Hironobu Hashimoto

Randomized, double-blind, phase III trial of palonosetron versus granisetron in the triplet regimen for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy: TRIPLE study

BACKGROUNDnThere has been no phase III study of comparing the efficacy of first- and second-generation 5-HT3 receptor antagonists in the triplet regimen with dexamethasone and aprepitant for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy (HEC).nnnPATIENTS AND METHODSnPatients with a malignant solid tumor who would receive HEC containing 50 mg/m(2) or more cisplatin were randomly assigned to either palonosetron (0.75 mg) arm (Arm P) or granisetron (1 mg) arm (Arm G), on day 1, both arms with dexamethasone (12 mg on day 1 and 8 mg on days 2-4) and aprepitant (125 mg on day 1 and 80 mg on days 2-3). The primary end point was complete response (CR; no vomiting/retching and no rescue medication) at the 0-120 h period and secondary end points included complete control (CC; no vomiting/retching, no rescue medication, and no more than mild nausea) and total control (TC; no vomiting/retching, no rescue medication, and no nausea).nnnRESULTSnBetween July 2011 and June 2012, 842 patients were enrolled. Of 827 evaluable, 272 of 414 patients (65.7%) in Arm P had a CR at the 0-120 h period when compared with 244 of 413 (59.1%) in Arm G (P = 0.0539). Both arms had the same CR rate of 91.8% at the acute (0-24 h) period, while at the delayed (24-120 h) period, Arm P had a significantly higher CR rate than Arm G (67.2% versus 59.1%; P = 0.0142). In secondary end points, Arm P had significantly higher rates than Arm G at the 0-120 h period (CC rate: 63.8% versus 55.9%, P = 0.0234; TC rate: 47.6% versus 40.7%, P = 0.0369) and delayed periods (CC rate: 65.2% versus 55.9%, P = 0.0053; TC rate: 48.6% versus 41.4%, P = 0.0369).nnnCONCLUSIONnThe present study did not show the superiority of palonosetron when compared with granisetron in the triplet regimen regarding the primary end point.nnnCLINICAL TRIAL REGISTRY IDENTIFIERnUMIN000004863.

Randomized Controlled Study Comparing Two Doses of Intravenous Granisetron (1 and 3 mg) for Acute Chemotherapy-induced Nausea and Vomiting in Cancer Patients: A Non-inferiority Trial

OBJECTIVEnThe aim of this study was to assess the non-inferiority of 1 mg to 3 mg granisetron (GRN) injection for the treatment of acute chemotherapy-induced nausea and vomiting (CINV) and to evaluate the tolerability of GRN given at 1 mg in Japanese cancer patients.nnnMETHODSnPatients with cancer receiving highly emetogenic chemotherapy were enrolled in this single-blind randomized controlled study. Patients were randomly assigned to receive GRN at a single dose of 1 or 3 mg. The primary endpoint was the rate of complete protection from emetic events (no vomiting, no retching and no need for rescue medication) during the first 24 h following the initiation of chemotherapy.nnnRESULTSnThere were 89 patients in the 1 mg group and 90 patients in the 3 mg group. Complete protection was achieved in 70 patients (78.7%) in the 1 mg group and 73 (81.1%) patients in the 3 mg group. The one-sided test did not reveal non-inferiority of either dose of GRN to the other at a 5% significance level.nnnCONCLUSIONSnOur data failed to show the non-inferiority of 1 mg of GRN to 3 mg of GRN administered as a single dose. However, the rate of complete protection from nausea and vomiting was similar in the two groups. Given the recommended dosage in the guidelines and the economic need for reduction of medical care expenses in Japan, prophylactic administration of GRN at 1 mg may be an appropriate, alternative treatment for acute CINV in cancer patients.

A double-blind randomized phase II dose-finding study of olanzapine 10 mg or 5 mg for the prophylaxis of emesis induced by highly emetogenic cisplatin-based chemotherapy

PurposeThe aim of this phase II study was to evaluate the efficacy and safety of two doses (10 and 5xa0mg) of olanzapine in combination with standard antiemetic treatment (aprepitant, palonosetron, and dexamethasone) for patients receiving highly emetogenic chemotherapy (HEC).MethodsA multi-institutional, double-blind, randomized phase II, dose-finding study of olanzapine was performed in patients with a malignant solid tumor who were receiving HEC with cisplatin (≥xa050xa0mg/m2). Patients were randomly assigned either olanzapine 10 or 5xa0mg orally on days 1–4, combined with standard antiemetic treatment. The primary endpoint was a complete response (CR; no emesis and no use of rescue medications) in the delayed phase (24–120xa0h after the start of cisplatin treatment).Results153 patients were randomized to the 10xa0mg group (nxa0=xa076) or the 5xa0mg group (nxa0=xa077). The CR rate in the delayed phase was 77.6% (80% CI: 70.3–83.8, Pxa0=xa00.01) in the 10xa0mg group and 85.7% (80% CI: 79.2–90.7, Pxa0<xa00.001) in the 5xa0mg group (P value for H0: complete response ratexa0≤xa065%). The most common adverse event was somnolence, which had an incidence of 53.3 and 45.5% in the 10 and 5xa0mg olanzapine groups, respectively.ConclusionsBoth doses of 10 and 5xa0mg olanzapine provided a significant improvement in delayed emesis. A dose of 5xa0mg olanzapine was determined as the recommended dose for a further phase III study based on higher CR and lower somnolence rates.Clinical Trial InformationUMIN000014214

Biomarkers of skin toxicity induced by anti-epidermal growth factor receptor antibody treatment in colorectal cancer

Skin toxicity is a common symptom of anti-epidermal growth factor receptor (EGFR) antibody treatment and is also a predictive marker of its efficacy in colorectal cancer patients. However, severe skin disorders induced by such antibodies negatively impact on the quality of life of patients and decreases drug compliance during treatment. If we can predict the high-risk group susceptible to severe skin toxicity before treatment, we can undertake the early management of any arising skin disorders and formulate a more accurate prognosis for anti-EGFR antibody treatment. Previous studies have identified molecular markers of skin toxicity induced by anti-EGFR antibody, such as EGFR polymorphisms, the expression of inflammatory chemokines and serum levels of EGFR ligands. A clinical trial was undertaken involving the escalation of cetuximab doses, guided by the grade of skin toxicity observed, such as no or low-grade, in metastatic colorectal cancer (the EVEREST study). The dose escalation of cetuximab was confirmed by a safety profile and had the tendency to achieve a higher response rate in KRAS wild-type patients. A large, prospective randomized trial is now ongoing (EVEREST 2) and the results of this trial may contribute to personalized medicine in KRAS wild-type colorectal cancer patients.

Amrubicin in patients with platinum-refractory metastatic neuroendocrine carcinoma and mixed adenoneuroendocrine carcinoma of the gastrointestinal tract

Although the same treatment strategy as used for small cell lung cancer, including second-line chemotherapy, is generally applied to metastatic neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine carcinoma (MANEC) of the gastrointestinal tract (GIT; GIT-NEC/MANEC), the efficacy of amrubicin (AMR) for GIT-NEC/MANEC is not well known. We retrospectively analyzed platinum-refractory GIT-NEC/MANEC patients who received AMR between February 2004 and July 2012 at the National Cancer Center Hospital. The AMR dose administered was 30–45u2009mg/m2 on days 1–3 every 3–4 weeks. The overall response rate according to Response Evaluation Criteria in Solid Tumors guidelines, version 1.0, progression-free survival, overall survival, and adverse events by National Cancer Institute-Common Terminology Criteria for Adverse Events guidelines, version 4.0 were evaluated. Nineteen patients received AMR. The response rate for 16 assessable patients was 18.8% (95% confidence interval, 4.1–45.7), the median progression-free survival was 3.8 months (2.3–5.3), and the median overall survival was 7.7 months (7.1–8.2). Grade 3/4 neutropenia occurred in 52.6% of patients and febrile neutropenia occurred in 10.5%. Other nonhematological toxicities were mild and treatment-related deaths were not observed. AMR may have a modest effect, with tolerable toxicities, on patients with platinum-refractory GIT-NEC/MANEC. Further prospective evaluations are warranted.

A double-blind randomized Phase II study of olanzapine 10 mg versus 5 mg for emesis induced by highly emetogenic chemotherapy

A randomized Phase II dose-finding trial comparing olanzapine 10 mg with olanzapine 5 mg for patients receiving highly emetogenic chemotherapy with cisplatin was started in June 2014. The purpose of the trial is to evaluate the efficacy and safety of the two olanzapine doses and to determine which is more promising as a test arm for comparison with the current standard antiemetic care (a combination of aprepitant, a 5-HT3 receptor antagonist and dexamethasone) in a subsequent Phase III trial. Patients receiving cisplatin-containing regimens will be randomized to the olanzapine 10 or 5 mg arm. A total of 150 patients will be accumulated from nine institutions over 2 years. The primary endpoint is complete response defined as no emetic episodes and no use of rescue medications in the delayed (24-120 h) phase. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000014214.

A Double-blind, Placebo-controlled Study of the Safety and Efficacy of Vitamin K1 Ointment for the Treatment of Patients with Cetuximab-induced Acneiform Eruption

A double-blind, placebo-controlled study evaluating the efficacy and safety of vitamin K1 ointment for the treatment of patients with cetuximab-induced acneiform eruption has started. Vitamin K1 ointment and placebo are applied twice daily for 8 consecutive weeks after the development of acneiform eruptions. Vitamin K1 ointment is applied in the middle of one side (face, neck or chest) and placebo is applied to the other side. The primary endpoint is the regression rate of acneiform eruptions on right- and left-side lesions in the same patient, compared with baseline at the final evaluation in the 10-week trial. The secondary endpoints include adverse events of acneiform eruption and other adverse events.

Reasons for avoidance of bevacizumab with first-line FOLFOX for advanced colorectal cancer

BackgroundThe addition of bevacizumab to standard chemotherapy has significant clinical benefits in metastatic colorectal cancer. However, its use is often avoided due to patient condition or disease status.MethodsOf 228 consecutive patients receiving first-line FOLFOX-based regimens from June 2007 to June 2009, 96 patients (42xa0%) received FOLFOX alone without bevacizumab. We retrospectively examined the reasons why bevacizumab was not combined with FOLFOX.ResultsAmong 96 patients for whom the addition of bevacizumab was avoided, 73 patients (76xa0%) had bevacizumab-related contraindications including hypertension, proteinuria, bleeding, thromboembolic events, wound-healing complications and gastrointestinal perforation. Other avoidance reasons were conditions precluding the use of bevacizumab in 15 patients (16xa0%), economic problems and anxiety about adverse events in 8 patients (8xa0%), and unknown reasons in 3 patients.ConclusionsBevacizumab-related contraindications were the main reason for drug avoidance, though economic problems and anxiety about rare but serious adverse events were also factors for avoidance of bevacizumab.

Risk factors associated with chemotherapy-induced nausea and vomiting in the triplet antiemetic regimen including palonosetron or granisetron for cisplatin-based chemotherapy: analysis of a randomized, double-blind controlled trial

PurposeThe triplet antiemetic regimen is recommended for cisplatin-based highly emetogenic chemotherapy, in the current guidelines for antiemetic prophylaxis. Although risk factors related to chemotherapy-induced nausea and vomiting (CINV) have been identified by several prior studies, there are only few studies evaluating risk factors associated with the prophylactic triplet antiemetic therapy, particularly in palonosetron use. The present study aimed to reveal the risk factors related to CINV development in patients receiving cisplatin and to compare CINV risk factors between palonosetron and granisetron use.MethodsIn total, 825 patients in a phase III trial receiving palonosetron with graniestron were evaluated. Multivariate logistic regression models were used to predict risk factors associated with CINV development. Additionally, risk factors associated with CINV development were separately evaluated in each treatment group.ResultsMultivariate analysis of the entire study group revealed that sex, age, cisplatin dose, and granisetron use were significant and independent factors affecting CINV development in the overall phase. Similarly, sex and age were risk factors for CINV in both treatment groups. Kaplan–Meier curves classified by each treatment group showed no significant difference between the groups among patients without any risk factors for CINV (Pu2009=u20090.353). Conversely, complete response rates for patients with at least one risk factor were higher in patients receiving palonosetron (Pu2009=u20090.049).ConclusionsThis analysis revealed the importance of previously reported CINV risk factors when using triplet antiemetics. Palonosetron might be preferred for patients with at least one risk factor.

Study protocol for J-SUPPORT 1604 (J-FORCE): a randomized, double blind, placebo-controlled Phase III study evaluating olanzapine (5 mg) plus standard triple antiemetic therapy for prevention of chemotherapy induced nausea and vomiting in patients receiving cisplatin-based highly emetogenic chemotherapy

The Guidelines of the Japan Society of Clinical Oncology recommend standard triple antiemetic therapy with aprepitant, a 5-hydroxytryptamine type 3 receptor antagonist and dexamethasone for patients receiving highly emetogenic chemotherapy. Recently, a Phase III study demonstrated the significance of adding of olanzapine (10 mg) to standard triple antiemetic therapy. Olanzapine is associated with somnolence, and we have previously conducted a randomized Phase II study to evaluate the efficacy and safety of 10 mg and 5 mg olanzapine. Lower dose of olanzapine reduced the incidence of somnolence. Therefore, we conducted a randomized, double blind, placebo-controlled, Phase III study to evaluate the efficacy of olanzapine (5 mg) combined with standard triple antiemetic therapy for cisplatin-based highly emetogenic chemotherapy. This study initiated in Feb 2017. A total of 690 patients are planned to be enrolled over a period of 2 years. This study has been registered at the UMIN Clinical Trials Registry as UMIN000024676.