Christel Rushing

Patient-Oncologist Cost Communication, Financial Distress, and Medication Adherence

BACKGROUND Little is known about the association between patient-oncologist discussion of cancer treatment out-of-pocket (OOP) cost and medication adherence, a critical component of quality cancer care. METHODS We surveyed insured adults receiving anticancer therapy. Patients were asked if they had discussed OOP cost with their oncologist. Medication nonadherence was defined as skipping doses or taking less medication than prescribed to make prescriptions last longer, or not filling prescriptions because of cost. Multivariable analysis assessed the association between nonadherence and cost discussions. RESULTS Among 300 respondents (86% response), 16% (n = 49) reported high or overwhelming financial distress. Nineteen percent (n = 56) reported talking to their oncologist about cost. Twenty-seven percent (n = 77) reported medication nonadherence. To make a prescription last longer, 14% (n = 42) skipped medication doses, and 11% (n = 33) took less medication than prescribed; 22% (n = 66) did not fill a prescription because of cost. Five percent (n = 14) reported chemotherapy nonadherence. To make a prescription last longer, 1% (n = 3) skipped chemotherapy doses, and 2% (n = 5) took less chemotherapy; 3% (n = 10) did not fill a chemotherapy prescription because of cost. In adjusted analyses, cost discussion (odds ratio [OR] = 2.58; 95% CI, 1.14 to 5.85; P = .02), financial distress (OR = 1.64, 95% CI, 1.38 to 1.96; P < .001) and higher financial burden than expected (OR = 2.89; 95% CI, 1.41 to 5.89; P < .01) were associated with increased odds of nonadherence. CONCLUSION Patient-oncologist cost communication and financial distress were associated with medication nonadherence, suggesting that cost discussions are important for patients forced to make cost-related behavior alterations. Future research should examine the timing, content, and quality of cost-discussions.

Preoperative or postoperative radiotherapy versus surgery alone for retroperitoneal sarcoma: a case-control, propensity score-matched analysis of a nationwide clinical oncology database

BACKGROUND Recruitment into clinical trials for retroperitoneal sarcoma has been challenging, resulting in termination of the only randomised multicentre trial in the USA investigating perioperative radiotherapy. Nonetheless, use of radiotherapy for retroperitoneal sarcoma has increased over the past decade, substantiated primarily by its established role in extremity sarcoma. In this study, we used a nationwide clinical oncology database to separately compare overall survival for patients with retroperitoneal sarcoma who had surgery and preoperative radiotherapy or surgery and postoperative radiotherapy versus surgery alone. METHODS We did two case-control, propensity score-matched analyses of the National Cancer Data Base, which included adult patients with retroperitoneal sarcoma who were diagnosed from 2003 to 2011. Patients were included if they had localised, primary retroperitoneal sarcoma. Patients were classified into three groups based on use of radiotherapy: preoperative radiotherapy, postoperative radiotherapy, and no radiotherapy (surgery alone). Patients were excluded if they received both preoperative radiotherapy and postoperative radiotherapy, or if they received intraoperative radiotherapy. Parallel propensity score-matched datasets were created for patients who received preoperative radiotherapy versus those who received no radiotherapy and for patients who received postoperative therapy versus those who received no radiotherapy. Propensity scores were calculated with logistic regression, with multiple imputation and backwards elimination, with a significance level to stay of 0·05. Matching was done with a nearest-neighbour algorithm and matched 1:2 for the preoperative radiotherapy dataset and 1:1 for the postoperative radiotherapy dataset. The primary objective of interest was overall survival for patients who received preoperative radiotherapy or postoperative radiotherapy compared with those who received no radiotherapy within the propensity score-matched datasets. FINDINGS 9068 patients were included in this analysis: 563 in the preoperative radiotherapy group, 2215 in the postoperative radiotherapy group, and 6290 in the no radiotherapy group. Matching resulted in two comparison groups (preoperative radiotherapy vs no radiotherapy, and postoperative radiotherapy vs no radiotherapy) with negligible differences in all demographic, clinicopathological, and treatment-level variables. In the matched case-control analysis for preoperative radiotherapy median follow-up time was 42 months (IQR 27-70) for the preoperative radiotherapy group versus 43 months (25-64) for the no radiotherapy group; median overall survival was 110 months (95% CI 75-not estimable) versus 66 months (61-76), respectively. In the matched case-control analysis for postoperative radiotherapy median follow-up time was 54 months (IQR 32-79) for patients in the postoperative radiotherapy group and 47 months (26-72) for patients in the no radiotherapy group; median overall survival was 89 months (95% CI 79-100) versus 64 months (59-69), respectively. Both preoperative radiotherapy (HR 0·70, 95% CI 0·59-0·82; p<0·0001) and postoperative radiotherapy (HR 0·78, 0·71-0·85; p<0·0001) were significantly associated with improved overall survival compared with surgery alone. INTERPRETATION To the best of our knowledge, this is the largest study to date of the effect of radiotherapy on overall survival in patients with retroperitoneal sarcoma. Radiotherapy was associated with improved overall survival compared with surgery alone when delivered as either preoperative radiotherapy or postoperative radiotherapy. Together with the results from the ongoing randomised EORTC trial (62092-22092; NCT01344018) investigating preoperative radiotherapy for retroperitoneal sarcoma pending, these data might provide additional support for the increasing use of radiotherapy for patients with retroperitoneal sarcoma undergoing surgical resection. FUNDING Department of Surgery, Duke University School of Medicine.

Patient-Reported Outcomes After Choice for Contralateral Prophylactic Mastectomy

PURPOSE The rate of contralateral prophylactic mastectomies (CPMs) continues to rise, although there is little evidence to support improvement in quality of life (QOL) with CPM. We sought to ascertain whether patient-reported outcomes and, more specifically, QOL differed according to receipt of CPM. METHODS Volunteers recruited from the Army of Women with a history of breast cancer surgery took an electronically administered survey, which included the BREAST-Q, a well-validated breast surgery outcomes patient-reporting tool, and demographic and treatment-related questions. Descriptive statistics, hypothesis testing, and regression analysis were used to evaluate the association of CPM with four BREAST-Q QOL domains. RESULTS A total of 7,619 women completed questionnaires; of those eligible, 3,977 had a mastectomy and 1,598 reported receipt of CPM. Women undergoing CPM were younger than those who did not choose CPM. On unadjusted analysis, mean breast satisfaction was higher in the CPM group (60.4 v 57.9, P < .001) and mean physical well-being was lower in the CPM group (74.6 v 76.6, P < .001). On multivariable analysis, the CPM group continued to report higher breast satisfaction (P = .046) and psychosocial well-being (P = .017), but no difference was reported in the no-CPM group in the other QOL domains. CONCLUSION Choice for CPM was associated with an improvement in breast satisfaction and psychosocial well-being. However, the magnitude of the effect may be too small to be clinically meaningful. Such patient-reported outcomes data are important to consider when counseling women contemplating CPM as part of their breast cancer treatment.

A leave-one-out cross-validation SAS macro for the identification of markers associated with survival

A proper internal validation is necessary for the development of a reliable and reproducible prognostic model for external validation. Variable selection is an important step for building prognostic models. However, not many existing approaches couple the ability to specify the number of covariates in the model with a cross-validation algorithm. We describe a user-friendly SAS macro that implements a score selection method and a leave-one-out cross-validation approach. We discuss the method and applications behind this algorithm, as well as details of the SAS macro.

Out-of-Pocket Costs, Financial Distress, and Underinsurance in Cancer Care

This cross-sectional survey study examines financial distress and cost expectations among patients with cancer presenting for anticancer therapy.

Phase I study of alphaviral vector (AVX701) in colorectal cancer patients: comparison of immune responses in stage III and stage IV patients.

Meeting abstracts AVX701 is an alphaviral replicon particle vaccine expressing a modified carcinoembryonic antigen gene (CEA(6D)). We previously reported the preliminary results of a Phase I/II study of AVX701 in metastatic colorectal cancer patients (Morse, J Clin Invest. 2010; 120: 3234–3241).

Partnering with engaged patients accelerates research

DUNYA M. ATISHA, MD,* TRACIE D. LOCKLEAR, PhD, URSULA A. ROGERS, BS, CHRISTEL N. RUSHING, MS, GREGORY P. SAMSA, PhD, AND AMY P. ABERNETHY, MD, PhD Department of Surgery, Division of Plastic Surgery, Morsani College of Medicine, University of South Florida, Tampa, Florida Center for Learning Health Care, Duke University Medical Center, Durham, North Carolina Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina Health Policy and Management Gillings, School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Biomarker Signatures Correlate with Clinical Outcome in Refractory Metastatic Colorectal Cancer Patients Receiving Bevacizumab and Everolimus

A novel combination of bevacizumab and everolimus was evaluated in refractory colorectal cancer patients in a phase II trial. In this retrospective analysis, plasma samples from 49 patients were tested for over 40 biomarkers at baseline and after one or two cycles of drug administration. Analyte levels at baseline and change on-treatment were correlated with progression-free survival (PFS) and overall survival (OS) using univariate Cox proportional hazard modeling. Multivariable analyses were conducted using Cox modeling. Significant changes in multiple markers were observed following bevacizumab and everolimus treatment. Baseline levels of six markers significantly correlated with PFS and OS, including CRP, Gro-α, IGFBP-1, TF, ICAM-1, and TSP-2 (P < 0.05). At C2D1, changes of IGFBP-3, TGFβ-R3, and IGFBP-2 correlated with PFS and OS. Prognostic models were developed for OS and PFS (P = 0.0002 and 0.004, respectively). The baseline model for OS consisted of CRP, Gro-α, and TF, while the on-treatment model at C2D1 included IGFBP-2, IGFBP-3, and TGFβ-R3. These data demonstrated that multiple biomarkers were significantly modulated in response to bevacizumab and everolimus. Several markers correlated with both PFS and OS. Interestingly, these markers are known to be associated with inflammation and IGF signaling, key modulators of mTOR biology. Mol Cancer Ther; 14(4); 1048–56. ©2015 AACR.

Direct Evidence of Target Inhibition with anti-VEGF, EGFR, and mTOR Therapies in a Clinical Model of Wound Healing

Purpose: In early clinical testing, most novel targeted anticancer therapies have limited toxicities and limited efficacy, which complicates dose and schedule selection for these agents. Confirmation of target inhibition is critical for rational drug development; however, repeated tumor biopsies are often impractical and peripheral blood mononuclear cells and normal skin are often inadequate surrogates for tumor tissue. Based upon the similarities of tumor and wound stroma, we have developed a clinical dermal granulation tissue model to evaluate novel targeted therapies. Experimental Design: A 4-mm skin punch biopsy was used to stimulate wound healing and a repeat 5-mm punch biopsy was used to harvest the resulting granulation tissue. This assay was performed at pretreatment and on-treatment evaluating four targeted therapies, bevacizumab, everolimus, erlotinib, and panitumumab, in the context of three different clinical trials. Total and phosphorylated levels VEGFR2, S6RP, and EGFR were evaluated using ELISA-based methodologies. Results: Significant and consistent inhibition of the VEGF pathway (using VEGFR2 as the readout) was observed in granulation tissue biopsies from patients treated with bevacizumab and everolimus. In addition, significant and consistent inhibition of the mTOR pathway (using S6RP as the readout) was observed in patients treated with everolimus. Finally, significant inhibition of the EGFR pathway (using EGFR as the readout) was observed in patients treated with panitumumab, but this was not observed in patients treated with erlotinib. Conclusions: Molecular analyses of dermal granulation tissue can be used as a convenient and quantitative pharmacodynamic biomarker platform for multiple classes of targeted therapies. Clin Cancer Res; 21(15); 3442–52. ©2015 AACR.

A Phase I Trial of the IGF‐1R Antibody Ganitumab (AMG 479) in Combination with Everolimus (RAD001) and Panitumumab in Patients with Advanced Cancer

PURPOSE This study evaluated the maximum tolerated dose or recommended phase II dose (RPTD) and safety and tolerability of the ganitumab and everolimus doublet regimen followed by the ganitumab, everolimus, and panitumumab triplet regimen. MATERIALS AND METHODS This was a standard 3 + 3 dose escalation trial. Doublet therapy consisted of ganitumab at 12 mg/kg every 2 weeks; doses of everolimus were adjusted according to dose-limiting toxicities (DLTs). Panitumumab at 4.8 mg/kg every 2 weeks was added to the RPTD of ganitumab and everolimus. DLTs were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Pretreatment and on-treatment skin biopsies were collected to assess insulin-like growth factor 1 receptor and mammalian target of rapamycin (mTOR) target modulation. RESULTS Forty-three subjects were enrolled. In the doublet regimen, two DLTs were observed in cohort 1, no DLTs in cohort -1, and one in cohort -1B. The triplet combination was discontinued because of unacceptable toxicity. Common adverse events were thrombocytopenia/neutropenia, skin rash, mucositis, fatigue, and hyperglycemia. In the doublet regimen, two patients with refractory non-small cell lung cancer (NSCLC) achieved prolonged complete responses ranging from 18 to >60 months; one treatment-naïve patient with chondrosarcoma achieved prolonged stable disease >24 months. In dermal granulation tissue, the insulin-like growth factor receptor and mTOR pathways were potently and specifically inhibited by ganitumab and everolimus, respectively. CONCLUSION The triplet regimen of ganitumab, everolimus, and panitumumab was associated with unacceptable toxicity. However, the doublet of ganitumab at 12 mg/kg every 2 weeks and everolimus five times weekly had an acceptable safety profile and demonstrated notable clinical activity in patients with refractory NSCLC and sarcoma. IMPLICATIONS FOR PRACTICE This trial evaluated the maximum tolerated dose or recommended phase II dose and safety and tolerability of the ganitumab and everolimus doublet regimen followed by the ganitumab, everolimus, and panitumumab triplet regimen. Although the triplet regimen of ganitumab, everolimus, and panitumumab was associated with unacceptable toxicity, the doublet of ganitumab at 12 mg/kg every 2 weeks and everolimus at five times weekly had an acceptable safety profile and demonstrated notable clinical activity in patients with refractory non-small cell lung cancer and sarcoma.