With this study, we sought to characterise the impact of pro-inflammatory cytokines on the outcomes of gemcitabine monotherapy (GEM) in patients with pancreatic cancer (PC). Treatment-naive patients with advanced PC and no obvious infections were eligible for enrolment. All of the patients were scheduled to undergo systemic chemotherapy. Serum pro-inflammatory cytokines were measured using an electro-chemiluminescence assay method before chemotherapy. High cytokine levels were defined as values greater than the median. Clinical data were collected prospectively. Sixty patients who received GEM were included in the analysis. High IL-6 and IL-1β levels were poor prognostic factors for overall survival in a multivariate analysis (P=0.011 and P=0.048, respectively). Patients with both a high IL-6 level and a high IL-1β level exhibited shortened overall and progression-free survival, a reduction in the tumour control rate, and a high dose intensity of GEM compared with patients with low levels of both IL-6 and IL-1β. The serum levels of IL-6 and IL-1β predict the efficacy of GEM in patients with advanced PC.

Objectives High serum level of interleukin 6 (IL-6) is associated with high degree of tumor progression and systemic weakness. Anti–IL-6 therapy possibly improves the deterioration of clinical characteristics in patients with high IL-6 level. However, IL-6–related factors in patients with treatment-naive advanced pancreatic cancer (PC) have not been established. The goal of this study was to identify IL-6–related factors in patients with advanced PC who were scheduled to undergo first-line chemotherapy. Methods Patients with treatment-naive advanced PC were eligible for inclusion in this study. Patients who did not receive first-line chemotherapy were excluded. Serum IL-6 levels and clinical parameters were prospectively recorded. Analyses were performed to identify risk factors for high IL-6 levels. Results Eighty patients were analyzed. IL-6–related factors were advanced age (P < 0.01), the presence of liver metastasis (P < 0.01), the large volume of liver metastasis (P < 0.01), severe fatigue (P = 0.02), high carcinoembryonic antigen levels (P = 0.02), anemia (P < 0.01), and high C-reactive protein levels (P = 0.02) in multivariate analyses. Decreased skeletal muscle mass tended to be associated with high IL-6 levels. Conclusions High serum IL-6 was related to advanced age, the presence of hepatic metastasis, large tumor burden in liver, severe fatigue, high carcinoembryonic antigen, high C-reactive protein, and anemia in patients with treatment-naive advanced PC.

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. 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. This is the first randomized trial to evaluate the efficacy and safety of a multimodal intervention specific for elderly patients with advanced cancer. Registered at August 23, 2017. Registry number: UMIN000028801 .

Purpose: Cachexia influences the patient’s physical wellbeing and quality of life, and the patient’s ability to tolerate their cancer therapies, especially cytotoxic chemotherapy. The purpose of this study was to investigate the frequency and timing of onset of cancer cachexia during chemotherapy and its association with prognosis and toxicity in patients with pancreatic ductal adenocarcinoma (PDAC). Methods: We performed a retrospective study in patients who underwent first-line chemotherapy after diagnosis of advanced PDAC between 6 June 2008 and 31 March 2017. Base cachexia (weight loss up to 6 months before starting first-line chemotherapy) and follow-up cachexia (after starting first-line chemotherapy) were defined as weight loss > 2% with a body mass index (BMI) < 20 kg/m² or weight loss > 5%. Results: A total of 150 patients were registered. The median age and BMI were 65 years and 21.7 kg/m², respectively. Base cachexia occurred in 50% of patients. Follow-up cachexia occurred in 32% within 12 weeks of starting first-line chemotherapy, reaching 64% at 1 year. Overall survival was not significantly different between patients with and without follow-up cachexia, regardless of whether cancer cachexia occurred within 12, 24, or 48 weeks of starting first-line treatment. Appetite loss, fatigue, nausea, and diarrhea were more frequent in patients with follow-up cachexia than in those without follow-up cachexia. Conclusion: Follow-up cachexia had an early onset, but was not a prognostic factor for overall survival in patients with PDAC. Some adverse events tended to be more frequent in patients with follow-up cachexia than in those without follow-up cachexia.

Systemic chemotherapy is one of the most important treatment modalities for advanced hepatocellular carcinoma (HCC). Before the introduction of sorafenib, cytotoxic agents, hormonal therapies, or many combinations of these were the mainly used modalities for systemic chemotherapy of advanced HCC. However, such regimens were of only limited value in clinical practice, because some randomized controlled studies comparing promising regimens with no treatment or doxorubicin alone failed to show any overall survival advantage. In two pivotal phase III placebo-controlled studies, the SHARP trial and the Asia-Pacific trial, sorafenib was demonstrated to significantly delay the time to progression and the overall survival time in patients with advanced HCC. Therefore, sorafenib therapy has come to be acknowledged as a standard therapy for advanced HCC worldwide. After the introduction of sorafenib, a number of phase III trials of various molecular-targeted agents vs. sorafenib as first-line chemotherapy and of various molecular-targeted agents vs. placebo as second-line chemotherapy have been conducted to determine if any of these agents could offer a survival benefit, however, none of the agents examined so far has been demonstrated to provide any survival benefit over sorafenib or placebo. Recently, favorable treatment efficacies have been reported in some clinical trials of molecular-targeted agents in the biomarker-enriched population. Development of individualized cancer treatments using molecular-targeted agents based on the results of genome-sequencing is aggressively ongoing. Furthermore, immune-oncologic agents, such as anti-CTLA-4 antibody and anti-PD-1/PD-L1 antibody, have been reported to provide promising outcomes. Thus, various novel systemic chemotherapeutic agents are currently under development, and further improvements in the treatment outcomes are expected.

BACKGROUND: Neural invasion (N-inv) induces the neural damage and pain in pancreatic cancer (PCa). Benign nerve injury evokes allodynia through neuroinflammation in the neural root, which might be seen in PCa. Macrophages have the potential to release excitatory cytokines after nerve injury and so may play a role in the generation of chronic neuropathic pain. The aim of this study is to represent N-inv–induced allodynia in patients with PCa and to characterize allodynia-related neuroinflammation as macrophage accumulation on dorsal root ganglion (DRG) in the N-inv animal model (N-inv model). METHODS: Treatment-naïve patients with advanced PCa with no opioid use were enrolled in the clinical study. To evaluate allodynia, the current perception threshold on epigastric skin and pain score from questionnaire were measured. The association between the degrees of radiological N-inv and allodynia was evaluated. In the animal experiments, we used the N-inv model, which is established by the inoculation of the human PCa cell line into the left sciatic nerve of mice and mimics the invasion behavior of human PCa. The change of sensation was weekly measured at right hind paw, and the expressions of mRNA and protein were investigated on DRG at 6 weeks in the N-inv and sham models. The effect of macrophage depletion using liposome-encapsulated clodronate (Lp-CLD) was evaluated in the N-inv model. Tumor size and the degree of macrophage accumulation on DRG or around the tumor were investigated. RESULTS: In the clinical study, 43 patients were analyzed. The threshold of epigastric skin at 2000 Hz touch and pressure sensation was decreased in patients with severe N-inv, compared to patients without severe N-inv. Patients with severe N-inv showed a high pain score. In the animal experiments, the N-inv model decreased the threshold of right hind paw at 5 and 6 weeks. The macrophage-related gene expression and F4/80-positive macrophages were increased in the left DRG. Lp-CLD–induced macrophage depletion induced an increase of the threshold in the right hind paw and a decrease of CD206-positive macrophages accumulation in the left DRG. Lp-CLD had no effect for tumor size. CONCLUSIONS: The present study first showed that the N-inv–induced allodynia was spread in patients with PCa and in the N-inv model. Allodynia was related to the amount of macrophages at DRG in the N-inv model. The neuroinflammation may be a target for researching the N-inv-induced pain mechanism and developing novel analgesics.