Neighborhood and Individual Socioeconomic Disadvantage and Survival Among Patients With Nonmetastatic Common Cancers.

Importance: Disadvantaged neighborhood-level and individual-level socioeconomic status (SES) have each been associated with suboptimal cancer care and inferior outcomes. However, independent or synergistic associations between neighborhood and individual socioeconomic disadvantage have not been fully examined, and prior studies using simplistic neighborhood SES measures may not comprehensively assess multiple aspects of neighborhood SES. Objective: To investigate the associations of neighborhood SES (using a validated comprehensive composite measure) and individual SES with survival among patients with nonmetastatic common cancers. Design, Setting, and Participants: This prospective, population-based cohort study was derived from the Surveillance, Epidemiology, and End Results-Medicare database from January 1, 2008, through December 31, 2011, with follow-up ending on December 31, 2017. Participants included older patients (≥65 years) with breast, prostate, lung, or colorectal cancer. Exposures: Neighborhood SES was measured using the area deprivation index (ADI; quintiles), a validated comprehensive composite measure of neighborhood SES. Individual SES was assessed by Medicare-Medicaid dual eligibility (yes vs no), a reliable indicator for patient-level low income. Main Outcomes and Measures: The primary outcome was overall mortality, and the secondary outcome was cancer-specific mortality. Hazard ratios (HRs) for the associations of ADI and dual eligibility with overall and cancer-specific mortality were estimated via Cox proportional hazards regression. Statistical analyses were conducted from January 23 to April 15, 2021. Results: A total of 96 978 patients were analyzed, including 25 968 with breast, 35 150 with prostate, 16 684 with lung, and 19 176 with colorectal cancer. Median age at diagnosis was 76 years (IQR, 71-81 years) for breast cancer, 73 years (IQR, 70-77 years) for prostate cancer, 76 years (IQR, 71-81 years) for lung cancer, and 78 years (IQR, 72-84 years) for colorectal cancer. Among lung and colorectal cancer patients, 8412 (50.4%) and 10 486 (54.7%), respectively, were female. The proportion of non-Hispanic White individuals among breast cancer patients was 83.7% (n = 21 725); prostate cancer, 76.8% (n = 27 001); lung cancer, 83.5% (n = 13 926); and colorectal cancer, 81.1% (n = 15 557). Neighborhood-level and individual-level SES were independently associated with overall mortality, and no interactions were detected. Compared with the most affluent neighborhoods (ADI quintile 1), living in the most disadvantaged neighborhoods (ADI quintile 5) was associated with higher risk of overall mortality (breast: HR, 1.34; 95% CI, 1.26-1.43; prostate: HR, 1.51; 95% CI, 1.42-1.62; lung: HR, 1.21; 95% CI, 1.14-1.28; and colorectal: HR, 1.24; 95% CI, 1.17-1.32). Individual socioeconomic disadvantage (dual eligibility) was associated with higher risk of overall mortality (breast: HR, 1.22; 95% CI, 1.15-1.29; prostate: HR, 1.29; 95% CI, 1.21-1.38; lung: HR, 1.14; 95% CI, 1.09-1.20; and colorectal: HR, 1.23; 95% CI, 1.17-1.29). A similar pattern was observed for cancer-specific mortality. Conclusions and Relevance: In this cohort study, neighborhood-level deprivation was associated with worse survival among patients with nonmetastatic breast, prostate, lung, and colorectal cancer, even after accounting for individual SES. These findings suggest that, in order to improve cancer outcomes and reduce health disparities, policies for ongoing investments in low-resource neighborhoods and low-income households are needed.

Assessment of Pembrolizumab Therapy for the Treatment of Microsatellite Instability-High Gastric or Gastroesophageal Junction Cancer Among Patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 Clinical Trials.

IMPORTANCE: Immunotherapy has been associated with improved outcomes among patients who have received previous treatment for microsatellite instability-high (MSI-H) tumors. OBJECTIVE: To evaluate the antitumor activity of pembrolizumab therapy vs chemotherapy among patients with MSI-H advanced gastric or gastroesophageal junction (G/GEJ) cancer regardless of the line of therapy in which it was received. DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of the phase 2 KEYNOTE-059 (third-line treatment or higher) single-arm trial and the phase 3 KEYNOTE-061 (second-line treatment) and KEYNOTE-062 (first-line treatment) randomized trials included patients with advanced G/GEJ cancer from 52 sites in 16 countries enrolled in KEYNOTE-059, 148 sites in 30 countries enrolled in KEYNOTE-061, and 200 sites in 29 countries enrolled in KEYNOTE-062. Patients were enrolled from March 2, 2015, to March 26, 2016, in KEYNOTE-059; from June 4, 2015, to July 26, 2016, in KEYNOTE-061; and from September 18, 2015, to May 26, 2017, in KEYNOTE-062, with data cutoff dates of August 8, 2018; October 26, 2017; and March 26, 2019; respectively. INTERVENTIONS: Pembrolizumab monotherapy in KEYNOTE-059, pembrolizumab monotherapy or chemotherapy (paclitaxel) in KEYNOTE-061, and pembrolizumab monotherapy, pembrolizumab plus chemotherapy (cisplatin and 5-fluorouracil or capecitabine), or chemotherapy alone in KEYNOTE-062. MAIN OUTCOMES AND MEASURES: Response was assessed centrally using Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1; MSI-H status was determined centrally by polymerase chain reaction testing. RESULTS: At data cutoff, 7 of 174 patients (4.0%) in KEYNOTE-059, 27 of 514 patients (5.3%) in KEYNOTE-061, and 50 of 682 patients (7.3%) in KEYNOTE-062 had MSI-H tumors. Among those with MSI-H tumors, the median overall survival was not reached (NR) for pembrolizumab in KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 or for pembrolizumab plus chemotherapy in KEYNOTE-062. The median progression-free survival (PFS) for pembrolizumab was NR (95% CI, 1.1 months to NR) in KEYNOTE-059 and 17.8 months (95% CI, 2.7 months to NR) in KEYNOTE-061 (vs 3.5 months [95% CI, 2.0-9.8 months] for chemotherapy). In KEYNOTE-062, the median PFS was 11.2 months (95% CI, 1.5 months to NR) for pembrolizumab, NR (95% CI, 3.6 months to NR) for pembrolizumab plus chemotherapy, and 6.6 months (95% CI, 4.4-8.3 months) for chemotherapy. The objective response rate (ORR) for pembrolizumab was 57.1% in KEYNOTE-059 and 46.7% (vs 16.7% for chemotherapy) in KEYNOTE-061. In KEYNOTE-062, the ORR was 57.1% for pembrolizumab , 64.7% for pembrolizumab plus chemotherapy, and 36.8% for chemotherapy. CONCLUSIONS AND RELEVANCE: Findings from this study indicate that MSI-H status may be a biomarker for pembrolizumab therapy among patients with advanced G/GEJ cancer regardless of the line of therapy in which it was received. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02335411, NCT02370498, and NCT02494583.

Development and Validation of the PREMM5 Model for Comprehensive Risk Assessment of Lynch Syndrome.

Purpose Current Lynch syndrome (LS) prediction models quantify the risk to an individual of carrying a pathogenic germline mutation in three mismatch repair (MMR) genes: MLH1, MSH2, and MSH6. We developed a new prediction model, PREMM5, that incorporates the genes PMS2 and EPCAM to provide comprehensive LS risk assessment. Patients and Methods PREMM5 was developed to predict the likelihood of a mutation in any of the LS genes by using polytomous logistic regression analysis of clinical and germline data from 18,734 individuals who were tested for all five genes. Predictors of mutation status included sex, age at genetic testing, and proband and family cancer histories. Discrimination was evaluated by the area under the receiver operating characteristic curve (AUC), and clinical impact was determined by decision curve analysis; comparisons were made to the existing PREMM1,2,6 model. External validation of PREMM5 was performed in a clinic-based cohort of 1,058 patients with colorectal cancer. Results Pathogenic mutations were detected in 1,000 (5%) of 18,734 patients in the development cohort; mutations included MLH1 (n = 306), MSH2 (n = 354), MSH6 (n = 177), PMS2 (n = 141), and EPCAM (n = 22). PREMM5 distinguished carriers from noncarriers with an AUC of 0.81 (95% CI, 0.79 to 0.82), and performance was similar in the validation cohort (AUC, 0.83; 95% CI, 0.75 to 0.92). Prediction was more difficult for PMS2 mutations (AUC, 0.64; 95% CI, 0.60 to 0.68) than for other genes. Performance characteristics of PREMM5 exceeded those of PREMM1,2,6. Decision curve analysis supported germline LS testing for PREMM5 scores ≥ 2.5%. Conclusion PREMM5 provides comprehensive risk estimation of all five LS genes and supports LS genetic testing for individuals with scores ≥ 2.5%. At this threshold, PREMM5 provides performance that is superior to the existing PREMM1,2,6 model in the identification of carriers of LS, including those with weaker phenotypes and individuals unaffected by cancer.

Beyond gastric adenocarcinoma: Multimodality assessment of common and uncommon gastric neoplasms.

Despite advances in molecular biology, imaging, and treatment, gastric neoplasms remain a significant cause of morbidity and mortality; gastric adenocarcinoma is the fifth most common malignancy and third most common cause of death worldwide (Brenner et al., Methods Mol Biol 472:467-477, 2009; Howson et al. Epidemiol Rev 8:1-27, 1986; Roder, Gastric Cancer 5(Suppl 1):5-11, 2002; Ferlay et al., GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. International Agency for Research on Cancer, 2013). Because of both the frequency at which malignant gastric tumors occur as well as the worldwide impact, gastric neoplasms remain important lesions to identify and characterize on all imaging modalities. Despite the varied histologies and behaviors of these neoplasms, many have similar imaging features. Nonetheless, the treatment, management, and prognosis of gastric neoplasms vary by pathology, so it is essential for the radiologist to make every effort to differentiate between these lesions and raise the less common entities as differential diagnostic considerations when appropriate.

Feasibility of computer-based self-administered cancer-specific geriatric assessment in older patients with gastrointestinal malignancy.

BACKGROUND: The Cancer-Specific Geriatric Assessment (CSGA) is a primarily self-administered paper survey of validated measures. METHODS: We developed and tested the feasibility of a computer-based CSGA in patients ≥70 years of age who were receiving treatment for gastrointestinal malignancies at the Dana-Farber Cancer Institute. From December 2009 to June 2011, patients were invited to complete the CSGA at baseline (start of new treatment) and follow-up (at the first of 4 months later or within 4 weeks of completing treatment). Feasibility endpoints were proportion of eligible patients consented, proportion completing CSGA at baseline and follow-up, time to complete CSGA, and proportion of physicians reporting CSGA results that led to a change in clinical decision-making. RESULTS: Of the 49 eligible patients, 38 consented (76% were treatment naive). Median age was 77 years (range: 70-89 years), and 48% were diagnosed with colorectal cancer. Mean physician-rated Karnofsky Performance Status was 87.5 at baseline (SD 8.4) and 83.5 at follow-up (SD 8). At baseline, 92% used a touchscreen computer; 97% completed the CSGA (51% independently). At follow-up, all patients used a touchscreen computer; 71% completed the CSGA (41% independently). Mean time to completion was 23 minutes at baseline (SD 8.4) and 20 minutes at follow-up (SD 5.1). The CSGA added information to clinical assessment for 75% at baseline (n = 27) and 65% at follow-up (n = 17), but it did not alter immediate clinical decision-making. CONCLUSION: The computer-based CSGA feasibility endpoints were met, although approximately half of patients required assistance. The CSGA added information to clinical assessment but did not affect clinical decision-making, possibly due to limited alternate treatment options in this subset of patients.

Impact of hospital volume on recurrence and survival after surgery for gastric cancer.

BACKGROUND: Some, but not all, studies using registry data have suggested a small but significant long-term survival advantage following a curative surgical resection of gastric cancer at hospitals where the volume of such surgeries is high. However, because such data may be significantly influenced by the impact of postoperative mortality, and may be imbalanced for factors important to survival, the true nature of this relationship remains uncertain. METHODS: We conducted a nested volume-outcome study in a sample of 448 surgical survivors with stage IB through IV (M0) gastric and gastroesophageal junction adenocarcinoma, previously randomized to adjuvant chemoradiation after surgery or surgery alone, to measure the effect of hospital surgical volume, as assessed by Medicare claims data, on overall survival and gastric cancer recurrence. RESULTS: In this selected sample of postoperative survivors, hospital surgical volume was not predictive of overall survival (P = 0.46) or disease-free survival (P = 0.43) at a median follow-up of 8.9 years. However, patients who underwent either a D1 or D2 dissection at a high- or moderate-volume center experienced an adjusted hazard ratio of 0.80 (95% CI, 0.53-1.20) for overall survival and 0.78 (95% CI, 0.53-1.14) for disease-free survival compared with those patients resected at a low-volume hospital; these results were not statistically significant. When a D0 resection was performed, hospital procedure volume showed no impact on survival. CONCLUSIONS: Excluding the impact of perioperative mortality by utilizing prospectively recorded data from a large postoperative adjuvant trial, hospital procedure volume had no overall effect on long-term gastric cancer survival. The potential benefit of moderate- to high-volume centers for patients who underwent a D1 or D2 dissection requires confirmation in larger studies.

Assessment of a dietary questionnaire in cancer patients receiving cytotoxic chemotherapy.

PURPOSE: Few studies have examined the influence of diet on survival and chemotherapy-associated toxicities in patients with cancer. Although several comprehensive dietary questionnaires have been validated and calibrated in healthy populations, similar studies have not been performed among cancer patients. METHODS: Two hundred patients with colorectal, breast, or neuroendocrine cancer undergoing treatment with cytotoxic chemotherapy completed a self-administered, 131-item, semiquantitative food frequency questionnaire. Using the questionnaire, we calculated dietary intakes of carotenoids, tocopherols, and fatty acids, and correlated these values with relevant biomarkers measured in simultaneously collected plasma specimens. RESULTS: The Pearson correlation coefficients for various carotenoids as measured by the questionnaire, with the corresponding measurements in plasma specimens, ranged from 0.33 to 0.44 (all P < .001), adjusted for total energy intake, body mass index, age, sex, smoking status, and total plasma cholesterol. Similarly, the adjusted correlation between self-reported total vitamin E intake and plasma alpha-tocopherol was 0.34 (P < .001). Correlations between questionnaire and plasma measurements of trans-fat, eicosapentaenoic acid, and docosahexaenoic acid were 0.55, 0.29, and 0.42 (all P < .001), respectively. These levels of correlation are consistent with those reported in similar studies of self-reported diet in otherwise healthy populations. CONCLUSION: Among patients with cancer receiving cytotoxic chemotherapy, questionnaire-based measurements of various micronutrients and dietary factors appeared to predict meaningful differences in the corresponding measurements in plasma specimens. This dietary questionnaire could offer an informative and practical means for assessing the influence of diet in cancer patients receiving chemotherapy.

Cost-effectiveness projections of oxaliplatin and infusional fluorouracil versus irinotecan and bolus fluorouracil in first-line therapy for metastatic colorectal carcinoma.

BACKGROUND: The results of a randomized comparison study (N9741) showed that oxaliplatin and infusional fluorouracil (FU) (FOLFOX) was superior to the previous standard of care in the United States, irinotecan and bolus FU (IFL), as first-line therapy for patients with metastatic colon carcinoma. The trade-offs between costs and survival for these two regimens have not been explored. METHODS: A post-hoc, incremental cost-effectiveness (ICE) projection using simulated cohorts of patients starting FOLFOX or IFL was tracked for major clinical events, toxicities, and survival. Recurrence and survival risks were based on clinical trial data. Resource use was projected using observed dose intensity, duration of therapy, delays in therapy, and toxicities Grade > 2 in N9741. The frequency, costs, and consequences of second-line therapy were examined. The time frame was 5 years, and the perspective was that of Medicare as a third-party payer. RESULTS: Initial treatment with FOLFOX versus IFL had an average incremental cost of dollars 29,523, a survival benefit of 4.4 months, and an ICE of dollars 80,410 per life year (LY), dollars 111,890 per quality-adjusted LY, and dollars 89,080 per progression-free year. By using the 95% confidence interval for the time to progression observed in N9741, the ICE associated with FOLFOX ranged from dollars 121,220 to dollars 59,250 per LY. In the clinical trial, dose delays and skipped doses were frequent. If progression-free patients were treated without delay for the first year or lifetime, then the ICE for FOLFOX increased to dollars 117,910 and dollars 222,200 per LY, respectively. The ICE increased to dollars 84,780 per LY when the model incorporated a revised IFL schedule with lower early toxicity and similar rates of treatment with second-line regimens. CONCLUSIONS: FOLFOX provided substantial benefits that incurred substantial additional costs. The ICE for FOLFOX fell into the upper range of commonly accepted oncology interventions in the context of the United States healthcare system.

Patients' perceptions of quality of care for colorectal cancer by race, ethnicity, and language.

PURPOSE: To identify opportunities for improving care, we evaluated patients' perceptions of the quality of their cancer care by race, ethnicity, and language. PATIENTS AND METHODS: We surveyed a population-based cohort of 1,067 patients with colorectal cancer in northern California approximately 9 months after diagnosis. Adjusting for clinical and demographic factors, mean problem scores were analyzed on a 100-point scale for six domains of care. RESULTS: Mean problem scores were highest for health information (47.8), followed by treatment information (32.3), psychosocial care (31.7), coordination of care (21.3), confidence in providers (13.1), and access to cancer care (12.7). In adjusted comparisons with white patients, African American patients reported more problems with coordination of care (difference, 9.8; P < .001), psychosocial care (difference, 7.2; P = .03), access to care (difference, 6.6; P = .03), and health information (difference, 12.5; P < .001). Asian/Pacific Islander patients reported more problems than did white patients with coordination of care (difference, 13.2; P < .001), access to care (difference, 15.5; P < .001), and health information (difference, 12.6; P = .004). Hispanic patients tended to report more problems with coordination of care (difference, 4.4; P = .06), access to care (difference, 5.8; P = .08), and treatment information (difference, 7.0; P = .06). Non-English-speaking white patients reported more problems than other white patients with coordination of care (difference, 21.9; P < .001), psychosocial care (difference, 16.1; P = .009), access to care (difference, 19.8; P = .003), and treatment information (difference, 17.8; P = .002). Non-English-speaking Hispanic patients reported more problems than other Hispanic patients with confidence in providers (difference, 16.9; P = .01). CONCLUSION: Efforts to improve patients' experiences with cancer care should address disparities by race, ethnicity, and language, particularly in coordination of care, access to care, and the provision of relevant information.

Two schedules of second-line irinotecan for metastatic colon carcinoma.

BACKGROUND: In a recently reported, randomized trial, it was found that a regimen of irinotecan once every 3 weeks for patients with advanced colorectal carcinoma was associated with a lower incidence of severe diarrhea compared with weekly treatment, and both regimens had similar efficacy. METHODS: Resource utilization was captured prospectively for all 291 patients who were included in the trial. Utilities were estimated by transformation of the global quality-of-life (QOL) item on the Eastern Organization for Research and Treatment of Cancer QLQ-C30 instrument. RESULTS: Patients in the every-3-week arm incurred an average incremental cost of $1362, because they received higher average weekly doses and because the every-3-week regimen resulted in less toxicity, allowing delivery of 97% of the planned doses compared with delivery of only 75% of the planned doses in the weekly arm. This lower toxicity also resulted in offsetting savings from decreased hospitalization and less requirement for supportive medications. Non-chemotherapy-related treatment administration costs also were lower, because the every-3-week regimen could be delivered with half the number of infusions. Utility declined less in the every-3-week arm, resulting in a saving of 6.3 quality-adjusted days. The base-case cost:utility ratio was $78,627 per quality-adjusted life year for patients on the every-3-week schedule. However, that ratio was very sensitive to the cost of irinotecan. CONCLUSIONS: The schedule of irinotecan once every 3 weeks schedule was more costly but achieved lower toxicity, resulting in modestly improved utility. The cost-per-utility ratio was comparable to other commonly accepted contemporary treatments.

Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-I.

Farnesyl:protein transferase (FPTase) inhibitors were developed as anti-Ras drugs, but they fail to inhibit Ki-Ras activity because Ki-Ras can be modified by geranylgeranyl:protein transferase type-I (GGPTase-I). L-778,123, an inhibitor of FPTase and GGPTase-I, was developed in part because it can completely inhibit Ki-Ras prenylation. To support the clinical development of L-778,123, we developed pharmacodynamic assays using peripheral blood mononuclear cells (PBMCs) to measure the inhibition of prenylation of HDJ2 and Rap1A, proteins that are FPTase- and GGPTase-I substrates, respectively. We validated these assays in animal models and show that inhibition of HDJ2 prenylation in mouse PBMCs correlates with the concentration of FPTase inhibitors in blood. In dogs, continuous infusion of L-778,123 inhibited both HDJ2 and Rap1A prenylation in PBMCs, but we did not detect inhibition of Ki-Ras prenylation. We reported previously results from the first L-778,123 Phase I trial that showed a dose-dependent inhibition of HDJ2 farnesylation in PBMCs. In this report, we present additional analysis of patient samples from this trial and a second Phase I trial of L-778,123, and demonstrate the inhibition of both HDJ2 and Rap1A prenylation in PBMC samples. This study represents the first demonstration of GGPTase-I inhibition in humans. However, no inhibition of Ki-Ras prenylation by L-778,123 was detected in patient samples. These results confirm the pharmacologic profile of L-778,123 in humans as a dual inhibitor of FPTase and GGPTase-I, but indicate that the intended target of the drug, Ki-Ras, was not inhibited.