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

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

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

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

Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors

Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11

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

A case of adenosquamous pancreatic cancer with a KRAS G12C mutation with an exceptional response to immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths, with adenosquamous carcinoma of the pancreas (ASCP), a rare variant, representing 1-10% of cases. Standard chemotherapy trials for pancreatic cancer exclude ASCP, leaving its optimal treatment uncertain. This report describes a 68-year-old male with metastatic ASCP and a KRAS G12C mutation, progressing through multiple lines of systemic therapy, including targeted inhibition of KRAS G12C. Notably, the patient exhibited a robust response to single-agent immune checkpoint inhibition (ICI) with pembrolizumab, despite intact mismatch repair proteins. The limited success of traditional therapies in pancreatic cancer, coupled with the rarity of ASCP, presents a challenge in establishing effective treatment strategies. While KRAS G12C inhibitors demonstrated modest benefits, this case highlights the remarkable response to ICI in a patient with squamous histology. The distinct tumor microenvironment of ASCP, characterized by squamous differentiation, may contribute to this exceptional response. This underscores the need for further research and clinical trials focused on ICI in ASCP, with an ongoing multi-center phase 2 trial investigating outcomes in this specific subset

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

Exercise Guidelines in Pancreatic Cancer Based on the Dietz Model.

Pancreatic and gastrointestinal cancers are associated with debility, frailty, and chemotherapy regiments with significant toxicity. Practical exercise guidelines to combat these ailments and optimize functional status are lacking. We present a model for exercise for these cancers based on the Dietz framework for rehabilitation in cancer. The Dietz framework for rehabilitation describes four phases of rehabilitation including preventative (prehabilitation), restorative, supportive, and palliative. We present practical guidelines for exercise at each phase. Prehabilitation seeks to optimize functional performance typically prior to surgical resection and may occur concurrently with neoadjuvant therapy. Restorative rehabilitation occurs following the development of a physical deficit such as after surgery and may utilize skilled therapies in the inpatient, subacute, outpatient, and home settings to address functional impairments. Supportive rehabilitation occurs during stable disease or remission and depends on the frequent monitoring of functional status and particularly the development of chemotherapy-induced neuropathy to ensure timely exercise interventions. Palliative rehabilitation occurs at the end stage of life and shifts to a focus on patient comfort and safety. Exercise is a critical component of treatment in cancer demonstrating numerous quality-of-life benefits. The customization of exercise recommendations to individual patients based on their functional status and phase in treatment is essential for safety and adherence