Hiroyasu Oda

Co-administration of proton pump inhibitors ameliorates nephrotoxicity in patients receiving chemotherapy with cisplatin and fluorouracil: a retrospective cohort study

PurposeThe nephrotoxicity of cisplatin (CDDP) is its dose-limiting side effect, and is caused by renal accumulation of CDDP mainly via organic cation transporter 2 (OCT2). Because proton pump inhibitors (PPIs) are known to inhibit OCT2 activity, PPI might ameliorate CDDP-induced nephrotoxicity. In the present study, we retrospectively investigated the effect of co-administration of PPI on CDDP-induced nephrotoxicity.MethodsWe analyzed the impact of PPI on the development of nephrotoxicity in 133 patients who received CDDP and fluorouracil (5-FU) therapy for the treatment of esophageal cancer or head and neck cancer. Nephrotoxicity that developed within 14 days following CDDP administration was evaluated in accordance with Common Terminology Criteria for Adverse Events ver. 4.0 for acute kidney injury.ResultsThe rate of nephrotoxicity in patients with PPI (12%, n = 33) was significantly lower than that in patients without PPI (30%, n = 100). Severe nephrotoxicity greater than Grade 2 was not observed in patients with PPI, whereas the rate of hematological toxicity was comparable between patients with and without PPI. Kaplan–Meier analysis showed that the time to nephrotoxicity following CDDP administration was significantly prolonged in patients with PPI. Multivariate analysis revealed that co-administration of PPI with CDDP and 5-FU was an independent factor significantly contributing to the amelioration of nephrotoxicity (odds ratio 0.239, p = 0.033).ConclusionsThese findings indicate that co-administration of clinical doses of PPI could ameliorate nephrotoxicity without exacerbation of hematological toxicity in patients receiving CDDP and 5-FU therapy.

A Case of Hyperammonemia Associated with High Dihydropyrimidine Dehydrogenase Activity

Over the past decades, 5-Fluorouracil (5-FU) has been widely used to treat several types of carcinoma, including esophageal squamous cell carcinoma. In addition to its common side effects, including diarrhea, mucositis, neutropenia, and anemia, 5-FU treatment has also been reported to cause hyperammonemia. However, the exact mechanism responsible for 5-FU-induced hyperammonemia remains unknown. We encountered an esophageal carcinoma patient who developed hyperammonemia when receiving 5-FU-containing chemotherapy but did not exhibit any of the other common adverse effects of 5-FU treatment. At the onset of hyperammonemia, laboratory tests revealed high dihydropyrimidine dehydrogenase (DPD) activity and rapid 5-FU clearance. Our findings suggested that 5-FU hypermetabolism may be one of the key mechanisms responsible for hyperammonemia during 5-FU treatment.

Pertuzumab, trastuzumab and eribulin mesylate therapy for previously treated advanced HER2-positive breast cancer: a feasibility study with analysis of biomarkers

The standard treatment for advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer is the triple combination of pertuzumab, trastuzumab and docetaxel, but some patients cannot tolerate taxane. To explore a non-taxane triple therapy, we conducted a feasibility study of pertuzumab, trastuzumab and eribulin mesylate (PTE) therapy for previously treated advanced HER2-positive breast cancer with analyses of quality of life and biomarkers. Ten patients were enrolled, two of whom had a history of docetaxel allergy. The median number of prior regimens was 3. The most common Grade 3 toxicities were leukopenia (70%) and neutropenia (70%). Grade 4 or 5 adverse events were not observed. An improving trend for the Functional Assessment of Cancer Therapy-Breast (FACT-B) score at 3 months was observed. Eight cases were included in the biomarker analysis. The peripheral CD8+ T cell/ CD4+Foxp3+ regulatory T cells (Tregs) ratio was significantly increased (p = 0.039). The frequency of peripheral Tregs was associated with the trastuzumab trough concentration (p = 0.019). In a non-clinical analysis, Eribulin mesylate significantly inhibited Ser473 Akt phosphorylation in PIK3CA wild-type cells and mutated cells. These results suggest that PTE therapy is a feasible and promising option for advanced HER2-positive breast cancer. Further investigation is warranted.

Abstract P4-13-21: A pilot study of pertuzumab, trastuzumab and eribulin for patients with advanced HER2 positive breast cancer

[Introduction] The triple therapy of pertuzumab, trastuzumab and taxanes (docetaxel or paclitaxel) is coming into widespread use, because of the beneficial effects on HER2 positive breast cancer. However, we don9t have enough information about the efficacy and safety of other agents with trastuzumab and pertuzumab (TP). We studied triple therapy of pertuzumab, trastuzumab and eribulin (PTE) for advanced HER2 positive breast cancer to assess the efficacy, safety and QOL prospectively (UMIN000012018). [Patients and methods] Responses were assessed by RECIST criteria v1.1. Adverse events (AEs) were graded according to CTCAE v4.0. Patients with advanced HER2 positive breast cancer were treated with pertuzumab (840 mg loading then 420 mg, day 1), trastuzumab (8 mg/kg loading then 6 mg/kg, day 1), and eribulin (1.4 mg/m2, day 1 and 8) every 3 weeks. Dose reduction was allowed when patients developed febrile neutropenia, grade 3-5 non-hematologic toxicity or skipped day 8 eribulin administration because of neutrophil count [Results] Ten patients were enrolled. Median age of patients was 60 years-old (35-75). Median number of prior chemoregimen for metastatic disease was 3 (0-5). Two patients had a history of docetaxel allergy. Median number of PTE cycle was 6 (3-12). Eight patients reduced eribulin doses 1.4 mg/m2 to 1.1 mg/m2 because of AEs (2 patients), skipped day 8 eribulin (4 patients), or physician9s choice (2 patients). One complete response, 1 partial response and 5 stable disease were achieved at 3 months. Two patients (1 CR and 1 SD) stopped eribulin and received TP as maintenance therapy. At 3 months, all 3 patients with progressive disease developed brain metastasis. Two patients had extracranial progressive lesions, but 1 patient had partial response for extracranial disease. The common treatment-related AEs were leukopenia, neutropenia, lymphopenia diarrhea, hypokalemia and stomatitis. Grade 3 AEs were leukopenia (7 patients), neutropenia (8 patients), lymphopenia (2 patients), febrile neutropenia (1 patient), hypokalemia (1 patient) and peripheral neuropathy (1 patient). Grade 4/5 AEs were not observed. Nine patients could be assessed QOL. FACT-B TOI, FACT-G and FACT-B total score had a tendency to be improved at 3 months. [Conclusion] The PTE therapy showed appropriate clinical effect for extracranial lesions and maintained QOL of patients with advanced HER2 positive breast cancer. It may be a choice for patients who have taxane-resistant diseases or a history of taxane allergy. Many patients needed to reduce eribulin dosage. When the PTE therapy is referred to advanced HER2 positive breast cancer patients as a palliative chemotherapy, eribulin (1.1mg/m2) might be a reasonable dosage. Citation Format: Ishihara M, Tamaru S, Oda H, Yamashita Y, Tono Y, Mizuno T, Katayama N. A pilot study of pertuzumab, trastuzumab and eribulin for patients with advanced HER2 positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-21.

1012PTHE PRESENCE OF SECOND PRIMARY ESOPHAGEAL TUMOR (SPET) IS STILL AN INDEPENDENT NEGATIVE PROGNOSTIC FACTOR FOR HEAD AND NECK CANCER (HNC) PATIENTS: A RETROSPECTIVE STUDY

ABSTRACT Aim: Head and neck cancer (HNC) patients have a high incidence of primary esophageal tumor. Moreover, second primary esophageal tumor (SPET) also had a negative impact on survival of HNC patients and previous studies reported that 3-year survival rate of HNC patients with SPET was 0-15%. Therefore, the establishment of optimal management for HNC patients with SPET is crucial. Recent advances in endoscopy such as magnifying endoscopy enabling early detection of esophageal tumor and the novel treatment may lead to improve survival for HNC patients with SPET. Methods: A total of 226 HNC patients who underwent magnifying esophagogastroduodenoscopy at our institute from October 2005 to September 2012 were retrospectively examined in this study. We investigated the incidence of SPET, the difference in the therapeutic outcome between HNC patients with and without SPET and the prognostic value of the presence of SPET in HNC patients. Results: Out of 226 HNC patients, 34 patients (15%) had SPET during their clinical course. The median age was 71 years (range 51 to 88) and 33 patients were male. All patients had squamous cell esophageal carcinoma. The majority of patients (79%) had SPET with stage 0 (26%) or 1(53%) disease. Out of 34 patients with SPET, 10 patients (29%) underwent endoscopic resection for SPET and 10 patients (29%) underwent simultaneous chemoradiation therapy with cisplatin plus continuous infusional 5-fluorouracil for HNC and SPET. The median over survival was 23.9 months in HNC patients with SPET, as compared with 27.0 months in HNC patients without SPET. The 3-years survival rates in HNC patients with SPET and in HNC patients without SPET were 50.9% and 72.0 %, respectively. Multivariate analysis identified the clinical stage of HNC (p = 0.01, hazard ratio 2.36) and the presence of SPET (p = 0.03, hazard ratio 1.9) as significant and independent determinants of overall survival. Conclusions: Our study suggested that although survival of HNC patients with SPET might be considerably improved due to early detection and treatment of SPET, the presence of SPET still remained an independent negative prognostic factor for HNC patients. Disclosure: All authors have declared no conflicts of interest.