Citations

Abstract Background: It is documented that inequities in research participation by minority and underrepresented populations limits the progression of personalized medicine for cancer treatment for these groups. A lack of understanding essential information during the consent process and poor physician-patient communication have been noted as two overarching barriers to patients participating in translational, clinical and biospecimen research. To address these major patient barriers, we developed a plain language research literacy support (RLS) tool to improve the consent process and facilitate dialogue between physicians/research staff and patients. We describe the tool's iterative development process and testing of the developed culturally appropriate RLS tool. Methods: We tested the tool among: 1) patient participants ≥18 years of age, who were able to read and speak English from communities associated with five academic centers in the Midwest and Northeast United States; and 2) eligible recruiters who were employed at an academic center and actively recruiting patients into research. The development process for the RLS tool consisted of two phases: cognitive and beta testing. During cognitive testing, we solicited feedback from patient and recruiter participants about the content and format of the tool including low literacy language, pictures and recommendations for additional content. The tool consisted of concept cards to provide information to assist patients in making an informed decision about participating in research. During beta testing, a condensed version of the tool was tested to assess acceptability and change in knowledge about research participation. Results: Participants included 155 patients (52: cognitive testing phase; 103: beta testing phase) and 20 recruiter participants. Patient participants were mostly females (71%). Self-identified race of patients included: Whites (43%), African Americans (32%), Native Americans (20%), and other (6%). In addition, 23% of patient participants self-identified as Hispanic. During the cognitive testing phase, patient participants reported that the information was clearly laid out and the tool explained the different steps in the recruitment and enrollment process. Patient participants indicated they had learned new information related to randomization, standard of care, coded-information, and biobanking. Although some patient participants acknowledged the cards contained a great deal of information, most reported that the information was essential. Several participants suggested cards be tailored for the Native American population. Recruiters indicated that the cards provided useful information and would assist patients and research staff. During beta testing phase, 98% of participants agreed the information on the cards helped them understand clinical research. After reviewing the cards, 49% of patient participants reported that they would be very likely to participate in research and 32% reported being somewhat likely to participate in research. The majority (61%) of participants indicated that if invited to participate in a research study, they would prefer that the cards would be mailed to them in advance while 34% wanted to review the cards at their medical appointment. Half of the participants preferred accessing the cards on a computer if administered in a video format. Conclusion: The RLS tool was well received among patient and recruiter participants, making it a potentially valuable resource for enrollment of minority and underrepresented patients into health research. The next step will be to test the RLS tool for effectiveness in a randomized controlled trial. Citation Format: Erika E. de la Riva, Rodney Haring, Elisa M. Rodriguez, Evelyn Gonzalez, Mira Katz, Nikia Clark, Whitney Ann E. Henry, Rosa O. Ortiz, Barret J. Zimmermann, Marla L. Clayman, Deborah O. Erwin, Judith S. Kaur, Melissa A. Simon. Development and beta testing of a culturally appropriate research literacy support tool to increase research participation among minority and underrepresented populations. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr A11.

Abstract Purpose/Objectives: The optimal clinical target volume (CTV) for internal mammary node irradiation (IMNI) is uncertain in an era of increasingly conformal volume-based treatment planning for breast cancer. We mapped the location of gross internal mammary lymph node (IMN) metastases in order to identify areas at highest risk for harboring occult disease. Methods and Materials: Patients with axial imaging of IMN disease, including fluorodeoxyglucose F-18 (FDG18) positron emission tomography (PET-CT) and magnetic resonance imaging (MRI), were identified from a breast cancer registry. The IMN location was transferred by a radiation oncologist and breast radiologist onto the corresponding anatomic position on representative axial CT images of a patient in the treatment position. Distribution of lymph nodes, and their location was compared with consensus group guidelines of IMN target delineation. Results: Sixty-seven patients with 130 IMN metastases were mapped. The location was in the first three intercostal spaces in 102 of 130 (78%) nodal metastases. Eighteen of 130 (14%) IMN were located caudal to the third intercostal space, while 10 of 130 (8%) IMN were located cranial to the first intercostal space, including 3 patients with isolated IMN metastases at that location in the absence of distant disease. Of the 102 nodal metastases within the first three intercostal spaces, 54 (53%) were located within the RTOG consensus volume. Relative to the internal mammary (IM) vessels, 19 (19%) nodal metastases were located medially with a mean distance of 2.2 mm (SD 2.9 mm), while 29 (28%) were located laterally with a mean distance of 3.6 mm (SD 2.5 mm). Ninety and ninety-five percent of lymph nodes within the first three intercostal spaces would have been encompassed within a 4 mm and 6 mm medial and lateral expansion on the IM vessels, respectively. Conclusions: For women with indications for elective IMNI, a 4 mm medial and lateral expansion on the IM vessels within the first 3 intercostal spaces may be appropriate. In women with known IMN involvement, cranial extension to the confluence of the IM vein with the brachiocephalic vein +/- caudal extension to the 4th or 5th interspace with a 6 mm medial and lateral expansion may be considered, provided that normal tissue constraints are met. Citation Format: Jethwa KR, Kahila MM, Hunt KN, Brown LC, Corbin KS, Park SS, Yan ES, Boughey JC, Mutter RW. Delineation of internal mammary nodal target volumes in breast cancer radiotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-10-09.

Abstract Background: Post-mastectomy radiotherapy improves survival in women with node-positive breast cancer. Pencil beam scanning proton therapy is attractive due to potential to reduce the dose to the heart and lungs compared with traditional photon techniques while improving conformality and limiting skin dose compared with passively scanned proton therapy. The optimal dose and fractionation for pencil-beam scanning proton therapy remains unknown. Trial Design: This is a multi-center open label phase II randomized controlled trial to determine the safety of 15 fraction vs 25 fraction pencil beam scanning proton radiotherapy after mastectomy in patients requiring regional nodal irradiation. Eligibility Criteria: Patients ≥ 18 years with primary, non-inflammatory invasive breast cancer who have undergone mastectomy with or without immediate reconstruction and chest wall and regional nodal irradiation planned. Aims: To determine whether the 24 month complication rate (defined as grade 3 or greater late adverse events, and unplanned surgical intervention in patients who undergo mastectomy with reconstruction) of 15 fraction chest wall and regional node pencil beam scanning proton radiotherapy is acceptable relative to 25 fraction chest wall and regional nodal pencil beam scanning proton radiotherapy and worthy of further investigation. Statistical methods: The study is designed as a non-inferiority/superiority “hybrid” design using the approach of Freidlin et al. It is Using a one-sided type I error rate of 0.05 (corresponding equivalently to constructing a 1-sided 95% confidence limit), 72 evaluable patients will have 80% power to reject the null hypothesis that the 24-month complication rate in the experimental arm is higher than that of the control arm by more than 10% (i.e. rule out inferiority) under the alternative hypothesis that the complication rate in the experimental arm is 5% less than that of the control arm (i.e. superiority). However, the design will have only 41% power when the two treatment arms are equivalent (i.e. the complication rate is 10% for both arms). Accrual: The study opened in June 2016. Five of a planned eighty-two patients have been accrued to date. Citation Format: Mutter RW, Park SS, Hieken TJ, Vargas CE, Mei-Yin PC, Kathryn RJ, Hector VR, Kimberly CS, Elizabeth YS, Daniel VW. A randomized trial of 15 fraction vs 25 fraction pencil beam scanning proton radiotherapy after mastectomy in patients requiring regional nodal irradiation [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-03-03.

Respiratory motion is traditionally assessed using tumor motion magnitude. In proton therapy, respiratory motion causes density variations along the beam path that result in uncertainties of proton range. This work has investigated the use of water‐equivalent thickness (WET) to quantitatively assess the effects of respiratory motion on calculated dose in passively scattered proton therapy (PSPT). A cohort of 29 locally advanced non‐small cell lung cancer patients treated with 87 PSPT treatment fields were selected for analysis. The variation in WET (ΔWET) along each field was calculated between exhale and inhale phases of the simulation four‐dimensional computed tomography. The change in calculated dose (ΔDose) between full‐inhale and full‐exhale phase was quantified for each field using dose differences, 3D gamma analysis, and differential area under the curve (ΔAUC) analysis. Pearson correlation coefficients were calculated between ΔDose and ΔWET. Three PSPT plans were redesigned using field angles to minimize variations in ΔWET and compared to the original plans. The median ΔWET over 87 treatment fields ranged from 1‐9 mm, while the ΔWET 95th percentile value ranged up to 42 mm. The ΔWET was significantly correlated to the ΔDose for all metrics analyzed. The patient plans that were redesigned using ΔWET analysis to select field angles were more robust to the effects of respiratory motion, as ΔAUC values were reduced by more than 60% in all three cases. The tumor motion magnitude alone does not capture the potential dosimetric error due to respiratory motion because the proton range is sensitive to the motion of all patient anatomy. The use of ΔWET has been demonstrated to identify situations where respiratory motion can impact the calculated dose. Angular analysis of ΔWET may be capable of designing radiotherapy plans that are more robust to the effects of respiratory motion.PACS number(s): 87.55.‐x

The purpose of the present study was to compare the impact of pulmonary function, body habitus, and stereotactic body radiation therapy (SBRT) immobilization on setup and reproducibility for upper lung tumor. From 2008 through 2011, our institution's prospective SBRT database was searched for patients with upper lung tumors. Two SBRT immobilization strategies were used: full‐length BodyFIX and thermoplastic S‐frame. At simulation, free‐breathing, four‐dimensional computed tomography was performed. For each treatment, patients were set up to isocenter with in‐room lasers and skin tattoos. Shifts from initial and subsequent couch positions with cone‐beam computed tomography (CBCT) were analyzed. Accounting for setup uncertainties, institutional tolerance of CBCT‐based shifts for treatment was 2, 2, and 4 mm in left–right, anterior–posterior, and cranial–caudal directions, respectively; shifts exceeding these limits required reimaging. Each patient's pretreatment pulmonary function test was recorded. A multistep, multivariate linear regression model was performed to elucidate intervariable dependency for three‐dimensional calculated couch shift parameters. BodyFIX was applied to 76 tumors and S‐frame to 17 tumors. Of these tumors, 41 were non–small cell lung cancer and 15 were metastatic from other sites. Lesions measured , 1.1 to 2 (50%), 2.1 to 3 (25%), and cm. Errors from first shifts of first fractions were significantly less with S‐frame than BodyFIX (). No difference in local control (LC) was found between S‐frame and BodyFIX (); two‐year LC rate was 94%. Multivariate modeling confirmed that the ratio of forced expiratory volume in the first second of expiration to forced vital capacity, body habitus, and the immobilization device significantly impacted couch shift errors. For upper lung tumors, initial setup was more consistent with S‐frame than BodyFIX, resulting in fewer CBCT scans. Patients with obese habitus and poor lung function had more SBRT setup uncertainty; however, outcome and probability for LC remained excellent.PACS number: 89.20.‐a

The objective of this study was to evaluate and understand the systematic error between the planned three‐dimensional (3D) dose and the delivered dose to patient in scanning beam proton therapy for lung tumors. Single‐field and multifield optimized scanning beam proton therapy plans were generated for ten patients with stage II‐III lung cancer with a mix of tumor motion and size. 3D doses in CT datasets for different respiratory phases and the time‐weighted average CT, as well as the four‐dimensional (4D) doses were computed for both plans. The 3D and 4D dose differences for the targets and different organs at risk were compared using dose‐volume histogram (DVH) and voxel‐based techniques, and correlated with the extent of tumor motion. The gross tumor volume (GTV) dose was maintained in all 3D and 4D doses, using the internal GTV override technique. The DVH and voxel‐based techniques are highly correlated. The mean dose error and the standard deviation of dose error for all target volumes were both less than 1.5% for all but one patient. However, the point dose difference between the 3D and 4D doses was up to 6% for the GTV and greater than 10% for the clinical and planning target volumes. Changes in the 4D and 3D doses were not correlated with tumor motion. The planning technique (single‐field or multifield optimized) did not affect the observed systematic error. In conclusion, the dose error in 3D dose calculation varies from patient to patient and does not correlate with lung tumor motion. Therefore, patient‐specific evaluation of the 4D dose is important for scanning beam proton therapy for lung tumors.PACS number: 87.55.D

492 Background: Beclin 1 interacts with its cofactor UVRAG to promote autophagy, a cellular degradation process induced by cellular stress. While cells with defective autophagy are prone to genomic instability, it is unknown whether Beclin 1 and/or UVRAG can regulate DNA damage/repair. Methods: Colorectal cancer cell lines (HT-29, DLD1) with Beclin 1 or UVRAG siRNA were irradiated ± 5-FU. DNA damage (pATM, pH2Ax, 53BP1, RAD51), cell death (annexin V, caspase-3, clonogenic survival), and centrosome number (γ-tubulin staining), were determined. Beclin 1 protein expression was analyzed in pretreatment endoscopic biopsies from 96 rectal carcinoma patients who received radiation + 5-FU followed by surgery. Results: Beclin 1 or UVRAG knockdown was shown to enhance DNA double-strand breaks (DSBs) and cell death induced by radiation ± 5-FU. Suppression of either gene increased the percentage of irradiated cells with nuclear foci expressing 53BP1 (nonhomologous end joining), but not RAD51 (homologous recombination). Beclin 1 was shown to regulate UVRAG, and a UVRAG deletion mutant defective in Beclin 1 binding decreased protection against radiation-induced DSBs. Knockdown of Beclin 1 or UVRAG increased centrosome number in irradiated cells. While autophagy inhibition by ATG5 or LC3 siRNA enhanced radiation-induced DSBs, they did not alter centrosome number suggesting independence from autophagy. In rectal carcinomas, high vs low level Beclin 1 expression was detected in 56 (58.3%) and 40 (41.7%) tumors, respectively. Pre-treatment Beclin 1 was not associated with clinicopathological variables. However, high vs low Beclin 1 predicted a significantly reduced pathological response (macroscopic vs. microscopic or no residual tumor) to chemoradiation (high: 14.2% vs. low: 40%; p = 0.017). High vs low Beclin 1 was independently associated with poorer overall survival (HR, 4.30; 95% CI, 1.42-16.47; p = 0.009). Conclusions: Beclin 1 and UVRAG confer protection against radiation-induced DNA damage and maintain centrosome stability. The ability of Beclin 1 overexpression to confer resistance to chemoradiation, suggests its potential utility as a predictive biomarker in rectal cancer.

396 Background: The 12-gene Oncotype DXColon Cancer Assay is clinically validated as a predictor of recurrence risk in stage II colon cancer patients following surgery. We previously reported that the 12-gene assay led to 45% change in physician treatment (Tx) recommendations in a prospective study in MMR-P stage IIA colon cancer patients. Here, from the same prospective study, we report the influence of the 12-gene assay on patient Tx decisions, physician confidence, concordance in Tx choice between physicians and patients, and patient decisional conflict. Methods: Consecutive patients with resected stage IIA colon cancer who were candidates for adjuvant chemotherapy were enrolled by 105 physicians from 17 sites. Patient's tumor specimens were assessed by the 12-gene assay (RT-PCR) and MMR (IHC). Prior to and after receiving these results, patients completed surveys including (1) their Tx decisions (observation (Obs) vs. 5FU-monotherapy (5FU) vs. 5FU + oxaliplatin (Oxal)) and (2) indicators of decisional conflict. Results: 190 of 221 patients enrolled were evaluable including 139 who were MMR-P. Pre-assay: 46% of patients chose Obs, 3% 5FU, 7% Oxal, 2% other and 41% were undecided. Post-assay: 75% chose Obs, 12% 5FU, 11% Oxal, 3% other (undecided was not a possible response). Post-assay 129 (96%) of 135 definitive Tx decisions (Obs, 5FU, or Oxal) were concordant between patients and physicians compared to 49 (66%) of 74 definitive decisions pre-assay. In the majority of cases, patients (85%) and physicians (69%) reported that the assay influenced their Tx decisions. Assay results increased physician confidence in Tx recommendations in 126 (84%) and provided additional clinically relevant information to physicians in 129 (86%) of cases. Patient decisional conflict was significantly lower after assay results (p<0.001). Conclusions: In this prospective study, quantitative recurrence risk information provided by the 12-gene assay influenced Tx decisions for a majority of patients and physicians, increased physician confidence, improved concordance in Tx choice between patients and physicians and decreased patient decisional conflict.

453 Background: A 12-gene assay (Oncotype DX Colon Cancer) has been clinically validated as a predictor of recurrence risk in stage 2 colon cancer patients following surgery. We conducted the first prospective study to characterize the impact of Recurrence Score results on medical oncologists’ recommendations regarding adjuvant chemotherapy in T3, Mismatch Repair-proficient (MMR-P) stage 2 colon cancer patients. Methods: Consecutive patients with resected stage 2A colon cancer who were candidates for adjuvant chemotherapy were consented and enrolled by 105 medical oncologists from 17 sites in the Mayo Clinic Cancer Research Consortium. Each patient’s tumor specimen was assessed by the Recurrence Score test (quantitative RT-PCR) and MMR (IHC). Prior to and after receiving these results, physicians completed surveys indicating their planned treatments given hypothetical or known MMR results, recorded as Observation (Obs), 5FU-based chemotherapy (5FU), or 5FU + Oxaliplatin (Oxal). Change in treatment recommendation intensity from baseline to follow-up was defined as: increased if change from Obs to 5FU +/- Oxal or from 5FU to 5FU+Oxal, decreased if change from 5FU + Oxal to 5FU or Obs, or from 5FU to Obs, or no change. Results: 187 of 221 patients enrolled were evaluable including 141 who were MMR-P (avg age 63, 65% ECOG PS 0, med tumor size 5 cm, 11% high grade, 91% with 12+ nodes examined). In the primary analysis treatment recommendations changed for 63 (45%) of 141 MMR-P patients, with intensity decreasing for 47 (33%) and increasing for 16 (11%). Recommendations for chemotherapy (5-FU +/- Oxal) decreased from 73 (52%) patients pre-assay to 42 (30%) post-assay. Increased treatment intensity was more likely at higher Recurrence Score values and decreased intensity at lower Recurrence Score values (p=0.011), and any change was more likely when MMR status was unknown at baseline (p = 0.041). Conclusions: In this prospective study, quantitative recurrence risk information provided by the Recurrence Score test was associated with treatment recommendation changes for 45% of T3 MMR-P stage II colon cancer patients. Use of the 12-gene assay may lead to overall reductions in chemotherapy.

391 Background: Prior economic analysis of a 12-gene assay (Oncotype DX), compared with patterns of care reported in the NCCN database of patients with stage II, T3, DNA mismatch repair proficient (MMR-P) colon cancer, predicted that the assay would save medical costs and improve patient well-being (Hornberger et al., Value Health, 2012). This study assessed the validity of those findings with actual adjuvant chemotherapy (aCT) recommendations. Methods: Outcomes and costs were estimated for patients with stage II, T3, MMR-P colon cancer using a Markov model. A study of 141 patients from 17 sites in the Mayo Clinic Cancer Research Consortium collected data on aCT recommended before and after knowledge of the 12-gene assay results (Srivastava et al. abstract). Quality-adjusted life years (QALY) and medical resource use after recurrence were computed using guideline-validated state-transition probability estimation methods. Risk of progression and incidence of adverse events with different aCT regimens were based on published literature. Drug and administration costs for aCT were obtained from 2012 Medicare fee schedules. One-way sensitivity analyses were conducted to evaluate parameter influence on economic impact. Results: After receiving the 12-gene assay results, physician recommendations in favor of aCT decreased 22% (95% CI 11%-32%; McNemar test p<0.001) from 73 (52%) to 42 (30%) patients. Oxaliplatin aCT and 5-FU monotherapy recommendations each declined 11%. Average aCT costs decreased $5,738 for drugs, $668 for administration, and $3,268 for adverse events management. Overall, average total direct medical costs decreased $4,203. The net effect on average patient well-being was a gain of 0.083 QALYs. Total medical costs are most influenced by change in aCT recommendations, 5-FU monotherapy efficacy, and oxaliplatin drug acquisition cost. Savings are expected to persist even if the cost of oxaliplatin dropped by >75% due to generic substitution. Conclusions: The 12-gene assayhas been shown to alter aCT recommendations for patients with stage II, T3, MMR-P colon cancer. This study provides real-world confirmation that these changes in aCT reduce direct medical costs and improve patient well-being.