Nintedanib plus Chemotherapy for Small Cell Lung Cancer with Comorbid Idiopathic Pulmonary Fibrosis.

Rationale: A fatal acute exacerbation (AE) occasionally develops during chemotherapy for small cell lung cancer (SCLC) with comorbid idiopathic pulmonary fibrosis (IPF).Objectives: This study aimed to assess the safety and efficacy of carboplatin, etoposide, and nintedanib combination therapy for unresectable SCLC with comorbid IPF.Methods: The NEXT-SHIP study is a multicenter, single-arm, phase 2 trial for unresectable SCLC with IPF (Japan Registry of Clinical Trials registry number jRCTs031190119). The patients received carboplatin, etoposide, and nintedanib (150 mg twice daily). The primary endpoint was the incidence of IPF-AE at 28 days after the last administration of cytotoxic chemotherapy, and the sample size was set at 33 (5.0% expected, 20.0% threshold).Results: A total of 33 patients were registered; 87.9% were male, the median age was 73 years, the median percentage forced vital capacity was 85.2%, and 51.5% had honeycomb lungs. The median observation period was 10.5 months. The incidence of IPF-AE at 28 days after the last administration of cytotoxic chemotherapy was 3.0% (90% confidence interval [CI], 0.2-13.6). The objective response rate was 68.8% (95% CI, 50.0-83.9). The median progression-free survival and overall survival times were 4.2 months (95% CI, 4.2-5.5) and 13.4 months (95% CI, 8.1-21.6), respectively. The most common adverse event of grade 3 or higher was neutropenia (81.8%), followed by leukopenia (39.4%) and thrombocytopenia (30.3%).Conclusions: This study met its primary endpoint regarding the incidence of IPF-AEs with promising results for efficacy. Carboplatin, etoposide, and nintedanib combination therapy may be one of the standard treatment options for SCLC with comorbid IPF.Clinical trial registered with the Japan Registry of Clinical Trials (jRCTs031190119).

Multicenter, Retrospective Study to Evaluate Necitumumab Plus Cisplatin and Gemcitabine After Immune Checkpoint Inhibitors in Advanced Squamous Cell Lung Cancer in Japan: The NINJA Study.

Introduction: Necitumumab plus gemcitabine and cisplatin (GCN) is a standard therapy for patients with advanced lung squamous cell carcinoma (LSqCC). However, the efficacy and tolerability of GCN in second-line or later treatment for patients previously treated with immune checkpoint inhibitors (ICIs) remain unknown. Methods: This multicenter, retrospective, cohort study assessed the efficacy and tolerability of GCN initiated between November 1, 2019 and March 31, 2022 as second-line to fourth-line treatment in patients with advanced LSqCC who had been pretreated with ICIs. The primary end point was progression-free survival (PFS). Results: A total of 93 patients from 35 institutions in Japan were enrolled. The median PFS, median overall survival (OS), and objective response rate were 4.4 months (95% confidence interval [CI]: 3.8-5.3), 13.3 months (95% CI: 9.6-16.5), and 27.3% (95% CI: 18.3-37.8), respectively. The median PFS, median OS, and objective response rate for second-line, third-line, and fourth-line treatment groups were 4.8 months, 3.8 months, and 4.3 months (p = 0.24); 15.7 months, 11.6 months, and 10.1 months (p = 0.06); and 31.0%, 13.6%, and 37.5% (p = 0.22), respectively. The severity of GCN-related skin disorders was associated with longer PFS (p < 0.05) and OS (p < 0.05). The frequencies of grade ≥3 skin disorders, hypomagnesemia, pneumonitis, and febrile neutropenia were 16.1%, 7.5%, 1.1%, and 4.3%, respectively. There were no treatment-related deaths. Conclusions: GCN for ICI-pretreated patients with LSqCC seems tolerable and offers promising efficacy regardless of treatment line, and ICI pretreatment might enhance GCN efficacy.

Prophylactic treatment of dacomitinib-induced skin toxicities in epidermal growth factor receptor-mutated non-small-cell lung cancer: A multicenter, Phase II trial.

BACKGROUND: Dacomitinib significantly improves progression-free survival and overall survival (OS) compared with gefitinib in patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. However, dacomitinib often causes skin toxicities, resulting in treatment discontinuation. We aimed to evaluate a prophylactic strategy for skin toxicity induced by dacomitinib. METHODS: We performed a single-arm, prospective, open-label, multi-institutional phase II trial for comprehensive skin toxicity prophylaxis. Patients with NSCLC harboring EGFR-activating mutations were enrolled and received dacomitinib with comprehensive prophylaxis. The primary endpoint was the incidence of skin toxicity (Grade ≥2) in the initial 8 weeks. RESULTS: In total, 41 Japanese patients participated between May 2019 and April 2021 from 14 institutions (median age 70 years; range: 32-83 years), 20 were male, and 36 had a performance status of 0-1. Nineteen patients had exon 19 deletions and L858R mutation. More than 90% of patients were perfectly compliant with prophylactic minocycline administration. Skin toxicities (Grade ≥2) occurred in 43.9% of patients (90% confidence interval [CI], 31.2%-56.7%). The most frequent skin toxicity was acneiform rash in 11 patients (26.8%), followed by paronychia in five patients (12.2%). Due to skin toxicities, eight patients (19.5%) received reduced doses of dacomitinib. The median progression-free survival was 6.8 months (95% CI, 4.0-8.6 months) and median OS was 21.6 months (95% CI, 17.0 months-not reached). CONCLUSION: Although the prophylactic strategy was ineffective, the adherence to prophylactic medication was quite good. Patient education regarding prophylaxis is important and can lead to improved treatment continuity.

Staphylococcus haemolyticus attenuates the antibacterial effect of teicoplanin via aggregates and biofilms.

OBJECTIVES: This study aimed to determine the inhibitory and bactericidal effects of teicoplanin (TEC) on TEC-susceptible Staphylococcus haemolyticus isolated from a patient with cancer in whom infection persisted despite TEC therapy. We also focused on the biofilm-forming ability of the isolate in vitro. METHODS: S. haemolyticus clinical isolate (strain 1369A) and its control strain, ATCC 29970 were cultured in Luria-Bertani (LB) broth with TEC. The inhibitory and bactericidal effects of TEC on planktonic, adherent, biofilm-dispersed, and biofilm-embedded cells of these strains were analyzed by using a biofilm formation/viability assay kit. The expression of biofilm-related genes was measured using quantitative real-time polymerase chain reaction (qRT-PCR). Biofilm formation was determined by using scanning electron microscopy (SEM). RESULTS: The clinical isolate of S. haemolyticus had enhanced ability to bacterial growth, adherence, aggregation, and biofilm formation, thus the inhibitory and bactericidal effects of TEC on planktonic, adherent, biofilm-dispersed, and biofilm-embedded cells of the isolate were attenuated. Additionally, TEC induced cell aggregation, biofilm formation, and some biofilm-related gene expression of the isolate. CONCLUSION: The clinical isolate of S. haemolyticus is resistant to TEC treatment due to cell aggregation and biofilm formation.

Ramucirumab Plus Docetaxel for Patients with Non-small cell Lung Cancer with Brain Metastases: A Multicenter, Open-Label Single-Arm Phase II Trial.

BACKGROUND: Ramucirumab plus docetaxel combination therapy (DOC/RAM) for advanced non-small cell lung cancer (NSCLC) achieves favorable outcomes; however, efficacy and safety for patients with brain metastases are still unclear. METHODS: Eligible patients included those with advanced NSCLC with measurable asymptomatic brain metastases that progressed after chemotherapy. Patients were intravenously administered ramucirumab (10 mg/kg) and docetaxel (60 mg/m2) every 21-day cycle. RESULTS: Due to difficulties in accumulating the planned 65 participants, enrollment was terminated early when 25 patients were enrolled. Primary endpoint: Median progression-free survival (PFS) was 3.9 months (95% CI, 1.8-5.3). Secondary endpoints: Median intracranial progression-free survival was 4.6 months (95% CI, 2.5-5.9); median overall survival was 20.9 months (95% CI, 6.6-not possible to estimate); objective response rate was 20% (95% CI, 6.8-40.7); disease control rate was 68% (95% CI, 46.5-85.1). The most common grade 3 or higher toxicities were neutropenia in 10 patients (40%). Neither intracranial hemorrhage nor grade 5 adverse events were observed. Patients with higher serum soluble vascular endothelial growth factor receptor 2 concentrations at the start of treatment had slightly longer PFS. CONCLUSION: No clinical concerns were identified with DOC/RAM for NSCLC with brain metastases in this study. Further investigation with a larger sample size is needed to determine the tolerability and safety of these populations (Trial Identifiers: University Hospital Medical Information Network in Japan [UMIN000024551] and Japan Registry of Clinical Trials [jRCTs071180048]).

Predictors of central line-associated bloodstream infections in cancer patients undergoing chemotherapy through implanted venous access ports: a retrospective, observational study.

Background: Central venous catheters (CVCs) are sometimes superior to peripheral vascular access for chemotherapy. Central line-associated bloodstream infections (CLABSIs) are an important complication of CVCs in chemotherapy. Methods: A retrospective, observational study was conducted to investigate patients with implanted venous access ports (PORTs) from July 2010 to June 2021 in a teaching hospital. General conditions of the PORTs, backgrounds, and characteristics of patients were compared between CLABSI cases and uninfected cases to identify predictors of CLABSI. Results: A total of 566 patients with PORTs who underwent chemotherapy were enrolled in this study, with CLABSI identified in 41 patients, for a total of 436,597 catheter-days. The median duration of PORT use was 26 vs. 494 days (P<0.001) in the CLABSI and uninfected groups, respectively. There were no significant differences in tumor classification, staging, white blood cell (WBC) count, neutrophil proportion, lymphocyte proportion, albumin, C-reactive protein (CRP), and performance status between the CLABSI and uninfected groups. Multivariable analysis showed that antibiotic usage within the previous week, total protein (TP), and immediate PORT use were independently associated with CLABSI, and their odds ratios (ORs) were 4.89 [95% confidence interval (CI): 1.67, 14.35], 1.95 (95% CI: 1.14, 3.53), and 3.13 (95% CI: 1.18, 8.30), respectively. The area under the curve (AUC) of the receiver-operating characteristic curve for TP was 0.63, and the cutoff value was 5.9 g/dL. Conclusions: PORT implantation should be avoided in patients who had antibiotic treatment episodes within 1 week, especially for those with low serum TP levels.

A phase II study of S-1 and cisplatin with concurrent thoracic radiotherapy followed by durvalumab for unresectable, locally advanced non-small-cell lung cancer in Japan (SAMURAI study): primary analysis.

Background: The standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT) followed by durvalumab, based on the PACIFIC study. Although multiple Japanese phase II studies have shown high efficacy and tolerability of CRT with cisplatin plus S-1 (SP), no prospective study using durvalumab after SP-based CRT has been reported. Objectives: We conducted a multicenter phase II study of this approach, the interim analysis of which showed a high transition rate to durvalumab consolidation therapy. Here, we report the primary analysis results. Design: In treatment-naïve LA-NSCLC, cisplatin (60 mg/m2, day 1) and S-1 (80-120 mg/body, days 1-14) were administered with two 4-week cycles with concurrent thoracic radiotherapy (60 Gy) followed by durvalumab (10 mg/kg) every 2 weeks for up to 1 year. Methods: The primary endpoint was 1-year progression-free survival (PFS). The expected 1-year PFS and its lower limit of the 80% confidence interval (CI) were set as 63% and 47%, respectively, based on the results of TORG1018 study. Results: In all, 59 patients were enrolled, with 51 (86.4%) proceeding to durvalumab. The objective response rate throughout the study was 72.9% (95% CI: 59.7-83.6%). After median follow-up of 21.9 months, neither median PFS nor OS was reached. The 1-year PFS was 72.5% (80% CI: 64.2-79.2%, 95% CI: 59.1-82.2%), while the 1-year overall survival was 91.5% (95% CI: 80.8-96.4%). No grade 5 adverse events were observed throughout the study. The most common adverse event during the consolidation phase was pneumonitis (any grade, 78.4%; grade ⩾3, 2.0%). Eventually, 52.5% of patients completed 1-year durvalumab consolidation therapy from CRT initiation. Conclusion: This study of durvalumab after SP-based CRT met its primary endpoint and found a 1-year PFS of 73% from CRT initiation. This study provides the first prospective data on the prognosis and tolerability of durvalumab consolidation from the initiation of CRT. Trial registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127.

A Phase II Trial on Osimertinib as a First-Line Treatment for EGFR Mutation-Positive Advanced NSCLC in Elderly Patients: The SPIRAL-0 Study.

BACKGROUND: Osimertinib is one of the standard first-line treatments for advanced non-small cell lung cancer in patients with epidermal growth factor receptor (EGFR) mutations, because it achieves significantly longer progression-free survival (PFS) than conventional first-line treatments (hazard ratio: 0.46). However, the efficacy and safety of osimertinib as a first-line treatment for patients aged ≥75 years remain unclear. METHODS: This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. The primary endpoint was 1-year PFS rate; secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety. RESULTS: Thirty-eight patients were included in the analysis. The 1-year PFS rate was 59.4% (95% confidence interval [CI], 46.1%-72.7%), which did not meet the primary endpoint (the threshold 1-year PFS rate of 50% predicted using data from the NEJ003 study). The most common grade 3/4 adverse events were rash/dermatitis acneiform/ALT increased/hypokalemia (2 patients, 5%). Seven patients developed pneumonitis (17.5%). There were no other cases of treatment discontinuation due to adverse events other than pneumonitis. CONCLUSION: Although this study did not meet the primary endpoint, osimertinib was tolerable for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. (Japan Registry of Clinical Trials [JRCT] ID number: jRCTs071180007).

Prospective analysis of factors precluding the initiation of durvalumab from an interim analysis of a phase II trial of S-1 and cisplatin with concurrent thoracic radiotherapy followed by durvalumab for unresectable, locally advanced non-small cell lung cancer in Japan (SAMURAI study).

Background: The standard of care for unresectable, locally advanced non-small cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT) followed by durvalumab, based on the PACIFIC trial. Disease progression and pneumonitis were reported as the main reasons to preclude the initiation of durvalumab in multiple retrospective studies. However, the transition rate and the reasons for failure to proceed to consolidation therapy with durvalumab after CRT were not evaluated prospectively. Although phase II studies in Japan have shown high efficacy and tolerability of CRT with cisplatin + S-1 (SP), no prospective study using durvalumab after SP-based CRT has yet been reported. We therefore conducted a phase II study to verify the efficacy and safety of durvalumab following SP-based CRT. In this interim analysis, we report the transition rate and the reasons for its failure. Methods: In treatment-naïve LA-NSCLC, cisplatin (60 mg/m2, day 1) and S-1 (80-120 mg/body, days 1-14) were administered with two 4-week cycles with concurrent thoracic radiotherapy (60 Gy) followed by durvalumab every 2 weeks for up to 12 months. The primary endpoint was 12 month progression-free survival rate. Results: Fifty-nine patients were enrolled, of whom 86.4% (51/59) proceeded to durvalumab. All of them initiated durvalumab within 42 days after CRT [median 18 days (range: 3-38)], including 27.5% (14/51) in <14 days. Common reasons for failure to proceed to durvalumab were disease progression (2/59, 3.4%) and adverse events (6/59, 10.2%). Among the latter cases, four resumed treatment and proceeded to durvalumab within 42 days on off-protocol. The objective response rate and the disease control rate were 62.7% and 93.2%, respectively. The incidences of ⩾grade 3 pneumonitis, febrile neutropenia, and esophagitis were 0%, 8.5%, and 3.4%, respectively. Conclusion: Regarding durvalumab after CRT, this interim analysis of the SAMURAI study clarified the high transition rate, early introduction, and reasons for failure to proceed to consolidation therapy, which were not determined in the PACIFIC trial. Trial registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127.

Effect of Adjuvant and Palliative Chemotherapy in Large Cell Neuroendocrine Carcinoma of the Lung: A Systematic Review and Meta-Analysis.

BACKGROUND: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare subset of lung carcinoma with poor overall survival. METHODS: A systematic review following a meta-analysis of studies was performed to identify the effect of different selections of chemotherapy in LCNEC. Articles providing overall survival data for adjuvant chemotherapy or palliative chemotherapy for LCNEC were eligible. The odds ratio (OR) of mortality at one or two years after chemotherapy was evaluated. RESULTS: A total of 16 reports were finally included in the quantitative synthesis, involving a total of 5916 LCNEC patients. Adjuvant chemotherapy was administered to 1303 patients, and palliative chemotherapy was administered to 313 patients using either a small cell lung cancer (SCLC) or a non-small cell lung cancer (NSCLC) regimen. The OR for adjuvant chemotherapy was 0.73 (95% confidence interval (CI): 0.59 to 0.89, p = 0.002). The SCLC regimen showed an OR of 0.52 (95% CI: 0.11 to 2.38, p = 0.40) after one year, and 0.32 (95% CI: 0.11 to 0.89, p = 0.03) after two years, compared with the NSCLC regimen. CONCLUSIONS: Adjuvant chemotherapy for pulmonary large cell neuroendocrine carcinoma improved the outcome after surgery. The SCLC regimen showed better survival than the NSCLC regimen as palliative chemotherapy.

Effectiveness of Cell-Free and Concentrated Ascites Reinfusion Therapy in the Treatment of Malignancy-Related Ascites: A Systematic Review and Meta-Analysis.

BACKGROUND: Malignancy-related ascites (MRA) is one of the symptoms causing discomfort in advanced cancer patients. Cell-free and concentrated ascites reinfusion therapy (CART) is one of the palliative treatments widely conducted in Japan only. METHODS: A systematic review following a meta-analysis of CART was performed. The efficiency and adverse events were evaluated. RESULTS: A total of 2567 patients and 6013 procedures of CART were identified in this study. The mean volume of MRA collected was 4.29 (95% confidence interval (CI) 3.47-5.11) L, and the volume reinfused after concentrating was 0.49 (95% CI 0.39-0.60) L. A total of 86.1 (95% CI 77.1-95.2) g protein and 42.9 (95% CI 36.0-50.0) g albumin was reinfused. The mean time to the next paracentesis was 20.7 (95% CI 15.6-25.8) days. The body weight was reduced by 3.38 (95% CI 1.90-4.86; p < 0.01) kg, and abdominal circumference was reduced by 7.86 (95% CI 6.58-9.14; p < 0.001) cm. Serum albumin increased an average of 0.14 (95% CI -0.01-0.28; p = 0.07) mg/dL the day after CART. Abdominal distension, dyspnea, and fatigue were alleviated by 6.0 (95% CI 5.59-6.51), 2.66 (95% CI 2.05-3.28), and 2.64 (95% CI 1.86-3.42) points using a numerical rating scale system ranging from 0 to 10. Overall, 17% (95% CI 0.03-0.31%) of patients had improved performance status after CART. Significant body temperature elevation was observed, at an average of 0.4 °C (95% CI 0.18-0.62 °C). CONCLUSIONS: CART might be a safe and effective palliative therapy in MRA and further clinical trials are necessary.

[Strategy with Immune Checkpoint Inhibitors for ES‒SCLC].

As a treatment strategy for various carcinoma, immune checkpoint inhibitors(ICIs)can prolong overall survival with ICI monotherapy, ICIs combination therapy, or chemotherapy and ICI combination therapy. It has been validated in clinical trials and is recognized as a key drug in the treatment of cancer. In two large phase Ⅲ trials(IMpower133 and CASPIAN), the strategy of anti PD‒L1 antibody, such as atezolizumab and durvalumab, with chemotherapy was prolonged overall survival compared with the chemotherapy alone in extensive stage small cell lung cancer. Although attention should be paid to immune‒related adverse events, treatment discontinuation rates for adverse events in both trials were considered to be comparable to those in the chemotherapy alone group, indicating that treatment was tolerated. Currently, carboplatin plus etoposide plus atezolizumab combination therapy or platinum agent(carboplatin or cisplatin)plus etoposide plus durvalumab combination therapy is recommended grade 1A in the Guidelines for Diagnosis and Treatment of the Lung Cancer/ Malignant Pleural Mesothelioma/Thymic Tumors 2020 as the first‒line treatment for extensive stage small cell lung cancer in Japan. This article presents an overview of each clinical trials and clinical questions.

A phase II study of S-1 and cisplatin with concurrent thoracic radiotherapy followed by durvalumab for unresectable, locally advanced non-small-cell lung cancer in Japan (SAMURAI study).

BACKGROUND: Based on the results of the PACIFIC study, chemoradiotherapy followed by 1-year consolidation therapy with durvalumab was established as the standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC). However, some topics not foreseen in that design can be explored, including progression-free survival (PFS) and overall survival (OS) after the start of chemoradiotherapy, the proportion of patients who proceeded to consolidation therapy with durvalumab, and the optimal chemotherapeutic regimens. In Japan, the combination regimen of S-1 + cisplatin (SP), for which the results of multiple clinical studies have suggested a good balance of efficacy and tolerability, is frequently selected in clinical settings. However, the efficacy and safety of consolidation therapy with durvalumab following this SP regimen have not been evaluated. We therefore planned a multicenter, prospective, single-arm, phase II study. METHODS: In treatment-naïve LA-NSCLC, two cycles of combination chemotherapy with S-1 (80-120 mg/body, Days 1-14) + cisplatin (60 mg/m2, Day 1) will be administered at an interval of 4 weeks, with concurrent thoracic radiotherapy (60 Gy). Responders will then receive durvalumab every 2 weeks for up to 1 year. The primary endpoint is 1-year PFS rate. DISCUSSION: Compared with the conventional standard regimen in Japan, the SP regimen is expected to be associated with lower incidences of pneumonitis, esophagitis, and febrile neutropenia, which complicate the initiation of consolidation therapy with durvalumab, and have higher antitumor efficacy during chemoradiotherapy. Therefore, SP-based chemoradiotherapy is expected to be successfully followed by consolidation therapy with durvalumab in more patients, resulting in prolonged PFS and OS. Toxicity and efficacy results of the SP regimen in this study will also provide information important to the future establishment of the concurrent combination of chemoradiotherapy and durvalumab. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127.

Pretreatment neutrophil-to-lymphocyte ratio predicts treatment efficacy and prognosis of cytotoxic anticancer drugs, molecular targeted drugs, and immune checkpoint inhibitors in patients with advanced non-small cell lung cancer.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has recently attracted attention as a prognostic predictor in patients with non-small cell lung cancer (NSCLC) who receive immune checkpoint inhibitors (ICIs). However, the utility of NLR in relation to cytotoxic anticancer drugs or molecular targeted drugs remains unclear. We determined if NLR could predict the treatment efficacy and prognosis in NSCLC patients who receive cytotoxic anticancer drugs or molecular targeted drugs, as well as ICIs, in a cross-sectional manner. METHODS: Of 658 patients with advanced NSCLC who received first-line systemic treatment in our hospital between 2008 and 2019, 312 who met the analytical criteria were included in the study. We retrospectively analyzed the ability of NLR with a cut-off value of 5 to predict time to treatment failure (TTF) and overall survival (OS) in patients who received the following treatments: first-line treatment with molecular targeted drugs (mt group, n=100); first-line treatment with cytotoxic anticancer drugs (wt group, n=212); and first-line treatment with cytotoxic anticancer drugs followed by ICIs (ICI group, n=58). RESULTS: In the high- and low-NLR mt subgroups, median TTFs were 6.7 and 14.9 months (P<0.01), respectively, and median survival times (MSTs) were 17.8 and 39.1 months (P<0.01), respectively. In the high- and low-NLR wt subgroups, median TTFs were 1.5 and 5.8 months (P<0.01), and MSTs were 6.3 and 20.7 months (P<0.01), respectively. In the high- and low-NLR ICI subgroups, median TTFs were 1.3 and 6.8 months (P<0.01), and MSTs were 9.2 and 25.8 months (P<0.01), respectively. Multivariate analysis identified NLR as a significant independent predictor of TTF [hazard ratio (HR) 1.89, P=0.01; HR 2.51, P<0.01; and HR 5.06, P<0.01 in the mt, wt, and ICI groups, respectively) and OS (HR 3.81, P<0.01; HR 2.59, P<0.01; and HR 2.48, P<0.01, respectively). CONCLUSIONS: This study showed that NLR might be a predictor of treatment efficacy and prognosis in advanced NSCLC patients who receive various systemic treatments. This finding of consistent applicability of NLR to a wide variety of systemic treatments is of great significance.

Real-world efficacy of atezolizumab in non-small cell lung cancer: A multicenter cohort study focused on performance status and retreatment after failure of anti-PD-1 antibody.

BACKGROUND: Atezolizumab is a programmed death-ligand 1 (PD-L1) targeted monoclonal antibody that inhibits PD-L1 interacting with its receptors PD-1 and B7-1, thereby enhancing anticancer immunity. Some real-world efficacy and safety studies of anti-PD-1 antibody have been previously reported. However, there have been no reports investigating the efficacy of atezolizumab monotherapy in clinical practice which have focused on performance status and previous anti-PD-1 antibody treatment. METHODS: We retrospectively reviewed consecutive advanced NSCLC patients who received atezolizumab monotherapy between April 2018 and February 2019 at eight institutions. A total of 152 patients with NSCLC were enrolled in this study. RESULTS: A total of 38 patients (25%) had already been treated with anti-PD-1 treatment (nivolumab or pembrolizumab) before atezolizumab. The median OS and TTF was 384 days (12.8 months) (95% confidence interval [CI]: 206-424), and 42 days (1.4 months) (95% CI: 27-56) in all patients, respectively. ECOG PS 0 had significantly longer OS (median OS; not reached, p < 0.0001) and TTF (median TTF; 63 days, p = 0.012) compared with PS 1 or 2-3. Most retreated patients were unable to continue atezolizumab for a longer period, but seven patients (18.4%) were able to continue atezolizumab over four months as an ICI retreatment. CONCLUSIONS: In previously treated advanced NSCLC patients, atezolizumab monotherapy demonstrated good efficacy and safety regardless of heavily treated patients in real-world clinical practice, and ECOG PS 0 was a favorable predictive factor. The efficacy of retreatment with atezolizumab was limited but was well tolerated in patients treated with prior anti-PD-1 antibody.

Importance and Difficulty of Differentiating BMA-induced AFF Prodromal Symptoms from Hormonal Therapy-related Femoral Pain.

We herein report a case of breast cancer in a 74-year-old woman treated with exemestane as fourth-line hormonal therapy and bone-modifying agents for long time. She suddenly developed a right femoral shaft fracture during treatment. Her femoral fracture had a beaking sign on radiogram. Given this finding, her fracture was ultimately diagnosed as atypical femoral fracture (AFF). In this case, it was difficult to recognize the difference between groin pain as a prodromal symptom of AFF and that due to an adverse reaction to hormonal therapy. Therefore, clinicians should recognize the difficulty of this differentiation and consider the situation with caution.

Successful Treatment with Taxane-Based Chemotherapy in Advanced Sebaceous Carcinoma: A Case Report and Literature Review.

For sebaceous carcinoma (SC), a rare malignant tumor, no standard chemotherapy regimen for patients with distant metastasis has been studied. We experienced a case of eyelid SC with multiple lung metastases that responded to combination chemotherapy with carboplatin and paclitaxel with 11-month progression-free survival (PFS). This patient also responded to second-line treatment with docetaxel, another taxane, with 7-month PFS, resulting in at least 18 months of survival at the time of reporting. This report shows that taxane-based chemotherapy may be effective for advanced SC, for which no standard therapy has been established.

Significance of Earlier Initiation of Chemotherapy for Lung Cancer Complicated with Primary or Secondary Nephrotic Syndrome following Its Appropriate Differential Diagnosis.

We encountered a case of primary lung cancer complicated with membranous nephropathy as primary nephrotic syndrome. Because treatment approaches vary greatly for primary and secondary nephrotic syndrome, a renal biopsy was performed for diagnosis. Much time was required to make a definitive diagnosis of primary nephrotic syndrome, as opposed to paraneoplastic nephrotic syndrome. Consequently, the subsequent chemotherapy was ineffective and caused significant toxicity due to reduced performance status (PS) and progression of hypoalbuminemia. Therefore, it is imperative that a diagnosis be made and treatment be initiated without delay before PS declines and hypoalbuminemia progresses.

Need for Flexible Adjustment of the Treatment Schedule for Aprepitant Administration against Erlotinib-Induced Refractory Pruritus and Skin Rush.

Common dermatological side-effects associated with erlotinib, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), include pruritus and skin rash, which are mediated by substance P, leading to the occasional discontinuation of cancer treatment. Aprepitant is an antagonist of neurokinin-1 receptor, through which substance P activates the pruritogens. Thus, aprepitant is expected to offer a promising option for the treatment of erlotinib-induced pruritus. However, the appropriate treatment schedule for aprepitant administration is under consideration. Here, we discuss the need for flexible adjustment of the treatment schedule for aprepitant administration against erlotinib-induced refractory pruritus and skin rush. A 71-year-old female smoker presented with stage IV EGFR-mutated lung adenocarcinoma. She was started on erlotinib at 150 mg/day. However, by 28 days, severe pruritus and acneiform skin rush resistant to standard therapies occurred, resulting in the interruption of erlotinib therapy. After recovery, she was restarted on erlotinib at 100 mg/day. However, severe pruritus and skin rush developed again within 2 weeks. Then, we started the first 3-day dose of aprepitant (125 mg on day 1, 80 mg on day 3, and 80 mg on day 5) based on the results of the previous prospective study, which showed the success rate of 100% with at least the second dose of aprepitant. However, the pruritus and skin rush exacerbated again within 4 weeks. Therefore, we started the second 3-day dose of aprepitant, but in vain. At this point, as the patient-centered medicine, bi-weekly schedule of the 3-day dose of aprepitant was considered and, then, adopted. As the results, the pruritus and skin rush remained well-controlled throughout the subsequent treatment with erlotinib.

Promising Combination Therapy with Bevacizumab and Erlotinib in an EGFR-Mutated NSCLC Patient with MET Amplification Who Showed Intrinsic Resistance to Initial EGFR-TKI Therapy.

In lung cancer, several potential mechanisms of intrinsic and acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been explored, including mesenchymal-epithelial transition factor (MET) signaling pathway activation. On the other hand, vascular endothelial growth factor (VEGF) production of EGFR-mutated lung cancer cells is stimulated by predominantly activated MET signaling pathway. Therefore, the inhibition of VEGF axis as the downstream target of MET signaling pathway seems promising. Here, for the first time, we report the potential efficacy of combination therapy with bevacizumab and erlotinib in an EGFR-mutated NSCLC patient with MET amplification who showed intrinsic resistance to initial EGFR-TKI therapy. The patient was a 60-year-old male smoker, showing performance status (PS) 2, who presented with stage IV lung adenocarcinoma (cT4N2M1a) harboring the EGFR exon 19 deletion mutation. He was started on gefitinib at 250 mg/day. However, by 28 days, his symptoms further deteriorated along with the increased tumor size, resulting in PS 3. Then, repeat biopsy was performed, showing the positive MET amplification and the preserved EGFR exon 19 deletion mutation. Therefore, on the basis of the potential efficacy for activated MET signaling pathway as well as the confirmed safety by the known phase II trial for EGFR-mutated patients, the patient was started on combination therapy with bevacizumab at 15 mg/kg every 3 weeks plus erlotinib at 150 mg/day. By 21 days, his symptoms gradually improved along with the decreased tumor size, resulting in better PS with no severe toxicities.