Pancreatic cancer cachexia: a review of mechanisms and therapeutics.

Over the last decade, we have gained new insight into the pathophysiology of cachexia associated with pancreatic cancer. Unfortunately, its treatment is complex and remains a challenge. Pancreatic cancer cachexia is a multifactorial syndrome characterized by uncompensated adipose tissue and skeletal muscle loss in the setting of anorexia that leads to progressive functional impairment. This paper will review the current concepts of pancreatic cancer cachexia, its assessment and pathophysiology as well as current and future treatments. The successful management of pancreatic cancer cachexia will likely require a multimodal approach that includes nutritional support and combination pharmaceutical interventions

Pancreatic Cancer Cachexia: Current Concepts and Clinical Management

There has been great progress over the last decade in understanding the pathophysiology of cachexia associated with pancreatic cancer. However, there is a large need to find better therapeutic options to successfully manage this complex and challenging condition. Patients with pancreatic cancer have some of the highest prevalence and often the most severe degrees of cachexia, which is described as a multifactorial metabolic syndrome that is associated with unintended weight loss of adipose tissue and skeletal muscle in the setting of anorexia. This chapter will review the current concepts surrounding pancreatic cancer cachexia, its clinical diagnosis, pathophysiology, and its known and proposed therapeutics. A multimodal approach utilizing nutritional support and pharmaceutical therapies is proposed to lead to the most successful management of pancreatic cancer cachexia

Pancreas Cancer-Associated Weight Loss.

Unintentional weight loss in patients with pancreatic cancer is highly prevalent and contributes to low therapeutic tolerance, reduced quality of life, and overall mortality. Weight loss in pancreatic cancer can be due to anorexia, malabsorption, and/or cachexia. Proper supportive care can stabilize or reverse weight loss in patients and improve outcomes. We review the literature on supportive care relevant to pancreatic cancer patients, and offer evidence-based recommendations that include expert nutritional assessment, counseling, supportive measures to ensure adequate caloric intake, pancreatic enzyme supplementation, nutritional supplement replacement, orexigenic agents, and exercise. Pancreatic Cancer Action Network-supported initiatives will spearhead the dissemination and adoption of these best supportive care practices. IMPLICATIONS FOR PRACTICE: Weight loss in pancreatic cancer patients is endemic, as 85% of pancreatic cancer patients meet the classic definition of cancer cachexia. Despite its significant prevalence and associated morbidity, there is no established approach to this disease entity. It is believed that this is due to an important knowledge gap in understanding the underlying biology and lack of optimal treatment approaches. This article reviews the literature regarding pancreas cancer-associated weight loss and establishes a new framework from which to view this complex clinical problem. An improved approach and understanding will help educate clinicians, improve clinical care, and provide more clarity for future clinical investigation

18F-FDG PET Predicts Hematologic Toxicity in Patients with Locally Advanced Anal Cancer Treated With Chemoradiation

Purpose: Hematologic toxicity (HT) during chemoradiation therapy (CRT) for anal cancer can lead to treatment breaks that compromise efficacy. We hypothesized that CRT-induced HT correlates with changes in active bone marrow (ABM) characterized by pre-/post-CRT positron emission tomography (PET)/computed tomography. Methods and materials: Data from 36 patients with anal cancer who were treated with 18F-fluorodeoxyglucose PET/computed tomography scans 2 weeks before and 6 to 16 weeks after CRT were analyzed. Complete blood counts with differential within 2 weeks from, weekly during, and 2 week after treatment were obtained. HT was defined as baseline complete blood count change to nadir and posttreatment recovery. Total bone marrow was segmented into 2 subregions: lumbosacral (LS) pelvis (L5 vertebrae, sacrum, and coccyx) and lower pelvis (LP) (ilium, femoral head/neck, and greater and lesser trochanter). PET ABM was characterized as the volume having standard uptake value (SUV) greater than the mean uptake of unirradiated extrapelvic bone marrow. PET variables of pre-/post-CRT and HT predictors were analyzed by linear regression. Results: Average pelvic ABM was significantly reduced from 52% to 41% in pre- to post-CRT PET scans for all patients (P = .0012). Regional analysis indicated significant post-CRT reduction of LS-ABM (P 50 Gy) in terms of acute hematologic ΔWBC (P = .021) and ΔANC(P = .028). HT increased with increasing volume of ABM receiving 40 Gy. The results also suggest that ABM V40 Gy ≤ 20% to 25% may significantly reduce the risk of HT. Conclusions: HT was significantly associated with ΔABM in patients with anal cancer who were treated with CRT. LS-ABM was a robust surrogate for evaluating CRT-induced HT. Our results suggest implementation of ABM dosimetric constraints, V40 Gy ≤ 20-25%, may significantly reduce HT and lead to decreased treatment delays associated with clinical outcomes

Do changes in health reveal the possibility of undiagnosed pancreatic cancer? Development of a risk-prediction model based on healthcare claims data.

Background and objectiveEarly detection methods for pancreatic cancer are lacking. We aimed to develop a prediction model for pancreatic cancer based on changes in health captured by healthcare claims data.MethodsWe conducted a case-control study on 29,646 Medicare-enrolled patients aged 68 years and above with pancreatic ductal adenocarcinoma (PDAC) reported to the Surveillance Epidemiology an End Results (SEER) tumor registries program in 2004-2011 and 88,938 age and sex-matched controls. We developed a prediction model using multivariable logistic regression on Medicare claims for 16 risk factors and pre-diagnostic symptoms of PDAC present within 15 months prior to PDAC diagnosis. Claims within 3 months of PDAC diagnosis were excluded in sensitivity analyses. We evaluated the discriminatory power of the model with the area under the receiver operating curve (AUC) and performed cross-validation by bootstrapping.ResultsThe prediction model on all cases and controls reached AUC of 0.68. Excluding the final 3 months of claims lowered the AUC to 0.58. Among new-onset diabetes patients, the prediction model reached AUC of 0.73, which decreased to 0.63 when claims from the final 3 months were excluded. Performance measures of the prediction models was confirmed by internal validation using the bootstrap method.ConclusionModels based on healthcare claims for clinical risk factors, symptoms and signs of pancreatic cancer are limited in classifying those who go on to diagnosis of pancreatic cancer and those who do not, especially when excluding claims that immediately precede the diagnosis of PDAC

Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: phase III RESOLVE study

Ibrutinib; Metastatic pancreatic adenocarcinoma; Phase IIIIbrutinib; Adenocarcinoma de páncreas metastásico; Fase IIIIbrutinib; Adenocarcinoma de pàncrees metastàtic; Fase IIIFirst-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) includes nab-paclitaxel/gemcitabine. Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumor activity through tumor microenvironment modulation. The safety and efficacy of first-line ibrutinib plus nab-paclitaxel/gemcitabine treatment in patients with PDAC were evaluated. Patients and methods RESOLVE (NCT02436668) was a phase III, randomized, double-blind, placebo-controlled study. Patients (histologically-confirmed PDAC; stage IV diagnosis ≥6 weeks of randomization; Karnofsky performance score ≥70) were randomized to once-daily oral ibrutinib (560 mg) or placebo plus nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2). Primary endpoints were overall survival (OS) and investigator-assessed progression-free survival (PFS); overall response rate and safety were assessed. Results In total, 424 patients were randomized (ibrutinib arm, n = 211; placebo arm, n = 213). Baseline characteristics were balanced across arms. After a median follow-up of 25 months, there was no significant difference in OS between ibrutinib plus nab-paclitaxel/gemcitabine versus placebo plus nab-paclitaxel/gemcitabine (median of 9.7 versus 10.8 months; P = 0.3225). PFS was shorter for ibrutinib plus nab-paclitaxel/gemcitabine compared with placebo plus nab-paclitaxel/gemcitabine (median 5.3 versus 6.0 months; P < 0.0001). Overall response rates were 29% and 42%, respectively (P = 0.0058). Patients in the ibrutinib arm had less time on treatment and received lower cumulative doses for all agents compared with the placebo arm. The most common grade ≥3 adverse events for ibrutinib versus placebo arms included neutropenia (24% versus 35%), peripheral sensory neuropathy (17% versus 8%), and anemia (16% versus 17%). Primary reasons for any treatment discontinuation were disease progression and adverse events. Conclusions Ibrutinib plus nab-paclitaxel/gemcitabine did not improve OS or PFS for patients with PDAC. Safety was consistent with known profiles for these agents.This work was supported by Pharmacyclics LLC, an AbbVie Company (no grant number)

A pilot study evaluating concordance between blood-based and patient-matched tumor molecular testing within pancreatic cancer patients participating in the Know Your Tumor (KYT) initiative

Recent improvements in next-generation sequencing (NGS) technology have enabled detection of biomarkers in cell-free DNA in blood and may ultimately replace invasive tissue biopsies. However, a better understanding of the performance of blood-based NGS assays is needed prior to routine clinical use. As part of an IRBapproved molecular profiling registry trial of pancreatic ductal adenocarcinoma (PDA) patients, we facilitated blood-based NGS testing of 34 patients from multiple community-based and high-volume academic oncology practices. 23 of these patients also underwent traditional tumor tissue-based NGS testing. cfDNA was not detected in 9/34 (26%) patients. Overall concordance between blood and tumor tissue NGS assays was low, with only 25% sensitivity of blood-based NGS for tumor tissue NGS. Mutations in KRAS, the major PDA oncogene, were only detected in 10/34 (29%) blood samples, compared to 20/23 (87%) tumor tissue biopsies. The presence of mutations in circulating DNA was associated with reduced overall survival (54% in mutation-positive versus 90% in mutation-negative). Our results suggest that in the setting of previously treated, advanced PDA, liquid biopsies are not yet an adequate substitute for tissue biopsies. Further refinement in defining the optimal patient population and timing of blood sampling may improve the value of a blood-based test. © Pishvaian et al

Randomised phase III trial of trabectedin versus doxorubicin-based chemotherapy as first-line therapy in translocation-related sarcomas

Abstract Aim This randomised phase III trial evaluated first-line trabectedin versus doxorubicin-based chemotherapy (DXCT) in patients with advanced/metastatic translocation-related sarcomas (TRS). Methods Patients were randomly assigned (1:1) to receive trabectedin 1.5mg/m 2 24-h intravenous (i.v.) infusion every 3weeks (q3wk) ( Arm A ), or doxorubicin 75mg/m 2 i.v. q3wk, or doxorubicin 60mg/m 2 i.v. plus ifosfamide (range, 6–9g/m 2 ) i.v. q3wk ( Arm B ). Progression-free survival (PFS) by independent review was the primary efficacy end-point. Results One hundred and twenty-one patients were randomised; 88 of them had TRS confirmed by central pathology review (efficacy population). Twenty-nine PFS events were assessed by independent review (16 with trabectedin; 13 with DXCT). PFS showed non-significant difference between arms (stratified log rank test, p =0.9573; hazard ratio=0.86, p =0.6992). At the time of this analysis, 63.9% and 58.3% of patients were alive in trabectedin and DXCT arms, respectively. There was no statistically significant difference in survival curves. Response rate according to Response Evaluation Criteria in Solid Tumours (RECIST) v.1.0 was significantly higher in DXCT arm (27.0% versus 5.9%), but response according to Choi criteria showed fewer differences between treatment arms (45.9% versus 37.3%). Safety profile was as expected for both arms, with higher incidence of severe neutropenia, alopecia and mucositis in the DXCT arm. Conclusion Neither trabectedin nor doxorubicin-based chemotherapy showed significant superiority in the first-line treatment of patients with advanced translocation-related sarcoma

Cultured circulating tumor cells and their derived xenografts for personalized oncology

AbstractRecent cancer research has demonstrated the existence of circulating tumor cells (CTCs) in cancer patient's blood. Once identified, CTC biomarkers will be invaluable tools for clinical diagnosis, prognosis and treatment. In this review, we propose ex vivo culture as a rational strategy for large scale amplification of the limited numbers of CTCs from a patient sample, to derive enough CTCs for accurate and reproducible characterization of the biophysical, biochemical, gene expressional and behavioral properties of the harvested cells. Because of tumor cell heterogeneity, it is important to amplify all the CTCs in a blood sample for a comprehensive understanding of their role in cancer metastasis. By analyzing critical steps and technical issues in ex vivo CTC culture, we developed a cost-effective and reproducible protocol directly culturing whole peripheral blood mononuclear cells, relying on an assumed survival advantage in CTCs and CTC-like cells over the normal cells to amplify this specified cluster of cancer cells