緩和・支持療法

高度催吐性抗悪性腫瘍薬投与患者を対象としたPro-NETU臨床第II相試験

演　　者：: 乾直輝¹，菅原俊一², 金原正志³, 森瀬昌宏⁴, 吉森浩三⁵, 今村文生⁶, 福井朋也⁷,
湊浩一⁸, 岩島明⁹, 久保田馨¹⁰, 佐伯俊昭¹¹, 田村友秀¹²
所属機関：: ¹浜松医科大学・呼吸器内科, ²仙台厚生病院・呼吸器内科, ³広島市立広島市民病院・呼吸器内科, ⁴名古屋大学・呼吸器内科, ⁵結核予防会複十字病院・呼吸器内科, ⁶大阪国際がんセンター・呼吸器内科, ⁷北里大学・呼吸器内科, ⁸群馬県立がんセンター・呼吸器内科, ⁹長岡中央綜合病院・呼吸器内科, ¹⁰日本医科大学・呼吸器内科, ¹¹埼玉医科大学国際医療センター・乳腺腫瘍科, ¹²聖路加国際病院・呼吸器内科

Objective
This randomized, double-blind, placebo controlled, dose-ranging phase II study assessed efficacy and safety profile of single intravenous administration of Pro-NETU, a novel NK₁-receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting (CINV) in Japanese patients receiving highly emetogenic chemotherapy (HEC).

Method
Patients aged ≧20 years who had not undergone HEC or moderately emetogenic chemotherapy and were scheduled to receive cisplatin (CDDP) (≧70 mg/m²) based regimen, were randomly assigned to either Pro-NETU (90 mg or 260 mg) or placebo arm both in combination with palonosetron (0.75 mg iv) and dexamethasone (DEX). Primary endpoint was complete response (CR: no vomiting and no rescue medication) rate in the overall phase (0-120 hours after chemotherapy initiation). Safety and tolerability were assessed as secondary endpoints and the frequency of infusion site reaction (ISR) was also investigated.

Results
A total of 594 patients were randomized. Of these, 194, 195, and 195 in the placebo, 90-, and 260-mg arms, respectively, were evaluable for efficacy. The overall CR rate was 54.7% for the placebo, 63.8% for the 90-mg (Standardized LS Mean difference, 9.1%; p=0.061 adjusted by allocation factors of age and gender), and 76.8% for the 260-mg arm (Standardized LS Mean difference, 22.0%; p<0.001). Secondary efficacy analyses supported the outcomes in favor of 260-mg arm. Safety profiles were comparable between the three arms. The incidence of ISR related to Pro-NETU 260 mg was low (1.0%).

Discussion and conclusions
Pro-NETU (260 mg) combined with palonosetron and DEX has shown to be superior to palonosetron and DEX in the prevention of CINV. Safety data suggested that Pro-NETU is safe and has a low risk for developing ISR in CDDP setting.

AC療法施行乳がん患者を対象とした化学療法誘発性悪心・嘔吐の包括的リスク因子解析

演　　者：: 松本恵実¹，辻大樹¹, 金容壱³, 中道秀徳², 山本圭祐², 長田莉花¹, 佐原由莉¹, 松澤明希¹, 塩川満², 伊藤邦彦¹
所属機関：: ¹静岡県立大学・臨床薬効解析学, ²聖隷浜松病院・薬剤部, ³聖隷浜松病院・化学療法科

Background
Chemotherapy-induced nausea and vomiting (CINV) lead to a significant deterioration in the quality of life of cancer patients receiving chemotherapy. We had previously reported that ABCB12677G>T/A was associated with a complete response proportion of acute phase (CR_0-24) CINV in patients who had received doxorubicin and cyclophosphamide (AC) combination chemotherapy along with a prophylactic dual antiemetic regimen using granisetron (GRA) and dexamethasone (DEX).
Purpose
This study aimed to confirm whether ABCB1 2677G>T/A was associated with CR_0-24 and to explore genetic factors affecting delayed phase (CR_0-24) CINV in patients with breast cancer treated with a triple antiemetic regimen, which included aprepitant (APR).
Methods
This prospective, single-center study included a total of 167 chemotherapy-naïve patients with breast cancer who received a standard dose of AC combination chemotherapy; GRA, DEX, and APR were administered prior to chemotherapy. The utilization of rescue therapy, episodes of vomiting, and daily symptoms were recorded in each patient’s diary during the first 120 h after chemotherapy. CR_0-24 was compared between minor homozygous (TT, AA, and TA) and non-homozygous (GG, GA, and GT) allelic groups of ABCB1 2677G>T/A. Fourteen genetic polymorphisms were genotyped and their associations with CRs were investigated. Multivariate logistic regression analysis was performed using age, alcohol consumption, and the significant genetic risk factors with a P-value of <0.10 in the univariate analysis to explore the potential risk factors associated with CR_0-24 and CR_24–120.
Results
The proportion of patients who achieved CR_0–24 was 59% both in homozygous and in non-homozygous allelic groups of ABCB1 2677G>T/A. This difference was not statistically significant. TACR1 -117T>G in CR_0–24 and ABCB1 2677G>T/A and TACR1 1323C>T in CR_24–120 were extracted by univariate analysis. Multivariate logistic regression analysis adjusted for potential risk factors showed that TACR1 1323TT (OR: 2.294, P = 0.028) was a significant determinant of CR_24–120 in the triple antiemetic regimen.
Conclusion
No significant association was found between ABCB1 2677G>T/A and CR_0–24. However, it was observed that the polymorphism of TACR1, which encodes the neurokinin 1 receptor, might be a potential genetic risk factor for the development of delayed phase CINV.

がん治療中の口腔粘膜炎に対するインドメタシンスプレー製剤の疼痛軽減効果の研究

演　　者：: 長岡広香¹，百賢二², 濵野淳¹, 宮路天平³, 小山田隼佑⁴, 川口崇⁵, 本間真人⁶, 山口拓洋⁷, 森田達也⁸, 木澤義之⁹
所属機関：: ¹筑波大学附属病院・緩和ケアセンター, ²東京大学医科学研究所附属病院・薬剤部, ³東京大学・臨床試験データ管理学, ⁴JORTC・データセンター統計部門, ⁵東京薬科大学・医療実務薬学, ⁶筑波大学附属病院・薬剤部, ⁷東北大学・医学統計学, ⁸聖隷三方原病院・緩和支持療法科, ⁹神戸大学附属病院・緩和支持療法科

Introduction:
Oropharyngeal mucositis(OM) pain due to anticancer chemo- and radiotherapy have highly negative impact on patient QOL and would sometimes necessitate unwanted dose reductions or treatment interruptions in cancer therapy. There is no high-quality study to evaluate the analgesic efficacy of indomethacin (IM) oral spray (OS) for OM pain, though anti-inflammatory agents are recommended for OM pain management.

Objective:
We conducted this randomized, placebo-controlled, double-blind trial to evaluate the analgesic efficacy and safety of IM-OS for OM pain due to anticancer chemo- and radiotherapy.

Methods:
We enrolled adult cancer patients who have OM pain due to anticancer chemo- and radiotherapy with Brief Pain Inventory (BPI) item-5 was 4 or higher. Patients were randomly assigned in a 1:1 ratio to receive either IM-OS or saline-OS, given four times regardless of meals.

Measurement:
Our primary endpoint was the intergroup differences of BPI-item 6 between before spray and after 30 minutes. Secondary endpoints were BPI-item 6 at after 15, 60, 120, 180 and 240 minutes, intergroup differences of Numerical Rating Scale (NRS) of taking meals, Clinical Global Impressions (CGI) improvement, and adverse event.

Results:
From July 2015 through December 2016, a total of 60 patients were assigned to receive IM-OS (n=33) or saline-OS (n=27). There was significant intergroup differences in BPI-item 6 between before spray and after 30 minutes (-1.3, 95% CI:-1.94 to -0.57, p=0.0005), which persist for 180 minutes. The intergroup differences in NRS of liquid drinkability and easiness of conversation were significant respectively (p=0.0267, p=0.0171). CGI improvement was significant in IM-OS group and there was no adverse event.

Conclusion:
IM-OS reduce OM pain due to anticancer chemo- and/or radio-therapy. IM-OS would reduce the difficulty of taking meals.

全量ドレナージとKM-CARTによる大量癌性腹水に対する積極的症状緩和と新たな治療戦略

演　　者：: 松﨑圭祐¹
所属機関：: ¹要町病院・腹水治療センター

Objective: To improve the symptoms of refractory ascites, I had developed a novel cell-free and concentrated ascites reinfusion therapy (KM-CART). KM-CART is easier to use and can be applied for massive malignant ascites. The effectiveness of KM-CART in alleviating symptoms and personalized medicine are hereby reported.
Methods: A total of 3,750 patients, including 659 pancreatic cancers, 632 ovarian cancers, 618 gastric cancers, 488 colon cancers, and 2,397 patients with other disorders, underwent KM-CART between February 2009 and December 2017. It is performed by removing the entire volume of ascitic fluid and administering the recovered autologous proteins (maximum, 420g) into blood vessels by infusion.
Results: Ascitic fluid was removed to the greatest extent possible (0.8-27.0 L; mean, 6.1 L). The mean filtered concentrate was 570 mL and recovered autologous proteins was 63.4g (maximum, 420g). Side effects consisted of only mild fever, with no serious side effects. Symptom scores improved for all 10 items and mean lower leg circumference also decreased by 2.8 cm, indicating the effectiveness of KM-CART in improving the ADL of patients. In addition, many patients resumed chemotherapy as a result of regaining the motivation to fight disease. These patients were able to transition to their homes over the long-term. Furthermore, over 2.4x10⁵ cancer cells were recovered from the membrane filter washing fluid, and these cells were able to be used for dendritic cell vaccine therapy. Moreover, active proliferation of cancer cells was observed on day 8.
Conclusion: The KM-CART system was considered easy to use and very safe, and the recovery of large volumes of autologous proteins was thought to have improved general status, nutrition, and immune status, as well as subjective symptoms. In addition, the recovered cancer cells were able to be used for drug sensitivity tests and immune cell therapy, indicating the new treatment strategies for malignant ascites.

Oncofertility外来：最近の動向

演　　者：: 白石晃司¹，松山豪泰¹
所属機関：: ¹山口大学・泌尿器科

Background: One of the most important issues of cancer patients' care is addressing potential threats to their reproductive health.Health care providers should understand the patients' needs and manage them properly.
Patients and Methods: We retrospectively reviewed the database of our male infertility clinic from 2008 to 2017 and analyzed cancer types, reproductive evaluation and infertility treatment.
Results: In 6,011 male infertility patients, 189 oncology-related patients with the mean age of 36 years (range: 23-45) were found (3.1%) and the number of patients were increasing every year. Patients were categorized into 4 types: 1) postchemotherapy azoospermia (PCA) (n=97), 2) needs for sperm cryopreservation (n=40), 3) evaluation of their reproductive function during or after the treatment (n=31) and 4) infertility due to sexual dysfunction (n=21). The major cancer types included testicular cancer, Hodgkin's lymphoma, colorectal cancer non-Hodgkin's lymphoma, leukemia and the others. Microdissection testicular sperm extraction was done for 78 patients and a total of 28 patients (36%) could obtain sperms for intracytoplasmic sperm injection and there were 8 live births from 6 patients. Sexual dysfunction was mainly caused by colorectal surgery with overlapped pathophysiology of erectile and ejaculatory dysfunctions. PDE5 inhibitors, vacuum device, TENGA, anti-depressant and retrieval of bladder sperms were provided for these patients. Recent trend was increasing number of patients who were receiving tyrosine kinase inhibitorsand immuno-oncology drugs for fertility evaluation. Oligozoospermia, but not azoospermia, was frequently observed in these patients.
Conclusions: As the cancer treatments become complex, patients' background and needs for infertility treatment also become heterogenous, indicating that we have to provide proper informations and treatments flexibly. Even in the PCA cases, current reproductive technologies may open therapeutic windows.

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