Toshiro Mizuno

Evaluation of Trastuzumab Without Chemotherapy as a Post-operative Adjuvant Therapy in HER2-positive Elderly Breast Cancer Patients: Randomized Controlled Trial [RESPECT (N-SAS BC07)]†

OBJECTIVE This trial is conducted to investigate the benefit of trastuzumab monotherapy compared with a combination therapy of trastuzumab and chemotherapy in women over 70 years with human epidermal growth factor receptor type-2-positive primary breast cancer. METHODS Inclusion criteria are the following: histologically diagnosed as invasive breast cancer and received curative operation for primary breast cancer; Stage I, IIA, IIB or IIIA/M0; and baseline left ventricular ejection fraction is ≥55%. Patients are randomized to receive either trastuzumab (8 mg/kg loading dose, 6 mg/kg every 3 weeks for 1 year) plus chemotherapy selected from regimens specified on the protocol or trastuzumab monotherapy. The primary endpoint is disease-free survival. Secondary endpoints are overall survival, relapse-free survival, safety, health-related quality of life, comprehensive geriatric assessment and cost effectiveness. RESULTS Patients recruitment has been commenced in October 2009. Enrollment of 300 patients is planned during the 4-year recruitment period. CONCLUSIONS We hereby report the study concept.

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 Multicenter Phase-II Study of 5-FU, Leucovorin and Oxaliplatin (FOLFOX6) in Patients with Pretreated Metastatic Colorectal Cancer

OBJECTIVE Infusional 5-fluorouracil and leucovorin with oxaliplatin is one of the standard regimens for patients with pretreated metastatic colorectal cancer, as well as for first-line chemotherapy. FOLFOX4 has shown its efficacy in pivotal trials, but patients must make twice-weekly hospital visits. FOLFOX6 is a more convenient regimen, requiring a visit once every two weeks. The objective of this study was to evaluate the efficacy and safety profile of FOLFOX6 in Japanese patients with pretreated colorectal cancer. METHOD Fifty-one metastatic colorectal cancer patients who failed to respond to first-line chemotherapy were enrolled in the study from April to July 2005. Oxaliplatin, 5-fluorouracil and l-leucovorin were administered every two weeks. Oxaliplatin (100 mg/m(2)) and l-leucovorin (200 mg/m(2)) were given intravenously over 2 h followed by 5-fluorouracil bolus 400 mg/m(2) i.v. and 46-h infusion of 2400 mg/m(2). The primary endpoint was the response rate. RESULTS Two patients had no measurable lesions and were excluded from the efficacy analysis. Of the 49 eligible patients, one complete response and 6 partial responses were observed, resulting in a response rate (RR) of 14.3% (95% confidence interval: 5.9-27.2%). Median time to treatment failure and progression-free survival was 4.4 and 5.3 months, respectively. Overall survival was 11.4 months. The incidence of grade 2/3 (Debiopharm neurotoxicity criteria) peripheral neuropathy was 41.2%, whereas the overall incidence of grade 3/4 neutropenia was 43.2%. CONCLUSION The results of our study suggest that FOLFOX6 had an acceptable profile in terms of both efficacy and safety in previously treated colorectal cancer patients.

Elevated Fibrin-Related Markers in Patients with Malignant Diseases Suspected of Having Thrombotic Disorders:

Background: Most patients with malignant diseases are frequently complicated with some type of thrombosis, such as disseminated intravascular coagulation (DIC) or deep vein thrombosis (DVT)/pulmonary embolism (PE). Objective: The cohort and retrospective study was designed to examine the frequency of thrombosis in patients with malignant diseases and to evaluate the efficacy of D-dimer and soluble fibrin (SF) for the diagnosis of thrombosis. Patients/Methods: The plasma concentrations of D-dimer and SF were measured in patients with malignant diseases suspected of having thrombosis. D-dimer and SF were measured using a latex aggregation assay. Results: Thrombosis was observed in 23.3% of the patients with malignant diseases. Disseminated intravascular coagulation was frequently observed in patients with hepatoma, and DVT/PE was frequently observed in patients with colon cancer, lung cancer, and uterine cancer. The plasma levels of D-dimer and SF were increased in malignant diseases, especially hepatoma. Plasma levels of D-dimer and SF were significantly higher in patients with thrombosis in comparison to patients without thrombosis. A receiver operating characteristic (ROC) analysis showed the D-dimer and SF levels to be useful in the diagnosis of thrombosis. Conclusion: Elevated D-dimer and SF levels might indicate a high risk of thrombosis in patients with malignant disease; however, these assays still need to be standardized.

Spontaneous Tumor Lysis Syndrome in a Patient with a Dedifferentiated Endometrial Adenocarcinoma

Tumor lysis syndrome (TLS) is an oncological emergency caused by massive cytolysis of malignant cells. This syndrome eventually induces metabolic abnormalities. TLS is observed mainly among tumors with rapid cell proliferation or high sensitivity to antineoplastic treatment. In rare cases, TLS occurs without any cytotoxic treatment. Previous reports have shown that alternative stress including proceeding infection or an operation might play a role in TLS. However, exact mechanism of spontaneous TLS remains unknown. Here, we describe a case of a 59-year-old woman who presented with dedifferentiated endometrial adenocarcinoma and developed TLS without any cytotoxic chemotherapy. Although spontaneous TLS in solid malignancies are extremely rare, clinicians should consider the possibilities of TLS especially in aggressive solid tumors.

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.

Esophageal squamous cell neoplasia is an independent negative prognostic factor for head and neck cancer patients

BackgroundPatients with head and neck cancer (HNC) have a high incidence of esophageal squamous cell neoplasms (ESCN). ESCN also has a negative impact on the survival of HNC patients. However, recent endoscopic advances enable the early detection of ESCN, and novel treatments may lead to improving survival rates for HNC patients with ESCN.MethodsHNC patients who underwent magnifying esophagogastroduodenoscopy (EGDS) from 2005 to 2012 were included in this study (n = 226). We analyzed the prevalence and prognostic value of ESCN in HNC patients and the difference in overall survival between HNC patients with and without ESCN.ResultsThirty-four patients (15%) developed an ESCN during their clinical course. Of the 34 patients, 10 patients underwent endoscopic resection for ESCN and 10 patients underwent simultaneous chemoradiation therapy for HNC and ESCN. The 3-year survival rates in HNC patients with and without ESCN were 53% and 70%, respectively. Multivariate analysis identified the advanced clinical stage of the HNC [hazard ratio (HR) = 2.15; 95% confidence interval (CI) = 1.18–3.93; p = 0.012] and the presence of ESCN (HR = 1.73; 95% CI = 1.00–2.97; p = 0.049) as significant and independent determinants of overall survival.ConclusionsOur study suggests that although the survival of HNC patients with ESCN may be improved by routine EGDS during tumor surveys and by advances in endoscopy, the presence of ESCN still remains an independent negative prognostic factor for HNC patients.

Genetic Risk Factors Associated With Antiemetic Efficacy of Palonosetron, Aprepitant, and Dexamethasone in Japanese Breast Cancer Patients Treated With Anthracycline-based Chemotherapy

Introduction: Breast cancer patients often receive anthracycline‐based chemotherapy, and chemotherapy‐induced nausea and vomiting (CINV) remains one of the most uncomfortable and distressing adverse reactions. Poor control of CINV reduces the relative dose intensity of chemotherapy agents, which has been associated with poor clinical outcomes and shorter survival. The aim of the present study was to identify genetic risk factors associated with anthracycline‐based CINV. Patients and Methods: We evaluated CINV attributable to anthracycline‐based chemotherapy in Japanese breast cancer patients treated with an antiemetic regimen that included palonosetron, aprepitant, and dexamethasone. Furthermore, we investigated the associations between CINV and single nucleotide polymorphisms in 6 candidate genes. Results: Emesis episodes were rarely observed in the 125 patients included in the present survey (7.2%; n = 9); however, significant nausea occurred in more than one half of the patients (52.8%; n = 66). In particular, acute significant nausea was not effectively controlled. Multivariate logistic regression analysis revealed that the ABCG2 (rs2231142) AA genotype is significantly associated with acute significant nausea (odds ratio, 4.87; 95% confidence interval, 1.01‐23.60; P = .049). Conclusion: The findings of the present study provide significant insights for developing personalized antiemetic strategies for breast cancer patients receiving anthracycline‐based chemotherapy.

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.