Association of age with survival in older patients with cutaneous melanoma treated with immune checkpoint inhibitors.

INTRODUCTION: Several types of immune checkpoint inhibitors (ICIs) are approved to treat advanced melanoma, but their effectiveness has not been compared in older patients treated outside of a clinical trial. Moreover, evidence suggests that a patient's response to ICI therapy may vary by age and type of ICI. The purpose of this study was to compare survival by ICI type in older patients with melanoma and to investigate treatment effect modification by age. MATERIALS AND METHODS: Using the SEER-Medicare database, we identified patients with cutaneous melanoma (2012-2015) treated with an ICI (CTLA-4, PD-1, or combination CTLA-4 + PD-1 inhibitors). Cox proportional hazards regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for ICI types. We used an interaction term and stratified models to test for treatment effect modification by age. RESULTS: Of the 1435 patients included in our analysis, 790 (55.1%) received CTLA-4 inhibitors, 512 (35.7%) received PD-1 inhibitors, and 133 (9.3%) were treated with combination ICIs. Median survival ranged from 13.4 months (95%CI: 10.7-16.3) for CTLA-4 inhibitors to 23.5 months (95%CI: 16.2-30.0) for combination ICIs. In multivariable models, the risk of death was lower with PD-1 inhibitors compared to CTLA-4 inhibitors (HR = 0.78, 95%CI: 0.68-0.89). An age*ICI type interaction term was significant (p < 0.001), and survival gains were greater the older age group (≥80) compared to the younger group (65-79). DISCUSSION: In a population-based setting, we identified important differences in survival by ICI type in older patients with melanoma treated with ICIs, with prolonged survival associated with PD-1 inhibitors compared to CTLA-4 inhibitors.

Immune checkpoint inhibitors retain effectiveness in older patients with cutaneous metastatic melanoma.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have dramatically changed the treatment landscape for advanced melanoma, but their use in older patients remains understudied. An age-related decline in immune function is of concern when treating older patients because host immune factors can influence clinical outcomes with immunotherapy. Therefore, we aimed to evaluate the effectiveness of ICIs in patients 65 years and older. METHODS: Using the SEER-Medicare data, we evaluated survival by first systemic treatment type in a retrospective cohort study of patients aged 65 years and older who were diagnosed with stage IV cutaneous melanoma between 2012 and 2015. Cox proportional hazards regression was used to estimate hazard ratios (HR) and their corresponding 95% confidence intervals. RESULTS: A total of 541 patients were included in this study. Median survival differed significantly between groups (p < 0.0001) and was longest in patients treated with PD-1 inhibitors (34.0 months), followed by CTLA-4 inhibitors (16.8 months), targeted therapy (9.7 months), chemotherapy (7.1 months), and no systemic therapy (3.6 months). The ICI survival benefit persisted after adjusting for age, sex, comorbidities, M stage, the presence of brain metastases, and evaluation at an NCI-designated cancer center. Hazard ratios comparing ICIs to no systemic therapy were 0.35 (95% CI: 0.24-0.52) for PD-1 inhibitors and 0.48 (95% CI: 0.37-0.63) for CTLA-4 inhibitors. We did not observe a difference in ICI effectiveness by age group (65-74 vs ≥75). CONCLUSIONS: In a nationally representative cohort of patients with advanced melanoma, ICI therapy delivered in a real world setting significantly improved survival in patients aged 65 years and older.

Racial Disparities in Incidence of Young-Onset Colorectal Cancer and Patient Survival.

BACKGROUND & AIMS: Increasing rates of young-onset colorectal cancer (CRC) have attracted substantial research and media attention, but we know little about racial disparities among younger adults with CRC. We examined racial disparities in young-onset CRC by comparing CRC incidence and relative survival among younger (<50-year-old) adults in 2 time periods. METHODS: Using data from the Surveillance, Epidemiology, and End Results program of cancer registries, we estimated CRC incidence rates (per 100,000 persons 20-49 years old) from 1992 through 2014 for different periods (1992-1996 vs 2010-2014) and races (white vs black). Relative survival was calculated as the ratio of observed survival to expected survival in a comparable cancer-free population. RESULTS: From 1992-1996 to 2010-2014, CRC incidence increased from 7.5 to 11.0 per 100,000 in white individuals and from 11.7 to 12.7 per 100,000 in black individuals. The increase in rectal cancer was larger in whites (from 2.7 to 4.5 per 100,000) than in blacks (from 3.4 to 4.0 per 100,000); in the 2010-2014 period, blacks and whites had similar rates of rectal cancer. Compared with whites, blacks had smaller increases in relative survival with proximal colon cancer but larger increases in survival with rectal cancer (from 55.3% to 70.8%). CONCLUSION: In an analysis of the Surveillance, Epidemiology, and End Results database, we found racial disparities in incidence of young-onset CRC and patient survival for cancer of the colon but minimal difference for rectal cancer. Well-documented and recent increases in young-onset CRC have largely been due to increases in rectal cancer, especially in whites.

Racial Differences in Stage IV Colorectal Cancer Survival in Younger and Older Patients.

INTRODUCTION: African Americans (AAs) compared with European Americans (EAs) have poorer stage-specific survival from colorectal cancer (CRC). Recent reports have indicated that the racial difference in survival has worsened over time, especially among younger patients. To better characterize this association, we used population-based Surveillance, Epidemiology, and End Results registry data to evaluate the effect of race on stage IV CRC survival in patients aged < 50 and ≥ 50 years. PATIENTS AND METHODS: The population included 16,782 patients diagnosed with stage IV colon and rectal adenocarcinoma from January 1, 2004 and December 31, 2011. Cox proportional hazards regression was used to evaluate the association between race and other prognostic factors and the risk of death in each age group. RESULTS: Younger AAs compared with EAs had a greater prevalence of proximal CRC at diagnosis, a factor associated with a significantly greater risk of death in both races. Among patients < 50 years old, AAs had a greater risk of death compared with EAs (hazard ratio, 1.35; 95% confidence interval, 1.20-1.51), which was attenuated in patients ≥ 50 years of age (hazard ratio, 1.10; 95% confidence interval, 1.04-1.16); P for interaction = .01. CONCLUSION: The results revealed poor overall survival for AAs compared with EAs, especially for those < 50 years of age. The greater prevalence of proximal CRC at diagnosis among younger AAs (vs. EAs) might contribute to the racial difference in survival. Future studies are needed to understand how the colonic location affects the efficacy of treatment regimens.

Bayesian accelerated failure time model for space-time dependency in a geographically augmented survival model.

In this paper, we extend the spatially explicit survival model for small area cancer data by allowing dependency between space and time and using accelerated failure time models. Spatial dependency is modeled directly in the definition of the survival, density, and hazard functions. The models are developed in the context of county level aggregated data. Two cases are considered: the first assumes that the spatial and temporal distributions are independent; the second allows for dependency between the spatial and temporal components. We apply the models to prostate cancer data from the Louisiana SEER cancer registry.

Socioeconomic Status in Relation to the Risk of Ovarian Cancer in African-American Women: A Population-Based Case-Control Study.

We investigated the association between socioeconomic status and ovarian cancer in African-American women. We used a population-based case-control study design that included case patients with incident ovarian cancer (n = 513) and age- and area-matched control participants (n = 721) from 10 states who were recruited into the African American Cancer Epidemiology Study from December 2010 through December 2014. Questionnaires were administered via telephone, and study participants responded to questions about several characteristics, including years of education, family annual income, and risk factors for ovarian cancer. After adjustment for established ovarian cancer risk factors, women with a college degree or more education had an odds ratio of 0.71 (95% confidence interval (CI): 0.51, 0.99) when compared with those with a high school diploma or less (P for trend = 0.02); women with family annual incomes of $75,000 or more had an odds ratio of 0.74 (95% CI: 0.47, 1.16) when compared with those with incomes less than $10,000 (P for trend = 0.055). When these variables were dichotomized, compared with women with a high school diploma or less, women with more education had an adjusted odds ratio of 0.72 (95% CI: 0.55, 0.93), and compared with women with an income less than $25,000, women with higher incomes had an adjusted odds ratio of 0.86 (95% CI: 0.66, 1.12). These findings suggest that ovarian cancer risk may be inversely associated with socioeconomic status among African-American women and highlight the need for additional evidence to more thoroughly characterize the association between socioeconomic status and ovarian cancer.

Race and Prevalence of Large Bowel Polyps Among the Low-Income and Uninsured in South Carolina.

BACKGROUND: Compared to whites, blacks have higher colorectal cancer incidence and mortality rates and are at greater risk for early-onset disease. The reasons for this racial disparity are poorly understood, but one contributing factor could be differences in access to high-quality screening and medical care. AIMS: The present study was carried out to assess whether a racial difference in prevalence of large bowel polyps persists within a poor and uninsured population (n = 233, 124 blacks, 91 whites, 18 other) undergoing screening colonoscopy. METHODS: Eligible patients were uninsured, asymptomatic, had no personal history of colorectal neoplasia, and were between the ages 45-64 years (blacks) or 50-64 years (whites, other). We examined the prevalence of any adenoma (conventional, serrated) and then difference in adenoma/polyp type by race and age categories. RESULTS: Prevalence for ≥1 adenoma was 37 % (95 % CI 31-43 %) for all races combined and 36 % in blacks <50 years, 38 % in blacks ≥50 years, and 35 % in whites. When stratified by race, blacks had a higher prevalence of large conventional proximal neoplasia (8 %) compared to whites (2 %) (p value = 0.06) but a lower prevalence of any serrated-like (blacks 18 %, whites 32 %; p value = 0.02) and sessile serrated adenomas/polyps (blacks 2 %, whites 8 % Chi-square p value; p = 0.05). CONCLUSIONS: Within this uninsured population, the overall prevalence of adenomas was high and nearly equal by race, but the racial differences observed between serrated and conventional polyp types emphasize the importance of taking polyp type into account in future research on this topic.

The association of age and race and the risk of large bowel polyps.

BACKGROUND: Blacks have a higher incidence of colorectal cancer and a younger age at diagnosis compared with whites. Few studies have investigated racial differences in risk of metachronous adenomas and serrated polyps and whether this risk differs by polyp characteristics or age of patient. METHODS: We analyzed data pooled from three placebo-controlled adenoma chemoprevention trials to explore racial differences in the risk of large bowel polyps in patients ≤50 and >50 years of age. Using generalized linear regression, we estimated risk ratios (RR) and 95% confidence intervals (CI) as measures of the association between race and risk of one or more adenomas or serrated polyps after randomization. RESULTS: Among the 2,605 subjects who completed at least one follow-up exam, blacks ≤50 years of age had a higher risk of any conventional adenoma (RR, 1.70; 95% CI, 0.99-2.92) and advanced neoplasms (RR, 4.05; 95% CI, 1.43-11.46) and a nonsignificantly lower risk of serrated polyps (RR, 0.75; 95% CI, 0.34-1.62) compared with whites. Among patients >50 years, there was no racial difference in risk of adenomas (RR, 1.08; 95% CI, 0.92-1.27) or advanced neoplasms (RR, 1.05; 95% CI, 0.71- 1.56). However, blacks had a significantly lower risk of serrated polyps (RR, 0.65; 95% CI, 0.49-0.87) than whites. CONCLUSIONS: Our results demonstrate a higher risk of metachronous adenomas in blacks compared with whites at younger ages. IMPACT: Our results suggest that the racial disparity in colorectal cancer incidence may be due to an excess of neoplasia in younger blacks.

Prognostic factors in relation to racial disparity in advanced colorectal cancer survival.

INTRODUCTION: Colorectal cancer mortality rates are significantly greater in AA than in EA individuals, and the disparity is worsening. We investigated the relationship between race and metastatic CRC (mCRC) survival in younger and older patients. PATIENTS AND METHODS: Using data from the Hollings Cancer Center (Charleston, SC), we studied the role of clinical, pathologic, and treatment-related factors on the disparity in survival. We carried out a retrospective cohort study of 82 mCRC patients (26 AA, 56 EA). The data source was medical record data from June 1, 2004 through May 31, 2008 with follow-up through June 30, 2010. Using Kaplan-Meier methods, we generated median survival time according to race and age (< 61, ≥ 61 years). Cox proportional hazards regression models were used to model the risk of death according to race. RESULTS: The median age was 56.7 years for AA and 61.6 years for EA patients. Compared with EA, median survival in AA patients was 59% worse in younger patients (12.7 vs. 31.0 months) and 29% worse in older patients (11.7 vs. 16.4 months). The risk of death among younger AA compared with EA patients was 2.45 (95% confidence interval [CI], 1.15-5.23) and among older patients was 1.16 (95% CI, 0.49-2.73). CONCLUSION: Our results highlight the importance of considering younger age, clinical prognostic markers, and tumor phenotypes as potential sources of the disparity in advanced stage CRC.

Racial disparities in advanced-stage colorectal cancer survival.

PURPOSE: African-Americans (AA) have a higher incidence of and lower survival from colorectal cancer (CRC) compared with European Americans (EA). In the present study, statewide, population-based data from South Carolina Central Cancer Registry are used to investigate the relationship between race and age on advanced-stage CRC survival. METHODS: The study population was comprised of 3,865 advanced pathologically documented colon and rectal adenocarcinoma cases diagnosed between 01 January 1996 and 31 December 2006: 2,673 (69 %) EA and 1,192 (31 %) AA. Kaplan-Meier methods were used to generate median survival time and corresponding 95 % confidence intervals (CI) by race, age, and gender. Factors associated with survival were evaluated by fitting Cox proportional hazards regression models to generate hazard ratios (HR) and 95 % CI. RESULTS: We observed a significant interaction between race and age on CRC survival (p = 0.04). Among younger patients (<50 years), AA race was associated with a 1.34 times (95 % CI 1.06-1.71) higher risk of death compared with EA. Among older patients, we observed a modest increase in risk of death among AA men compared with EA [HR 1.16 (95 % CI 1.01-1.32)] but no difference by race between women [HR 0.94 (95 % CI 0.82-1.08)]. Moreover, we observed that the disparity in survival has worsened over the past 15 years. CONCLUSIONS: Future studies that integrate clinical, molecular, and treatment-related data are needed for advancing understanding of the racial disparity in CRC survival, especially for those <50 years old.

Comparing virtual consults to traditional consults using an electronic health record: an observational case-control study.

BACKGROUND: Patients have typically received health care through face-to-face encounters. However, expansion of electronic communication and electronic health records (EHRs) provide alternative means for patient and physicians to interact. Electronic consultations may complement regular healthcare by providing "better, faster, cheaper" processes for diagnosing, treating, and monitoring health conditions. Virtual consultation between physicians may provide a method of streamlining care, potentially saving patients the time and expense of added visits. The purpose of this study was to compare physician usage and patient satisfaction with virtual consultations (VCs) with traditional consultations (TCs) facilitated within an EHR. METHODS: We conducted an observational case-control survey study within Kaiser Permanente, Colorado. A sample of patients who had VCs requested by physicians (N = 270) were matched with patients who had TCs requested by physicians (N = 270), by patient age, gender, reason for the consult, and specialty department. These patients (VC and TC), were invited to participate in a satisfaction survey. In addition, 205 primary care physicians who submitted a VC or TC were surveyed. RESULTS: During the study period, 58,146 VC or TC were requested (TC = 96.3%). Patients who completed a satisfaction survey (267 out of 540 patients, 49.4% response rate) indicated they were satisfied with their care, irrespective of the kind of consult (mean 10-point Likert score of 8.5). 88 of 205 primary care physicians surveyed (42.9%) returned at least one survey; VC and TC survey response rates and consulted departments were comparable (p = 0.13). More TCs than VCs requested transfer of patient care (p = 0.03), assistance with diagnosis (p = 0.04) or initiating treatment (p =0.04). Within 3 weeks of the consultation request, 72.1% of respondents reported receiving information from VCs, compared with 33.9% of the TCs (p < 0.001). Utility of information provided by consultants and satisfaction with consultations did not differ between VCs and TCs. CONCLUSIONS: Referring physicians received information from consultants more quickly from VCs compared with TCs, but the value and application of information from both types of consultations were similar. VCs may decrease the need for face-to-face specialty encounters without a decrease in the patient's perception of care.

Increased rheumatoid factor interference observed during immunogenicity assessment of an Fc-engineered therapeutic antibody.

Protein therapeutics may elicit an anti-therapeutic antibody (ATA) response in patients. This response depends on a number of factors including patient population, disease state, route of delivery or characteristics specific to the product. Therapeutics for immunological indications often target relatively young and healthy patients with hyperactive immune systems who have periodic flares and remissions. The hyperactive immune system of these patients can add several levels of bioanalytical complexity due to the presence of cross reactive molecules such as autoantibodies. In addition, the long-term chronic dosing regimen often necessary in this patient population can increase their risks of immunogenicity against the therapeutic and lead to safety concerns. Therefore, development of a sensitive and drug-tolerant ATA method is important. Bridging ATA assays are usually very sensitive and drug-tolerant methods for immunogenicity assessment; however these methods are particularly vulnerable to any factor that is able to bridge the conjugated therapeutics used as reagents and can generate false positive signal. Although there are many potential interfering factors in serum, rheumatoid factors (RFs), autoantibodies associated with rheumatoid arthritis (RA), are of particular concern in this type of assay. MTRX1011A is a non-depleting anti-CD4 monoclonal antibody therapeutic that was clinically tested in RA patients. This paper will discuss the bioanalytical challenges encountered during development of a clinical ATA assay for MTRX1011A. These challenges highlight interference due to patient disease state, in this case presence of RF in RA patients, as well as specific molecule-related interference caused by an engineered mutation in the Fc region of MTRX1011A designed to enhance its binding to the neonatal Fc receptor (FcRn). We will discuss the characterization work used to identify the cross-reactive epitope and our strategy to overcome this interference during development of an effective ATA assay to support clinical evaluation of MTRX1011A.