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Unveiling Discrepant and Rare Dihydropyrimidine Dehydrogenase (DPYD) Results Using an In-House Genotyping Test: A Case Series

D. Grace Nguyen, Sarah A. Morris, Annabel Chen, Donald C. Moore, Sarah L. Hanson, Chris Larck, Laura W. Musselwhite, John D. Turner, Mohamed E. Salem, Simeon O. Kwange, Alicia Hamilton, Nury Steuerwald, and Jai N. Patel

Fluoropyrimidine chemotherapy is a primary component of many solid tumor treatment regimens, particularly those for gastrointestinal malignancies. Approximately one-third of patients receiving fluoropyrimidine-based chemotherapies experience serious adverse effects. This risk is substantially higher in patients carrying DPYD genetic variants, which cause reduced fluoropyrimidine metabolism and inactivation (ie, dihydropyridine dehydrogenase [DPD] deficiency). Despite the known relationship between DPD deficiency and severe toxicity risk, including drug-related fatalities, pretreatment DPYD testing is not standard of care in the United States. We developed an in-house DPYD genotyping test that detects 5 clinically actionable variants associated with DPD deficiency, and genotyped 827 patients receiving fluoropyrimidines, of which 49 (6%) were identified as heterozygous carriers. We highlight 3 unique cases: (1) a patient with a false-negative result from a commercial laboratory that only tested for the c.1905 + 1G>A (*2A) variant, (2) a White patient in whom the c.557A>G variant (typically observed in people of African ancestry) was detected, and (3) a patient with the rare c.1679T>G (*13) variant. Lastly, we evaluated which DPYD variants are detected by commercial laboratories offering DPYD genotyping in the United States and found 6 of 13 (46%) did not test for all 5 variants included on our panel. We estimated that 20.4% to 81.6% of DPYD heterozygous carriers identified on our panel would have had a false-negative result if tested by 1 of these 6 laboratories. The sensitivity and negative predictive value of the diagnostic tests from these laboratories ranged from 18.4% to 79.6% and 95.1% to 98.7%, respectively. These cases underscore the importance of comprehensive DPYD genotyping to accurately identify patients with DPD deficiency who may require lower fluoropyrimidine doses to mitigate severe toxicities and hospitalizations. Clinicians should be aware of test limitations and variability in variant detection by commercial laboratories, and seek assistance by pharmacogenetic experts or available resources for test selection and result interpretation.

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Failure to Undergo Resection Following Neoadjuvant Therapy for Resectable Pancreatic Cancer: A Secondary Analysis of SWOG S1505

Jordan M. Cloyd, Sarah Colby, Katherine A. Guthrie, Andy M. Lowy, E. Gabrielle Chiorean, Phillip Philip, Davendra Sohal, and Syed Ahmad

Background: Neoadjuvant therapy (NT) is increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC), and yet reasons for not undergoing subsequent pancreatectomy are poorly understood. Given the importance of completing multimodality therapy, we investigated factors associated with failure to undergo surgical resection following NT for PDAC. Methods: SWOG S1505 was a multicenter phase II randomized trial of preoperative mFOLFIRINOX or gemcitabine/nab-paclitaxel prior to planned pancreatectomy for patients with potentially resectable PDAC. Associations between clinical, demographic, and hospital-level characteristics and receipt of surgical resection were estimated via multiple logistic regression. Differences in overall survival from 18 weeks postrandomization (scheduled time of surgery) according to resection status were assessed via Cox regression models. Results: Among 102 eligible patients, 73 (71.6%) underwent successful pancreatectomy, whereas 29 (28.4%) did not, primarily because of progression (n=11; 10.8%) or toxicity during NT (n=9; 8.8%). Weight loss during NT (odds ratio [OR], 0.34; 95% CI, 0.11–0.93) and the hospital’s city size (small: OR, 0.24 [95% CI, 0.07–0.80] and large: OR, 0.28 [95% CI, 0.10–0.79] compared with midsize) were significantly associated with a lower probability of surgical resection in adjusted models, whereas age, sex, race, body mass index, performance status, insurance type, geographic region, treatment arm, tumor location, chemotherapy delays/modifications, and hospital characteristics were not. Surgical resection following NT was associated with improved overall survival (median, 23.8 vs 10.8 months; P<.01) even after adjusting for grade 3–5 adverse events during NT, performance status, and body mass index (hazard ratio, 0.55; 95% CI, 0.32–0.95). Conclusions: Failure to undergo resection following NT was relatively common among patients with potentially resectable PDAC and associated with worse survival. Although few predictive factors were identified in this secondary analysis of the SWOG S1505 randomized trial, further research must focus on risk factors for severe toxicities during NT that preclude surgical resection so that patient-centered interventions can be delivered or alternate treatment sequencing can be recommended.

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Real-World Use of Hypofractionated Radiotherapy for Primary CNS Tumors in the Elderly, and Implications on Medicare Spending

Kathryn R. Tringale, Andrew Lin, Alexandra M. Miller, Atif Khan, Linda Chen, Melissa Zinovoy, Yoshiya Yamada, Yao Yu, Luke R.G. Pike, and Brandon S. Imber

Background: For elderly patients with high-grade gliomas, 3-week hypofractionated radiotherapy (HFRT) is noninferior to standard long-course radiotherapy (LCRT). We analyzed real-world utilization of HFRT with and without systemic therapy in Medicare beneficiaries treated with RT for primary central nervous system (CNS) tumors using Centers for Medicare & Medicaid Services data. Methods: Radiation modality, year, age (65–74, 75–84, or ≥85 years), and site of care (freestanding vs hospital-affiliated) were evaluated. Utilization of HFRT (11–20 fractions) versus LCRT (21–30 or 31–40 fractions) and systemic therapy was evaluated by multivariable logistic regression. Medicare spending over the 90-day episode after RT planning initiation was analyzed using multivariable linear regression. Results: From 2015 to 2019, a total of 10,702 RT courses (ie, episodes) were included (28% HFRT; 65% of patients aged 65–74 years). A considerable minority died within 90 days of RT planning initiation (n=1,251; 12%), and 765 (61%) of those received HFRT. HFRT utilization increased (24% in 2015 to 31% in 2019; odds ratio [OR], 1.2 per year; 95% CI, 1.1–1.2) and was associated with older age (≥85 vs 65–74 years; OR, 6.8; 95% CI, 5.5–8.4), death within 90 days of RT planning initiation (OR, 5.0; 95% CI, 4.4–5.8), hospital-affiliated sites (OR, 1.4; 95% CI, 1.3–1.6), conventional external-beam RT (vs intensity-modulated RT; OR, 2.7; 95% CI, 2.3–3.1), and no systemic therapy (OR, 1.2; 95% CI, 1.1–1.3; P<.001 for all). Increasing use of HFRT was concentrated in hospital-affiliated sites (P=.002 for interaction). Most patients (69%) received systemic therapy with no differences by site of care (P=.12). Systemic therapy utilization increased (67% in 2015 to 71% in 2019; OR, 1.1 per year; 95% CI, 1.0–1.1) and was less likely for older patients, patients who died within 90 days of RT planning initiation, those who received conventional external-beam RT, and those who received HFRT. HFRT significantly reduced spending compared with LCRT (adjusted β for LCRT = +$8,649; 95% CI, $8,544–$8,755), whereas spending modestly increased with systemic therapy (adjusted β for systemic therapy = +$270; 95% CI, $176–$365). Conclusions: Although most Medicare beneficiaries received LCRT for primary brain tumors, HFRT utilization increased in hospital-affiliated centers. Despite high-level evidence for elderly patients, discrepancy in HFRT implementation by site of care persists. Further investigation is needed to understand why patients with short survival may still receive LCRT, because this has major quality-of-life and Medicare spending implications.

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Loneliness and Mortality Risk Among Cancer Survivors in the United States: A Retrospective, Longitudinal Study

Jingxuan Zhao, Jennifer B. Reese, Xuesong Han, and K. Robin Yabroff

Background: Loneliness, a subjective feeling of being isolated, is a prevalent concern for elderly people and more so among cancer survivors because a cancer diagnosis and its subsequent treatment may result in long-term adverse health effects. This study aimed to examine the association of loneliness and mortality risk among cancer survivors in the United States. Methods: We identified a longitudinal cohort of cancer survivors aged ≥50 years from the nationally representative panel surveys of the 2008–2018 Health and Retirement Study. Follow-up for vital status was through 2020. Loneliness was measured using an 11-item abbreviated version of the UCLA Loneliness Scale (Version 3), including questions about lacking companionship and feeling isolated from others. A score was assigned according to the responses to each question, with 1 for least lonely, 2 for moderately lonely, and 3 for the loneliest option. Items were summed to create total loneliness scores for each individual, which were categorized into 4 levels: 11–12 (low/no loneliness), 13–15 (mild loneliness), 16–19 (moderate loneliness), and 20–33 (severe loneliness) based on the sample distribution. Time-varying Cox proportional hazard models with age as a time scale were used to examine the association of loneliness and survival among cancer survivors. Results: A total of 3,447 cancer survivors with 5,808 person-years of observation were included, with 1,402 (24.3%), 1,445 (24.5%), 1,418 (23.6%), and 1,543 (27.6%) reporting low/no, mild, moderate, and severe loneliness, respectively. Compared with survivors reporting low/no loneliness, survivors reporting greater loneliness had a higher mortality risk, with the highest adjusted hazard ratios (aHRs) among the loneliest group (aHR, 1.67 [95% CI, 1.25–2.23]; P=.004) following a dose–response association. Conclusions: Elevated loneliness was associated with a higher mortality risk among cancer survivors. Programs to screen for loneliness among cancer survivors and to provide resources and support are warranted, especially considering the widespread social distancing that occurred during the COVID-19 pandemic.

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Geographic Accessibility and Completion of Initial Low-Dose CT-Based Lung Cancer Screening in an Urban Safety-Net Population

Sofia Yi, Rutu A. Rathod, Vijaya Subbu Natchimuthu, Sheena Bhalla, Jessica L. Lee, Travis Browning, Joyce O. Adesina, Minh Do, David Balis, Juana Gamarra de Wiliams, Ellen Kitchell, Noel O. Santini, David H. Johnson, Heidi A. Hamann, Simon J. Craddock Lee, Amy E. Hughes, and David E. Gerber

Background: Recent modifications to low-dose CT (LDCT)–based lung cancer screening guidelines increase the number of eligible individuals, particularly among racial and ethnic minorities. Because these populations disproportionately live in metropolitan areas, we analyzed the association between travel time and initial LDCT completion within an integrated, urban safety-net health care system. Methods: Using Esri’s StreetMap Premium, OpenStreetMap, and the r5r package in R, we determined projected private vehicle and public transportation travel times between patient residence and the screening facility for LDCT ordered in March 2017 through December 2022 at Parkland Memorial Hospital in Dallas, Texas. We characterized associations between travel time and LDCT completion in univariable and multivariable analyses. We tested these associations in a simulation of 10,000 permutations of private vehicle and public transportation distribution. Results: A total of 2,287 patients were included in the analysis, of whom 1,553 (68%) completed the initial ordered LDCT. Mean age was 63 years, and 73% were underrepresented minorities. Median travel time from patient residence to the LDCT screening facility was 17 minutes by private vehicle and 67 minutes by public transportation. There was a small difference in travel time to the LDCT screening facility by public transportation for patients who completed LDCT versus those who did not (67 vs 66 min, respectively; P=.04) but no difference in travel time by private vehicle for these patients (17 min for both; P=.67). In multivariable analysis, LDCT completion was not associated with projected travel time to the LDCT facility by private vehicle (odds ratio, 1.01; 95% CI, 0.82–1.25) or public transportation (odds ratio, 1.14; 95% CI, 0.89–1.44). Similar results were noted across travel-type permutations. Black individuals were 29% less likely to complete LDCT screening compared with White individuals. Conclusions: In an urban population comprising predominantly underrepresented minorities, projected travel time is not associated with initial LDCT completion in an integrated health care system. Other reasons for differences in LDCT completion warrant investigation.

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Revisiting the Association of ECOG Performance Status With Clinical Outcomes in Diverse Patients With Cancer

Deepika Kumar, Elad Neeman, Shiyun Zhu, Hongxin Sun, Dinesh Kotak, and Raymond Liu

Background: The ECOG performance status (PS) scale was developed to support national clinical trials, but the degree to which ECOG PS predicts clinical outcomes in patient subgroups outside of clinical trials is relatively unknown. This study examined associations between ECOG PS and adverse outcomes in a diverse community oncology population. Patients and Methods: In this retrospective cohort study, demographic and clinical characteristics, including the most recent ECOG PS between January 1, 2017, and December 31, 2019, were examined for patients receiving cancer treatment within Kaiser Permanente Northern California (KPNC). Proportional hazard models were used to evaluate the effect of ECOG PS on adverse outcomes. Results: A total of 21,730 patients were identified. Overall, most patients had an ECOG PS of 0 (42.5%) or 1 (42.5%). In multivariable analysis, an ECOG PS of 3 or 4 was associated with higher risk of 30-day emergency department visits (adjusted hazard ratio [aHR], 3.85; 95% CI, 3.47–4.26), 30-day hospitalizations (aHR, 4.70; 95% CI, 4.12–5.36), and 6-month mortality (aHR, 7.34; 95% CI, 6.64–8.11) compared with an ECOG PS of 0. Additionally, we found that upper gastrointestinal and stage IV cancers were associated with a higher risk of adverse outcomes compared with breast and stage I cancers, respectively. When adjusted for ECOG PS, African American race, Asian race, and female sex were associated with a lower risk of mortality than White race and male sex. An ECOG PS of 3 or 4 was more predictive of mortality in younger patients and those with breast cancer (P<.001). Conclusions: ECOG PS and upper gastrointestinal and stage IV cancers were independently associated with increased risk of emergency department visits, hospitalizations, and mortality, whereas African American and Asian race and female sex were associated with decreased risk of mortality. An ECOG PS of 3 or 4 was more predictive of an increased risk of mortality in younger patients and patients with breast cancer. These findings can enhance the use of ECOG PS for clinical decision-making and defining eligibility for clinical trials.

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Breakthrough Therapy Cancer Drugs and Indications With FDA Approval: Development Time, Innovation, Trials, Clinical Benefit, Epidemiology, and Price

Daniel Tobias Michaeli and Thomas Michaeli

Background: The breakthrough therapy designation (BTD) facilitates the development of drugs with a large preliminary benefit in treating serious or life-threatening diseases. This study analyzes the FDA approval, trials, benefits, unmet needs, and pricing of breakthrough and nonbreakthrough therapy cancer drugs and indications. Patients and Methods: We analyzed 355 cancer indications with FDA approval (2012–2022). Breakthrough and nonbreakthrough indications were compared regarding their FDA approval, innovativeness, clinical trials, epidemiology, and price. Data were extracted from FDA labels, the Global Burden of Disease study, and the Centers for Medicare & Medicaid Services. Hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS), and relative risk (RR) of tumor response were meta-analyzed across randomized controlled trials. Objective response rates (ORRs) were meta-analyzed for single-arm trials. Results: We identified 137 breakthrough and 218 nonbreakthrough cancer indications. The median clinical development time was 3.2 years shorter for breakthrough drugs than for nonbreakthrough drugs (5.6 vs 8.8 years; P=.002). The BTD was more frequently granted to biomarker-directed indications (46% vs 34%; P=.025) supported by smaller trials (median, 149 vs 326 patients; P<.001) of single-arm (53% vs 27%; P<.001) and phase I or II design (61% vs 31%; P<.001). Breakthrough indications offered a greater OS (HR, 0.69 vs 0.74; P=.031) and tumor response (RR, 1.48 vs 1.32; P=.006; ORR, 52% vs 40%; P=.004), but not a PFS benefit (HR, 0.53 vs 0.58; P=.212). Median improvements in OS (4.8 vs 3.2 months; P=.002) and PFS (5.4 vs 3.3 months; P=.005) but not duration of response (8.7 vs 4.7 months; P=.245) were higher for breakthrough than for nonbreakthrough indications. The BTD was more frequently granted to first-in-class drugs (42% vs 28%; P=.001) and first-in-indication treatments (43% vs 29%; P<.001). There were no differences in treatment and epidemiologic characteristics between breakthrough and nonbreakthrough drugs. Breakthrough drugs were more expensive than nonbreakthrough drugs (mean monthly price, $38,971 vs $22,591; P=.0592). Conclusions: The BTD expedites patient access to effective and innovative, but also expensive, new cancer drugs and indications.

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Life Years Gained From the FDA Accelerated Approval Program in Oncology: A Portfolio Model

Ágnes Benedict, Gábor Szabó, Kinga Marczell, Bridget Doherty, and Silas Martin

Background: Although the FDA Accelerated Approval Program (AAP) has come under scrutiny, the population-level health benefit of the program has not been quantified. Therefore, the objective of this study was to estimate the number of life years gained among patients with cancer that can be attributable to the therapies receiving FDA accelerated approvals in oncology between 2006 and 2022 in the United States. Methods: The data sources used were FDA listings, FDA approval letters and labels, published clinical trial data and other publications including relative effectiveness estimates, and the Ipsos Oncology Uptake Tool for product uptake. Data for 130 oncology treatments approved by the FDA under the AAP were extracted and validated. We developed a decision analytic model to estimate the survival gain for each indication and to accumulate life years gained for consecutive cohorts of patients receiving the therapies. Life year gains were estimated with and without the AAP, and the incremental life years gained were attributed to the program. Results: The analysis estimated that through December 2022 in the United States, the program gained approximately 263,000 life years across 69 products for which overall survival data were available, for approximately 911,000 patients with cancer. Conclusions: Policy discussions about the evaluation of AAP cannot be complete without assessing its impact on its most important target outcome: patient survival. To date, there has been no estimation of the life year gain delivered by the AAP. Our research shows that substantial number of life years were gained for patients with high unmet need by the cancer therapies approved through the program.

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Health Care Lobbying and Oncology

Nirmal Choradia, Aaron Mitchell, and Ryan Nipp

Background: The health care industry spends more on lobbying than any other industry, with more than $700 million spent in 2022. However, health care lobbying related to cancer has not been characterized. In this study, we sought to describe overall health sector lobbying spending and oncology-related lobbying spending across patient and clinician organizations. Methods: We obtained lobbying data from and the Federal Election Commission. Overall health sector lobbying spending was categorized by OpenSecrets into 4 groups: pharmaceuticals/health products, health services/health maintenance organizations (HMOs), hospitals/nursing homes, and health professionals. We then identified and categorized 4 oncology-related lobbying groups: oncology physician professional organizations (OPPOs), prospective payment system (PPS)–exempt cancer hospitals, patient advocacy organizations, and provider networks (eg, US Oncology Network). We described temporal trends in lobbying spending from 2014 to 2022, in both overall dollar value (inflation-adjusted 2023 dollars) and in per-physician spending (using American Association of Medical Colleges [AAMC] data for number of hematologists/oncologists) using a Mann-Kendall trend test. Results: Among the overall health sector lobbying, pharmaceuticals/health products had the greatest increase in lobbying spending, with an increase from $294 million in 2014 to >$376 million in 2022 (P=.0006). In contrast, lobbying spending by health professionals did not change, remaining at $96 million (P=.35). Regarding oncology-related lobbying, OPPOs and PPS-exempt cancer hospitals had a significant increase of 170% (P=.016) and 62% (P=.009), respectively. Per-physician spending also demonstrated an increase from $60 to $134 for OPPOs and from $168 to $226 for PPS-exempt cancer hospitals. Overall, OPPO lobbying increased as a percentage of overall physician lobbying from 1.16% in 2014 to 3.76% in 2022. Conclusions: Although overall health sector lobbying has increased, physician/health professional lobbying has remained relatively stable in recent years, spending for lobbying by OPPOs has increased. Continued efforts to understand the utility and value of lobbying in health care and across oncology are needed as the costs of care continue to increase.

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Barriers and Facilitators Impacting Lung Cancer Screening Uptake Among Black Veterans: A Qualitative Study

Neelima Navuluri, Tiera Lanford, Abigail Shapiro, Govind Krishnan, Angela B. Johnson, Isaretta L. Riley, Leah L. Zullig, Christopher E. Cox, and Scott Shofer

Background: Racial disparities in lung cancer screening (LCS) are well established. Black Veterans are among those at the highest risk for developing lung cancer but are less likely to complete LCS. We sought to identify barriers and facilitators to LCS uptake among Black Veterans. Patients and Methods: A qualitative study using semistructured interviews was conducted with 32 Black Veterans to assess for barriers, facilitators, and contextual factors for LCS and strategies to improve screening. Veterans were purposively sampled by age, sex, and LCS participation status (ie, patients who received a low-dose CT [LDCT], patients who contacted the screening program but did not receive an LDCT, and patients who did not connect with the screening program nor receive an LDCT). Interview guides were developed using the Theoretical Domains Framework and Health Belief Model. Data were analyzed using rapid qualitative analysis. Results: Barriers of LCS uptake among Black Veterans include self-reported low LCS knowledge and poor memory, attention, and decision processes associated with the centralized LCS process. Facilitators of LCS uptake among Black Veterans include social/professional role; identity and social influences; perceived susceptibility, threat, and consequences due to smoking status and military or occupational exposures; emotion, behavioral regulation, and intentions; and high trust in providers. Environmental context and resources (eg, transportation) and race and racism serve as contextual factors that did not emerge as having a major impact on LCS uptake. Strategies to improve LCS uptake included increased social messaging surrounding LCS, various forms of information dissemination, LCS reminders, balanced and repeated shared decision-making discussions, and streamlined referrals. Conclusions: We identified addressable barriers and facilitators for LCS uptake among Black Veterans that can help focus efforts to improve disparities in screening. Future studies should explore provider perspectives and test interventions to improve equity in LCS.