancer harbored coexisting EGFR mutation.

BACKGROUND: The EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) fusion oncogene represents a novel molecular target in a small subset of non-small-cell lung cancers (NSCLCs). The EML4-ALK fusion gene occurs generally in NSCLC without mutations in epidermal growth factor receptor (EGFR) and KRAS. CASE PRESENTATION: We report that a case of EML4-ALK-positive NSCLC with EGFR mutation had a response of stable disease to both an EGFR tyrosine kinase inhibitor (EGFR-TKI) and ALK inhibitor. CONCLUSIONS: We described the first clinical report of a patient with EML4-ALK-positive NSCLC with EGFR mutation that had a response of stable disease to both single-agent EGFR-TKI and ALK inhibitor. EML4-ALK translocation may be associated with resistance to EGFR-TKI, and EGFR signaling may contribute to resistance to ALK inhibitor in EML4-ALK-positive NSCLC.

A case of pneumocystis pneumonia associated with everolimus therapy for renal cell carcinoma.

A 76-year-old female with advanced renal cell carcinoma had been treated with everolimus for 3 months. She visited our hospital because of a cough and fever lasting a few days. Chest X-rays showed bilateral infiltrative shadows, and a chest computed tomography scan showed homogeneous ground-glass opacities with mosaic patterns, especially in the apical region. The laboratory results revealed a decreased white blood cell count with lymphocytopenia and high levels of lactate dehydrogenase, C-reactive protein and KL-6. Pneumonitis was suspected and, therefore, everolimus therapy was interrupted. At that time, the pneumonitis was thought to be drug-induced interstitial lung disease. However, it was not possible to rule out pneumocystis pneumonia, because the patient was immunocompromised and the computed tomography findings suggested the possibility of pneumocystis pneumonia. The pneumonitis progressed rapidly and the patient developed respiratory failure, so we performed bronchoalveolar lavage to make a definitive diagnosis, and simultaneously started treatment with prednisolone and trimethoprim-sulfamethoxazole to cover both interstitial lung disease and pneumocystis pneumonia. A polymerase chain reaction assay of the bronchoalveolar lavage fluid was positive for Pneumocystis carinii DNA, and the serum level of ß-d-glucan was significantly elevated. Thus, the patient was diagnosed with pneumocystis pneumonia, which was cured by the treatment. Interstitial lung disease is a major adverse drug reaction associated with everolimus, and interstitial lung disease is the first condition suspected when a patient presents with pneumonitis during everolimus therapy. Pneumocystis pneumonia associated with everolimus therapy is rare, but our experience suggests that pneumocystis pneumonia should be considered as a differential diagnosis when pneumonitis is encountered in patients receiving everolimus therapy.

Influence of background cardiovascular risk factors on VEGF inhibitor-related adverse vascular events in patients with non-small cell lung cancer: a retrospective study.

PURPOSE: Vascular endothelial growth factor (VEGF) inhibitors are widely used in chemotherapy for non-small lung cancer (NSCLC). The purpose of the current study was to examine the impact of background cardiovascular risk factors on VEGF inhibitor-related adverse vascular events (VEGF-related AVEs) in patients with NSCLC who also had comorbidities. METHODS: We conducted a retrospective study of 118 NSCLC patients treated with bevacizumab or ramucirumab from April 2010 to December 2022. We compared baseline cardiovascular risk factors with VEGF-related AVEs. RESULTS: VEGF-related AVEs and discontinuation due to VEGF-related AVEs were reported in 54 patients and 21 patients, respectively. VEGF-related AVEs were significantly more common with male sex, smoking history, history of hypertension, dyslipidemia, diabetes mellitus, or cardiovascular disease. Discontinuation due to VEGF-related AVEs was significantly more common in patients with history of hypertension or chronic kidney disease. VEGF-related AVEs were significantly more common in patients with ≥ 3 cardiovascular risk factors than patients with < 3. Discontinuation due to VEGF-related AVEs was significantly more common in patients with ≥ 4 cardiovascular risk factors than patients with < 4. Multivariate analysis demonstrated that male sex, hypertension, and ≥ 6 cycles of VEGF inhibitors were each associated with VEGF-related AVEs and hypertension was associated with discontinuation due to VEGF-related AVEs. CONCLUSION: Our study demonstrated that history of hypertension was independently associated with increased risk of both VEGF-related AVEs and discontinuation due to VEGF-related AVEs. In conclusion, we need to be aware of VEGF-related AVEs when using VEGF inhibitors for patients with ≥ 3 cardiovascular risk factors.

Chemotherapy versus best supportive care in advanced lung cancer and idiopathic interstitial pneumonias: A retrospective multi-centre cohort study.

BACKGROUND: The clinical questions of whether chemotherapy as initial treatment, compared with best supportive care (BSC), improves overall survival (OS) and whether it increases the occurrence risk of acute exacerbation of idiopathic interstitial pneumonia (IIP) in patients with advanced-stage lung cancer and IIP remain inconclusive. This study addresses these issues, given that chemotherapy-related acute exacerbation of IIP may be a direct cause of mortality in these patients. METHODS: We enrolled 1003 patients from 110 Japanese institutions and collected clinical profiles from 707 and 296 patients in the chemotherapy (men: women, 645:62; mean age, 70.4 ± 6.9 years) and BSC (men: women, 261:35; mean age, 75.2 ± 7.8) groups, respectively. We used propensity score matching to create 222 matched pairs from both groups using patient demographic data (age, sex, smoking status, performance status, history of acute exacerbation of IIP, desaturation on exertion, clinical diagnosis of IIP, high-resolution computed tomography findings, serum fibrotic markers, pulmonary function status, and lung cancer histopathology). Logistic or Cox regression analyses were performed using matched data to assess the effects of chemotherapy on the risk of acute exacerbation of IIP or OS, respectively. RESULTS: In the well-matched cohort, chemotherapy improved OS (hazard ratio: 0.629, 95% confidence interval [CI]: 0.506-0.783, p < 0.0001); however, it involved significant acute exacerbation of IIP (odds ratio: 1.787, 95% CI: 1.026-3.113) compared to BSC. CONCLUSIONS: Compared with BSC, chemotherapy can improve OS in patients with advanced-stage lung cancer and IIP; however, it increases the risk of acute exacerbation of IIP.

Standard versus low-dose nab-paclitaxel in previously treated patients with advanced non-small cell lung cancer: A randomized phase II trial (JMTO LC14-01).

BACKGROUND: Nab-paclitaxel (nab-PTX) has better transfer to tumor tissue than cremophor-based paclitaxel. It suggests that the optimum dose of nab-PTX might be lower than the dose and schedule that is widely used. We designed a randomized phase II trial to examine the clinical utility and safety of nab-PTX in patients with previously treated advanced non-small cell lung cancer (NSCLC). METHODS: Patients were randomly allocated (1:1) to receive nab-PTX monotherapy at 100 mg/m2 (group A) or 70 mg/m2 (group B). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: Finally, 81 patients were randomized. Similar results were observed in both groups for PFS (3.75 vs. 3.71 months), OS (13.50 vs. 16.13 months), or ORR (20.5% vs. 23.1%). The incidences of grade 3 or worse AEs were 57.5% in group A and 41.5% in group B. The proportion of serious side effects was 10.0% in group A and 4.9% in group B. CONCLUSION: Both standard dose and low dose of nab-PTX monotherapy are active for previously treated NSCLC patients with better safety profile. Therefore, nab-PTX 70 mg/m2 dose and schedule in the trial would be a reasonable option.

Carboplatin and weekly paclitaxel in combination with bevacizumab for the treatment of advanced non-small cell lung cancer complicated by idiopathic interstitial pneumonias: A feasibility study.

BACKGROUND: Idiopathic interstitial pneumonias are an independent risk factor of lung cancer, and a chemotherapy-induced acute exacerbation is the most common lethal complication in Japanese patients. The safety and efficacy of carboplatin and weekly paclitaxel for the treatment of non-small cell lung cancer with idiopathic interstitial pneumonias has been previously reported in prospective studies. However, carboplatin + paclitaxel with bevacizumab is currently the standard therapy. We conducted a multicenter, phase II study to confirm the safety and efficacy of carboplatin + weekly paclitaxel + bevacizumab for the treatment of patients with lung cancer complicated by idiopathic interstitial pneumonias. METHODS: Chemotherapy-naïve patients with advanced-stage or patients with post-operative recurrent non-squamous non-small cell lung cancer complicated by idiopathic interstitial pneumonias were enrolled. Patients received carboplatin (area under the curve: 5.0) and bevacizumab (15 mg/kg) on day 1 and paclitaxel (100 mg/m2) on days 1, 8, and 15 of each 4-week cycle. RESULTS: Seventeen patients less than the predetermined number were enrolled and received a median of four treatment cycles (range: 1-6). One patient (5.9%; 95% confidence interval: 0.1-28.7%) had acute exacerbation of interstitial pneumonia related to the study treatment which improved after corticosteroid treatment. The overall response rate was 52.9%. The median progression-free survival, median survival time, and 1-year survival were 5.7 months, 12.9 months, and 52.9%, respectively. CONCLUSION: The addition of bevacizumab to carboplatin and weekly paclitaxel might be safe and effective for the treatment of advanced non-small cell lung cancer complicated by idiopathic interstitial pneumonias. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000008189.

Carboplatin plus nanoparticle albumin-bound paclitaxel for the treatment of thymic carcinoma.

Thymic carcinoma is a relatively rare type of malignant tumor. The present retrospective study evaluated the efficacy and safety of carboplatin plus nanoparticle albumin-bound paclitaxel for the treatment of advanced thymic carcinoma. The study included data from 12 patients with advanced thymic carcinoma treated in the Nippon Medical School Hospital (Tokyo, Japan). Response to treatment, patient survival and treatment safety were assessed. The objective response rate was 66.7% (8/12 patients). Disease control was achieved in 11 patients (91.7%). At the median follow-up time of 27.6 months (range, 6.2-75.1 months), the median progression-free survival and median first-line overall survival times were 16.7 months [95% confidence interval (CI), 13.2-37.7] and 14.3 months (95% CI, 4.7-54.6), respectively. There was no occurrence of febrile neutropenia or treatment-related death. The results of the present study showed that carboplatin plus nanoparticle albumin-bound paclitaxel was effective and safe. Therefore, it is a promising chemotherapy regimen for the treatment of advanced thymic carcinoma.

Real-world outcomes of chemotherapy for lung cancer patients undergoing hemodialysis: A multicenter retrospective cohort study (NEJ-042).

INTRODUCTION: Malignant tumors are the major cause of death in hemodialysis patients. Management of these patients remains challenging as there is no evidence that chemotherapy is beneficial, and a lack of information about actual clinical practice. METHODS: This multicenter retrospective study included hemodialysis patients who were diagnosed with lung cancer from January 2002 to June 2018. We reviewed their clinical information including patient characteristics associated with lung cancer and end-stage renal disease, regimen, efficacy and safety of chemotherapy, and outcomes. RESULTS: A total of 162 patients from 22 institutions in Japan were registered. Of 158 eligible patients, 91 received chemotherapy (80 as palliative chemotherapy and 11 as chemoradiotherapy) and 67 received best supportive care only regardless of cancer stage. In small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) patients who received cytotoxic chemotherapy, the objective response rates (ORR) and median overall survival (OS) were 68.1 %, 12.3 months and 37.0 %, 8.5 months, respectively. The ORR and median OS in patients with EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors (TKI) were 44.4 % and 38.6 months. The treatment-related adverse events (Grade 3 or higher) induced by cytotoxic chemotherapy were myelosuppression and febrile neutropenia; treatment-related death (TRD) was observed in one patient. TRD occurred in 3 of 18 patients who received EGFR-TKI. CONCLUSION: Chemotherapy should be considered for hemodialysis patients with EGFR-mutant NSCLC and SCLC. However, the survival benefits of chemotherapy for NSCLC patients with EGFR-wild type are unclear; physicians should carefully consider whether to offer chemotherapy to this patient subset.