Anti-CTLA-4 Antibody Might Be Effective Against Non-small Cell Lung Cancer With Large Size Tumor.

BACKGROUND/AIM: Immunotherapy using immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). Although several ICI options are available, the treatment regimen for NSCLC with large size tumors (large NSCLC) is controversial and the efficacy of anti-CTLA-4 antibody is unclear. This study thus investigated potential biomarkers for CTLA-4 blockade. PATIENTS AND METHODS: The correlation between tumor diameter and treatment duration was examined in patients with advanced NSCLC treated with anti-PD-1 antibody monotherapy in our institution. In addition, the ratio of tumor-infiltrating CD8+ T cells and regulatory T (Treg) cells in small and large size NSCLC was also evaluated using immunohistochemical staining. Finally, the efficacy of treatment with anti-CTLA-4 antibody against large NSCLC was investigated. RESULTS: A negative correlation was found between tumor diameter and treatment duration in patients treated with anti-PD-1 antibody monotherapy. Immuno-histochemical staining revealed that Treg cell infiltration was significantly higher in large NSCLC tumors than in small tumors. Among the patients with large NSCLC, the ICI regimen including anti-CTLA-4 antibody showed significant efficacies. CONCLUSION: Anti-PD-1 antibody monotherapy might be less effective against large NSCLC due to the infiltration of Treg cells. Therefore, it might be appropriate for large NSCLC to select a treatment including an anti-CTLA-4 antibody, which can target Treg cells.

An Liquid Chromatography-Tandem Mass Spectrometry Method for the Simultaneous Determination of Afatinib, Alectinib, Ceritinib, Crizotinib, Dacomitinib, Erlotinib, Gefitinib, and Osimertinib in Human Serum.

BACKGROUND: Routine therapeutic drug monitoring is a promising approach for the rational use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and anaplastic lymphoma kinase (ALK) inhibitors. The purpose of this study was to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of 5 EGFR-TKIs (afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib) and 3 ALK inhibitors (alectinib, ceritinib, and crizotinib). METHODS: A 100-mL aliquot of serum was diluted with 100 µL of 1% aqueous ammonia containing internal standards and then purified using the supported liquid extraction method. LC-MS/MS was conducted in positive ionization mode, and the method was validated according to published guidelines. RESULTS: Calibration curves were linear across concentration ranges examined. The intra- and interassay accuracies were 90.7%-110.7% and 94.7%-107.6%, respectively. All intra- and interassay imprecision values were ≤10.1%. The EGFR-TKIs and ALK inhibitors examined in this study, except osimertinib, which could be stored on ice for at least 5 hours, were stable at room temperature for 3 hours. For the internal standard-normalized matrix factors, the mean recovery and percent coefficient of variation values ranged between 54%-112% and 1.7%-11.7%, respectively. This method successfully determined serum concentrations of afatinib, alectinib, erlotinib, gefitinib, and osimertinib in clinical samples. Serum levels of kinase inhibitors consistently reflected those reported in previous studies. CONCLUSIONS: An LC-MS/MS method suitable for the simultaneous determination of 5 EGFR-TKIs and 3 ALK inhibitors in serum was developed and validated. The newly developed method enabled the determination of 5 of 8 target drugs examined in clinical samples. However, a large number of clinical samples need to be analyzed to verify the usefulness of the method.

Effect of Systemic Corticosteroid Therapy on the Efficacy and Safety of Nivolumab in the Treatment of Non-Small-Cell Lung Cancer.

INTRODUCTION: Corticosteroids are used to treat immune-related adverse events (irAEs) associated with nivolumab. However, patients with non-small-cell lung cancer who are administered corticosteroids before the initiation of nivolumab treatment are commonly excluded from clinical trials. The appropriate timing for corticosteroid administration in relation to nivolumab treatment, effects of corticosteroids on the efficacy of nivolumab, and resulting adverse events are not clearly understood. In this study, the effects of differences in the timing of corticosteroid administration on nivolumab efficacy and the resulting adverse events were examined. METHODS: A retrospective study was conducted with 109 patients who were treated with nivolumab at Sapporo Minami-Sanjo Hospital between December 2015 and March 2018. RESULTS: Of the 109 patients treated with nivolumab, 12 patients were administered corticosteroids before the first cycle of nivolumab (pre-CS), and 33 patients were administered corticosteroids after the first cycle of nivolumab (post-CS). These 2 groups were compared with the control group comprising 64 patients who were not administered corticosteroids (non-CS). The objective response rate in the post-CS group was significantly higher than that in the non-CS group, and the disease control rate in the pre-CS group was significantly lower than that in the non-CS group. The overall survival time and progression-free survival time in the pre-CS group were significantly shorter than those observed in the non-CS group; however, these did not differ from those in the post-CS group. CONCLUSIONS: These results suggest that corticosteroids administered to patients with non-small-cell lung cancer after initiation of nivolumab treatment did not affect the disease prognosis. Thus, corticosteroids can be administered immediately for rapid treatment of irAEs.

Large Cell Neuroendocrine Carcinoma Harboring an Anaplastic Lymphoma Kinase (ALK) Rearrangement with Response to Alectinib.

Anaplastic lymphoma kinase (ALK) rearrangement is most commonly observed in lung adenocarcinoma in a subset of lung cancer. Large cell neuroendocrine carcinoma (LCNEC) harboring an ALK rearrangement is very rare. Based on the findings from a transbronchial lung biopsy, a 75-year-old non-smoking woman was diagnosed with LCNEC with multiple liver and bone metastases. After seven cycles of cytotoxic chemotherapy, her genotype testing demonstrated ALK rearrangement. Subsequently, she was administered alectinib and exhibited a partial response.

[Comparative Study of the Antiemetic Palonosetron for Lung Cancer Patients Treated with a Divided Dose of Cisplatin].

Palonosetron(Palo)is a second-generation 5-hydroxytryptamine 3 receptor antagonist(5-HT3RA)effective in suppressing chemotherapy-induced nausea and vomiting in both acute and delayed phases.Most studies have reported Palo as an effective antiemetic for cisplatin(CDDP)chemotherapy(≥50mg/m2)administered on an intermittent basis.To assess the antiemetic efficacy of Palo, we performed a retrospective study in 16 patients with lung cancer who received Palo with split-dose CDDP, ifosfamide, and irinotecan(CPT-11)triple combination(CIC)therapy at Sapporo Minami-Sanjo Hospital between October 2010 and January 2012.T he CIC regimen consisted of CPT-11(50-60mg/m2)administered on days 1, 8, and 15, in addition to CDDP(15-20mg/m2)and ifosfamide(1,500mg/kg)for 4 consecutive days.On day 1, ramosetron was replaced with Palo in patients who had insufficient antiemetic control in accordance with guidelines on the management of highly emetogenic chemotherapy(HEC).There was a lower incidence of grade 1 or higher nausea(62.5%)in patients in the Palo-combination group than in those in the non-Palo-combination group(87.5%).No incidence of grade 3 or higher nausea was reported in either group.On the fifth day of chemotherapy, the incidence of nausea was significantly lower in the Palo-combination group(43.8%)than in the non-Palo-combination group(81.3%)(p<0.05).In addition, there was a significant decrease in the number of days of incidence and a significant increase in the number of days since the last episode was observed in the Palo-combination group.These results suggest that Palo, in particular, decreases the incidence of nausea and extends the number of days since its occurrence; moreover, it is effective in accelerating recovery.In conclusion, this study suggests that Palo exhibits excellent antiemetic efficacy in patients administered split doses of CDDP.

[Comparative study of an antiemetic NK1 receptor-antagonist in lung cancer patients treated with divided doses for Cisplatin].

Aprepitant is a NK1 receptor-antagonist with a novel mechanism of action for chemotherapy-induced nausea and vomiting (CINV), and is recommended as a prophylactic by many international and domestic guidelines. However, domestic clinical trials of aprepitant have only been conducted using a single dose in patients who were treated with cisplatin(CDDP), and there is no evidence to support administration of aprepitant in divided doses. We administered aprepitant in divided doses to patients who were also being treated with cisplatin, ifosfamide, and irinotecan(CIC), and had CINV due to prophylactic administration of a 5-HT3 receptor antagonist and dexamethasone. This was done in order to evaluate the antiemetic effect of aprepitant. The patients with"No vomiting"increased significantly from 25% to 83%, and the"Days with nausea"in patients also decreased significantly. Consequently, administration of aprepitant in addition to current antiemetic therapy in divided doses, as well as in single doses, exhibited a greater antiemetic effect in CDDP-treated patients.

[Comparison of ramosetron and azasetron for prevention of acute and delayed cisplatin-induced emesis in lung cancer patients].

We performed a retrospective study that compared the efficacy and safety of ramosetron with azasetron in a case of acute and delayed emesis induced by cisplatin (CDDP)-included chemotherapy in patients with lung cancer. The study subjects were 100 lung cancer patients treated with combination therapy of cisplatin, ifosfamide, irinotecan (CIC therapy). The ramosetron group and azasetron group received, respectively, ramosetron 0.3 mg or azasetron 10 mg intravenous injection, 30 minutes prior to CDDP. All patients received 32 mg of dexamethasone intravenously. Protection from emesis showed no significant difference between two treatment groups. However, the grade of nausea was significantly lower in the ramosetron group than in the azasetron group. Furthermore, chlorpromazine hydrochloride for use as a rescue medication was required by significantly fewer in the ramosetron group than in the azasetron group. Adverse effects were observed in 27 cases in the ramosetron group and 24 cases in the azasetron group. However, because the symptoms were all mild, we did not consider there was any safety problem. In conclusion, it was suggested that ramosetron is a clinically useful treatment for acute and delayed emesis induced by cisplatin-induced chemotherapy in patients with lung cancer.

[Comparison of dexamethasone 8 mg and 16 mg for the prevention of acute and delayed cisplatin-induced emesis in patients with lung cancer].

We performed a retrospective study that compared the efficacy and safety of dexamethasone (DEX) 8 mg with DEX 16 mg in cases of acute and delayed emesis induced by cisplatin (CDDP) chemotherapy in patients with lung cancer. Sixty-eight lung cancer patients treated with combination cisplatin, ifosfamide, and irinotecan therapy were studied. The DEX 8 mg group and the DEX 16 mg group received DEX intravenous injection 30 min prior to CDDP. All patients then received a 5-HT(3) antagonist intravenous injection 30 min before CDDP. Protection from acute nausea (day 1) was significantly superior in the DEX 16 mg group compared with the DEX 8 mg group (DEX 8 mg, 76.5%; DEX 16 mg, 100%). Protection from delayed emesis (day 1) was significantly superior in the DEX 16 mg group compared with the DEX 8 mg group. There was no reported severe nausea (grade 3) and vomiting (grade 2) in the DEX 16 mg group. Furthermore, perphenazine hydrochloride for use as rescue medication was required by significantly fewer patients in the DEX 16 mg group than in the DEX 8 mg group (DEX 8 mg, 41.2%; DEX 16 mg, 0%). Adverse effects were observed in 10 cases (nine reports of generalized fatigability, two of headache) in the DEX 8 mg group and in 16 cases (11 reports of generalized fatigability, one of pruritus) in the DEX 16 mg group. However, because the symptoms were all mild, we did not consider that there was any safety problem. In conclusion, DEX 16 mg is a clinically useful treatment for acute and delayed emesis induced by cisplatin-induced chemotherapy in patients with lung cancer.

Establishment of pharmaceutical management for patient care during lung cancer chemotherapy and its quantitative evaluation.

Pharmacists should play an important role in controlling the pharmaceutical management of the patients. Although the quantitative evaluations of pharmaceutical management are required systematically, no guideline is presented for patient care during lung cancer chemotherapy. We established a complete pharmaceutical management system and evaluated the performance of the system. Patients admitted to Hokkaido Keiaikai Minami-ichijo Hospital for lung cancer chemotherapy treatment from 2003.5 to 2003.11 were enrolled in this study after signing formal written consents. The pharmaceutical management system that was established involves a unified system consisting of a standard care plan and worksheets by the Problem Oriented System (POS). The system can apply to inpatients for their comprehensive evaluation of pharmaceutical management. The incidence of pharmaceutical problems reported, pharmacist interventions to the physicians, and the bedside pharmaceutical management were increased significantly after applying the system. More than 98% acceptance of interventions by pharmacists to the physicians was indicated. A high rate of intervention for adverse drug reaction (ADR) was demonstrated, due to the information about patient conditions is essential in managing ADR. The total pharmaceutical management system established is expected to give quality improvements of pharmaceutical care along with its efficiency.

Phase I study of carboplatin, irinotecan and docetaxel on a divided schedule with recombinant human granulocyte colony stimulating factor support in patients with stage IIIB or IV non-small cell lung cancer.

A phase I study was conducted to determine dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of carboplatin combined with irinotecan and docetaxel on a divided schedule with recombinant human granulocyte colony stimulating factor (rhG-CSF) support in patients with stage IIIB or IV non-small cell lung cancer. Carboplatin was given at the dose of AUC5 on day 1. Irinotecan and docetaxel on days 1 and 8 were administered at a starting dose of 40 and 30 mg/m2 as level 1. Subsequent levels were: irinotecan/docetaxel (in mg/m2), 50/30 (level 2), 60/30 (level 3) and 60/35 (level 4). rhG-CSF was given at 50 mg/m2 on days 5-15. Cycles were repeated every 3 weeks. Between May 1999 and April 2001, 31 patients were registered in this phase I study. Level 4 was judged as the MTD. The DLTs were considered diarrhea and febrile neutropenia. The overall response rate was 32.3% and median survival was 490 days with 1-year survival of 65.1%. We conclude that both irinotecan 60 mg/m2 and docetaxel 30 mg/m2 on days 1 and 8 in combination with an AUC5 of carboplatin on day 1 with rhG-CSF support is recommended for phase II study. The response rate and survival data in this phase I study are encouraging. We considered that the pathogenesis of diarrhea involved not only direct cytotoxic damage to the mucosa, but also bacterial overgrowth.