Immunohistochemical analysis of B7-H3 expression in patients with lung cancer following various anti-cancer treatments.

B7 homolog 3 protein (B7-H3), an immune checkpoint molecule belonging to the B7 family, has been studied as a target for the development of anti-cancer treatment; however, changes in B7-H3 expression during the clinical course remain unknown. This retrospective study aimed to investigate changes in B7-H3 expression of lung cancer specimens in patients with advanced lung cancer following various anti-cancer treatments. The immunohistochemistry (IHC) score was evaluated on a 0-3 scale, and B7-H3 expression was considered positive for grade ≥ 2. The difference in IHC scores before and after anti-cancer treatment was defined as the change in B7-H3 expression. Among 160 patients with lung cancer who received anti-cancer treatment, 88 (55%) and 101 (63%) had B7-H3 expression before and after anti-cancer treatment, respectively. Before treatment, B7-H3 expression was significantly more common in squamous cell carcinoma specimens than in adenocarcinoma specimens (95% vs. 49%, P < 0.001). Of the 19 patients with squamous cell carcinoma, 18 (95%) continued to have high (IHC score: 3) B7-H3 expression following treatment. In contrast, of the 130 patients with adenocarcinoma, 46 (35%) and 17 (13%) showed an increased and a decreased expression, respectively. Patients who received targeted therapy had a significant increase in B7-H3 expression compared with those who received chemotherapy alone (P = 0.015). Overall, squamous cell carcinoma specimens maintained high B7-H3 expression during the clinical course, whereas adenocarcinoma specimens showed changes in expression following anti-cancer treatments. Our results provide the basis for further studies on the development of anti-cancer treatments targeting B7-H3.

Prognostic impact of pneumonitis after durvalumab therapy in patients with locally advanced non-small cell lung cancer.

BACKGROUND: Prognostic data on Japanese patients receiving durvalumab after chemoradiotherapy (CRT) for locally advanced non-small cell lung cancer (LA-NSCLC) are insufficient. Whether pneumonitis has prognostic implications in patients with LA-NSCLC who have received durvalumab also remains unclear. METHODS: We retrospectively assessed the data of 82 consecutive patients who had received durvalumab after CRT at our institution between May 2018 and August 2020. A multi-state model was used to establish the associations between co-variables and progression-free survival (PFS). RESULTS: The median observation period for all the censored cases was 14.5 months (5.7-28.9 months), the median PFS was 22.7 months, and the 12-month PFS rate was 62.3% (95% CI: 50.2%-72.3%). The median percentage of the lung volume receiving a radiation dose in excess of 20 Gray (V20) was 22% (4%-35%). Thirteen patients (16%) had Grade 1 pneumonitis before receiving durvalumab, and 62 patients developed pneumonitis after durvalumab (Grades 1, 2, and 3 in 25 [30%], 32 [39%], and 4 [5%], respectively). Twenty-four patients (29%) completed the 1-year durvalumab treatment period, 16 patients (20%) were continuing to receive treatment, and 42 (51%) had discontinued treatment. In a multi-state analysis, patients with pneumonitis before durvalumab therapy had a poorer PFS than those without pneumonitis (HR: 4.29, p = 0.002). The development of Grade 2 or higher pneumonitis after durvalumab was not a significant prognostic factor for PFS (HR: 0.71, p = 0.852). CONCLUSION: Grade 2 or higher pneumonitis after durvalumab was not a prognostic factor of PFS in LA-NSCLC patients received durvalumab.

Long-term survival data of patients with limited disease small cell lung cancer: a retrospective analysis.

INTRODUCTION: In patients with limited disease small cell lung cancer (LD-SCLC) treated with concurrent chemoradiotherapy (CCRT), long-term survival data have not been fully evaluated. Moreover, the association between long-term prognosis and prognostic factors has not been sufficiently investigated. METHODS: In this retrospective study, we evaluated the efficacy of CCRT in 120 patients with LD-SCLC with a plan for curative CRT using concurrent accelerated hyperfractionated radiotherapy. RESULTS: The patients had a median age of 65.5 years, predominantly male (73%), and had clinical stage III disease (80%). The median follow-up time for overall survival (OS) was 72.2 months, median OS was 42.5 months, and the 3-year and 5-year survival rates were 52.4% and 41.8%, respectively. The median progression-free survival (PFS) was 12.5 months, and the 3-year and 5-year PFS rates were 37.6% and 33.6%, respectively. The 5-year OS rates of patients who achieved PFS at each time point were 70.9%, 83.6%, and 91.9% at 12, 24, and 36 months, respectively. The gradual increase in the 5-year OS rate following PFS extension and initial depression of the Kaplan-Meier curve showed disease progression frequently occurred in the first 2 years after initiation of CCRT. The Cox proportional hazards model showed no significant factors correlated with long-term survival through univariate and multivariate analyses. Although the prognostic factors associated with long-term prognosis in LD-SCLC were not identified, the 5-year survival rate was 41.8%, and among patients without disease progression at 2 years, the 5-year survival rate was 83.6%. CONCLUSION: These data suggested that the prognosis of patients with LD-SCLC was improving.

Efficacy of platinum agents for stage III non-small-cell lung cancer following platinum-based chemoradiotherapy: a retrospective study.

BACKGROUND: Platinum-based chemoradiotherapy is the standard treatment for unresectable stage III non-small-cell lung cancer (NSCLC). However, few studies have evaluated the efficacy of subsequent chemotherapy for relapsed NSCLC following platinum-based chemoradiotherapy. This study aimed to evaluate the efficacy of platinum-doublet chemotherapy as a second-line treatment for patients with unresectable stage III NSCLC. METHODS: We retrospectively evaluated patients with unresectable stage III NSCLC treated with cytotoxic chemotherapy following platinum-based chemoradiotherapy who were registered in a nationwide registry NSCLC database. Patients were divided into the platinum-doublet chemotherapy (platinum) group and single-agent chemotherapy (non-platinum) group based on the type of second-line chemotherapy. RESULTS: The platinum group (n = 119) showed significantly better overall survival (OS) than the non-platinum group (n = 201) (median OS: 21.5 vs. 10.5 months, hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.40-0.73, p < 0.001). OS from the beginning of chemoradiotherapy was also significantly better in the platinum group than in the non-platinum group (median OS: 34.9 vs. 21.8 months, HR: 0.58, 95% CI: 0.43-0.79, p = 0.001). In the multivariate analysis, platinum-doublet chemotherapy as second-line therapy, female sex, clinical stage IIIA, and duration of ≥ 8.6 months from the beginning of first-line therapy to the beginning of second-line therapy were associated with significantly better OS. CONCLUSION: Platinum-doublet chemotherapy as a second-line therapy may prolong survival in unresectable stage III NSCLC patients following platinum-based chemoradiotherapy. Thus, re-administration of platinum agents may be a promising treatment for unresectable stage III NSCLC treated with platinum-based chemoradiotherapy.

Impact of weight loss on treatment with PD-1/PD-L1 inhibitors plus chemotherapy in advanced non-small-cell lung cancer.

PURPOSE: Programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors plus chemotherapy have become the standard first line of treatment in patients with advanced non-small-cell lung cancer (NSCLC). However, few studies have explicitly focused on the impact of weight loss on the efficacy of PD-1/PD-L1 inhibitors plus chemotherapy. Thus, we evaluated the clinical implications of weight loss on the survival outcomes in patients who received this treatment. METHODS: We conducted a retrospective review of medical records of patients with advanced NSCLC who were treated with PD-1/PD-L1 inhibitors plus chemotherapy from December 2018 to December 2020. Significant weight loss was defined as an unintentional weight loss of 5% or more over 6 months. We evaluated the progression-free survival (PFS) and overall survival (OS) of patients with or without weight loss. RESULTS: Among the 80 included patients, 37 (46%) had weight loss, and were associated with a lower objective response rate (30 vs 51%, P < 0.05), poorer PFS (2.3 vs 12.0 months, P < 0.05), and poorer OS (10.8 vs 23.9 months, P < 0.05) than those without weight loss. The Cox proportional-hazard ratios (95% confidence interval) of weight loss were 1.77 (1.01-3.10) for PFS and 2.90 (1.40-6.00) for OS, with adjustments for Eastern Cooperative Oncology Group performance status, PD-L1 tumour proportion score, histology, and central nervous system metastases. CONCLUSION: Pre-treatment weight loss may reduce treatment efficacy and shorten survival time in patients receiving PD-1/PD-L1 inhibitors plus chemotherapy. Early evaluation and intervention for weight loss might improve oncological outcomes in patients with advanced NSCLC.

Proposing synchronous oligometastatic non-small-cell lung cancer based on progression after first-line systemic therapy.

Despite the importance of accurate disease definitions for effective management and treatment decisions, there is currently no consensus on what constitutes oligometastatic non-small-cell lung cancer (NSCLC). Predominant patterns of initial progressive disease (PD) after first-line systemic therapy have been shown to be a substantial basis for local ablative therapy (LAT) for all disease sites in patients with oligometastatic NSCLC, suggesting that these patterns could be helpful in defining synchronous oligometastatic NSCLC. Therefore, this retrospective study aimed to propose a threshold number of metastases for synchronous oligometastatic NSCLC, based on the pattern of initial PD after first-line systemic therapy. The cut-off threshold number of metastases compatible with synchronous oligometastatic NSCLC was determined using receiver operating characteristic (ROC) curve analyses of PD at the initially involved sites alone. ROC analysis of 175 patients revealed that the presence of 1-3 metastases before first-line treatment (sensitivity, 85.9%; specificity, 97.3%; area under the curve, 0.91) was compatible with oligometastatic NSCLC, therefore we divided patients into oligometastatic NSCLC and non-oligometastatic NSCLC groups. Multivariate logistic regression analyses revealed oligometastatic NSCLC to be the only independent predictor of PD at initially involved sites alone (odds ratio 165.7; P < .001). The median survival times in patients with oligometastatic or non-oligometastatic NSCLC were 23.0 and 10.9 mo (hazard ratio, 0.51; P = .002), respectively. Based on these findings, we propose synchronous oligometastatic NSCLC as 1-3 metastases in accordance with patterns of initial progression. The result of our study might be contributory to provide a common definition of synchronous oligometastatic NSCLC.

Retrospective analysis of osimertinib re-challenge after osimertinib-induced interstitial lung disease in patients with EGFR-mutant non-small cell lung carcinoma.

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has exhibited efficacy in patients with EGFR-mutant non-small cell lung cancer (NSCLC). Interstitial lung disease (ILD) is a fatal adverse event of osimertinib treatment, and it requires treatment discontinuation. There are few reports regarding the safety and efficacy of osimertinib re-challenge in patients who experienced osimertinib-induced ILD. This retrospective study assessed this treatment option. We retrospectively collected data for patients treated with osimertinib who developed ILD at Shizuoka Cancer Center from April 2016 to March 2020. ILD was diagnosed by two doctors based on imaging tests and blood tests to exclude other causes. Among 215 patients treated with osimertinib, 28 developed ILD. The median age of patients with ILD was 69.5 years (range, 39.0-80.0). In addition, 29% of patients were men, and 46% had a history of smoking. Eleven patients were re-administered EGFR TKIs, including eight patients treated with osimertinib and three patients treated with alternative EGFR TKIs. Among patients re-challenged with osimertinib, none who previously experienced grade 1 ILD exhibited ILD relapse, even with the same osimertinib dose and without the concurrent administration of systemic steroids. Meanwhile, one of the four patients who previously exhibited grade 2 ILD experienced despite a dose reduction for osimertinib and systemic steroid administration. For patients with EGFR-mutant NSCLC who experience grade 1 ILD during osimertinib therapy, osimertinib re-challenge may be suitable when no other treatments are available.

Rechallenge with previously administered epidermal growth factor receptor-tyrosine kinase inhibitors in EGFR-mutated non-small cell lung cancer with leptomeningeal metastasis.

Objectives In EGFR-mutated non-small cell lung cancer (NSCLC) patients, approximately 80-90% of leptomeningeal metastasis (LM) develops after failed initial treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI). However, the efficacy of rechallenging with previously administered EGFR-TKIs in patients with EGFR-mutated NSCLC and the LM that develops following EGFR-TKI treatment failure remains unknown. Materials and methods We retrospectively reviewed medical records of patients with EGFR-mutated NSCLC and LM, from November 2011 to August 2019. The patients were classified according to the LM treatment type: switched to previously unadministered EGFR-TKIs (Switch-TKI) or rechallenge with previously administered EGFR-TKIs (Rechallenge-TKI). Results In total, 50 patients treated with EGFR-TKI after LM diagnosis were included; 35 were treated with Switch-TKI and 15 with Rechallenge-TKI. The median overall survival (OS) from the time of LM diagnosis was 6.2 months in all study patients. According to the treatment type, the median OS from the time of LM diagnosis was 6.9 months in Switch-TKI patients and 4.9 months in Rechallenge-TKI patients. There was no significant difference in the OS between the Switch-TKI and Rechallenge-TKI groups (P = 0.864). Thirty-five patients were treated with erlotinib and 15 with osimertinib; Regardless of the type for EGFR-TKI, there was no significant difference in OS between patients treated with Switch-TKI and those treated with Rechallenge-TKI. Conclusion Rechallenge of previously administered EGFR-TKIs may be a therapeutic option for LM development after EGFR-TKI treatment failure in patients with EGFR-mutated NSCLC, not only switching to previously unadministered EGFR-TKIs.

Association between oligo-residual disease and patterns of failure during EGFR-TKI treatment in EGFR-mutated non-small cell lung cancer: a retrospective study.

BACKGROUND: Local ablative therapy (LAT) may be beneficial for patients with epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) with oligo-residual disease after treatment with EGFR tyrosine kinase inhibitor (EGFR-TKI). However, this has not been fully established. This study aimed to evaluate the predominant progressive disease (PD) pattern limited to residual sites of disease after treatment with EGFR-TKI. METHODS: Patients with advanced EGFR-mutated NSCLC treated with EGFR-TKIs as first-line therapy were retrospectively analysed during a 7-year period. Oligo-residual disease was defined as the presence of 1 - 4 lesions (including the primary site) at 3 months from the start of EGFR-TKI treatment. The predictive factors of PD patterns after EGFR-TKI treatment were evaluated. RESULTS: A total of 207 patients were included. Three months after the start of EGFR-TKI treatment, 66 patients (32%) had oligo-residual disease. A total of 191 patients had PD, 60 with oligo-residual disease and 131 with non-oligo-residual disease. Regarding the pattern, 44 patients (73%) with oligo-residual disease and 37 patients (28%) with non-oligo-residual disease had PD limited to the residual sites. Multivariate logistic regression analysis at 3 months from the start of EGFR-TKI treatment revealed that oligo-residual disease (P < 0.001), the lack of residual central nervous system metastases (P = 0.032), and initial treatment with osimertinib (P = 0.028) were independent predictors of PD limited to residual disease sites. CONCLUSIONS: This study provided a rationale for LAT to all sites of residual disease in patients with oligo-residual disease during EGFR-TKI treatment.

Long-term outcomes in extensive disease small cell lung cancer patients treated without immune checkpoint inhibitors.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) combined with chemotherapy have been approved as first-line treatment for patients with untreated extensive disease-small cell lung cancer (ED-SCLC). However, there are few reports about the long-term outcomes in patients with ED-SCLC treated without ICIs. Thus, we analyzed the long-term outcomes in patients with ED-SCLC. METHODS: We retrospectively examined the medical records of patients with SCLC who were treated at our hospital between September 2002 and September 2019. The main inclusion criteria were as follows: (i) histological or cytological confirmation of SCLC, (ii) diagnosed with ED-SCLC and (iii) received chemotherapy, not including ICIs, as the first-line treatment. To assess the trends of treatment outcomes, we compared the survival outcomes between 2002-2010 (early) and 2011-2019 (late) groups. RESULTS: A total of 314 patients were included in this study. Patient characteristics at the time of first-line treatment were as follows: median age was 69 years; 82% of the patients were male and 70% had a performance status of 0 or 1. The median follow-up time of overall survival (OS) was 7.4 years, and 89% of the patients died. The median progression-free survival and survival time were 4.9 and 12.1 months, respectively. Five-year survival rate was 2%. There was no significant difference in survival between the early and late groups. CONCLUSIONS: We found that the long-term outcomes in ED-SCLC patients treated without ICIs were poor. Prior to the approval of ICI treatment for ED-SCLC, there was no improvement in the OS for ~20 years.

Detection of programmed cell death-ligand 1 using 22C3 antibody in patients with unresectable stage III non-small cell lung cancer receiving chemoradiotherapy.

BACKGROUND: The expression of programmed cell death-ligand 1 (PD-L1) is a biomarker for administering immune check point inhibitors in patients with advanced stage non-small cell lung cancer. Although the consolidation therapy of durvalumab after definitive chemoradiotherapy has become the new standard of care for patients with unresectable stage III non-small cell lung cancer, the prevalence and prognostic role of PD-L1 expression in this population remain unclear. METHODS: We retrospectively reviewed data from patients with unresectable stage III non-small cell lung cancer who received definitive chemoradiotherapy at our institution between 2012 and 2017. Levels of PD-L1 were assessed using 22C3 antibody, and associations of progression-free and overall survival rates with PD-L1 statuses at a tumor proportion score cutoff of 1% were analyzed. RESULTS: Among the 104 patients enrolled, PD-L1 statuses were as follows: tumor proportion score < 1%, 73 (70.2%); 1-49%, 21 (20.2%); and ≥ 50%, 10 (9.6%). The number of patients with stage III non-small cell lung cancer with pretreatment PD-L1 tumor proportion score ≥ 1% was less than the number with advanced stage disease. There was no association between patient characteristics and PD-L1 status, and no significant differences were observed in progression-free and overall survival rates relative to PD-L1 status. CONCLUSION: Expression of PD-L1 in patients with stage III non-small cell cancer before chemoradiotherapy should be assessed because of the low prevalence of tumors with tumor proportion scores ≥ 1%. Further studies are needed to clarify whether durvalumab improves survival after definitive chemoradiotherapy, irrespective of tumor PD-L1 expression.

PD-L1 expression and response to pembrolizumab in patients with EGFR-mutant non-small cell lung cancer.

Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer is less likely to express programmed death-ligand 1 (PD-L1) than tumors with wild-type EGFR and is associated with poor response to pembrolizumab. To understand the relationship between EGFR mutation and PD-L1 expression in pembrolizumab response, we retrospectively evaluated the factors contributing to the high tumor proportion score in 155 EGFR-mutant non-small cell lung cancer cases and their associated response to pembrolizumab. Uncommon EGFR mutations were significantly associated with a PD-L1 tumor proportion score ≥ 50% compared to common EGFR mutations. The objective response rate to pembrolizumab of 14 patients was 36%, including 22% in patients with common EGFR mutations, 60% in patients with uncommon EGFR mutations and 75% in patients with both uncommon mutations and a PD-L1 tumor proportion score ≥ 50%. A PD-L1 tumor proportion score ≥ 50% was more frequent in non-small cell lung cancer patients harboring uncommon EGFR mutations and was associated with pembrolizumab efficacy.

[Pneumonitis Induced by Immune Checkpoint Inhibitors].

Immune checkpoint inhibitors(ICIs)have shown efficacy in many clinical trials and have an important role in the treatment for advanced cancers.Many physicians recently have chances to use ICIs across tumor types.ICIs are associated with a unique set of toxic effects, which are defined as immune-related adverse events(irAEs).Drug -induced pneumonitis is considered to be one of important irAEs.Pneumonitis as irAE has been not so frequently observed, and all Grade in 0~10%and Grade 3 or 4 in 0~3% of patients receiving ICIs.However severe or life-threatening pneumonitis was observed in some cases, so that pneumonitis caused by ICIs has been clinically important.The incidence of pneumonitis caused by ICIs for Japanese patients is similar to previous reports.Symptoms of pneumonitis by ICIs are considered to be dyspnea and cough.Some patients are diagnosed as asymptomatic pneumonitis with abnormal radiographic findings.Cryptogenic organizing pneumonia(COP) pattern has been reported to be most frequently observed in radiographic patterns of pneumonitis caused by ICIs(43~65%). Since some cases shows pneumonitis with different radiographic pattern from other drug-induced pneumonitis, blood test and bronchoscopy may be useful for diagnosis.It has been recommended to treat patients with ICIs-related pneumonitis according to severity of pneumonitis.In most patients, pneumonitis is improved with corticosteroids and withdrawal of ICIs, though a few patients with severe pneumonitis may need immunosuppressants.It has been recommended for medical oncologists to consult and cooperate with pulmonologists for diagnosis and treatment of ICIs-related interstitial lung disease(ILD). The mechanism of pneumonitis induced by ICIs may differ from those of other drug-induced pneumonitis.Therefore, medical oncologists should be careful for ICIs-related pneumonitis as a new disease category in the treatment of ICIs.

Efficacy of second-line chemotherapy in patients with pulmonary large cell neuroendocrine carcinoma.

The efficacy of second-line chemotherapy in patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) is unclear. This study aimed to evaluate the efficacy of second-line chemotherapy in patients with pulmonary LCNEC. We retrospectively reviewed patients with pulmonary LCNEC or possible LCNEC (pLCNEC) who received platinum-based chemotherapy as the first-line treatment. Among these patients, we evaluated the efficacy of second-line treatment by comparing patients with small cell lung cancer (SCLC group). Of the 61 patients with LCNEC or pLCNEC (LCNEC group) who received first-line chemotherapy, 39 patients were treated with second-line chemotherapy. Among the 39 patients, 61.5% received amrubicin monotherapy. The median progression-free survival (PFS) and overall survival (OS) in the LCNEC groups were 3.3 and 8.3 months, respectively. No significant differences in the PFS (hazard ratio [HR]: 0.924, 95% confidence interval [CI] 0.647-1.320; P = 0.664) and OS (HR: 0.926; 95% CI 0.648-1.321; P = 0.670) were observed between the LCNEC and SCLC groups. In patients treated with amrubicin, the PFS (P = 0.964) and OS (P = 0.544) were not different between both the groups. Second-line chemotherapy, including amrubicin, may be considered as a treatment option for patients with pulmonary LCNEC.

Clinical impact of tumour burden on the efficacy of PD-1/PD-L1 inhibitors plus chemotherapy in non-small-cell lung cancer.

BACKGROUND: Programmed cell death 1 (PD-1)/programmed cell death ligand (PD-L1) inhibitors plus chemotherapy (ICI + Chemo) is the standard treatment for advanced non-small-cell lung cancer (NSCLC). However, the impact of tumour burden on the efficacy of ICI + Chemo remains unknown. METHODS: We retrospectively evaluated 92 patients with advanced NSCLC treated with ICI + Chemo. Tumour burden was assessed as the sum of the longest diameter of the target lesion (BSLD) and number of metastatic lesions (BNMLs). We categorised the patients into three groups based on the combined BSLD and BNML values. RESULTS: Sixty-eight patients (74%) had progressive disease or died. Forty-four patients (48%) in the low-BSLD group had a median progression-free survival (PFS) of 9.5 months, whereas patients in the high-BSLD group had a median PFS of 4.6 months (hazard ratio [HR] = 0.54, p = 0012). Twenty-five patients (27%) in the low-BNML group had a median PFS of 9.6 months, whereas patients in the high-BNML group had a median PFS of 6.5 months (HR = 0.51, p = 0.029). Low-BSLD and low-BNML were associated independently with improved PFS in multivariate analysis. Analysis of the tumour burden combined with BSLD and BNML revealed a trend towards improved PFS as the tumour burden decreased, with median PFS of 22.3, 8.7, and 3.9 months in the low- (N = 13), medium- (N = 42) and high-burden (N = 37) groups respectively. CONCLUSIONS: Our findings demonstrated that a high tumour burden negatively impacts the efficacy of ICI + Chemo in patients with advanced NSCLC.

Incidence and Treatment Outcome of Radiation Pneumonitis in Patients With Limited-stage Small Cell Lung Cancer Treated With Concurrent Accelerated Hyperfractionated Radiation Therapy and Chemotherapy.

Purpose: This study aimed to clarify the characteristics of and evaluate the risk factors for radiation pneumonitis (RP) induced by chemoradiation therapy (CRT) using accelerated hyperfractionated (AHF) radiation therapy (RT) in patients with limited-stage small cell lung cancer (LS-SCLC). Methods and Materials: Between September 2002 and February 2018, 125 patients with LS-SCLC were treated with early concurrent CRT using AHF-RT. Chemotherapy was comprised of carboplatin/cisplatin with etoposide. RT was administered twice daily (45 Gy/30 fractions). We collected data regarding onset and treatment outcomes for RP, and analyzed the relationship between RP and total lung dose-volume histogram findings. Uni- and multivariate analyses were performed to assess patient- and treatment-related factors for grade ≥2 RP. Results: The median age of patients was 65 years, and 73.6% of participants were men. In addition, 20% and 80.0% of participants presented with disease stage II and III, respectively. The median follow-up time was 73.1 months. Grades 1, 2, and 3 RP were observed in 69, 17, and 12 patients, respectively. Grades 4 to 5 RP were not observed. RP was treated with corticosteroids in patients with grade ≥2 RP, without recurrence. The median time from initiation of RT to onset of RP was 147 days. Three patients developed RP within 59 days, 6 within 60 to 89 days, 16 within 90 to 119 days, 29 within 120 to 149 days, 24 within 150 to 179 days, and 20 within ≥180 days. Among the dose-volume histogram parameters, the percentage of lung volume receiving >30 Gy (V30) was most strongly related to the incidence of grade ≥2 RP, and the optimal threshold to predict RP incidence was V30 ≥20%. On multivariate analysis, V30 ≥20% was an independent risk factor for grade ≥2 RP. Conclusions: The incidence of grade ≥2 RP correlated strongly with a V30 of ≥20%. Contrarily, the onset of RP induced by concurrent CRT using AHF-RT may occur later. RP is manageable in patients with LS-SCLC.

Trophoblast cell-surface antigen 2 expression in lung cancer patients and the effects of anti-cancer treatments.

BACKGROUND: Trophoblast cell-surface antigen 2 (TROP2) is expressed on the surface of trophoblast cells and many malignant tumor cells. However, data on TROP2 expression in advanced lung cancer are insufficient, and its changes have not been fully evaluated. METHODS: We assessed the prevalence and changes in TROP2 expression in patients with lung cancer who received anti-cancer treatments using immunohistochemical (IHC) analysis with an anti-TROP2 antibody (clone: SP295). IHC scores were graded from 0 to 3; grade ≥ 2 was considered positive for TROP2 expression. We defined a difference in IHC score, before and after anti-cancer treatments, as the change in TROP2 expression. RESULTS: Before anti-cancer treatment, TROP2 expression was observed in 89% (143/160) of the patients and was significantly more common in adenocarcinoma and squamous cell carcinoma than in neuroendocrine carcinoma (P < 0.001). After anti-cancer treatment, TROP2 expression was observed in 87% (139/160) of the patients. The distribution of TROP2 expression in post-treatment samples was analogous to that in pre-treatment samples when compared using the Wilcoxon signed-rank test (P = 0.509). However, an increase in TROP2 expression was seen in 19 (12%), and a decrease in 20 (13%) patients. Patients treated with targeted therapy showed significantly higher changes in TROP2 expression (P = 0.019) and thoracic radiotherapy was more likely to increase TROP2 expression than chemotherapy alone. CONCLUSION: Although some anti-cancer treatments might alter the TROP2 expression, TROP2 was expressed in most lung cancer specimens before and after anti-cancer treatments. These results support the development of TROP2-directed therapy against advanced lung cancer in various treatment lines.

Impact of losing adipose tissue on outcomes from PD-1/PD-L1 inhibitor monotherapy in non-small cell lung cancer.

BACKGROUND: Adipose tissue induces inflammation, which desensitizes the efficacy of immunotherapy. However, several reports show that the therapeutic effect of programed cell death 1 (PD-1)/programed death-ligand 1 (PD-L1) inhibitor(s) monotherapy is significantly better in obese patients. Therefore, the effect of adipose tissue on immunotherapy is unclear. METHODS: In this study, we retrospectively reviewed patients with advanced non-small cell lung cancer (NSCLC) who received PD-1/PD-L1 inhibitor monotherapy between May 2016 and December 2018. We classified patients into total adipose tissue maintenance or loss groups according to adipose tissue change during the 6 months before treatment and compared the therapeutic effect of PD-1/PD-L1 inhibitors between these groups along with the presence or absence of cachexia, a poor prognostic factor. RESULTS: Of the 74 patients, 40 (54.1%) were cachexic. Among cachexic patients, we found no clear difference in the overall response rate (ORR) and progression-free survival (PFS) between the total adipose tissue maintenance and loss group. However, among noncachexic patients, the total adipose tissue loss group had a higher ORR (64.7% vs. 23.5%, p < 0.05) and longer PFS (18.5 months vs. 2.86 months, p = 0.037) than the maintenance group. CONCLUSIONS: This study showed that decreasing adipose tissue without cachexia might favor the therapeutic effects of immunotherapy.

Predicting the efficacy of first-line immunotherapy by combining cancer cachexia and tumor burden in advanced non-small cell lung cancer.

BACKGROUND: Cancer cachexia and tumor burden predict efficacies of programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors and chemotherapy or pembrolizumab in non-small cell lung cancer (NSCLC). There are no predictive models that simultaneously assess cancer cachexia and tumor burden. METHODS: In the present retrospective study, we reviewed the medical records of patients with advanced NSCLC who received cancer immunotherapy as first-line systemic therapy. Clinical immune predictive scores were defined according to multivariate analysis of progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 157 patients were included in the present study (75 treated with PD-1/PD-L1 inhibitors + chemotherapy; 82, pembrolizumab monotherapy). Multivariate analysis for PFS revealed that PD-L1 tumor proportion scores <50%, a total target lesion diameter ≥76 mm, and cancer cachexia were independently associated with poor PFS. Multivariate analysis for OS revealed that ≥4 metastases and cancer cachexia were significantly associated with poor OS. In the immune predictive model, the median PFS was 21.7 months in the low-risk group (N = 41); 7.6 in the medium-risk group (N = 64); and 3.0 in the high-risk group (N = 47). The median OS were not reached, 22.4 and 9.1 months respectively. Our immune predictive model was significantly associated with PFS (p < 0.001) and OS (p < 0.001). CONCLUSION: We proposed the immune predictive model, including tumor burden and cancer cachexia, which may predict the efficacy and survival outcome of first-line immunotherapy in advanced NSCLC.