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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 ( 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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Health-Related Quality of Life in Patients With Metastatic Colorectal Cancer Undergoing Systemic Therapy With or Without Maximal Tumor Debulking

Lotte Bakkerus, Laurien M. Buffart, Tineke E. Buffart, Yannick M. Meyer, Barbara M. Zonderhuis, Cornelis J.A. Haasbeek, Kathelijn S. Versteeg, Olaf J.L. Loosveld, Jan Willem B. de Groot, Mathijs P. Hendriks, Cornelis Verhoef, Hendrik M.W. Verheul, and Elske C. Gootjes

Background: Maintaining a sufficient health-related quality of life (HRQoL) is important in the palliative treatment of patients with metastatic colorectal cancer (mCRC). The ORCHESTRA trial ( identifier: NCT01792934) is designed to prospectively evaluate overall survival benefit and impact on HRQoL of tumor debulking when added to first-line palliative systemic therapy in patients with multiorgan mCRC. In the present study, we report the HRQoL associated with this combination treatment compared with standard systemic therapy. Methods: Patients included in the ORCHESTRA trial with clinical benefit after 3 or 4 cycles of first-line palliative systemic therapy with fluoropyrimidines and oxaliplatin with or without bevacizumab were randomly assigned to maximal tumor debulking followed by systemic therapy versus systemic therapy alone. Patients completed the EORTC Quality of Life Questionnaire-Core 30 and the Multidimensional Fatigue Inventory questionnaire at prespecified time points during treatment. Between-group differences in HRQoL over time were evaluated with linear mixed model analyses. A pattern mixture approach was applied to correct for missing questionnaires due to progressive disease. Results: A total of 300 patients were randomized to the intervention arm (n=148) or the standard arm (n=152). No statistically significant or clinically relevant differences in HRQoL and fatigue were observed when tumor debulking was added to systemic therapy. In patients of both study arms, HRQoL after 1 year of treatment was not significantly different from HRQoL at the time of randomization. Patients in the intervention arm experienced serious adverse events (SAEs) twice as often as patients in the standard arm (P≤.001). Conclusions: Maximal tumor debulking in combination with palliative systemic therapy in patients with multiorgan mCRC was significantly associated with more SAEs resulting from local therapy but no difference in HRQoL compared with palliative systemic therapy alone. There is a remarkable lack of association between the occurrence of SAEs and impact on HRQoL.

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Highlights of the NCCN Oncology Research Program

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Identification and Characterization of Avoidable Hospital Admissions in Patients With Lung Cancer

Eric M. Lander, Xuanyi Li, Li-Ching Huang, Amanda S. Cass, Wade T. Iams, Emily A. Skotte, Jennifer G. Whisenant, Robert A. Ramirez, Sally J. York, Travis J. Osterman, Jennifer A. Lewis, Christine M. Lovly, Yu Shyr, and Leora Horn

Background: More than 50% of patients with lung cancer are admitted to the hospital while receiving treatment, which is a burden to patients and the healthcare system. This study characterizes the risk factors and outcomes of patients with lung cancer who were admitted to the hospital. Methods: A multidisciplinary oncology care team conducted a retrospective medical record review of patients with lung cancer admitted in 2018. Demographics, disease and admission characteristics, and end-of-life care utilization were recorded. Following a multidisciplinary consensus review process, admissions were determined to be either “avoidable” or “unavoidable.” Generalized estimating equation logistic regression models assessed risks and outcomes associated with avoidable admissions. Results: In all, 319 admissions for 188 patients with a median age of 66 years (IQR, 59–74 years) were included. Cancer-related symptoms accounted for 65% of hospitalizations. Common causes of unavoidable hospitalizations were unexpected disease progression causing symptoms, chronic obstructive pulmonary disease exacerbation, and infection. Of the 47 hospitalizations identified as avoidable (15%), the median overall survival was 1.6 months compared with 9.7 months (hazard ratio, 2.07; 95% CI, 1.34–3.19; P<.001) for unavoidable hospitalizations. Significant reasons for avoidable admissions included cancer-related pain (P=.02), hypervolemia (P=.03), patient desire to initiate hospice services (P=.01), and errors in medication reconciliation or distribution (P<.001). Errors in medication management caused 26% of the avoidable hospitalizations. Of admissions in patients receiving immunotherapy (n=102) or targeted therapy (n=44), 9% were due to adverse effects of treatment. Patients receiving immunotherapy and targeted therapy were at similar risk of avoidable hospitalizations compared with patients not receiving treatment (P=.3 and P=.1, respectively). Conclusions: We found that 15% of hospitalizations among patients with lung cancer were potentially avoidable. Uncontrolled symptoms, delayed implementation of end-of-life care, and errors in medication reconciliation were associated with avoidable inpatient admissions. Symptom management tools, palliative care integration, and medication reconciliations may mitigate hospitalization risk.