Proposal for Classifying the Emetogenicity of Oral Anticancer Agents with a Focus on PARP Inhibitors: A Prospective, Observational, Multicenter Study (JASCC-CINV 2002).

Background: Olaparib and niraparib (poly adenosine diphosphate [ADP]-ribose polymerase [PARP] inhibitors) have significant antitumor action in patients with ovarian cancer. However, the incidence of nausea and vomiting among patients on these drugs in clinical trials is rather high. There are no guidelines on antiemetic treatment for nausea caused by oral anticancer agents. This study aimed to investigate the incidence of nausea and vomiting caused by PARP inhibitors and the actual situation of antiemetic therapy in patients with gynecologic cancer. Methods: Patients with gynecologic cancer who were scheduled to receive PARP inhibitors were enrolled. Data on PARP inhibitor-induced nausea and vomiting were collected from patient diaries for 21 days. The primary endpoint was the incidence of vomiting during the 21 days after starting olaparib and niraparib. Results: Overall, between January 2020 and March 2023, 134 patients were enrolled. Of the 129 patients who were evaluated, 28 (21.7%) received prophylactic antiemetics for 21 days, and 101 (78.3%) did not. The overall incidence of PARP inhibitor-induced vomiting was 16.3%. The incidence of vomiting in the group that did not receive antiemetic prophylaxis was 13.9%. On dividing the group that did not receive antiemetic prophylaxis into the olaparib and niraparib subgroups, the incidence of vomiting was found to be 18.6% for the olaparib group and 10.3% for the niraparib group. Conclusion: The incidence of emesis without antiemetic prophylaxis among patients on olaparib and niraparib ranged from 10% to 30%. Therefore, olaparib and niraparib can be classified in the low emetogenic risk and prophylactic antiemetic therapy at the time of treatment initiation may be unnecessary.

Simultaneous suppression of lignin, tricin and wall-bound phenolic biosynthesis via the expression of monolignol 4-O-methyltransferases in rice.

Grass lignocelluloses feature complex compositions and structures. In addition to the presence of conventional lignin units from monolignols, acylated monolignols and flavonoid tricin also incorporate into lignin polymer; moreover, hydroxycinnamates, particularly ferulate, cross-link arabinoxylan chains with each other and/or with lignin polymers. These structural complexities make grass lignocellulosics difficult to optimize for effective agro-industrial applications. In the present study, we assess the applications of two engineered monolignol 4-O-methyltransferases (MOMTs) in modifying rice lignocellulosic properties. Two MOMTs confer regiospecific para-methylation of monolignols but with different catalytic preferences. The expression of MOMTs in rice resulted in differential but drastic suppression of lignin deposition, showing more than 50% decrease in guaiacyl lignin and up to an 90% reduction in syringyl lignin in transgenic lines. Moreover, the levels of arabinoxylan-bound ferulate were reduced by up to 50%, and the levels of tricin in lignin fraction were also substantially reduced. Concomitantly, up to 11 µmol/g of the methanol-extractable 4-O-methylated ferulic acid and 5-7 µmol/g 4-O-methylated sinapic acid were accumulated in MOMT transgenic lines. Both MOMTs in vitro displayed discernible substrate promiscuity towards a range of phenolics in addition to the dominant substrate monolignols, which partially explains their broad effects on grass phenolic biosynthesis. The cell wall structural and compositional changes resulted in up to 30% increase in saccharification yield of the de-starched rice straw biomass after diluted acid-pretreatment. These results demonstrate an effective strategy to tailor complex grass cell walls to generate improved cellulosic feedstocks for the fermentable sugar-based production of biofuel and bio-chemicals.

Disruption of p-coumaroyl-CoA:monolignol transferases in rice drastically alters lignin composition.

Grasses are abundant feedstocks that can supply lignocellulosic biomass for production of cell-wall-derived chemicals. In grass cell walls, lignin is acylated with p-coumarate. These p-coumarate decorations arise from the incorporation of monolignol p-coumarate conjugates during lignification. A previous biochemical study identified a rice (Oryza sativa) BAHD acyltransferase (AT) with p-coumaroyl-CoA:monolignol transferase (PMT) activity in vitro. In this study, we determined that that enzyme, which we name OsPMT1 (also known as OsAT4), and the closely related OsPMT2 (OsAT3) harbor similar catalytic activity toward monolignols. We generated rice mutants deficient in either or both OsPMT1 and OsPMT2 by CRISPR/Cas9-mediated mutagenesis and subjected the mutants' cell walls to analysis using chemical and nuclear magnetic resonance methods. Our results demonstrated that OsPMT1 and OsPMT2 both function in lignin p-coumaroylation in the major vegetative tissues of rice. Notably, lignin-bound p-coumarate units were undetectable in the ospmt1 ospmt2-2 double-knockout mutant. Further, in-depth structural analysis of purified lignins from the ospmt1 ospmt2-2 mutant compared with control lignins from wild-type rice revealed stark changes in polymer structures, including alterations in syringyl/guaiacyl aromatic unit ratios and inter-monomeric linkage patterns, and increased molecular weights. Our results provide insights into lignin polymerization in grasses that will be useful for the optimization of bioengineering approaches for the effective use of biomass in biorefineries.

Doublet or Triplet Antiemetic Prophylaxis for Nausea and Vomiting Induced by Trastuzumab Deruxtecan: an Open-Label, Randomized, and Multicenter Exploratory Phase 2 Study.

Background: Trastuzumab deruxtecan is classified as an anticancer agent that poses a moderate emetic risk in the international guidelines for antiemetic therapy. The guidelines recommend emesis prophylaxis using a two-drug combination therapy comprising a 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA) and dexamethasone (DEX). However, the high incidence of nausea and vomiting associated with trastuzumab deruxtecan is problematic. The National Comprehensive Cancer Network guideline version 1.2023 classified trastuzumab deruxtecan as having a high risk of emesis and changed its recommendation to a triplet regimen including a neurokinin-1 receptor antagonist (NK1RA). However, the emetogenic potential of trastuzumab-deruxtecan and the optimal antiemetic prophylaxis are controversial. Hence, this exploratory phase 2 study aimed to assess the efficacy and safety of treatment comprising 5-HT3RA and DEX with or without a NK1RA in preventing trastuzumab deruxtecan-induced nausea and vomiting. Methods: We conducted an open-label and randomized exploratory phase 2 study at 14 centers in Japan. Patients with breast cancer who were scheduled to receive trastuzumab deruxtecan were enrolled in this study. The patients were randomly assigned to receive granisetron and DEX (arm GD) or granisetron, DEX, and aprepitant (fosaprepitant; arm GDA). The primary endpoint was complete response (CR; no emesis or no rescue therapy) during the overall phase (120 h after the start of trastuzumab deruxtecan). Results: Between September 2020 and March 2023, 40 patients were randomly assigned to the GD (n = 19) or GDA (n = 21) arm. In the GDA arm, one patient who did not complete the use of the rescue medication listed in the diary was excluded from the efficacy analysis, which included the use of rescue medication. The CR rates during the overall phase were 36.8% and 70.0% in the GD and GDA arms, respectively (odds ratio 0.1334; 95% confidence interval [CI]: 0.0232-0.7672; P = 0.0190), with a difference of 33.2%. No grade 3 or 4 toxicity related to antiemetic therapy was observed. Conclusions: Patients receiving trastuzumab deruxtecan require triple therapy, including mandatory NK1RA administration.

Control and Risk Factors of Nausea and Vomiting in Patients With Cervical Cancer Receiving Radiotherapy.

BACKGROUND/AIM: Nausea and vomiting are two of the most distressing adverse events of cancer radiotherapy. The aim of this study was to examine the control rate and risk factors associated with nausea and vomiting in patients with cervical cancer receiving radiotherapy. PATIENTS AND METHODS: This retrospective study examined patients with cervical cancer who received radiotherapy alone or with concomitant cisplatin. Patients who received radiotherapy alone were not administered antiemetic premedication, while patients who received radiotherapy with concomitant weekly cisplatin (40 mg/m2) were administered antiemetic therapy comprising granisetron and dexamethasone. Risk factors for non-complete response (CR) were identified using multivariate logistic regression analysis. RESULTS: Multivariate analysis indicated that younger age and concomitant weekly cisplatin were significant factors associated with non-CR across 5 weeks of treatment in patients who received radiotherapy. The proportion achieving CR among younger patients (<65 years) who received radiotherapy alone or with concomitant cisplatin was significantly lower than that among older patients (≥65 years) (Concomitant cisplatin: 27% vs. 67%, p=0.049; Radiotherapy alone: 62% vs. 91%, p=0.166). However, the proportion of patients achieving CR across 5 weeks of treatment was insufficient in all groups except for those aged ≥ 65 years who received radiotherapy alone. CONCLUSION: Antiemetic prophylaxis should be considered for younger patients with cervical cancer undergoing radiotherapy alone. Further, neurokinin-1 receptor antagonist should be added to 5-hydroxytryptamine type-3 receptor antagonist and dexamethasone as antiemetic prophylactic therapy for patients with cervical cancer undergoing radiotherapy with concomitant weekly doses of 40 mg/m2 cisplatin.

Pharmaceutical intervention for adverse events improves quality of life in patients with cancer undergoing outpatient chemotherapy.

BACKGROUND: The effect of pharmaceutical intervention to treat adverse events on quality of life (QOL) in outpatients receiving cancer chemotherapy is unclear. We investigated whether pharmaceutical intervention provided by pharmacists in collaboration with physicians improves QOL with outpatient cancer chemotherapy. METHODS: We conducted a single-center retrospective descriptive study of pharmaceutical intervention for patients receiving outpatient cancer chemotherapy at Gifu University Hospital between September 2017 and July 2020. We assessed patient QOL using the Japanese version of the EuroQol 5 Dimension5 Level (EQ-5D-5L). Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. We compared the EQ-5D-5L utility value and incidence of grade 2 or higher adverse events before and after pharmaceutical intervention. RESULTS: Our analysis included 151 patients who underwent 210 chemotherapy cycles. Pharmaceutical intervention significantly improved patients' EQ-5D-5L utility values from 0.8197 to 0.8603 (P < 0.01). EQ-5D-5L utility values were significantly improved after pharmaceutical intervention for nausea and vomiting (pre-intervention 0.8145, post-intervention 0.8603, P = 0.016), peripheral neuropathy (pre-intervention 0.7798, post-intervention 0.7988, P = 0.032) and pain (pre-intervention 0.7625, post-intervention 0.8197, P = 0.035). Although not statistically significant, the incidence of grade 2 or higher adverse events, including nausea and vomiting, dermopathy, pain, oral mucositis, diarrhea and dysgeusia, tended to be lower post-intervention than pre-intervention. CONCLUSIONS: Pharmaceutical intervention by pharmacists in collaboration with physicians may improve QOL in patients undergoing outpatient cancer chemotherapy.

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.

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.

Cancer Cachexia Reduces the Efficacy of Nivolumab Treatment in Patients With Advanced Gastric Cancer.

BACKGROUND/AIM: Nivolumab is effective against advanced gastric cancer (AGC) refractory to or in patients intolerant of standard chemotherapy. This study was designed to clarify the impact of cancer cachexia in patients with AGC who received nivolumab. PATIENTS AND METHODS: We recruited AGC patients who were treated with nivolumab from October 2017 to December 2019. Clinical outcomes were compared between patients with and without cancer cachexia at the start of nivolumab. Cancer cachexia was defined as weight loss >5%; weight loss >2% and body mass index (BMI) <20; or sarcopenia and BMI <20. Primary endpoints were median overall survival (OS) and median time to treatment failure (TTF), while secondary endpoints were overall response rate (ORR) and incidence of adverse events. RESULTS: The study enrolled 44 patients. Median OS and TTF were significantly shorter in patients with cancer cachexia than in those without cancer cachexia (OS: 6.6 vs. 2.3 months; HR=2.65; 95%CI=1.28-5.49; p=0.008, TTF: 2.6 vs. 1.9 months; HR=2.17; 95%CI=1.09-4.32, p=0.027). On Cox proportional hazards analysis, cancer cachexia was significantly associated with shorter OS. The incidence of adverse events did not differ between the two groups. Nivolumab was associated with better OS and TTF outcomes in AGC patients without cachexia than in those with cachexia, albeit there was no difference in the incidence of adverse events. CONCLUSION: Cancer cachexia may be associated with worse clinical outcomes in patients with AGC treated with nivolumab.

Efficacy and safety of 5 mg olanzapine combined with aprepitant, granisetron and dexamethasone to prevent carboplatin-induced nausea and vomiting in patients with gynecologic cancer: A multi-institution phase II study.

PURPOSE: The aim of this study was to investigate the efficacy and safety of prophylactic administration of 5 mg olanzapine (OLZ) combined with neurokinin 1 receptor antagonist (NK1RA), 5-hydroxytryptamine type-3 receptor antagonist (5-HT3RA), and dexamethasone (DEX) to prevent nausea and vomiting in carboplatin (CBDCA) combination therapy for patients with gynecological cancer. METHODS: We conducted a single-arm, multi-institution, phase II study. Gynecological cancer patients scheduled to receive AUC ≥4 mg/mL/min CBDCA were enrolled. All patients received 5 mg OLZ (once daily after supper on days 1-4) combined with NK1RA, 5-HT3RA, and DEX. The primary end point was complete response (CR; no emesis and rescue therapy) during overall phase (120 h after the start of carboplatin administration). RESULTS: Between May 2018 and June 2019, 60 patients were enrolled from 3 institutions in Japan. A total of 57 patients who met the criteria were included in the efficacy and safety analysis. The CR rate for the overall phase was 78.9%. Acute (0-24 h) and delayed phases (24-120 h) were 96.5% and 80.7%, respectively. Somnolence was observed in 73.7% patients. However, somnolence of grade 2 or higher was observed in only 3.5% of cases. There were no grade 3 or 4 toxicities associated with OLZ. CONCLUSIONS: Preventive use of OLZ combined with standard triplet therapy had promising activity with manageable safety, suggesting that this combination could be an effective standard treatment option for patients with AUC ≥4 mg/mL/min CBDCA combination therapy.