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Referral, Uptake, and Outcome of Genetic Counseling and Testing in Patients With Early-Onset Colorectal Cancer

Hareem Syed, Joshua Sommovilla, Carol A. Burke, Sarah McGee, Carole Macaron, Brandie Heald, Ruishen Lyu, Stephanie L. Schmit, Kanika Nair, Suneel Kamath, Smitha Krishnamurthi, Alok A. Khorana, and David Liska

Background: The incidence of early-onset colorectal cancer (EOCRC) is rapidly increasing. Pathogenic germline variants (PGVs) are detected in 16% to 20% of patients who have EOCRC, highlighting a need for genetic counseling (GC) and multigene panel testing in these patients. We aimed to determine the rate of referral to GC and uptake and outcomes of germline testing in patients with EOCRC. Methods: We conducted a retrospective cohort study of patients aged <50 years diagnosed with colorectal cancer (CRC) from 2010 to 2019 at Cleveland Clinic. Demographic data were extracted, including age, sex, self-reported race, and family history of CRC. The proportions of patients with GC referral and completion of GC and genetic testing were investigated, and genetic testing results were analyzed. Multivariable logistic regression analysis was conducted to identify factors independently associated with GC referral and uptake. Results: A total of 791 patients with EOCRC (57% male and 43% female) were included; 62% were referred for GC, and of those who were referred, 79% completed a GC appointment and 77% underwent genetic testing. Of those who underwent testing, 21% had a PGV detected; 82% were in known CRC-associated genes, with those associated with Lynch syndrome and familial adenomatous polyposis the most common, and 11% were in other actionable genes. Referral to GC was positively associated with family history of CRC (odds ratio [OR], 2.11; 95% CI, 1.51–2.96) and more recent year of diagnosis (2010–2013 vs 2017–2019; OR, 5.36; 95% CI, 3.59–8.01) but negatively associated with older age at diagnosis (OR, 0.89; 95% CI, 0.86–0.92). Conclusions: Referral to GC for patients with EOCRC is increasing over time; however, even in recent years, almost 25% of patients were not referred for GC. We found that 1 in 5 patients with EOCRC carry actionable PGVs, highlighting the need for health systems to implement care pathways to optimize GC referral and testing in all patients with EOCRC.

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Should We Use COMM (Current Opioid Misuse Measure) to Screen for Opioid Abuse in Patients With Cancer Pain?

Natalie Moryl, Tito R. Mendoza, Susan D. Horn, Jelyn C. Eustaquio, Charles S. Cleeland, and Charles Inturrisi

Background: Growing concerns about opioid use disorder (OUD) and the resulting decrease in opioid availability for patients with cancer pain highlight the need for reliable screening tools to identify the subset of patients at increased risk for aberrant opioid use. Our study examines the utility of Current Opioid Misuse Measure (COMM) recommended by the NCCN Clinical Practice Guidelines in Oncology for Adult Cancer Pain. Patients and Methods: We analyzed prospectively collected patient-reported outcomes of 444 consecutive patients with cancer seen in pain clinics of a cancer center at 2 time points within 100 days. The relationship of COMM to other OUD screening tools, pain, opioid doses, patient demographics, and mortality was examined using univariate and multivariable logistic regression. We also examined individual items of COMM for face validity. Results: Among 444 patients who completed pain surveys at 2 time points, 157 (35.4%) did not complete COMM surveys. Using a COMM cutoff of ≥13, a total of 84 patients (29.3%; 84/287) scored positive for aberrant drug use. As patients remained on opioids for 49 to 100 days, the likelihood of improving COMM score (turning from positive to negative) was 6.1 times greater than the reverse. The number of patients with COMM ≥13 was 3.8 times higher than the number of patients with CPT diagnostic codes for OUD, 5.3 times higher than those with a positive urine drug screening, and 21 times higher than those with a positive CAGE (Cut Down, Annoyed, Guilty, Eye-Opener Questionnaire) score. COMM ≥13 was not associated with pain relief response (worst pain intensity score ≥2 points on the Brief Pain Inventory), opioid doses, gender, or age. Contrary to the intended use of COMM to identify aberrant opioid use, COMM ≥13 predicted mortality: patients with COMM ≥13 were 1.9 times more likely to die within 12 months. Conclusions: Our study found that using COMM in a cancer population may significantly overestimate the risk of opioid misuse. Using COMM without modifications can create an additional barrier to cancer pain management, such as limiting appropriate opioid use.

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Smoking Cessation and Pancreatic Cancer Risk in Individuals With Prediabetes and Diabetes: A Nationwide Cohort Study

Joo-Hyun Park, Jung Yong Hong, Jay J. Shen, Kyungdo Han, Young Suk Park, and Joon Oh Park

Background: Individuals with diabetes and prediabetes are at increased risk of pancreatic cancer. However, little is known about the effects of smoking or smoking cessation on pancreatic cancer risk in individuals with diabetes and prediabetes. We investigated the association between smoking status (particularly smoking cessation) and pancreatic cancer risk according to glycemic status. Patients and Methods: This nationwide cohort study included 9,520,629 adults without cancer who underwent the Korean National Health Screening in 2009 and were followed until 2018. Hazard ratios and 95% confidence intervals for pancreatic cancer were estimated after adjusting for potential confounders. Results: During the 78.4 million person-years of follow-up, 15,245 patients were newly diagnosed with pancreatic cancer. Among individuals with diabetes and prediabetes, current smoking synergistically increased pancreatic cancer risk (all P<.01). However, quitters with diabetes and prediabetes had a pancreatic cancer risk comparable to that of never-smokers (all P>.05). For pancreatic cancer in current smokers, quitters, and never-smokers, respectively, the hazard ratios were 1.48 (95% CI, 1.40–1.58), 1.11 (95% CI, 1.03–1.19), and 1.00 (reference) among individuals with normoglycemia; 1.83 (95% CI, 1.70–1.97), 1.28 (95% CI, 1.18–1.39), and 1.20 (95% CI, 1.14–1.26) among individuals with prediabetes; and 2.72 (95% CI, 2.52–2.94), 1.78 (95% CI, 1.63–1.95), and 1.63 (95% CI, 1.54–1.72) among individuals with diabetes. There were no differences in risk between quitters with a <20 pack-year smoking history and never-smokers in all glycemic status groups. Conclusions: Pancreatic cancer risk synergistically increased in current smokers with diabetes and prediabetes. However, smoking cessation reduced the synergistically increased risk of pancreatic cancer to the level of never-smokers, especially when smoking history was <20 pack-years. More individualized and intensive cancer prevention education should be underscored for individuals at an increased risk of pancreatic cancer beyond the one-size-fits-all approach.

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Vitamin D Insufficiency as a Risk Factor for Paclitaxel-Induced Peripheral Neuropathy in SWOG S0221

Ciao-Sin Chen, Gary Zirpoli, William E. Barlow, G. Thomas Budd, Bryan McKiver, Lajos Pusztai, Gabriel N. Hortobagyi, Kathy S. Albain, M. Imad Damaj, Andrew K. Godwin, Alastair Thompson, N. Lynn Henry, Christine B. Ambrosone, Kathleen A. Stringer, and Daniel L. Hertz

Background: Prior work suggests that patients with vitamin D insufficiency may have a higher risk of chemotherapy-induced peripheral neuropathy (CIPN) from paclitaxel. The objective of this study was to validate vitamin D insufficiency as a CIPN risk factor. Methods: We used data and samples from the prospective phase III SWOG S0221 (ClinicalTrials.gov identifier: NCT00070564) trial that compared paclitaxel-containing chemotherapy regimens for early-stage breast cancer. We quantified pretreatment 25-hydroxy-vitamin D in banked serum samples using a liquid chromatography-tandem mass spectrometry targeted assay. We tested the association between vitamin D insufficiency (≤20 ng/mL) and grade ≥3 sensory CIPN via multiple logistic regression and then adjusted for self-reported race, age, body mass index, and paclitaxel schedule (randomization to weekly or every-2-week dosing). We also tested the direct effect of vitamin D deficiency on mechanical hypersensitivity in mice randomized to a regular or vitamin D–deficient diet. Results: Of the 1,191 female patients in the analysis, 397 (33.3%) had pretreatment vitamin D insufficiency, and 195 (16.4%) developed grade ≥3 CIPN. Patients with vitamin D insufficiency had a higher incidence of grade ≥3 CIPN than those who had sufficient vitamin D (20.7% vs 14.2%; odds ratio [OR], 1.57; 95% CI, 1.14–2.15; P=.005). The association retained significance after adjusting for age and paclitaxel schedule (adjusted OR, 1.65; 95% CI, 1.18–2.30; P=.003) but not race (adjusted OR, 1.39; 95% CI, 0.98–1.97; P=.066). In the mouse experiments, the vitamin D–deficient diet caused mechanical hypersensitivity and sensitized mice to paclitaxel (both P<.05). Conclusions: Pretreatment vitamin D insufficiency is the first validated potentially modifiable predictive biomarker of CIPN from paclitaxel. Prospective trials are needed to determine whether vitamin D supplementation prevents CIPN and improves treatment outcomes in patients with breast and other cancer types.

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Volume 21 (2023): Issue 10 (Oct 2023)

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Changes in Prognostic Beliefs of Patients With Metastatic Cancer and Their Association With Changing Health Status

Isabella Gupta, Eric Andrew Finkelstein, Semra Ozdemir, and Chetna Malhotra

Background: Patients’ prognostic beliefs are known to influence treatment decisions. However, the evolution of these beliefs over an extended period in patients with metastatic cancer is understudied. We assessed longitudinal changes in prognostic beliefs and investigated their association with patients’ changing health status. Methods: We surveyed a cohort of 600 patients with solid metastatic cancer every 9 months, up to 54 months. At each time point, we assessed whether patients believed their current treatments would cure them (responses classified as accurate, inaccurate, or uncertain belief) and tested the association of their response with symptom burden and recent unplanned hospital admission. Results: Only 29% of patients had accurate prognostic belief at baseline, and 24% of patients changed from having accurate to uncertain/inaccurate belief at some point during follow-up. Patients who experienced greater symptom burden were less likely to report inaccurate (relative risk ratio [RRR], 0.87; 95% CI, 0.84–0.90) or uncertain prognostic belief (RRR, 0.90; 95% CI, 0.87–0.92), whereas those with a recent unplanned hospital admission were more likely to report inaccurate (RRR, 2.71; 95% CI, 1.48–4.94) or uncertain belief (RRR, 2.34; 95% CI, 1.34–4.07) compared with accurate belief. An increase in symptom burden was associated with change toward accurate belief (RRR, 1.75; 95% CI, 1.33–2.31) as opposed to no change. Conclusions: In our study of long-term changes in prognostic beliefs among patients with metastatic cancer, reported prognostic beliefs were unstable, changed from accurate to inaccurate/uncertain and vice versa, and were associated with their changing health status. Our findings imply that conversations about goals of care must occur regularly to factor in these changes.

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“Coming Full Circle”: Reintroduction of Radiotherapy Delaying Chemotherapy Followed by Craniospinal Radiotherapy for Infants With Medulloblastoma

Nicholas G. Gottardo

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Discussing Validation of the PREDICT Prognostication Tool in Patients With Breast Cancer

Paul D.P. Pharoah

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Early Increases in Blood Pressure and Major Adverse Cardiovascular Events in Patients With Renal Cell Carcinoma and Thyroid Cancer Treated With VEGFR TKIs

Vivek Narayan, Tao Liu, Yunjie Song, Joshua Mitchell, JoRean Sicks, Ilana Gareen, Lova Sun, Srinivas Denduluri, Ciaran Fisher, Jesse Manikowski, Mark Wojtowicz, Joseph Vadakara, Naomi Haas, Kenneth B. Margulies, and Bonnie Ky

Background: Although VEGFR tyrosine kinase inhibitors (TKIs) are a preferred systemic treatment approach for patients with advanced renal cell carcinoma (RCC) and thyroid carcinoma (TC), treatment-related cardiovascular (CV) toxicity is an important contributor to morbidity. However, the clinical risk assessment and impact of CV toxicities, including early significant hypertension, among real-world advanced cancer populations receiving VEGFR TKI therapies remain understudied. Methods: In a multicenter, retrospective cohort study across 3 large and diverse US health systems, we characterized baseline hypertension and CV comorbidity in patients with RCC and those with TC who are newly initiating VEGFR TKI therapy. We also evaluated baseline patient-, treatment-, and disease-related factors associated with the risk for treatment-related early hypertension (within 6 weeks of TKI initiation) and major adverse CV events (MACE), accounting for the competing risk of death in an advanced cancer population, after VEGFR TKI initiation. Results: Between 2008 and 2020, 987 patients (80.3% with RCC, 19.7% with TC) initiated VEGFR TKI therapy. The baseline prevalence of hypertension was high (61.5% and 53.6% in patients with RCC and TC, respectively). Adverse CV events, including heart failure and cerebrovascular accident, were common (occurring in 14.9% of patients) and frequently occurred early (46.3% occurred within 1 year of VEGFR TKI initiation). Baseline hypertension and Black race were the primary clinical factors associated with increased acute hypertensive risk within 6 weeks of VEGFR TKI initiation. However, early significant “on-treatment” hypertension was not associated with MACE. Conclusions: These multicenter, real-world findings indicate that hypertensive and CV morbidities are highly prevalent among patients initiating VEGFR TKI therapies, and baseline hypertension and Black race represent the primary clinical factors associated with VEGFR TKI–related early significant hypertension. However, early on-treatment hypertension was not associated with MACE, and cancer-specific CV risk algorithms may be warranted for patients initiating VEGFR TKIs.

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Erratum