2 Minute Medicine Rewind October 14, 2019

Oxaliplatin-Based Adjuvant Chemotherapy for Rectal Cancer After Preoperative Chemoradiotherapy (ADORE): Long-Term Results of a Randomized Controlled Trial

1. Adjuvant FOLFOX improves disease-free survival in patients with pathologic Stage II or III rectal cancer after upfront surgery and preoperative chemoradiotherapy, but is associated with a higher rate of adverse events.

Evidence Rating Level: 1 (Excellent)

Postoperative pathologic stage is one of the most important prognostic factors in patients with rectal cancer after surgery and preoperative chemoradiotherapy (CRT). Adjuvant chemotherapy is also recommended after surgery for patients with postoperative pathologic stages II and III rectal cancer. And, although only adjuvant fluoropyrimidines have demonstrated a survival benefit, oxaliplatin-based regimens are widely used in this setting based on the extrapolation of results from patients with colon cancer. In addition, most previous studies of oxaliplatin-based regimens have been designed based on clinical rather than pathologic staging. In this multicenter, randomized, controlled trial, 321 patients with postoperative ypStage II (ypT3-4N0) or III (ypTanyN1-2) rectal cancer after fluoropyrimidine-based preoperative CRT and total mesorectal excision (TME) were randomized to receive adjuvant chemotherapy with either fluorouracil and leucovorin (FL) or FOLFOX (oxaliplatin, leucovorin, and fluorouracil) to study disease-free survival (DFS). Researchers found that at 6 years of follow-up, the DFS rate was higher in the FOLFOX group than in the FL group (68.2% vs. 56.8%, respectively, HR 0.63, 95% CI 0.43 to 0.93, p=0.018). There was no statistically significant difference in 6-year overall survival (OS) between the two groups (FOLFOX 78.1% vs. FL 76.4%, HR 0.73, 95% CI 0.45 to 1.19, p=0.21). Exploratory subgroup analysis of DFS also revealed that FOLFOX treatment was favorable compared with FL in patients with ypStage III disease, male gender, age younger than 65 years, advanced pathologic stages, high-grade histology, minimally regressed tumor, an absence of lymphovascular or perineural invasion, and a longer than 6-week interval between CRT and surgery. Neutropenia (69.9% vs. 45.6%, p<0.001) and thrombocytopenia (26.0% vs. 2.0%, p<0.001) were, however, more common in the FOLFOX group, as were fatigue (28.3% vs. 17.4%, p=0.037), nausea (53.4% vs. 37.6%, p=0.007), and sensory neuropathy (70.5% vs. 5.4%, p<0.001); however, there was no significant difference in the occurrence of grade 3 or 4 adverse events between the two groups. Overall, this study suggests that adjuvant FOLFOX may improve disease-free survival in patients with postoperative ypStage II or III rectal cancer who received preoperative CRT and TME, but is associated with a higher rate of adverse events.

HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn’s Disease

1. Carriage of the HLA-DQA1*05 allele is significantly associated with the development of antibodies against anti-TNF agents.

Evidence Rating Level: 2 (Good)

Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologics for treating immune-mediated diseases. However, repeated administration can lead to the formation of anti-drug antibodies (immunogenicity), which can contribute to treatment failure. Thus, there is a critical need for methods to identify patients at an increased risk of immunogenicity to better inform treatment decisions. In this prospective cohort study, a genome-wide association study was performed on 1,240 biologic-naïve patients with active luminal Crohn’s disease starting infliximab or adalimumab to identify genomic variants associated with time to development of anti-drug antibodies. Immunogenicity was defined as an anti-drug antibody titer ≥10 AU/ml in a drug-tolerant ELISA assay. Significant association signals were confirmed in a replication cohort of 178 patients with inflammatory bowel disease. Researchers found that within the first 12 months, 44% of patients developed anti-drug antibodies (95% CI 41% to 48%), and 62% of patients did so within 36 months (95% CI 57% to 67%). After correcting for immunomodulator use, the rate of immunogenicity was greater in patients treated with infliximab (n=742) than adalimumab (n=498) (HR 3.21, 95% CI 2.61 to 3.95, p=1.18×10-28). Researchers also identified a short nucleotide polymorphism (SNP) on chromosome 6, rs2097432, which falls within the major histocompatibility complex (MHC) region, that is significantly associated with time to development of immunogenicity (b38_pos: 6:32622994; HR 1.70, 95% CI 1.48 to 1.94, p=4.24×10-13). This association was replicated in the independent cohort (HR 1.69, 95% CI, 1.26 to 2.28, p=8.80×10-4). At the human leukocyte antigen (HLA) allele group level, the HLA-DQA1*05 allele achieved genome-wide significance (HR 1.90, 95% CI 1.60 to 2.25, p=5.88×10-13). Fine-mapping and confirmatory sequencing of the HLA identified that the specific alleles HLA-DQA1*05:01 and HLA DQA1*05:05 mediated most of this risk. Concordantly, the highest rates of immunogenicity, 92% at 1 year, were observed in patients treated with infliximab monotherapy who carried HLA-DQA1*05. Conversely, the lowest rates of immunogenicity, 10% at 1 year, were observed in patients treated with adalimumab combination therapy who did not carry HLA-DQA1*05. This finding was confirmed in the replication cohort (HR 2.00, 95% CI 1.35 to 2.98, p=6.60×10-4). This association was consistent for patients treated with adalimumab (HR 1.89, 95% CI 1.32 to 2.70) or infliximab (HR 1.92, 95% CI 1.57 to 2.33). Overall, this study suggests that pre-treatment genetic testing for HLA-DQA1*05 may help personalize the choice of anti-TNF therapy and the need for combination therapy with an immunomodulator. However, due to the wide variation in the frequency of HLA-DQA1*05 across ethnic groups, further studies are required to assess the contribution of HLA-DQA1*05 to immunogenicity across populations.

Non-alcoholic fatty liver disease and risk of incident acute myocardial infarction and stroke: findings from matched cohort study of 18 million European adults

1. After adjustment for established cardiovascular risk factors, the diagnosis of non-alcoholic fatty liver disease (NAFLD) does not appear to be associated with risk of acute myocardial infarction or stroke. 

Evidence Rating Level: 2 (Good)

Recent studies indicate that non-alcoholic fatty liver disease (NAFLD) is associated with a higher risk of acute myocardial infarction and stroke. However, these studies only partially adjusted for known risk factors of cardiovascular disease, such as diabetes and lipid levels. In this matched retrospective cohort study, 120,795 adults with a diagnosis of NAFLD or non-alcoholic steatohepatitis (NASH) and no other liver diseases were identified from four primary care databases, and matched to 100 controls at the time of NAFLD diagnosis (index date) to study the incidence of fatal or non-fatal acute myocardial infarction (AMI) and ischemic or unspecific stroke. At baseline, traditional cardiovascular risk factors were more common in participants with NAFLD compared with matched controls, including smoking, a history of type 2 diabetes or hypertension, higher BMI and systolic blood pressure levels. Researchers found that, after adjustment for age, gender, and smoking, incident AMI was more common in patients with NAFLD or NASH (HR 1.17, 95% CI 1.05 to 1.30). However, in a subgroup analysis of patients with complete data on traditional risk factors for cardiovascular disease, researchers found no significant difference between patients with NAFLD or NASH and matched controls (HR 1.01, 95% CI 0.91 to 1.12).  Similarly, after adjustment for age, gender, and smoking, incident stroke was slightly more common in patients with NAFLD or NASH than in matched controls (HR 1.18, 95% CI 1.11 to 1.24), but in a subgroup analysis of patients with more complete data on risk factors, there was no significant difference (HR 1.04, 95% CI 0.99 to 1.09). In summary, this study suggests that a diagnosis of NAFLD or NASH is not associated with an increased risk of AMI or stroke after adjustment for cardiovascular risk factors, and that the risk of cardiovascular disease and need for preventative treatment should not be assessed differently in these patients.

Assessment of Combined Nivolumab and Bevacizumab in Relapsed Ovarian Cancer: A Phase 2 Clinical Trial

1. Nivolumab and bevacizumab combination therapy appears to be efficacious in relapsed epithelial ovarian cancer, especially in patients with platinum-sensitive disease.

Evidence Rating Level: 2 (Good)

Although previous investigations have indicated that the immune system plays an important role in ovarian cancer control, results from trials thus far on single-agent immune checkpoint inhibition have demonstrated limited clinical activity. Thus, it has been hypothesized that immune checkpoint inhibition could be potentiated by the addition of an agent that targets a separate pathway, such as bevacizumab, a VEGF-A inhibitor. In this phase II, single-arm study, 38 women with relapsed epithelial ovarian cancer (defined as disease recurrence within 12 months of their last platinum-based therapy) received intravenous nivolumab and intravenous bevacizumab once every 2 weeks to assess objective response rate (ORR) as measured by Response Evaluation Criteria for Solid Tumors (RECIST) 1.1. Secondary end points included evaluation of the ORR by platinum sensitivity, assessment of progression-free survival (PFS), investigation of the association of tumor PD-L1 with response to therapy, and safety. At baseline, 18 patients had platinum-resistant and 20 had platinum-sensitive disease, and the mean (SD) age was 63.0 (9.1) years. Researchers found that 11 patients responded to bevacizumab and nivolumab (ORR 28.9%, 95% CI 15.4% to 45.9%), 8 of which were patients with platinum-sensitive disease (ORR 40.0%, 95% CI 19.1% to 64.0%), and 3 of which were patients with platinum-resistant disease (ORR 16.7%, 95% CI 3.6% to 41.4%). Median progression-free survival (PFS) was 9.4 months (95% CI 6.7 months to NA), with a median PFS of 12.1 months (95% CI 8.4 months to NA) in platinum-sensitive patients and 7.7 months (95% CI 4.7 months to NA) in platinum-resistant patients. There were 10 confirmed or unconfirmed responses in patients with a PD-L1 tumor percentage lower than 1 (ORR 45.5%) and 2 in patients with a PD-L1 tumor percentage of 1 or more (ORR 14.3%). Adverse events were common; 34 participants (89.5%) experienced at least one treatment-related adverse event, and 9 participants (23.7%) experienced a grade 3 or higher treatment-related adverse event. This study was limited by the lack of a comparison arm and the small sample size. In summary, this study suggests that the combination of nivolumab and bevacizumab is efficacious in relapsed epithelial ovarian cancer, with greater activity in the platinum-sensitive setting. The results also reinforce the notion that PD-L1 expression may not be a reliable biomarker of response to immunotherapy in this disease.

Longitudinal Associations Between Income Changes and Incident Cardiovascular Disease: The Atherosclerosis Risk in Communities Study

1. Income drop is associated with a higher risk of subsequent cardiovascular disease, while income rise is associated with a lower risk of subsequent cardiovascular disease.

Evidence Rating Level: 2 (Good)

Low income has been robustly associated with an increased risk of cardiovascular disease (CVD). However, causality remains disputed, principally due to assertions that low income may be a marker of other characteristics that predict worse health maintenance behaviors. Therefore, it is critical to examine the impact of income changes on CVD to attempt to infer causality. In this retrospective cohort study, a subset of 8,989 men and women originally enrolled in the Atherosclerosis Risk in Communities (ARIC) study, an ongoing cohort of community-dwelling men and women in 4 US geographic regions, were studied to examine the association between change in household income and subsequent risk of incident CVD, comprising definite or probable MI, fatal coronary heart disease (CHD), incident heart failure (HF), or definite or probable stroke. Data censoring for this study was performed on December 31, 2016. In the approximately 6-year period between the first and third ARIC visits, 10% of participants experienced an income drop, (with mean household incomes falling from $40,516 to $14,655), 70% had incomes that remained relatively unchanged (with mean household incomes remaining similar from $43,897 to $43,057), and 20% experienced an income rise, (with mean household incomes rising from $26,099 to $53,347). After adjusting for all covariates, researchers found that those with an income drop had a significantly higher risk of incident CVD compared to those whose incomes remained relatively unchanged (HR 1.17, 95% CI 1.03 to 1.32), while those with an income rise had a significantly lower risk of incident CVD compared with those whose incomes remained relatively unchanged (HR 0.86, 95% CI 0.77 to 0.96). In fully adjusted analysis, white participants had a higher risk of incident CVD from an income drop compared with black participants (HR for white race 1.28, 95% CI 1.11 to 1.48 vs. HR for black race 1.01, 95% CI 0.79 to 1.29). Women had a lower risk of incident CVD from an income rise compared with men (HR for women 0.74, 95% CI 0.63 to 0.87 vs. HR for men 1.01, 95% CI 0.86 to 1.18). Overall, this study underlines the significant association between income and risk of cardiovascular disease, and emphasizes the need to increase awareness among healthcare providers of the impact of income changes on health.

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