Clinical Utility of Inflammatory and Nutritious Index as Therapeutic Prediction of Nivolumab plus Ipilimumab in Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Biomarkers for predicting the outcome of ipilimumab plus nivolumab (Nivo-Ipi) treatment in cancer patients have not been identified. Herein, we investigated the prognostic significance of inflammatory and nutritional markers in patients with advanced non-small cell lung cancer (NSCLC) receiving Nivo-Ipi. METHODS: Our study retrospectively analyzed 101 patients with advanced NSCLC who received Nivo-Ipi at a single institution. Inflammatory and nutritional indices were correlated with patient outcomes and included the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI), and Glasgow prognostic score (GPS). RESULTS: The NLR significantly correlated with the PLR, SII, PNI, ALI, and GPS. Regarding therapeutic efficacy, the NLR, SII, and PNI predicted a partial response, and all indices predicted progressive disease. In subgroup analyses, the SII, PNI, and ALI predicted the outcome of patients with adenocarcinoma, whereas only the PNI predicted the outcome of patients with non-adenocarcinoma. The PNI and SII were the most useful indices in patients with a programmed death ligand-1 expression level of <1% and ≥1%, respectively. CONCLUSION: The NLR, PLR, SII, PNI, ALI, and GPS were significantly associated with the outcome of Nivo-Ipi treatment in patients with NSCLC. The PNI was the most suitable marker regardless of histological type. The SII and PNI were the most promising markers for patients with and without PD-L1 expression, respectively.

Prognostic Potential of the Prognostic Nutritional Index in Non-Small Cell Lung Cancer Patients Receiving Pembrolizumab Combination Therapy with Carboplatin and Paclitaxel/Nab-Paclitaxel.

INTRODUCTION: Pembrolizumab (Pemb) therapy in conjunction with carboplatin and paclitaxel (PTX)/nab-PTX has been efficacious in treating non-small cell lung cancer (NSCLC). However, the response predictors of this combination therapy (Pemb-combination) remain undetermined. We aimed to evaluate whether Glasgow prognostic score (GPS), neutrophil-to-lymphocyte ratio (NLR), body mass index (BMI), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index (PNI) are potential factors in prognosticating the response to Pemb-combination therapy in advanced NSCLC patients. METHODS: We retrospectively recruited 144 NSCLC patients receiving first-line treatment with Pemb-combination therapy from 13 institutions between December 1, 2018, and December 31, 2020. GPS, NLR, BMI, PLR, and PNI were assessed for their efficacy as prognostic indicators. Cox proportional hazard models and the Kaplan-Meier method were used to compare the progression-free survival (PFS) and overall survival (OS) of the patients. RESULTS: The treatment exhibited a response rate of 63.1% (95% confidence interval [CI]: 55.0-70.6%). Following Pemb-combination administration, the median PFS and OS were 7.3 (95% CI: 5.3-9.4) and 16.5 (95% CI: 13.9-22.1) months, respectively. Contrary to PNI, NLR, GPS, BMI, and PLR did not display substantially different PFS in univariate analysis. However, multivariate analysis did not identify PNI as an independent prognostic factor for PFS. Furthermore, univariate analysis revealed that GPS, BMI, and PLR exhibited similar values for OS but not NLR and PNI. Patients with PNI ≥45 were predicted to have better OS than those with PNI <45 (OS: 23.4 and 13.9 months, respectively, p = 0.0028). Multivariate analysis did not establish NLR as an independent prognostic factor for OS. CONCLUSION: The PNI evidently predicted OS in NSCLC patients treated with Pemb-combination as first-line therapy, thereby validating its efficiency as a prognostic indicator of NSCLC.

Clinical Issue of Myasthenia Gravis Related to Immune Checkpoint Inhibitors.

PURPOSE OF REVIEW: Immune-related adverse events (irAEs) are pivotal in the management of immune checkpoint inhibitors (ICIs) across various human neoplasms. While common irAEs are manageable by oncologists, the detailed features of rare complications related to ICI therapy remain elusive. Among these, immune-related myasthenia gravis (irMG) stands out as a life-threatening disease. RECENT FINDINGS: Research articles published in English between 2017 and 2023 were identified using the PubMed database. Forty-six relevant research studies were examined to collate information for this review. The incidence of ICI-induced MG was found to be less than 1.0%, with approximately 20-30% of irMG patients presenting with overlap syndrome involving myocarditis and myositis. The detection of acetylcholine receptor antibodies (AChR-Ab) and elevated creatinine kinase (CK) levels proved useful in identifying 50-70% and 60-80% of cases, respectively. However, the utility of muscle-specific kinase antibodies (MuSK-Ab) in detecting irMG was limited due to a low positivity rate (0-5.3%). Ptosis emerged as the most common initial symptom of irMG, with an approximate positivity rate of 80%. Recommended treatment for irMG involves high-dose steroids in conjunction with plasmapheresis or immunoglobulins to mitigate the increased mortality associated with irMG. Early initiation of immunosuppressive therapy is imperative to prevent the worsening of irMG. Furthermore, facilitating a fulfilling social life post-hospitalization is crucial. This review sheds light on the clinical aspects and management strategies pertaining to irMG.

First-line nivolumab plus ipilimumab with or without chemotherapy for Japanese patients with non-small cell lung cancer: LIGHT-NING study.

OBJECTIVE: As first-line treatment for stage IV or recurrent non-small cell lung cancer, combination immunotherapy with nivolumab and ipilimumab, with or without chemotherapy, had demonstrated survival benefits over chemotherapy; however, data on Japanese patients are limited. METHODS: LIGHT-NING was a multicenter, observational study and retrospectively collected data. In this interim analysis, we analyzed patients who received combination immunotherapy between 27 November 2020 and 31 August 2021 for the treatment status, safety objectives (treatment-related adverse events and immune-related adverse events incidences), and effectiveness objectives (objective response rate and progression-free survival) to determine the characteristics and early safety information. RESULTS: We analyzed 353 patients, with a median follow-up of 7.1 (interquartile range, 5.0-9.7) months. Overall, 60.1 and 39.9% received nivolumab plus ipilimumab with and without chemotherapy, respectively. In these cohorts, the median age was 67 and 72 years; 10.8 and 35.5% were aged ≥75 years; 80.2 and 79.4% were male; 5.2 and 13.5% had a performance score ≥ 2; 32.1 and 27.0% developed grade 3-4 immune-related adverse events; treatment-related deaths were observed in 6 (2.8%) and 5 (3.5%) patients, respectively. Grade 3-4 immune-related adverse event incidence was the highest within the first month of treatment in both cohorts, although the immune-related adverse event risk persisted throughout. No new safety signals were observed at this interim analysis. The median progression-free survival was 6.0 (95% confidence interval, 5.2-7.6) and 5.8 (4.3-7.0) months in nivolumab plus ipilimumab with and without chemotherapy cohorts, respectively. CONCLUSIONS: LIGHT-NING offers valuable insights into combination immunotherapy for untreated patients with stage IV or recurrent non-small cell lung cancer in Japanese real-world settings.

Clinical significance of antinuclear antibody as prognostic marker for first-line pembrolizumab in advanced non-small cell lung cancer.

BACKGROUND: The relationship between antinuclear antibody (ANA) and the efficacy of programmed death-1 (PD-1) blockade remains controversial. Here, we investigated the prognostic significance of ANA titer in patients with non-small cell lung cancer (NSCLC) receiving pembrolizumab monotherapy as the first-line treatment, compared with that of platinum-based chemotherapy with PD-1 blockade. METHODS: Our clinical data based on the ANA titer (1:80) were retrospectively reviewed for patients with advanced NSCLC, who were treated with first-line pembrolizumab monotherapy and platinum-based chemotherapy with PD-1 blockade. Immunohistochemical staining for tumor-infiltrating lymphocytes such as CD4, CD8 and Foxp3 was performed. RESULTS: Among 106 patients treated with pembrolizumab, 19 (17.9%) tested high for ANA. Progression-free survival (PFS) and overall survival (OS) were significantly better in patients with high ANA than in those with low ANA, and high ANA was identified as an independent prognostic predictor, particularly in the subgroup with programmed death ligand-1 (PD-L1) ≥ 50%. However, no statistically significant difference in PFS and OS based on the ANA titer was observed in 59 patients treated with combinational chemotherapy and immunotherapy. High numbers of intratumoral Foxp3 and stromal CD8 were significantly associated with low ANA. CONCLUSIONS: Assessment of preexisting ANA titers was useful to prognose PD-1 blockade as a first-line setting, particularly for the PD-L1 ≥ 50% subgroup, but not in the case of combined immunotherapy and chemotherapy.

A Retrospective Study of the Efficacy and Safety of Naldemedine for Treatment of Opioid-Induced Constipation in Patients with Hepatobiliary Pancreatic Cancer.

Background and Objectives: Opioid analgesics, which are used for cancer-related pain management, cause opioid-induced constipation (OIC). Naldemedine, a peripheral opioid receptor antagonist, is an OIC-modifying agent, but no focused efficacy and safety analysis has been conducted for its use in hepatobiliary pancreatic cancers. We performed a multi-institutional study on the efficacy and safety of naldemedine in patients with hepatobiliary pancreatic cancer using opioids in clinical practice. Materials and Methods: We retrospectively evaluated patients with hepatobiliary pancreatic cancer (including liver, biliary tract, and pancreatic cancers) treated with opioids and naldemedine during hospitalization at ten institutions in Japan from June 2017 to August 2019. We assessed the frequency of bowel movements before and after the initiation of naldemedine therapy. Responders were defined as patients who defecated ≥3 times/week, with an increase from a baseline of ≥1 defecations/week over seven days after the initiation of naldemedine administration. Results: Thirty-four patients were observed for one week before and one week after starting naldemedine. The frequency of bowel movements increased by one over the baseline frequency or to at least thrice per week in 21 patients. The response rate was 61.7% (95% confidence interval: 45.4-78.0%). The median number of weekly bowel movements before and after naldemedine treatment was 2 (range: 0-9) and 6 (range: 1-17), respectively, in the overall population (n = 34); the increase in the number of bowel movements following naldemedine administration was statistically significant (Wilcoxon signed-rank test, p < 0.0001). Diarrhea was the predominant gastrointestinal symptom, and 10 (29.4%) patients experienced grade 1, grade 2, or grade 3 adverse events. The only other adverse event included fatigue in one patient; grade 2-4 adverse events were absent. Conclusions: Naldemedine is effective, and its use may be safe in clinical practice for patients with hepatobiliary pancreatic cancer receiving opioid analgesics.

Efficacy and safety of amrubicin monotherapy after atezolizumab plus carboplatin and etoposide in patients with relapsed small-cell lung cancer.

This study examined the activity and safety of amrubicin monotherapy among relapsed small-cell lung cancer (SCLC) patients who had previously been treated with atezolizumab plus carboplatin and etoposide (AteCE). This retrospective study evaluated patients with relapsed SCLC who were treated with previously AteCE combination therapy followed by amrubicin monotherapy between August 2019 and May 2021. Clinical efficacy and toxicity were analyzed. Overall, 40 patients were included: 12 and 28 patients had sensitive and refractory relapse, respectively. The response rate was 32.5% (25.0% in the sensitive group and 35.7% in the refractory group). The median progression-free survival (PFS) and overall survival (OS) from the first amrubicin treatment was 3.4 months (95% CI: 1.9-4.9 months) and 9.9 months (95% CI: 4.5-11.5 months), respectively. There was no significant between-group difference in median PFS (3.6 months vs. 3.2 months, p = 0.42) or median OS (11.2 months vs. 7.3 months, p = 0.78). Grade ≥ 3 hematological adverse events occurred as follows: decreased white blood cells in 52.5% of patients; decreased neutrophil count in 57.5%; and febrile neutropenia in 10.0%. Grade 3 pneumonitis was observed in one patient. There were no treatment-related deaths. Amrubicin is feasible and effective for relapsed SCLC patients previously treated with AteCE therapy. Although immune checkpoint inhibitor treatment (ICI) does not improve the effect of amrubicin, the toxicity is not increased, suggesting that amrubicin remains effective even after ICI administration. Thus, amrubicin after AteCE could be the preferred standard chemotherapeutic choice in patients with relapsed SCLC.

Post-Progression Survival Highly Influences Overall Survival in Driver Gene Mutation/Translocation Negative or Unknown Type of Non-Small Cell Lung Cancer.

INTRODUCTION: In stage I-III non-small cell lung cancer (NSCLC), which is considered operable, surgical resection is the most efficacious treatment and is considered to provide a cure. However, after complete surgical resection, approximately 50% of patients with stage I-IIIA NSCLC experience recurrence and death. Once postoperative recurrence of NSCLC occurs, the prognosis is significantly poor, and the course of treatment after recurrence may influence overall survival (OS). Consequently, we investigated the relationship between relapse-free survival (RFS), post-progression survival (PPS), and OS in patients with postoperative recurrence of NSCLC with driver gene mutation/translocation negative or unknown status. METHODS: Between January 2007 and September 2019, 101 patients with driver gene mutation/translocation negative or unknown status of NSCLC who underwent complete resection and in whom recurrence occurred were analyzed. The associations between RFS, PPS, and OS were analyzed at the individual patient level. RESULTS: Linear regression and Spearman rank correlation analyses revealed that PPS was strongly associated with OS (r = 0.83, p < 0.0001, R2 = 0.71), whereas RFS was moderately correlated with OS (r = 0.65, p < 0.0001, R2 = 0.48). In the multivariate analysis, performance status at relapse, administration of immune checkpoint inhibitors, and radiotherapy for oligo-recurrences were significantly associated with PPS (p < 0.001). CONCLUSION: Current analysis of individual-level data of patients who underwent complete resection implied that PPS had a higher impact on OS than RFS in patients with postoperative recurrence of driver gene mutation/translocation negative or unknown status of NSCLC. Additionally, current perceptions indicate that treatment beyond progression after complete surgical resection might strongly affect OS.

Effects of adding a neurokinin-1 receptor antagonist to 5 mg olanzapine, a 5-hydroxytryptamine-3 receptor antagonist, and dexamethasone for preventing carboplatin-induced nausea and vomiting: a propensity score-matched analysis.

BACKGROUND: Olanzapine has been reported to be an effective antiemetic in patients receiving carboplatin-based chemotherapy. However, the efficacy of a neurokinin-1 receptor antagonist (NK1RA) added to olanzapine, a 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA), and dexamethasone (DEX) has not been proven. This study aimed to assess the efficacy and safety of NK1RA, in combination with three-drug antiemetic regimens containing olanzapine, in preventing nausea and vomiting induced by carboplatin-based chemotherapy. METHODS: Data were pooled for 140 patients receiving carboplatin-based chemotherapy from three multicenter, prospective, single-arm, open-label phase II studies that evaluated the efficacy and safety of olanzapine for chemotherapy-induced nausea and vomiting. The propensity score of the co-administration of NK1RA was estimated for each patient using a logistic regression model that included age, sex, and carboplatin dose. We analyzed a total of 62 patients, who were treated without NK1RA (non-NK1RA group: 31 patients) and with NK1RA (NK1RA group: 31 patients). The patients were selected using propensity score matching. RESULTS: The complete response rate (without emetic episodes or with no administration of rescue medication) in the overall period (0-120 h post carboplatin administration) was 93.5% in the non-NK1RA group and 96.8% in the NK1RA group, with a difference of -3.2% (95% confidence interval, -18.7% to 10.9%; P = 1.000). In terms of safety, there was no significant difference between the groups in daytime sleepiness and concentration impairment, which are the most worrisome adverse events induced by olanzapine. CONCLUSIONS: The findings suggest that antiemetic regimens consisting of olanzapine, 5HT3RA, and DEX without NK1RA may be a treatment option for patients receiving carboplatin-based chemotherapy.

Clinical Outcomes of Postoperative Adjuvant Chemotherapy for Surgically Resected High-Grade Pulmonary Neuroendocrine Carcinoma.

INTRODUCTION: Data on the clinical outcomes of patients receiving adjuvant chemotherapy for surgically resected high-grade pulmonary neuroendocrine carcinoma (HGNEC) (large-cell neuroendocrine carcinoma and small-cell lung cancer) are limited. This study aimed to evaluate the prognostic significance of adjuvant chemotherapy in patients with HGNEC. METHODS: We retrospectively analyzed patients with surgically resected HGNEC at five institutions in Japan between January 2006 and May 2016. RESULTS: A total of 143 patients were enrolled. Among them, 65 received adjuvant chemotherapy. Four patients who participated in clinical trials were excluded; the remaining 61 patients were included in the study. Fifty-six patients received adjuvant small-cell lung cancer-based chemotherapy. Twenty-five of 29 patients who relapsed after postoperative adjuvant chemotherapy received chemotherapy. The most commonly administered chemotherapy agent was amrubicin. The 3-year relapse-free and overall survival rates were 55.2% and 66.8%, respectively. The median relapse-free and overall survival times for the 25 patients who received chemotherapy after relapse were 12.9 and 27.5 months, respectively. Among them, 22 relapsed within 2 years. Patients who received platinum-doublet chemotherapy after relapse tended to have better time to progression disease and overall survival than those who received single-agent chemotherapy. CONCLUSIONS: Most patients with HGNEC received small-cell lung cancer-based regimens as postoperative adjuvant chemotherapy. Those who relapsed after adjuvant chemotherapy were mainly treated with amrubicin. Our findings suggest that platinum-doublet chemotherapy tends to improve the time to progression disease and overall survival in patients who relapse after postoperative adjuvant chemotherapy.

Low-Dose Olanzapine Plus Granisetron and Dexamethasone for Carboplatin-Induced Nausea and Vomiting in Patients with Thoracic Malignancies: A Prospective Multicenter Phase II Trial.

BACKGROUND: Olanzapine is an inexpensive and durable agent for the treatment of chemotherapy-induced nausea and vomiting and is also superior to neurokinin-1 receptor antagonists in the control of nausea. This study aimed to investigate the efficacy and safety of a low dose of 5 mg olanzapine plus granisetron and dexamethasone for treatment of carboplatin (CBDCA)-induced nausea and vomiting in patients with thoracic malignancies. MATERIALS AND METHODS: We conducted a prospective, open-label, single-arm, multicenter, phase II trial in four centers in Japan. Registered patients were scheduled to receive area under the curve (AUC) ≥5 mg/mL per minute of CBDCA and had never received moderately to highly emetogenic chemotherapy. Patients received olanzapine 5 mg/day orally after supper for 4 days, in combination with granisetron and dexamethasone. Primary endpoint was complete response (CR; no emesis and no use of rescue medication) rate during the overall phase (0-120 hours). RESULTS: Between February 2018 and June 2020, 51 patients were enrolled, and 50 patients were evaluated. The CR rates in the overall (0-120 hours), acute (0-24 hours), and delayed phases (24-120 hours) were 94.0%, 100%, and 94.0%, respectively. No grade 3 or higher adverse effects of olanzapine were observed. CONCLUSION: Prophylactic antiemetic therapy with a low dose of 5 mg olanzapine plus granisetron and dexamethasone showed durable efficacy with an acceptable safety profile. This three-drug combination appears to be a reasonable treatment approach in patients with thoracic malignancies receiving an AUC ≥5 mg/mL per minute of CBDCA-based regimen. Clinical trial identification number: UMIN000031267. IMPLICATIONS FOR PRACTICE: The results of this phase II trial indicated that the prophylactic administration of low-dose of 5 mg olanzapine combined with granisetron and dexamethasone has promising activity with acceptable safety profile in patients with thoracic malignancy receiving high-dose carboplatin chemotherapy.

Post-Progression Survival Influences Overall Survival among Patients with Advanced Non-Small Cell Lung Cancer Undergoing First-Line Pembrolizumab Monotherapy.

BACKGROUND: Among patients with non-small cell lung cancer (NSCLC), the impact of first-line treatment on overall survival (OS) may be influenced by subsequent therapies. Thus, using patient-level data, we assessed the relationships of progression-free survival (PFS) and post-progression survival (PPS) with OS among patients with high-programmed death-ligand 1 (PD-L1) expression undergoing first-line pembrolizumab monotherapy for NSCLC. METHODS: We reviewed data from 133 patients with high PD-L1 expression undergoing first-line pembrolizumab monotherapy for NSCLC at 6 Japanese centers between February 2017 and December 2018. The correlations of PFS and PPS with OS were evaluated at the patient level. RESULTS: Linear regression analyses and Spearman's rank correlation coefficient revealed that PPS was strongly correlated with OS (r = 0.76, p < 0.05, R2 = 0.65), while PFS was only moderately correlated with OS (r = 0.71, p < 0.05, and R2 = 0.4). Furthermore, PPS was significantly associated with performance status at the end of pembrolizumab monotherapy, as well as the use of platinum-based combination chemotherapy after pembrolizumab monotherapy (both p < 0.05). CONCLUSIONS: Among patients with high PD-L1 expression undergoing first-line pembrolizumab monotherapy for NSCLC, PPS was more strongly correlated with OS, relative to the relationship between PFS and OS. Therefore, subsequent treatment appears to significantly influence OS in patients with disease progression following first-line pembrolizumab monotherapy.

Efficacy and safety of 5 mg olanzapine for nausea and vomiting management in cancer patients receiving carboplatin: integrated study of three prospective multicenter phase II trials.

BACKGROUND: The efficacy of olanzapine as an antiemetic agent in cancer chemotherapy has been demonstrated. However, few high-quality reports are available on the evaluation of olanzapine's efficacy and safety at a low dose of 5 mg among patients treated with carboplatin regimens. Therefore, in this study, we investigated the efficacy and safety of 5 mg olanzapine for managing nausea and vomiting in cancer patients receiving carboplatin regimens and identified patient-related risk factors for carboplatin regimen-induced nausea and vomiting treated with 5 mg olanzapine. METHODS: Data were pooled for 140 patients from three multicenter, prospective, single-arm, open-label phase II studies evaluating the efficacy and safety of olanzapine for managing nausea and vomiting induced by carboplatin-based chemotherapy. Multivariable logistic regression analyses were performed to determine the patient-related risk factors. RESULTS: Regarding the endpoints of carboplatin regimen-induced nausea and vomiting control, the complete response, complete control, and total control rates during the overall study period were 87.9, 86.4, and 72.9%, respectively. No treatment-related adverse events of grade 3 or higher were observed. The multivariable logistic regression models revealed that only younger age was significantly associated with an increased risk of non-total control. Surprisingly, there was no significant difference in CINV control between the patients treated with or without neurokinin-1 receptor antagonist. CONCLUSIONS: The findings suggest that antiemetic regimens containing low-dose (5 mg) olanzapine could be effective and safe for patients receiving carboplatin-based chemotherapy.

Opioid-induced constipation in patients with cancer pain in Japan (OIC-J study): a post hoc subgroup analysis of patients with lung cancer.

OBJECTIVE: To evaluate the opioid-induced constipation burden in the subgroup of patients with lung cancer who participated in the observational Opioid-Induced Constipation in Patients with Cancer Pain in Japan (OIC-J) study. METHODS: The prospective, observational study, OIC-J, included 212 patients with various tumour types, 33% of whom had lung cancer. The incidence of opioid-induced constipation was evaluated using several diagnostic criteria, as well as the physician's diagnosis and patient's subjective assessment. Following initiation of opioids, patients recorded details of bowel movements (i.e. date/time, Bristol Stool Scale form, sensations of incomplete evacuation or anorectal obstruction/blockage and degree of straining) in a diary for 2 weeks. Relationships between patient characteristics and opioid-induced constipation onset and effects of opioid-induced constipation on quality of life were explored. RESULTS: In total, 69 patients were included in this post hoc analysis. The incidence of opioid-induced constipation varied (39.1-59.1%) depending on which diagnostic criteria was used. Diagnostic criteria that included a quality component or a patient's feeling of bowel movement as an evaluation item (i.e. Rome IV, physician's diagnosis, Bowel Function Index, patient's assessment) showed higher incidences of opioid-induced constipation than recording the number of spontaneous bowel movements alone. Opioid-induced constipation occurred rapidly after initiating opioids and had a significant impact on Patient Assessment of Constipation Symptoms total score (P = 0.0031). Patient baseline characteristics did not appear to be predictive of opioid-induced constipation onset. CONCLUSIONS: In patients with lung cancer, opioid-induced constipation can occur quickly after initiating opioids and can negatively impact quality of life. Early management of opioid-induced constipation, with a focus on quality-of-life improvement and patient's assessments of bowel movements, is important for these patients.

Efficacy and Safety of Anti-Programed Death-1 Blockade in Previously Treated Large-Cell Neuroendocrine Carcinoma.

BACKGROUND: Large-cell neuroendocrine carcinoma (LCNEC) of the lung is a rare tumor with an aggressive clinical course. However, there is limited knowledge of its treatment strategy. This retrospective study aimed to assess the efficacy and safety of anti-programed death-1 (PD-1) blockade monotherapy in previously treated advanced LCNEC. METHODS: Eleven patients with previously treated advanced LCNEC who received immune checkpoint inhibitor monotherapy between January 2015 and November 2020 were retrospectively analyzed for efficacy and safety. RESULTS: Of a total of 11 patients (median [range] age, 66 [37-79] years; 8 men [73%] and 3 women [27%]), 8 patients had performance status (PS) 0-1 [73%] and 3 patients had PS 2 [27%]; 9 patients received 1 prior chemotherapy [82%] and 2 patients received 2 prior chemotherapies [18%]. The median follow-up duration was 4.6 months. Although PD-1 blockade was administered at median cycles of 3 (range, 1-12), overall response rate, median progression-free survival, and median overall survival were 9.1%, 2.7 months, and 4.6 months, respectively. Any adverse events were observed in 9 patients (82%), including 1 patient with grade 3 pneumonitis as a serious adverse event. CONCLUSION: Anti-PD-1 blockade monotherapy as a subsequent line for previously treated advanced LCNEC exhibited usefulness and tolerability and was identified as a valid treatment option.

Opioid-induced constipation in patients with cancer pain in Japan (OIC-J study): a post hoc subgroup analysis of patients with gastrointestinal cancer.

BACKGROUND: Constipation is a common side effect of opioid therapy. An observational study of opioid-induced constipation (OIC) in Japanese patients with cancer (OIC-J) included 212 patients with various tumor types. This post hoc analysis of OIC-J evaluated a subgroup of patients with gastrointestinal (GI) cancer. METHODS: Patients were aged ≥ 20 years, starting strong opioid therapy, had an ECOG PS of ≤ 2, and must have had ≥ 3 bowel movements during the week before enrollment. OIC was evaluated for 2 weeks after opioid initiation using the Rome IV diagnostic criteria for colorectal disorders, as well as physician's diagnosis, number of spontaneous bowel movements, Bowel Function Index score, and patient's self-assessment. Relationships between baseline characteristics and OIC incidence, and the effects of OIC on quality of life (QOL) were also explored. RESULTS: Fifty patients from OIC-J who had GI cancer [colon (50%), stomach (28%), and esophageal (22%)] were included. OIC incidence varied by which diagnostic criteria were used (46.0-62.0%) and occurred rapidly after initiating opioid therapy. The use of prophylactic laxatives reduced the overall incidence rate of OIC from 71.0% to 47.4%. No baseline characteristics, except comorbidities, were associated with OIC incidence. Change from baseline to day 15 in PAC-SYM total score was significantly greater for patients with OIC versus those without OIC (0.188 versus -0.362; P = 0.0011). CONCLUSIONS: This post hoc analysis suggests that OIC occurs rapidly in patients with GI cancer after initiating opioid therapy, and negatively impacts QOL. Early and effective intervention strategies may be particularly useful in this group. ADDITIONAL INFORMATION: Coauthor Makio Gamoh is deceased.

Post-Progression Survival Is Strongly Associated with Overall Survival in Patients Exhibiting Postoperative Relapse of Non-Small-Cell Lung Cancer Harboring Sensitizing EGFR Mutations.

Background and Objective: Patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitizing epidermal growth factor receptor (EGFR) mutations show a good response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). The subsequent treatments influence the evaluability of the efficacy of front-line therapy on overall survival (OS). Consequently, we evaluated the associations of relapse-free survival (RFS) and post-progression survival (PPS) with OS in patients who exhibited postoperative relapse of EGFR-mutated NSCLC. Materials and Methods: We analyzed the data of 35 patients with EGFR-mutated NSCLC who underwent complete resection between January 2007 and June 2019. The correlations of RFS and PPS with OS were evaluated at the individual patient level. Results: Linear regression and Spearman's rank correlation analyses demonstrated that the PPS highly correlated with OS (r = 0.91, p < 0.05, R2 = 0.85), whereas the RFS weakly associated with OS (r = 0.36, p < 0.05, R2 = 0.25). Age and performance status at relapse were significantly associated with PPS. Conclusion: Overall, PPS was more strongly and significantly associated with OS than RFS. These results suggest that the OS of our cohort may be affected by treatments, besides postoperative relapse. However, larger-scale prospective studies are needed to confirm these results.

Clinical Effectiveness of Immune Checkpoint Inhibitors in Non-Small-Cell Lung Cancer with a Poor Performance Status.

Immune checkpoint inhibitors (ICIs) are standard treatments for patients with lung cancer. PD-1/PD-L1 or CTLA4 antibodies are chosen as the first-line therapy, contributing to the long-term survival and tolerability. Unlike molecular targeting agents, such as gefitinib, lung cancer patients with a poor performance status (PS) display unsatisfactory clinical improvements after ICI treatment. Several previous reports also demonstrated that the PS is identified as one of the most probable prognostic factors for predicting poor outcomes after ICI treatment. However, first-line pembrolizumab seemed to be effective for lung cancer patients with a PS of 2 if PD-L1 expression was greater than 50%. Currently, the induction of ICIs in patients with lung cancer with a poor PS is controversial. These problems are discussed in this review.

Effectiveness and Safety of EGFR-TKI Rechallenge Treatment in Elderly Patients with Advanced Non-Small-Cell Lung Cancer Harboring Drug-Sensitive EGFR Mutations.

Background and Objectives: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective first-line chemotherapeutic agents for patients with advanced non-small-cell lung cancer (NSCLC) harboring drug-sensitive EGFR mutations. However, the effectiveness of EGFR-TKI rechallenge after first-line EGFR-TKI treatment is not sufficient in elderly patients (over 75 years of age) harboring drug-sensitive EGFR mutations. Therefore, we investigated the effectiveness and safety of EGFR-TKI rechallenge after first-line EGFR-TKI treatment in elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations. Materials and Methods: Between April 2008 and December 2015, we analyzed 78 elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations with first-line EGFR-TKI treatment at four Japanese institutions. We retrospectively evaluated the clinical effectiveness and safety profiles of EGFR-TKI rechallenge after first-line EGFR-TKI treatment in elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations (exon 19 deletion/exon 21 L858R mutation). Results: Twenty-two patients in the cohort were rechallenged with EGFR-TKI. The median age was 79.5 years (range 75-87 years). Despite the fact that it was a retrospective analysis, even with EGFR-TKI rechallenge treatment the response rate was 23%, progression-free survival was 5.3 months, and overall survival was 14.4 months. Common adverse events included rash acneiform, paronychia, diarrhea, and anorexia. There were no treatment-related deaths. Due to the occurrence of adverse events of grade 2 or more, dose reduction was performed in 15 (68.2%) of 22 cases. Conclusions: EGFR-TKI rechallenge treatment after first-line EGFR-TKI treatment in elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations was one of the limited, safe and effective treatment options for elderly EGFR-positive lung cancer patients.

Effects of Sex and Seasonal Climatic Changes on the Risk of Incidence of Anti-EGFR Therapy-Induced Rash in Cancer Patients: A Retrospective Study.

Background and Objectives: Seasonal climatic changes may affect the development of the rash that is characteristic of treatment with anti-epidermal growth factor receptor (EGFR) antibodies. We evaluated the association between seasons and rash incidence among patients with cancer. Materials and Methods: Data from patients with colorectal or head and neck cancer treated with cetuximab or panitumumab during summer (S group; n = 34) or winter (W group; n = 37) between June 2014 and February 2019 were collected to retrospectively examine patient characteristics and rash incidence ≤ 8 weeks after treatment initiation. Results: Rashes were observed in 73.5% (n = 25) and 78.4% (n = 29) and grade 3 rashes were observed in 17.6% (n = 6) and 2.7% (n = 1) of the patients in the S and W groups, respectively. The incidence of grade ≥ 2 rashes in males in the S group was higher than that in the rest of the patient groups (p < 0.01). Conclusions: The higher incidence of skin rashes in males during summer might be attributed to the effects of ultraviolet light, lack of skincare, male hormones, and secretion of anti-EGFR antibodies in sweat. These findings highlight the need for research on preventive measures for such rashes.