Outcomes of immune checkpoint inhibitor-induced liver toxicity managed by hepatologists in a multidisciplinary toxicity team.

AIM: To detect immune-related adverse events (irAEs) early and treat them appropriately, our institute established an irAE-focused multidisciplinary toxicity team in cooperation with various departments. This study aimed to evaluate a consultation system involving a team of hepatologists in terms of its utility for the management of severe immune checkpoint inhibitor (ICI)-induced liver toxicity. METHODS: To analyze the diagnosis and treatment of severe ICI-induced liver toxicity (Grade 2 requiring corticosteroid therapy and Grade 3 or higher), we examined patients' clinical courses before and after the hepatologist consultation system was established (pre-period, September 2014 to February 2019; post-period, March 2019 to March 2023). RESULTS: The median follow-up period was 392 days. Of the 1247 patients with advanced malignancies treated with ICIs, 66 developed severe ICI-induced liver toxicity (n = 22 and 44 in the pre- and post-periods, respectively). In the pre-period, hepatologist consultations were sought for 15/22 patients, whereas in the post-period, 42/44 patients were referred to and treated by hepatologists. The time from the onset of liver toxicity to the consultation was significantly shorter in the post-period than in the pre-period (mean 1.9 vs. 6.5 days, respectively; p = 0.012). The number of patients with a biopsy-confirmed diagnosis of ICI-induced liver toxicity was significantly higher in the post-period than in the pre-period (n = 22 vs. n = 3, respectively; p = 0.006). Finally, there were no cases of immune-related cholangitis in the pre-period, compared to five cases in the post-period. CONCLUSION: A hepatologist consultation system in an irAE-focused multidisciplinary toxicity team is useful for managing severe ICI-induced liver toxicity.

Durvalumab plus carboplatin-etoposide treatment in a patient with small-cell lung cancer on hemodialysis: a case report and literature review.

Little is known about the efficacy and safety of durvalumab plus carboplatin-etoposide treatment in patients with extensive-disease (ED) small-cell lung cancer (SCLC) on hemodialysis. Here, we present a case of a 67-year-old man with pleuroperitoneal communication on continuous ambulatory peritoneal dialysis who was diagnosed with ED-SCLC based on a cytological analysis of the peritoneal fluid. He was switched from peritoneal dialysis to hemodialysis and received durvalumab (1500 mg/body on day 1) plus carboplatin (area under the concentration-time curve = 5, 125 mg on day 1) and etoposide (50 mg/m2 on days 1 and 3) as first-line therapy. During the first cycle, grade 2 anemia, grade 3 neutropenia, and grade 3 upper gastrointestinal bleeding occurred; therefore, durvalumab and reduced doses of carboplatin and etoposide were administered. No other severe adverse events occurred, and a partial response was observed after four cycles. Our findings indicate that durvalumab plus carboplatin-etoposide treatment is safe and effective even in patients on hemodialysis.

Potential drug interactions between pazopanib and proton pump inhibitors/potassium-competitive acid blockers in patients with soft tissue sarcoma.

Because absorption of the oral drug pazopanib depends on gastric pH, concomitant use of proton pump inhibitors (PPIs)/potassium-competitive acid blockers (P-CABs) may inhibit pazopanib absorption by elevating the gastric pH. This study investigated to what extent the concomitant use of PPIs/P-CABs affects treatment with pazopanib in patients with soft tissue sarcoma. We retrospectively reviewed the medical records of patients with soft tissue sarcoma who had received at least one dose of pazopanib at our institution, among which those who had received concomitant PPIs/P-CABs were included in this analysis. Using paired sample t tests, the frequency of dose reduction or interruption of pazopanib and the major adverse events (AEs) were compared in each patient between periods with and without PPIs/P-CABs. Between January 2018 and December 2022, eight patients were eligible. The median time to treatment failure (TTF) was 3.9 months (2.1-38.2 months). Two patients received concomitant PPIs/P-CABs throughout their treatment with pazopanib. Among the other six patients, dose reduction or interruption of pazopanib occurred less frequently (P = 0.021), and neutropenia tended to be milder (P = 0.155) with the concomitant use of PPIs/P-CABs. Although the concomitant use of PPIs/P-CABs had no apparent effect on TTF in patients undergoing pazopanib treatment, dose reduction or interruption of pazopanib occurred less frequently, and neutropenia was milder, suggesting that concomitant use of PPIs/P-CABs might decrease the pharmacological activity of pazopanib. Supplementary Information: The online version contains supplementary material available at 10.1007/s13691-023-00638-2.

Adjustment of creatinine clearance for carboplatin dosing in Calvert's formula and clinical efficacy for lung cancer.

BACKGROUND: The Cockcroft-Gault formula is commonly used as a substitute for glomerular filtration rate (GFR) in Calvert's formula for carboplatin dosing, where adjusting serum creatinine measured using the enzymatic method with 0.2 mg/dL has been suggested in Japan. However, the effects of these adjustments on efficacy in patients with non-small-cell lung cancer remain unknown. METHODS: We conducted a post hoc analysis of the PREDICT1 study (CJLSG1201), a multicenter prospective observational trial of carboplatin-pemetrexed. Glomerular filtration rate values in Calvert's formula were back-calculated from the administered dosages of carboplatin and the reported value of the target area under the curve. We estimated the serum creatinine adjustments and divided the patients into crude and adjusted groups. RESULTS: Patients in the crude group (N = 169) demonstrated similar efficacy to those in the adjusted group (N = 104) in progression-free survival (PFS) and overall survival (OS) (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.76-1.35; p = 0.916 vs. HR, 0.87; 95% CI, 0.65-1.17; p = 0.363), with higher grade 3-4 hematologic toxicity. Among patients aged ≥75 years, the crude group (N = 47) showed superior efficacy compared with the adjusted group (N = 17) in PFS and OS (HR, 0.37; 95% CI, 0.20-0.69; p = 0.002 vs. HR, 0.43; 95% CI, 0.23-0.82; p = 0.010). CONCLUSIONS: Serum creatinine adjustment may be associated with similar efficacy compared to the crude serum creatinine value. In older patients, the adjustment should be cautiously applied owing to the potential for reduced efficacy.

A rapid and durable response to larotrectinib in a patient with NTRK fusion-positive secretory carcinoma originating from the external auditory canal.

For decades, no clear consensus existed on the standard treatment option for malignant tumors of the external auditory canal, an extremely rare disease. Here we report the case of a 55-year-old female patient with secretory carcinoma that originated from the left external auditory canal. Magnetic resonance imaging (MRI) at baseline showed that the tumor had extended to the medulla oblongata despite surgical and radiation treatments for more than 20 years from the initial diagnosis. Based on the results of a next-generation sequencing test of a formalin-fixed paraffin-embedded surgical specimen indicating that the tumor harbored ETV6-NTRK3 fusion, the patient was enrolled in a global basket study of larotrectinib, an oral selective tropomyosin receptor kinase (TRK) inhibitor. Three weeks after the start of larotrectinib treatment, MRI showed only small remnants of the tumor in the medulla oblongata and the patient's headache before the treatment had disappeared. Subsequent MRI after 12 weeks of treatment confirmed the complete disappearance of the tumor. The patient repeated grade 2 flu-like symptoms related to treatment, but did not experience any other grade 2 or worse treatment-related adverse events. TRK inhibitors, such as larotrectinib, exert potent antitumor activity against neurotrophic tyrosine receptor kinase (NTRK) fusion-positive tumors in a tumor-agnostic manner. To the best of our knowledge, this is the first report on NTRK fusion-positive secretory carcinoma of the external auditory canal, and this report provides a valuable insight into the management of the extremely rare but now treatable malignancy.

Direct Observation of Retinal Microvessels in Cancer Patients After Systemic Administration of Bevacizumab and Oxaliplatin.

BACKGROUND/AIM: Antiangiogenic chemotherapy is the backbone of the various anticancer therapies. To date no practical biomarker predicting their antitumor effects and toxicity has been reported. We aimed to determine the feasibility of direct retinal observation as a practical biomarker in antiangiogenic chemotherapy. PATIENTS AND METHODS: By direct retinal observation using a nonmydriatic retinal camera, we measured retinal microvessel diameters in 10 patients with colorectal cancer before and after intravenous infusion of bevacizumab and oxaliplatin. All patients also received oral capecitabine during their therapy. RESULTS: Retinal microvessel diameters were decreased from baseline temporarily by 14.5±6.5% after infusion of bevacizumab and oxaliplatin in five patients who responded to treatment and 8.8±6.2% in the other five patients (p=0.008). CONCLUSION: Measurement of retinal microvessel diameters by direct observation appears to be feasible in patients receiving systemic chemotherapy. The decrease of retinal microvessel diameters might indicate improved tumor response to treatment with bevacizumab-containing systemic chemotherapy.

Vitiligo and tumor response in a patient with amelanotic melanoma undergoing nivolumab treatment.

Vitiligo, an acquired depigmenting disorder of the skin that reacts against normal melanocytes, sometimes occurs as an immune-related adverse event in the treatment of melanoma with immune checkpoint inhibitors. It has been known that the occurrence of vitiligo is associated with a favorable therapeutic response in patients with melanoma, but it is not yet clear whether the association also applies to amelanotic melanoma, a minor subtype of melanoma with little or no melanin pigmentation. We report a patient with amelanotic melanoma of the esophagus who responded well to nivolumab treatment. Shortly after the tumor response, vitiligo was found on the patient's forearms. This case suggests that the occurrence of vitiligo is associated with a favorable response to nivolumab treatment for amelanotic melanoma.

Drug-induced thrombocytopenia associated with trastuzumab in a patient with HER2-positive recurrent gastric cancer.

Here, we report a 57-year-old female patient with HER2-positive recurrent gastric cancer who experienced drug-induced thrombocytopenia associated with trastuzumab, a humanized anti-HER2 monoclonal antibody. Shortly after the initiation of S-1, oxaliplatin, and trastuzumab chemotherapy, the patient experienced severe thrombocytopenia and did not respond to platelet transfusions. Based on the findings of increased numbers of polynuclear megakaryocytes in the bone marrow and an elevated level of platelet-associated IgG (PA-IgG), the patient was diagnosed with drug-induced thrombocytopenia (DITP). The platelet count recovered rapidly with oral prednisolone (1 mg/kg). Since we initially suspected oxaliplatin as the causal agent, S-1 was restarted as a monotherapy, followed by trastuzumab after a 3-week interval, without oxaliplatin. On the second day after the addition of trastuzumab, severe thrombocytopenia occurred again, which suggests that trastuzumab was responsible for the DITP. The patient no longer experienced severe thrombocytopenia during the subsequent S-1 and oxaliplatin chemotherapy, which supports this hypothesis.

Correction to: Vitiligo and tumor response in a patient with amelanotic melanoma undergoing nivolumab treatment.

[This corrects the article DOI: 10.1007/s13691-021-00515-w.].

Increased Risk of Thyroid Dysfunction by PD-1 and CTLA-4 Blockade in Patients Without Thyroid Autoantibodies at Baseline.

BACKGROUND: Previous studies showed that although the risk of thyroid dysfunction [thyroid immune-related adverse events (irAEs)] induced by anti-programmed cell death-1 antibodies (PD-1-Ab) was as low as 2% to 7% in patients negative for anti-thyroid antibodies (ATAs) at baseline, it was much higher (30%-50%) in patients positive for ATAs. However, whether a similar increase occurs with combination therapy using PD-1-Ab plus anti-cytotoxic T-lymphocyte antigen-4 antibody (CTLA-4-Ab) is unknown. METHODS: A total of 451 patients with malignancies treated with PD-1-Ab, CTLA-4-Ab, or a combination of PD-1-Ab and CTLA-4-Ab (PD-1/CTLA-4-Abs) were evaluated for ATAs at baseline and for thyroid function every 6 weeks for 24 weeks after treatment initiation and then observed until the last clinical visit. RESULTS: Of the 451 patients, 51 developed thyroid irAEs after immunotherapy [41 of 416 (9.9%) treated with PD-1-Ab, 0 of 8 (0%) treated with CTLA-4-Ab, and 10 of 27 (37.0%) treated with PD-1/CTLA-4-Abs]. The cumulative incidence of thyroid irAEs was significantly higher in patients who were positive vs negative for ATAs at baseline after both PD-1-Ab [28/87 (32.2%) vs 13/329 (4.0%), P < 0.001] and PD-1/CTLA-4-Abs [6/10 (60.0%) vs 4/17 (23.5%), P < 0.05] treatments. The risk of thyroid irAEs induced by PD-1/CTLA-4Abs, which was significantly higher than that induced by PD-1-Ab, in patients negative for ATAs at baseline was not statistically different from that induced by PD-1-Ab in patients positive for ATAs at baseline. CONCLUSIONS: This study showed that the incidence of thyroid irAEs was high and not negligible after PD-1/CTLA-4-Abs treatment even in patients negative for ATAs at baseline.

Prognostic impact of immune-related adverse events on patients with and without cardiovascular disease: a retrospective review.

BACKGROUND: The emergence of immune checkpoint inhibitors (ICIs) has brought about a paradigm shift in cancer treatment as the use of these drugs has become more frequent and for a longer duration. As a result of T-cell-mediated inflammation at the programmed cell death-1, programmed death-ligand-1, and cytotoxic T-lymphocyte antigen-4 pathways, immune-related adverse events (irAEs) occur in various organs and can cause a rare but potentially induced cardiotoxicity. Although irAEs are associated with the efficacy of ICI therapy and better prognosis, there is limited information about the correlation between irAEs and cardiotoxicity and whether the benefits of irAEs apply to patients with underlying cardiovascular disease. This study aimed to investigate the association of irAEs and treatment efficacy in patients undergoing ICI therapy with and without a cardiovascular history. METHODS: We performed a retrospective review of the medical records of 409 consecutive patients who received ICI therapy from September 2014 to October 2019. RESULTS: Median patient age was 69 years (29.6% were female). The median follow-up period was 278 days. In total, 69 (16.9%) patients had a history of any cardiovascular disease and 14 (3.4%) patients experienced cardiovascular irAEs after ICI administration. The rate of cardiovascular irAEs was higher in patients with prior non-cardiovascular irAEs than without. The prognosis of patients with irAEs ( +) was significantly better than that of the patients without irAEs (P < 0.001); additionally, this tendency did not depend on the presence or absence of a cardiovascular history. Furthermore, the Cox proportional hazards analysis revealed that irAEs were an independent predictor of mortality. CONCLUSIONS: Although cardiovascular irAEs may be related to prior non-cardiovascular irAEs under ICI therapy, the occurrence of irAEs had a better prognostic impact and this tendency was not affected by cardiovascular history.

Guidelines for clinical evaluation of anti-cancer drugs.

Clinical studies intended for regulatory approval must demonstrate the clinical benefits of the drug in a target population. Clinical development of a drug proceeds by stepwise clinical studies; after safety and pharmacokinetics are evaluated and the recommended dosage and administration are determined, efficacy and safety are evaluated in an exploratory manner, and finally clinical benefits are compared with conventional standard therapies. Guidelines for the clinical evaluation of anti-cancer drugs in Japan were established in 1991 and amended in 2006 after molecular-targeted drugs were introduced. Recent progress in the development of drugs acting on the immune system and cancer genomic medicine targeting rare but important molecular subtypes have altered the strategy for development of anti-cancer drugs. It is often difficult to conduct a confirmatory randomized controlled study using overall survival as the primary endpoint in rare molecular subtypes, and the primary evaluation of the efficacy of some drugs and subsequent approval is based on the tumor response. As conducting clinical studies for rare subtypes solely within Japan is difficult, drug development needs to be conducted within a global study. However, this requires robust monitoring to detect possible ethnic differences in pharmacokinetics and drug efficacy. Development using the conditional approval system for drugs enforced in 2020 may be considered, when clinical utility is evaluated based on surrogate endpoints. Because of these changes, we have revised the guidelines for the clinical evaluation of anti-cancer drugs in Japan. To promote global development of anti-cancer drugs involving Japan, the guidelines have been translated into English.

Phase I study of the antiprogrammed cell death-1 Ab spartalizumab (PDR001) in Japanese patients with advanced malignancies.

Spartalizumab is a humanized IgG4/κ mAb directed against human programmed cell death-1 (PD-1). In this phase I study, we investigated safety, pharmacokinetics, preliminary antitumor activity, and toxicity of spartalizumab in patients with advanced malignancies. Patients (n = 18) with a range of tumor types received spartalizumab i.v. at doses of 1, 3, and 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or discontinuation at the discretion of the investigator or patient. Most patients (61%) had received five or more prior lines of therapy. No dose-limiting toxicities were reported and, hence, the maximum tolerated dose was 10 mg/kg or more. Pharmacokinetics in Japanese patients aligned with those reported in a global dose-escalation study. The safety profile was consistent with other approved anti-PD-1 mAbs; the most common drug-related adverse events were maculopapular rash (22%), followed by malaise and increased blood alkaline phosphatase (11% each). Partial responses were reported in two patients (11%), one with transitional cell carcinoma and the other with hepatocellular carcinoma. In conclusion, this study confirmed the safety of spartalizumab given at a dose of up to 10 mg/kg every 2 weeks in Japanese patients with cancers.

Solitary fibrous tumor/hemangiopericytoma treated with temozolomide plus bevacizumab: a report of four cases and literature review.

Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a rare tumor derived from mesenchymal tissue. Although standard chemotherapy for SHT/HPC has not been established, temozolomide plus bevacizumab (TMZ+Bev) therapy for SFT/HPC has been reported. The effectiveness and safety of TMZ+Bev (temozolomide 150 mg/m2 orally on days 1-7 and days 15-21 and bevacizumab 5 mg/kg intravenously on day 8 and day 22 on a 28-day cycle), which was administered from December 2013 until April 2019 to four patients with SFT/HPC, were retrospectively analyzed. Four patients with SFT/HPC received TMZ+Bev. The age of the patients ranged from 41 to 75 years. Two were male, and the primary tumor sites were the meninges in three patients and the pleura in one. One achieved partial response; the others, stable disease (SD). The progression-free survival time ranged from 9.4 to 29.6 months according to RECIST v1.1. One patient died 59 months after using TMZ+Bev, and the others survived for 17 to 64 months. All patients experienced Grade 3 or higher lymphopenia, and three had Grade 3 or higher leukopenia and neutropenia. One patient subsequently received doxorubicin; another, pazopanib. TMZ+Bev therapy for SFT/HPC is safe and effective for maintaining long-term SD.

Chemotherapy for biliary tract cancer: real-world experience in a single institute.

The standard chemotherapy regimen for unresectable or recurrent biliary tract cancer is gemcitabine combined with cisplatin (GC). To evaluate the effectiveness and safety of chemotherapy in patients with unresectable or recurrent biliary tract cancer in the real world, we retrospectively analyzed the clinical courses of patients who underwent chemotherapy with GC from January 2015 to November 2019. Forty-eight patients underwent the GC regimen. One patient (2.1%) achieved a complete response, seven patients (14.6%) achieved a partial response, 26 patients (54.2) achieved stable disease, 11 patients (22.9%) achieved progressive disease, and 3 patients (6.3%) were not evaluable. The overall response rate was 16.7%. The median overall survival was 14.2 months (95% CI: 13.8-14.6), and the median progression-free survival was 7.7 months (95% CI: 4.2-11.2). Thirty-nine patients (81.3%) experienced grade 3 or higher severe adverse events as follows: 54.2% experienced neutropenia, 20.8% experienced anemia, 12.5% experienced thrombocytopenia and 20.8% experienced biliary tract infection. As a second-line chemotherapy, S-1 was used in seventeen patients, and stable disease was achieved in three patients (17.6%). The GC regimen for biliary tract cancer is effective and safe for unresectable or recurrent biliary tract cancer in routine clinical practice.

Correlation Between the Metabolic Conversion of a Capecitabine Metabolite, 5'-Deoxy-5-fluorocytidine, and Creatinine Clearance.

AIM: Capecitabine is a prodrug that is metabolized to its active form, 5-fluorouracil (5-FU), in three enzymatic steps. This prospective pharmacokinetic study evaluated cytidine deaminase (CDA) activity, the second drug-metabolizing enzyme that generates 5'-deoxy-5-fluorouridine (5'-DFUR) from 5'-deoxy-5-fluorocytidine (5'-DFCR), as well as creatinine clearance (CLcr). PATIENTS AND METHODS: Patients with colorectal cancer who received capecitabine plus oxaliplatin were selected. Pharmacokinetics of capecitabine and its metabolites, and CDA activity in plasma were analyzed. RESULTS: Eighteen patients were examined. The area under the plasma concentration-time curve (AUC) of 5'-DFUR showed a significant inverse correlation with CLcr (p=0.003). The metabolic ratio, i.e. the ratios of the AUC of 5'-DFUR plus that of 5-FU to the AUC of 5'-DFCR, significantly increased when CLcr decreased (p=0.001) but did not depend on plasma CDA activity. CONCLUSION: Metabolism of 5'-DFCR to form 5'-DFUR increased as CLcr decreased but the mechanism remains unknown.

Detection of bacteria in blood circulation in patients receiving cancer chemotherapy.

INTRODUCTION: Bacterial translocation, in which intestinal bacteria pass through the intestinal wall, enter the blood circulation, and spread to other sites of the body, is thought to cause bacteremia and sometimes febrile neutropenia (FN) in patients who receive cancer chemotherapy. MATERIALS AND METHODS: We collected blood samples from 39 patients with various cancers at baseline and after chemotherapy began (during chemotherapy) and explored how frequently bacteria could be detected in the blood using a highly-sensitive, bacterial rRNA-targeted reverse transcription quantitative polymerase chain reaction (PCR) assay. RESULTS: Bacterial traces, typically Escherichia coli and Enterobacter spp., were detected in 10 patients (25.6%) at baseline and 11 patients (28.2%) during chemotherapy. The bacterial traces were positive either at baseline or during chemotherapy in 3 (60%) of 5 patients who had FN, and 6 (46%) of 13 patients aged 65 years or older. CONCLUSION: These findings support the notion that bacterial translocation occurs in patients with cancer regardless of whether they receive chemotherapy and can lead to the development of FN and other treatment-related infections.

Clinical value of serum bone resorption markers for predicting clinical outcomes after use of bone modifying agents in metastatic bone tumors: A prospective cohort study.

Bone modifying agents (BMAs) have become a standard treatment to prevent skeletal-related events (SREs) in bone metastases (BMs). The aim of our study is to determine the clinical value of serum bone resorption markers for predicting clinical outcomes after using BMAs in patients with BM. Patients were enrolled between May 2013 and October 2017 at the Nagoya University Hospital, Japan. We prospectively observed changes in pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP) and tartrate-resistant acid phosphatase 5b (TRACP-5b) during treatment with BMAs. The relationship between serum markers before and after treatment and clinical outcomes such as progression of bone disease (BD), SREs and overall survival (OS) were evaluated. Pearson chi-square test and Kaplan-Meier product limit methods were used for analysis. Sixty-seven patients were analyzed. The primary tumor sites were 21 lung, 16 breast and 30 others. Forty and 27 patients were treated with Denosumab and Zoledronic acid, respectively. Progression of BDs, SREs and death were observed in 10, 16 and 31 cases, respectively. The median follow-up period after using BMAs was 12.3 (range 0.3-66.3) months. ICTP at 3-4 weeks was significantly correlated with increasing BD progression, SREs and death after treatment in both the whole and lung cancer cohorts. Base line ICTP and TRACP-5b were also associated with increasing BD progression in the whole cohort. Our study showed that early posttreatment ICTP is useful for predicting BD progression, SREs and OS after use of BMAs in patients with BM and even in patients with lung cancer BM.