Citations

Abstract Objective The study sought to describe patient-entered supplemental information on symptomatic adverse events (AEs) in cancer clinical research reported via a National Cancer Institute software system and examine the feasibility of mapping these entries to established terminologies. Materials and Methods Patients in 3 multicenter trials electronically completed surveys during cancer treatment. Each survey included a prespecified subset of items from the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Upon completion of the survey items, patients could add supplemental symptomatic AE information in a free text box. As patients typed into the box, structured dropdown terms could be selected from the PRO-CTCAE item library or Medical Dictionary for Regulatory Activities (MedDRA), or patients could type unstructured free text for submission. Results Data were pooled from 1760 participants (48% women; 78% White) who completed 8892 surveys, of which 2387 (26.8%) included supplemental symptomatic AE information. Overall, 1024 (58%) patients entered supplemental information at least once, with an average of 2.3 per patient per study. This encompassed 1474 of 8892 (16.6%) dropdowns and 913 of 8892 (10.3%) unstructured free text entries. One-third of the unstructured free text entries (32%) could be mapped post hoc to a PRO-CTCAE term and 68% to a MedDRA term. Discussion Participants frequently added supplemental information beyond study-specific survey items. Almost half selected a structured dropdown term, although many opted to submit unstructured free text entries. Most free text entries could be mapped post hoc to PRO-CTCAE or MedDRA terms, suggesting opportunities to enhance the system to perform real-time mapping for AE reporting. Conclusions Patient reporting of symptomatic AEs using a text box functionality with mapping to existing terminologies is both feasible and informative.

Purpose The US National Cancer Institute (NCI) Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) was developed to enable patient reporting of symptomatic adverse events in oncology clinical research. This study was designed to assess the feasibility and resource requirements associated with implementing PRO-CTCAE in a multicenter trial. Methods Patients with locally advanced rectal cancer enrolled in the National Cancer Institute–sponsored North Central Cancer Treatment Group (Alliance) Preoperative Radiation or Selective Preoperative Radiation and Evaluation before Chemotherapy and Total Mesorectal Excision trial were asked to self-report 30 PRO-CTCAE items weekly from home during preoperative therapy, and every 6 months after surgery, via either the Web or an automated telephone system. If participants did not self-report within 3 days, a central coordinator called them to complete the items. Compliance was defined as the proportion of participants who completed PRO-CTCAE assessments at expected time points. Results The prespecified PRO-CTCAE analysis was conducted after the 500th patient completed the 6-month follow-up (median age, 56 years; 33% female; 12% nonwhite; 43% high school education or less; 5% Spanish speaking), across 165 sites. PRO-CTCAE was reported by participants at 4,491 of 4,882 expected preoperative time points (92.0% compliance), of which 3,771 (77.2%) were self-reported by participants and 720 (14.7%) were collected via central coordinator backup. Compliance at 6-month post-treatment follow-up was 333 of 468 (71.2%), with 122 (26.1%) via backup. Site research associates spent a median of 15 minutes on PRO-CTCAE work for each patient visit. Work by a central coordinator required a 50% time commitment. Conclusion Home-based reporting of PRO-CTCAE in a multicenter trial is feasible, with high patient compliance and low site administrative requirements. PRO-CTCAE data capture is improved through centralized backup calls.

TPS389 Background: Recent data have shown that up to 25% of patients with advanced prostate cancer, including mCRPC, have a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM, or another homologous recombination DNA repair gene. Such mutations can be used as a molecular marker to select patients for targeted treatment with poly(ADP-ribose) polymerase inhibitors (PARPis), which are lethal to cells with HRD. Treatment with PARPis has shown preliminary evidence of antitumor activity in patients with mCRPC and a mutation in a homologous recombination DNA repair gene (Mateo et al. N Engl J Med. 2015;373:1697-708). These data provide a compelling rationale for evaluating rucaparib, a potent inhibitor of PARP1, PARP2, and PARP3, in patients with mCRPC associated with HRD. Methods: TRITON3 (NCT02975934) is a randomized, phase 3 study evaluating rucaparib 600 mg BID vs physician’s choice of abiraterone, enzalutamide, or docetaxel in patients with mCRPC and a deleterious germline or somatic BRCA1, BRCA2, or ATM mutation (identified by prior local testing or central testing during screening). Patients must have progressed on androgen receptor signaling–directed therapy in the mCRPC setting; prior PARPi treatment or chemotherapy for mCRPC are exclusion criteria. Patients will be randomly assigned in a 2:1 ratio to either rucaparib or physician’s choice, with the possibility for cross over from the comparator treatment to rucaparib upon radiographic progression confirmed by independent radiology review. The primary endpoint is radiographic progression-free survival (modified RECIST v1.1/PCWG3 criteria) assessed by independent radiology review. Secondary endpoints include objective response rate, duration of response, patient-reported outcomes, overall survival, and safety. Pretreatment blood samples collected from all patients will enable development of a noninvasive plasma-based companion diagnostic to select patients who may benefit from rucaparib treatment. Patients (≈400) will be enrolled at > 100 sites worldwide. Clinical trial information: NCT02975934.

PurposeTo develop a quality assurance (QA) tool that identifies inaccurate organ at risk (OAR) delineations.MethodsThe QA tool computed volumetric features from prior OAR delineation data from 73 thoracic patients to construct a reference database. All volumetric features of the OAR delineation are computed in three‐dimensional space. Volumetric features of a new OAR are compared with respect to those in the reference database to discern delineation outliers. A multicriteria outlier detection system warns users of specific delineation outliers based on combinations of deviant features. Fifteen independent experimental sets including automatic, propagated, and clinically approved manual delineation sets were used for verification. The verification OARs included manipulations to mimic common errors. Three experts reviewed the experimental sets to identify and classify errors, first without; and then 1 week after with the QA tool.ResultsIn the cohort of manual delineations with manual manipulations, the QA tool detected 94% of the mimicked errors. Overall, it detected 37% of the minor and 85% of the major errors. The QA tool improved reviewer error detection sensitivity from 61% to 68% for minor errors (P = 0.17), and from 78% to 87% for major errors (P = 0.02).ConclusionsThe QA tool assists users to detect potential delineation errors. QA tool integration into clinical procedures may reduce the frequency of inaccurate OAR delineation, and potentially improve safety and quality of radiation treatment planning.

Abstract Background: DNA methylation is a promising prognostic and predictive biomarker of response to treatment in advanced breast cancer (Fackler MJ. Can Res 2014). We evaluated whether baseline and change in tissue and serum methylation would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer treated with PST. Methods: TBCRC008 was a multicenter placebo-controlled trial that investigated pCR (no invasive cancer in breast/axilla) following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel with or without the histone deacetylase (HDAC) inhibitor vorinostat in 62 patients with HER2-negative breast cancer. We performed an exploratory planned biomarker study correlating baseline and change (D15) in tumor tissue and serum methylation with pCR. Methylation was measured using cumulative methylation index (CMI) in quantitative multiplexed methylation-specific polymerase chain reaction (QM-MSP) assays; cMethDNA assay for serum (Fackler MJ. Can Res 2014) and QM-MSP for tissue (Fackler MJ. Can Res 2004). The analysis population included all patients with available methylation and pCR data. Association between CMI level (log transformed baseline, D15, change) and pCR was evaluated using univariate as well as multivariable logistic regression models controlling for treatment arm and estrogen receptor (ER) status. Additional subgroup analyses assessed association of CMI level with pCR stratified by ER status and treatment arms, respectively. Spearman's correlation coefficient was performed to evaluate the correlation between tissue and serum CMI. Results: pCR data were available for 61 of 62 patients. One patient with unknown response was treated as a non-responder. The pCR rate was similar in both arms (vorinostat 25.8%, placebo 29%). Both tissue and serum CMI data were available in 55 (baseline), 50 (D15) and 46 (change) patients. Elevated serum methylation based on a predefined threshold (6.9 units) was identified in 23/59 (39%) patients. In univariate analysis, one log unit increase in tissue CMI levels at D15 was associated with a 40% lower chance of obtaining a pCR (odds ratio, OR=0.60, 95% CI 0.37-0.97; p=0.037). The multivariable analysis did not show a statistically significant association of tissue or serum CMI with pCR, although a similar trend in magnitude towards association with pCR was observed for D15 and change in tumor tissue CMI (OR 0.67 and 0.57, p=0.129 and 0.147 respectively). Subgroup analyses suggested a significant association between tissue CMI levels at D15 and pCR in the group treated with vorinostat [tissue OR: 0.44 (0.20, 0.93), p=0.03; serum OR 0.37 (0.13, 1.07), p=0.07] but not in the placebo group. No significant correlation was observed between tissue and serum CMI. Conclusion: This is the first study to evaluate the predictive role of tissue and serum methylation (CMI) in patients with early breast cancer treated with PST ± an HDAC inhibitor. Methylation was detected more frequently in tissue than serum. Tissue CMI levels at D15 may predict poor response to this regimen. Further evaluation of the predictive role of methylation in early breast cancer is warranted. Citation Format: Connolly RM, Fackler MJ, Zhang Z, Zhou XC, Goetz MP, Boughey JC, Walsh B, Carpenter J, Storniolo AM, Watkins S, Barielson E, Sukumar S, Stearns V. Tumor and serum DNA methylation in women receiving preoperative chemotherapy (PST) with or without vorinostat in primary operable HER2-negative breast cancer in TBCRC008 [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 P1-09-15.

1 Background: To determine whether the efficacy of a hypofractionated (H) schedule is no worse than a conventional (C) schedule in men with low-risk prostate cancer. Methods: From April 2006 to December 2009, one thousand one hundred fifteen men with low-risk prostate cancer (clinical stage T1-2a, Gleason ≤ 6, PSA < 10) were randomly assigned 1:1 to a conventional (C) schedule (73.8 Gy in 41 fractions over 8.2 weeks) or to a hypofractionated (H) schedule (70 Gy in 28 fractions over 5.6 weeks). The trial was designed to establish with 90% power and alpha = 0.05 that (H) results in 5-year disease-free survival (DFS) that is not lower than (C) by more than 7% (hazard ratio (HR) < 1.52). Secondary endpoints include freedom from biochemical recurrence (FFBR) and overall survival. At the third planned interim analysis (July 2015), the NRG Oncology Data Monitoring Committee recommended that the results of the trial be reported. Results: One thousand one hundred and one protocol eligible men were randomized: 547 to C and 554 to H. Median follow-up is 5.9 years. Baseline characteristics are not different according to treatment arm. At the time of analysis 185 DFS events have been observed; 99 in the C arm and 86 in the H arm. The estimated 7-year disease-free survival is 75.6% (95% CI 70.3, 80.1) in the C arm and 81.8% (77.5, 85.3) in the H arm. The DFS HR (C/H) is 0.85 (0.64, 1.14). Comparison of biochemical recurrence (HR = 0.77, (0.51, 1.17)) and overall survival (HR = 0.95, (0.65, 1.41)) also met protocol non-inferiority criteria. Grade ≥ 3 GI toxicity is 3.0% (C) vs. 4.6% (H), Relative risk (RR) for H vs. C 1.53, (95% CI 0.86, 2.83); grade ≥ 3 GU toxicity is 4.5% (C) vs. 6.4% (H), RR = 1.43 (0.86,2.37). Conclusions: In men with low-risk prostate cancer, 70 Gy in 28 fractions over 5.6 weeks is non-inferior to 73.8 Gy in 41 fractions over 8.2 weeks. Clinical trial information: NCT00331773.