A randomized phase II study of nutritional and exercise treatment for elderly patients with advanced non-small cell lung or pancreatic cancer: the NEXTAC-TWO study protocol.

BACKGROUND: Most advanced elderly cancer patients experience fatigue, anorexia, and declining physical function due to cancer cachexia, for which effective interventions have not been established. We performed a phase I study of a new nonpharmacological multimodal intervention called the nutritional and exercise treatment for advanced cancer (NEXTAC) program and reported the excellent feasibility of and compliance with this program in elderly patients with advanced cancer who were at risk for cancer cachexia. We report here the background, hypothesis, and design of the next-step multicenter, randomized phase II study to evaluate the efficacy of the program, the NEXTAC-TWO study. METHODS: Patients with chemo-naïve advanced non-small cell lung cancer or pancreatic cancer, age ≥ 70 years, performance status ≤2, with adequate organ function and without disability according to the modified Katz index will be eligible. In total, 130 participants will be recruited from 15 Japanese institutions and will be randomized into either the intervention group or a control group. Computer-generated random numbers are allocated to each participant. Stratification factors include performance status (0 to 1 vs. 2), site of primary cancer (lung vs. pancreas), stage (III vs. IV), and type of chemotherapy (cytotoxic vs. others). Interventions and assessment will be performed 4 times every 4 ± 2 weeks from the date of randomization. Interventions will consist of nutritional counseling, nutritional supplements (rich in branched-chain amino acids), and a home-based exercise program. The exercise program will include low-intensity daily muscle training and lifestyle education to promote physical activity. The primary endpoint is disability-free survival. It is defined as the period from the date of randomization to the date of developing disability or death due to any cause. This trial also plans to evaluate the improvements in nutritional status, physical condition, quality of life, activities of daily living, overall survival, and safety as secondary endpoints. Enrollment began in August 2017. The study results will demonstrate the efficacy of multimodal interventions for elderly cancer patients and their application for the maintenance of physical and nutritional conditions in patients with cancer cachexia. This work is supported by a grant-in-aid from the Japan Agency for Medical Research and Development. DISCUSSION: This is the first randomized trial to evaluate the efficacy and safety of a multimodal intervention specific for elderly patients with advanced cancer. TRIAL REGISTRATION: Registered at August 23, 2017. Registry number: UMIN000028801 .

Feasibility of early multimodal interventions for elderly patients with advanced pancreatic and non-small-cell lung cancer.

BACKGROUND: Combinations of exercise and nutritional interventions might improve the functional prognosis for cachectic cancer patients. However, high attrition and poor compliance with interventions limit their efficacy. We aimed to test the feasibility of the early induction of new multimodal interventions specific for elderly patients with advanced cancer Nutrition and Exercise Treatment for Advanced Cancer (NEXTAC) programme. METHODS: This was a multicentre prospective single-arm study. We recruited 30 of 46 screened patients aged ≥70 years scheduled to receive first-line chemotherapy for newly diagnosed, advanced pancreatic, or non-small-cell lung cancer. Physical activity was measured using pedometers/accelerometer (Lifecorder® , Suzuken Co., Ltd., Japan). An 8 week educational intervention comprised three exercise and three nutritional sessions. The exercise interventions combined home-based low-intensity resistance training and counselling to promote physical activity. Nutritional interventions included standard nutritional counselling and instruction on how to manage symptoms that interfere with patient's appetite and oral intake. Supplements rich in branched-chain amino acids (Inner Power® , Otsuka Pharmaceutical Co., Ltd., Japan) were provided. The primary endpoint of the study was feasibility, which was defined as the proportion of patients attending ≥4 of six sessions. Secondary endpoints included compliance and safety. RESULTS: The median patient age was 75 years (range, 70-84). Twelve patients (40%) were cachectic at baseline. Twenty-nine patients attended ≥4 of the six planned sessions (96.7%, 95% confidence interval, 83.3 to 99.4). One patient dropped out due to deteriorating health status. The median proportion of days of compliance with supplement consumption and exercise performance were 99% and 91%, respectively. Adverse events possibly related to the NEXTAC programme were observed in five patients and included muscle pain (Grade 1 in two patients), arthralgia (Grade 1 in one patient), dyspnoea on exertion (Grade 1 in one patient), and plantar aponeurositis (Grade 1 in one patient). CONCLUSIONS: The early induction of multimodal interventions showed excellent compliance and safety in elderly patients with newly diagnosed pancreatic and non-small-cell lung cancer receiving concurrent chemotherapy. We are now conducting a randomized phase II study to measure the impact of these interventions on functional prognosis.

Prognostic factors in patients with hepatocellular carcinoma refractory or intolerant to sorafenib.

OBJECTIVE: The aim of this study was to identify the prognostic factors in patients with advanced hepatocellular carcinoma (HCC) who are refractory or intolerant to sorafenib and to exclude unsuitable candidates from subsequent therapy. METHODS: The study cohort consisted of 111 patients who had discontinued sorafenib therapy. Uni- and multivariate analyses were conducted to identify the prognostic factors for survival after discontinuation of sorafenib therapy. RESULTS: The median age of the patients was 70 years, and 96 of them (86%) were male. The Eastern Cooperative Oncology Group performance status was 0-1 in 94 patients (85%). Forty patients (36%) were classified as Child-Pugh class A and 57 (51%) as Child-Pugh class B. The median survival time after discontinuation of sorafenib therapy was 146 days. Hepatitis C viral antibody negativity, presence of ascites, absence of a history of previous treatment excluding sorafenib, elevated serum total bilirubin level, and elevated serum α-fetoprotein level were identified as the independent unfavorable prognostic factors by multivariate analysis. The median survival time of the patients with 4 or 5 unfavorable prognostic factors was 59 days. CONCLUSIONS: We should judge the indication of any subsequent therapy carefully in patients with 4 or 5 of the aforementioned factors.

Phase I study of combination chemotherapy using sorafenib and transcatheter arterial infusion with cisplatin for advanced hepatocellular carcinoma.

The aims of this study were to evaluate the frequency of dose-limiting toxicities and to find the recommended dose of combination chemotherapy with sorafenib and transcatheter arterial infusion (TAI) using cisplatin for patients with advanced hepatocellular carcinoma (HCC), for whom surgical resection, local ablation therapy, or transcatheter arterial chemoembolization were not indicated. Patients received 800 mg sorafenib daily. Cisplatin was given at one of three dosages (level 1, 35 mg/m(2) /cycle; level 2, 50 mg/m(2) /cycle; and level 3, 65 mg/m(2) /cycle) from feeding arteries to the HCC. The treatment was repeated every 4-6 weeks up to a maximum of six cycles, until there were signs of tumor progression or unacceptable toxicity. The dose-limiting toxicities experienced by the 20 enrolled patients were grade 4 increased aspartate aminotransferase at level 1, grade 3 gastrointestinal hemorrhaging at level 1, and grade 3 hypertension at level 3. The common drug-related adverse events that were of severity grade 3 or 4 included the elevation of aspartate aminotransferase (30%), alanine aminotransferase (20%), amylase (30%), and lipase (30%). Partial response was seen in four patients (20%), and 13 patients (65%) had stable disease. The median overall survival and progression-free survival were 9.1 and 3.3 months, respectively. The combination of sorafenib at 800 mg/day with TAI of cisplatin at 65 mg/m(2) /cycle was determined to be the recommended regimen. A randomized phase II trial of sorafenib alone versus sorafenib plus TAI of cisplatin is currently underway. This study was registered at UMIN as trial number UMIN000001496.

Efficacy of sorafenib in patients with hepatocellular carcinoma refractory to transcatheter arterial chemoembolization.

BACKGROUND: The efficacy of sorafenib for hepatocellular carcinoma (HCC) patients refractory to transcatheter arterial chemoembolization (TACE) has not yet been clarified. We investigated the efficacy of sorafenib in HCC patients who were refractory to TACE (sorafenib group) and retrospectively compared the results with those of patients treated with hepatic arterial infusion chemotherapy using cisplatin (cisplatin group). METHODS: We evaluated the anti-tumor effect, the time to progression, and the overall survival in 48 patients in the sorafenib group and 66 patients in the cisplatin group. RESULTS: The disease control rate to sorafenib was 60.4 %, the median time to progression was 3.9 months, and the median survival time was 16.4 months in patients who were refractory to TACE. When compared with the cisplatin group, significant differences in the patient characteristics were not observed between the two groups with the exception of patient age; however, the disease control rate (cisplatin group 28.8 %, P = 0.001), time to progression (cisplatin group: median 2.0 months, hazard ratio 0.44, P < 0.01), and overall survival (cisplatin group: median 8.6 months, hazard ratio 0.57, P < 0.001) were significantly superior in the sorafenib group. The multivariate analysis also showed the sorafenib treatment to be the most significant factor contributing to prolongation of time to progression and overall survival. CONCLUSIONS: Sorafenib showed favorable treatment results in patients refractory to TACE. When compared with hepatic arterial infusion chemotherapy using cisplatin, sorafenib demonstrated a significantly higher disease control rate, a longer time to progression and increased overall survival.

[Chemotherapy].

In two pivotal randomized controlled trials, sorafenib, as compared to placebo, has been demonstrated to yield a significantly favorable disease control rate, and also favorable prolongation of progression-free survival and overall survival in patients with advanced hepatocellular carcinoma. At present, it is acknowledged as a standard treatment for advanced hepatocellular carcinoma and is available worldwide. Some randomized controlled trials performed to clarify the usefulness of adjuvant therapy after local treatment, including surgical resection, local ablative therapy and transcatheter arterial chemoembolization for hepatocellular carcinoma are ongoing. In addition, a number of new molecular -targeted agents and combined therapies are under development. On the other hand, intra-arterial chemotherapy, such as with 5-fluorouracil and cisplatin, 5-fluorouracil and interferon, and cisplatin alone, has been widely used for advanced hepatocellular carcinoma in Japan, because of the high response rates and favorable overall survival in advanced hepatocellular carcinoma patients. Survival benefit has, however, not been demonstrated in well-designed randomized controlled studies. It is important to clarify the appropriate candidates, proper treatment method and survival benefit of intra-arterial chemotherapy. After the introduction of sorafenib, chemotherapy for advanced hepatocellular carcinoma has been changing remarkably, and further improvements of chemotherapy for hepatocellular carcinoma are expected.