Impact of peripheral neuropathy induced by platinum in first-line chemotherapy on second-line chemotherapy with paclitaxel for advanced gastric cancer.

BACKGROUND: Fluoropyrimidine plus platinum, followed by paclitaxel (PTX) plus ramucirumab is a recommended treatment strategy for advanced gastric cancer (AGC). We investigated how peripheral neuropathy (PN), induced by platinum in first-line chemotherapy, affected the tolerability of second-line chemotherapy with PTX (2nd-PTX). METHODS: The subjects were AGC patients who received second-line chemotherapy with PTX (2nd-PTX) after the failure of platinum-based chemotherapy between March 2015 and June 2018. We retrospectively reviewed PN severity, and dose reduction and/or discontinuation due to PN during 2nd-PTX, and compared the cumulative incidence of grade 2 PN between the two groups according to first-line chemotherapy containing oxaliplatin (L-OHP) or cisplatin (CDDP). RESULTS: The L-OHP and CDDP groups consisted of 50 patients each. PN severity before 2nd-PTX was grade 1/2 in 46/12% of patients in the L-OHP group, and 100/0% in the CDDP group. The worst grades of chemotherapy-induced PN during 2nd-PTX were grades 1/2/3 in 40/34/14% of patients in the L-OHP group, and 36/18/0% in the CDDP group. Median time to grade 2 PN after starting second-PTX was 2.5 months in the L-OHP group and 8.6 months in the CDDP group (hazard ratio 3.34, p = 0.002). The frequencies of a PN-related dose reduction and/or discontinuation of PTX were 18% in the L-OHP group and 8% in the CDDP group (p = 0.234). CONCLUSIONS: The severity of PN and tolerability of 2nd-PTX may be affected by first-line chemotherapy with L-OHP or CDDP for AGC.

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.

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.

PURPOSE: The aim of this phase II study was to evaluate the efficacy and safety of two doses (10 and 5 mg) of olanzapine in combination with standard antiemetic treatment (aprepitant, palonosetron, and dexamethasone) for patients receiving highly emetogenic chemotherapy (HEC). METHODS: A 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 (≥ 50 mg/m2). Patients were randomly assigned either olanzapine 10 or 5 mg 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 (24-120 h after the start of cisplatin treatment). RESULTS: 153 patients were randomized to the 10 mg group (n = 76) or the 5 mg group (n = 77). The CR rate in the delayed phase was 77.6% (80% CI: 70.3-83.8, P = 0.01) in the 10 mg group and 85.7% (80% CI: 79.2-90.7, P < 0.001) in the 5 mg group (P value for H 0: complete response rate ≤ 65%). The most common adverse event was somnolence, which had an incidence of 53.3 and 45.5% in the 10 and 5 mg olanzapine groups, respectively. CONCLUSIONS: Both doses of 10 and 5 mg olanzapine provided a significant improvement in delayed emesis. A dose of 5 mg olanzapine was determined as the recommended dose for a further phase III study based on higher CR and lower somnolence rates. CLINICAL TRIAL INFORMATION: UMIN000014214.

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.

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

BACKGROUND: The 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. METHODS: Of 228 consecutive patients receiving first-line FOLFOX-based regimens from June 2007 to June 2009, 96 patients (42 %) received FOLFOX alone without bevacizumab. We retrospectively examined the reasons why bevacizumab was not combined with FOLFOX. RESULTS: Among 96 patients for whom the addition of bevacizumab was avoided, 73 patients (76 %) 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 (16 %), economic problems and anxiety about adverse events in 8 patients (8 %), and unknown reasons in 3 patients. CONCLUSIONS: Bevacizumab-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.

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.

Successful rechallenge for oxaliplatin hypersensitivity reactions in patients with metastatic colorectal cancer.

BACKGROUND: Discontinuation of oxaliplatin-containing regimens is sometimes necessary due to hypersensitivity reactions for which effective countermeasures have not yet been identified. PATIENTS AND METHODS: We retrospectively reviewed cases in which hypersensitivity reactions developed in 623 patients treated with oxaliplatin for colorectal cancer. Clinical outcomes of patients who underwent oxaliplatin rechallenge with rechallenge protocol (STEP 1: hydrocortisone, chlorpheniramine, and/or ranitidine; STEP 2: hydrocortisone with an escalating dose to 500 mg, and/or prolonged administration time of oxaliplatin; and STEP 3: STEP 2 plus a subcutaneous injection of epinephrine) were examined. RESULTS: Out of 623 patients, 126 (20.2%) patients developed hypersensitivity reactions. Out of these 126 patients, 99 (78.6%) underwent oxaliplatin rechallenge. As the initial oxaliplatin rechallenge, 19 patients received subsequent treatment without the rechallenge protocol and 80 patients received oxaliplatin with the rechallenge protocol of STEP 1 (n=64), STEP 2 (n=15), and STEP 3 (n=1). The median number of oxaliplatin rechallenges was 3 (range=1 to 29). The reason for treatment discontinuation was disease progression in 55 patients (56%) and hypersensitivity reactions in 21 patients (21%). Overall hypersensitivity reactions after rechallenge were observed in 59%, with grade 3/4 in 6%. CONCLUSION: The rechallenge protocol is an effective treatment option for patients with oxaliplatin hypersensitivity reactions.

Heparin potentiates the in vivo ectopic bone formation induced by bone morphogenetic protein-2.

Although bone morphogenetic proteins (BMPs) are clinically useful for bone regeneration, large amounts are required to induce new bone formation in monkeys and humans. We found recently that heparin stimulates BMP activity in vitro (Takada, T., Katagiri, T., Ifuku, M., Morimura, N., Kobayashi, M., Hasegawa, K., Ogamo, A., and Kamijo, R. (2003) J. Biol. Chem. 278, 43229-43235). In the present study, we examined whether heparin enhances bone formation induced by BMPs in vivo and attempted to determine the molecular mechanism by which heparin stimulates BMP activity using C2C12 myoblasts. Heparin enhanced BMP-2-induced gene expression and Smad1/5/8 phosphorylation at 24 h and thereafter, although not within 12 h. Heparitinase treatment did not affect the response of cells to BMP-2. In the presence of heparin, degradation of BMP-2 was blocked, and the half-life of BMP-2 in the culture medium was prolonged by nearly 20-fold. Although noggin mRNA was induced by BMP-2 within 1 h regardless of the presence of heparin, noggin failed to inhibit BMP-2 activity in the presence of heparin. Furthermore, simultaneous administration of BMP-2 and heparin in vivo dose-dependently induced larger amounts of mineralized bone tissue compared with BMP-2 alone. These findings clearly indicate that heparin enhances BMP-induced osteoblast differentiation not only in vitro but also in vivo. This study indicates that heparin enhances BMP-induced osteoblast differentiation in vitro and in vivo by protecting BMPs from degradation and inhibition by BMP antagonists.