Modulation of autophagy: a Phase II study of vorinostat plus hydroxychloroquine versus regorafenib in chemotherapy-refractory metastatic colorectal cancer (mCRC).

BACKGROUND: In metastatic colorectal cancer (mCRC), regorafenib (RGF), a multi-kinase inhibitor with angiogenic inhibition has modest effects on survival. We reported that autophagy modulation using hydroxychloroquine (HCQ), enhances the anticancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in mCRC, is well tolerated, and has comparable activity to RGF. Thus, we conducted a prospective study of VOR/HCQ versus RGF in mCRC. METHODS: This is a randomised, controlled trial of VOR 400 mg and HCQ 600 mg orally daily versus RGF 160 mg orally daily (3 weeks on/1 week off), every 4 weeks, in patients with mCRC. PRIMARY ENDPOINT: median progression-free survival (mPFS). Secondary endpoints: median overall survival (mOS); adverse events; pharmacodynamic analyses. RESULTS: From 2/2015-10/2017, 42 patients were randomised to VOR/HCQ and RGF. Median age was 58.4 years. mPFS on VOR/HCQ was 1.9 months versus 4.35 months with RGF (P = 0.032). There was no difference in mOS (P = 0.9). Treatment was tolerated in both arms. In both arms, there was improved anti-tumour immunity. CONCLUSIONS: VOR/HCQ had an inferior PFS when compared to RGF, although there was an increase in anti-tumour immunity in mCRC. VOR/HCQ has a favourable safety profile, and immune or tumour biomarkers may be used to identify clinical benefit of autophagy modulation in mCRC. CLINICAL TRIAL REGISTRATION: NCT02316340.

Early impact of the Patient Protection and Affordable Care Act on insurance among young adults with cancer: Analysis of the dependent insurance provision.

BACKGROUND: The Patient Protection and Affordable Care Act (ACA) included provisions to extend dependent health care coverage up to the age of 26 years in 2010. The authors examined the early impact of the ACA (before the implementation of insurance exchanges in 2014) on insurance rates in young adults with cancer, a historically underinsured group. METHODS: Using National Cancer Institute Surveillance, Epidemiology, and End Results data for 18 cancer registries, the authors examined insurance rates before (pre) (January 2007-September 2010) versus after (post) (October 2010-December 2012) dependent insurance provisions among young adults aged 18 to 29 years when diagnosed with cancer during 2007 through 2012. Using multivariate generalized mixed effect models, the authors conducted difference-in-differences analysis to examine changes in overall and Medicaid insurance after the ACA among young adults who were eligible (those aged 18-25 years) and ineligible (those aged 26-29 years) for policy changes. RESULTS: Among 39,632 young adult cancer survivors, the authors found an increase in overall insurance rates in those aged 18 to 25 years after the dependent provisions (83.5% for pre-ACA vs 85.4% for post-ACA; P<.01), but not among individuals aged 26 to 29 years (83.4% for pre-ACA vs 82.9% for post-ACA; P = .38). After adjusting for patient sociodemographics and cancer characteristics, the authors found that those aged 18 to 25 years had a 3.1% increase in being insured compared with individuals aged 26 to 29 years (P<.01); however, there were no significant changes noted in Medicaid enrollment (P = .17). CONCLUSIONS: The findings of the current study identify an increase in insurance rates for young adults aged 18 to 25 years compared with those aged 26 to 29 years (1.9% vs -0.5%) that was not due to increases in Medicaid enrollment, thereby demonstrating a positive impact of the ACA dependent care provisions on insurance rates in this population. Cancer 2016;122:1766-73. © 2016 American Cancer Society.

Most deprived Louisiana census tracts have higher hepatocellular carcinoma incidence and worse survival.

Background: Liver cancer incidence increased in the US from 1975 through 2015 with heterogeneous rates across subpopulations. Upstream or distal area-level factors impact liver cancer risks. Objective: The aim of this study was to examine the association between area-level deprivation and hepatocellular carcinoma (HCC) incidence and survival. We also explored the association between area deprivation and treatment modalities. Methods: Louisiana Tumor Registry identified 4,151 adult patients diagnosed with malignant HCC from 2011 to 2020 and linked residential address to census tract (CT)-level Area Deprivation Index (ADI) categorized into quartiles (Q1 = least deprived). ANOVA examined the association between ADI quartile and CT age-adjusted incidence rate (AAIR) per 100,000. Chi-square tested the distribution of demographic and clinical characteristics across ADI quartiles. Kaplan-Meier and proportional hazard models evaluated survival by deprivation quartile. Results: Among the 1,084 CTs with incident HCC, the average (SD) AAIR was 8.02 (7.05) HCC cases per 100,000 population. ADI was observed to be associated with incidence, and the mean (SD) AAIR increased from 5.80 (4.75) in Q1 to 9.26 (7.88) in Q4. ADI was also associated with receipt of surgery (p < 0.01) and radiation (p < 0.01) but not chemotherapy (p = 0.15). However, among those who received chemotherapy, people living in the least deprived areas began treatment approximately 10 days sooner than those living in other quartiles. Q4 patients experienced the worst survival with a median of 247 (95% CI 211-290) days vs. Q1 patients with a median of 474 (95% CI 407-547) days (p < 0.0001). Q4 had marginally poorer survival (HR 1.20, 1.05-1.37) than Q1 but the association became non-significant (HR 1.12, 0.96-1.30) when adjusted for rurality, liquor store density, sex, race/ethnicity, age, insurance, BMI, stage, hepatitis diagnosis, and comorbidities. Conclusion: Increasing neighborhood (CT) deprivation (ADI) was observed to be associated with increased HCC incidence and poorer HCC survival. However, the association with poorer survival becomes attenuated after adjusting for putative confounders.

Ethical challenges in oncology, explored through a series of vignettes.

The specialty of medical oncology poses many ethical dilemmas to the practicing physician. In this article, we have chosen to focus on three of those challenges, presenting them in the form of vignettes. The first dilemma deals with the difficulties physicians encounter secondary to the rising cost of cancer therapies when choosing and communicating about treatment plans with patients. The second scenario addresses difficulties associated with communicating prognosis to cancer patients, and the third challenge focuses on cancer treatment strategies for patients nearing the end of life.

Colon Cancer Survivorship in Patients Who Have Received Adjuvant Chemotherapy.

The number of colon cancer survivors in the United States is increasing due to improved early detection, better treatments that extend survival, and the growing aging population who are at high risk for cancer. Following initial active treatment, colon cancer survivors experience a wide range of long-term physical, psychological, and socio-economic effects that impact their overall well-being. Healthcare providers caring for survivors need to prioritize not only monitoring for cancer recurrence but also optimizing their overall health through addressing these long-term effects; managing their comorbidities; promoting healthy behaviors (like exercise, nutrition, and weight loss); and screening for a second primary cancer depending on their risk. Personalized survivorship care plans should be formulated clearly outlining the roles of various healthcare providers involved in their care. Our review article focuses on these various aspects of colon cancer survivorship, including surveillance for cancer recurrence specific to those who received adjuvant chemotherapy with curative intent.

Survivorship in Early-Stage Rectal Cancer Patients Who Have Received Combined Modality Therapy.

Survival rates in early-stage rectal cancer patients have increased over the past few decades. Societies such as the National Comprehensive Cancer Network (NCCN), American Cancer Society (ACS), American Society of Clinical Oncology (ASCO), and European Society of Medical Oncology (ESMO) have proposed guidelines related to cancer survivorship care including formal recommendations to address the needs in early-stage rectal cancer survivors. These guidelines, in addition to new clinical research findings in survivorship will be reviewed, specifically looking at physical, psychosocial, and financial concerns in rectal cancer survivorship.

Safety, Efficacy, and Biomarker Results from a Phase Ib Study of the Anti-DKK1 Antibody DKN-01 in Combination with Pembrolizumab in Advanced Esophagogastric Cancers.

Therapeutic combinations targeting innate and adaptive immunity and predictive biomarkers of response in esophagogastric cancer (EGC) are needed. We assessed safety and clinical utility of DKN-01 (a novel DKK1-neutralizing IgG4 antibody) combined with pembrolizumab and retrospectively determined DKK1 tumoral expression as a biomarker. Patients with advanced EGC received intravenous DKN-01 (150 or 300 mg) on days 1 and 15 with pembrolizumab 200 mg on day 1 in 21-day cycles. Clinical response was assessed by RECIST v1.1. Association of tumoral DKK1 mRNA expression (H-score: high ≥ upper-tertile, low < upper-tertile) with response was assessed with PD-L1 levels as a covariate. Sixty-three patients received DKN-01 150 mg (n = 2) or 300 mg (n = 61) plus pembrolizumab. Common adverse events were fatigue, anemia, blood alkaline phosphatase elevation, aspartate aminotransferase elevation, and hyponatremia. Among evaluable anti-PD-1/PD-L1-naïve patients receiving DKN-01 300 mg and pembrolizumab, objective response rate (ORR) was 11.4% (5/44) and 18.5% (5/27) in patients with gastroesophageal junction or gastric cancer (GEJ/GC). Among response-evaluable anti-PD-1/PD-L1-naïve patients with GEJ/GC and known tumoral DKK1 expression, ORR was 50% in DKK1-high and 0% in DKK1-low patients, median PFS was 22.1 vs. 5.9 weeks (HR, 0.24; 95% CI, 0.08-0.67), respectively, and median OS was 31.6 weeks vs. 17.4 weeks (HR, 0.41; 95% CI, 0.16-1.07), respectively. Association of DKK1 expression with PFS was independent of PD-L1 expression (adjusted HR, 0.21; 95% CI, 0.06-0.69). DKN-01 combined with pembrolizumab was well tolerated with no new safety signals. Antitumor activity was enriched in anti-PD-1/PD-L1-naïve patients with GEJ/GC whose tumors expressed high DKK1.

Talking Genes in Breast and Pancreatic Malignancies.

INTRODUCTION: Both breast and pancreatic cancers have high mortality rates. Breast cancer is the second leading cause of cancer death in females, while pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer death. Almost 4-16 % of individuals with pancreatic cancer have a family history of the disease. Intra-ductal papillary mucinous neoplasms (IPMNs) are cystic lesions that received more attention lately due to their associations with PDAC and other solid organ tumors, such as breast cancer. AIM: The purpose of this article is to discuss the association of the familiar pancreatic cancer (FPC), sporadic pancreatic cancer, and IPMNs with the breast cancer. RESULTS: Mutations in BRCA2, BRCA1, p16 and PALB2 play a major role in the genetic etiologies of familial pancreatic cancer. In familial and sporadic pancreatic cancers, mutations in BRCA2 are associated with a high incidence of PDAC, while mutations in BRCA1have shown inconsistent results. Data is insufficient to prove an association between IPMNs and breast cancer. CONCLUSION: The familial clustering of PDAC is not well understood. Further studies are required for greater comprehension of the genetic basis of PDAC and the association between IPMNs and breast cancer.

Let's Talk About Those Herbs You Are Taking: Ethical Considerations for Communication With Patients With Cancer About Complementary and Alternative Medicine.

Oncologists face ethical challenges when patients use potentially harmful complementary and alternative medicine in addition to or instead of conventional treatments for their cancer. For example, a patient may forego effective cancer treatment in favor of alternative therapies and suffer significant harm as a result. Similarly, false beliefs about the efficacy of complementary therapies may complicate the process of shared decision making about cancer treatment. In this vignette, we discuss clinicians' obligations and provide recommendations for ethically sound communication practices in this clinical context.

Metformin modifies disparity in hepatocellular carcinoma incidence in men with type 2 diabetes but without chronic liver diseases.

BACKGROUND: We assessed racial/ethnic disparity in hepatocellular carcinoma (HCC) incidence among men with type 2 diabetes (T2D) but without chronic liver diseases (CLD), and whether metformin use modified the disparity. METHODS: Study cohort: the nationwide Veterans Administration Health Care System electronic medical records among 40-89 years old men with T2D; without CLD, cancer, cardiovascular or renal diseases previously; insulin and thiazolidinedione naive. Logistic regression analyses compared HCC incidence between race/ethnicity groups under no metformin use adjusted for covariates and inverse propensity score weights (IPSW) for race/ethnicity. The generalizability technique integrated with IPSW was incorporated to compare covariates adjusted odds ratios (aOR) of HCC associated with metformin use among race/ethnicity groups. RESULTS: Study cohort: N = 84 433; 79.47% non-Hispanic white (NHW), 15.5% non-Hispanic African American (NHAA), 5.03% Hispanics; 36.76% metformin users; follow-up 6.10 ± 2.87 years; age 67.8 ± 9.8 years, HbA1c 6.57 ± 0.98%; 0.14% HCC cases. Under no metformin use, HCC incidence was lower for NHAA vs NHW (aOR = 0.60 [0.40-0.92]), similar between NHW and Hispanics. Metformin was associated with reduced HCC risk: aOR = 0.57 (0.40-0.81) for NHW; aOR = 0.35 (0.25-0.47) for NHAA; aOR = 0.31 (0.22-0.43) for Hispanics. Metformin dose >1000 mg/d was neutral for NHW; less effective for NHAA (P = 0.02); more effective for Hispanics (P = 0.002). CONCLUSIONS: In men with T2D but without CLD nor metformin use, HCC incidence was lower for NHAA compared to NHW or Hispanics; similar between NHW and Hispanics. Metformin use reduced HCC risk and modified the race/ethnicity disparity. IMPACT: Metformin's heterogeneous HCC prevention effect elucidates potential interventions to modify HCC disparity in patients with T2D.

Trends in Antineoplastic Receipt after Medicare Payment Reform: Implications for Future Oncology Payment Design.

BACKGROUND: The Medicare Modernization Act (MMA) reduced reimbursement for many antineoplastics delivered in outpatient settings, altering practice patterns for some cancers. To further evaluate the MMA's effect, we focus on colon cancer, where longstanding fluorouracil-based regimens were augmented in 2004 with 3 newly-approved drugs (oxaliplatin, bevacizumab, and/or cetuximab). Staggered implementation of MMA reimbursement changes (physician offices implemented reimbursement changes in 2005 vs hospital outpatient departments(OPD) in 2006) provide a natural experiment to examine policy effects. METHODS: Using the 2000-2009 SEER-Medicare data, we examined antineoplastic use among 59,642 stage II-IV colon cancer patients. Using multivariate logistic regression models, we conducted difference-in-differences analyses to examine an interaction between time (pre-post MMA) and setting (physician offices versus OPDs) on antineoplastic receipt, adjusting for patient and cancer characteristics. A significant interaction indicates different practice patterns in physician offices versus OPD during the staggered implementation. RESULTS: After the reimbursement change in 2007-09 relative to 2000-03, use of fluorouracil-based therapy decreased slightly (Marginal Probability(MP): -0.07 stage II; -0.05 stage III; -0.05 stage IV; p< 0.01), while use of new drugs increased substantially (MP: 0.48 stage II; 0.69 stage III, 0.79 stage IV; p< 0.01). The interaction between MMA implementation and physician office setting was significant when examining use of new agents for Stage IV disease only. CONCLUSIONS: Our results indicate that providers responded to reimbursement changes after the MMA by increasing use of newly approved agents, but the magnitude of the response was small and limited to individuals diagnosed with Stage IV disease.

Symptom Burden and Palliative Referral Disparities in an Ambulatory South Texas Cancer Center.

Background: The American Society of Clinical Oncology's recommendation for "dedicated palliative care services, early in the disease course, concurrent with active treatment" for cancer patients is a challenge for cancer centers to accommodate. Despite demonstrated benefits of concurrent care, disparities among socioeconomic and ethnic groups in access to supportive care services have been described. The aim of this project was to evaluate: (a) how insurance coverage and ethnicity impact patient symptom burden and, (b) how those factors influence palliative access for patients at a South Texas NCI-designated cancer center. Methods: During a 5-month prospective period, 604 patients from five ambulatory oncology clinics completed the 10 question Edmonton Symptom Assessment Scale (ESAS) surveys during their clinic visit. Patient demographics, ESAS scores, palliative referral decisions, and time to palliative encounters were collected. We compared symptom burden and time to consult based on ethnicity and insurance status (insured = Group A; under-insured and safety net = Group B). Results: The mean ESAS score for all patients at the initial visit was 19.9 (SD = 18.1). Safety net patients were significantly more likely to be Hispanic, younger in age, and have an underlying GI malignancy in comparison to insured patients; however, the symptom severity was similar between groups with over 40% of individuals reporting at least one severe symptom. Twenty-one referrals were made to palliative care. On average, Group B had 33.3 days longer wait times until their first potential visit (p < 0.01) when compared to Group A. Time to actual visit was on average 57.6 days longer for patients in Group B compared to patients in Group A (p = 0.01), averaging at 73.8 days for safety net patients. Conclusions: This project highlights the high symptom burden of oncology patients and disparities in access to services based on insurance coverage. This investigation revealed a 4-fold increase in the time to the first scheduled palliative care visit based on whether patients were insured vs. under-insured. While this study is limited by a small sample size, data suggest that under-insured oncology patients may have significant barriers to palliative care services, which may influence their cancer care quality.

Integrating Palliative Care Services in Ambulatory Oncology: An Application of the Edmonton Symptom Assessment System.

PURPOSE: Research in palliative care demonstrates improvements in overall survival, quality of life, symptom management, and reductions in the cost of care. Despite the American Society of Clinical Oncology recommendation for early concurrent palliative care in patients with advanced cancer and high symptom burden, integrating palliative services is challenging. Our aims were to quantitatively describe the palliative referral rates and symptom burden in a South Texas cancer center and establish a palliative referral system by implementing the Edmonton Symptom Assessment Scale (ESAS). METHODS: As part of our Plan-Do-Study-Act process, all staff received an educational overview of the ESAS tool and consultation ordering process. The ESAS form was then implemented across five ambulatory oncology clinics to assess symptom burden and changes therein longitudinally. Referral rates and symptom assessment scores were tracked as metrics for quality improvement. RESULTS: On average, one patient per month was referred before implementation of the intervention compared with 10 patients per month after implementation across all clinics. In five sample clinics, 607 patients completed the initial assessment, and 430 follow-up forms were collected over 5 months, resulting in a total of 1,037 scores collected in REDCap. The mean ESAS score for initial patient visits was 20.0 (standard deviation, 18.1), and referred patients had an initial mean score of 39.0 (standard deviation, 19.0). CONCLUSION: This project highlights the low palliative care consultation rate, high symptom burden of oncology patients, and underuse of services by oncologists despite improvements with the introduction of a symptom assessment form and referral system.

Ethics in oncology: an annotated bibliography of important literature.

The aim of this annotated bibliography about important articles in the field of ethics and oncology is to provide the practicing hematologist/oncologist with a brief overview of some of the important literature in this crucial area.