Citations

11615 Background: Deficiencies and barriers exist to delivering comprehensive and affordable cancer care. Understanding the variation in organizational commitment, existing programs, and expected outcomes for screening and management of financial distress is needed. Methods: Representatives from 17 of 27 NCCN Member Institutions (63%) completed an online survey in November 2018 conducted by the NCCN Best Practices Committee. Centers were classified based on number of unique patients seen per year, as large ( > 10,000) (76%), or small ( < 10,000) (34%). The survey focused on institutions’ screening and management practices for patient financial distress, perceived barriers in implementation, and leadership attitudes. Results: Routine screening for financial distress was reported by 77% of centers, and most used social worker assessments (94%). 56% screened patients throughout the cancer journey. Help with drug costs, meal or gas vouchers and payment plans were offered by 100% of centers. Formal pre-authorization programs and assistance with claims and denials was offered by 81%. Charity care for medical costs was provided by 100% of the large centers compared to only 33% of small centers (p = 0.03). Median number of social workers (24 vs. 3; p = 0.01) and pharmacy representatives (6 vs. 2; p = 0.02) was also different between large and small centers. 76% evaluated the impact of financial advocacy services through number of patients assisted (85%), bad debt and charity write-offs (85%) or patient satisfaction surveys (54%). 6% and 12% reported overall effectiveness of institutional practice for screening and management of financial distress as poor/ very poor respectively. Inadequate staffing and real time resources (69%), limited institutional budget (50%), lack of reimbursement (50%), and clinical time constraints (50%) were reported as potential barriers in provision of these services. 94% agreed about stronger integration of financial advocacy services into oncology practice and 84% felt that success of these services should be a quality metric. 31% of large centers vs. 100% of small centers plan to increase staffing in this area in the next 5 years. Conclusions: Majority of NCCN Member Institutions report screening and management programs for financial distress, though the actual practices and range of services vary widely. Information from this study can help centers benchmark their performance relative to similar cancer programs and identify best practices in this area.

11070 Background: Pazopanib is a tyrosine kinase inhibitor approved globally for advanced soft tissue sarcomas. The dose finding phase of this cooperative group trial assessed the dose limiting toxicities (DLT) and the maximally tolerated dose (MTD) of adding pazopanib to neoadjuvant chemoradiation or radiation therapy in children and adults with unresected intermediate/high-risk trunk and extremity non-rhabdomyosarcoma soft tissue sarcomas (NRSTS). Methods: ARST1321, a jointly designed intergroup study lead by Children's Oncology Group and NRG Oncology opened for enrollment in July 2014. Eligible adult and pediatric patients with newly diagnosed, unresected trunk/extremity NRSTS with plans for primary tumor resection were enrolled into either the Chemotherapy Cohort (those with chemosensitive NRSTS > 5 cm, grade 3, including all synovial sarcoma) or the Non-Chemotherapy Cohort (those with chemotherapy insensitive NRSTS of any size, grade 2/3, or any chemosensitive NRSTS for whom no chemotherapy was planned per discretion of patients and treatment teams). In the Chemotherapy Cohort, pazopanib was given with ifosfamide (7.5 grams/m2) and doxorubicin (75 mg/m2) plus 45 Gy preoperative RT starting after cycle 2. Primary tumor was resected at week 13, followed by chemotherapy and pazopanib to week 25. In the Non-Chemotherapy Cohort, pazopanib was given with 50 Gy preoperative RT, primary tumor was resected at week 10, and pazopanib continued to week 25. Feasibility was assessed through week 6 of therapy to determine pazopanib dose escalation/de-escalation based on DLT, total doses of pazopanib, and overall adverse event profile. Results: In the Chemotherapy Cohort, MTD was reached at Dose Level 1 (350 mg/m2 peds; 600 mg adults) with two DLTs (1 grade 3 ALT rise, 1 intolerability to therapy) in 10 patients. In the Non-Chemotherapy Cohort, 11 patients enrolled at Dose Level 1 (350 mg/m2 peds; 600 mg adults) without any observed DLTs and all received ≥75% of prescribed total pazopanib dose; MTD was reached at Dose Level 2 (450 mg/m2 peds; 800 mg adults) with 2 DLTs in ten patients enrolled (1 grade 3 dermatitis and 1 intolerability to therapy) and 9/10 receiving ≥75% of full dose. Conclusions: Pazopanib in combination with chemoradiation or radiation therapy alone was found to be safe in children and adults with NRSTS. Following this finding, ARST1321 opened in both arms using the newly determined pazopanib MTDs. Clinical trial information: NCT02180867.

11002 Background: Pazopanib is a multi-targeted tyrosine kinase inhibitor with activity in advanced soft tissue sarcoma. ARST1321 is a phase II study designed to compare the near complete pathologic response rate (≥ 90% necrosis) of preoperative chemoradiation +/- pazopanib in children and adults with intermediate/high risk chemotherapy-sensitive NRSTS. Methods: ARST1321 is a jointly designed COG and NRG Oncology study opened to enrollment in July 2014. Eligible adult (≥18 years) and pediatric ( < 18 years) patients with unresected, newly diagnosed truncal/extremity NRSTS were enrolled into the Chemotherapy Cohort ( > 5 cm, grade 2/3, protocol-designated chemotherapy-sensitive histology). Following a dose-finding phase, patients were randomized to receive (Regimen A) or not receive (Regimen B) pazopanib ( < 18 years: 350 mg/m2/day; ≥ 18 years: 600 mg/day) in combination with ifosfamide (7.5 gm/m2/cycle) and doxorubicin (75 mg/m2/cycle) + 45 Gy preoperative RT followed by primary resection at week 13, then adjuvant chemotherapy. Results: As of June 30, 2018, 81 eligible patients were enrolled and randomized. Week 13 response is available for 42 patients (60% of expected information). The rate of ≥ 90% pathologic necrosis was 58.3% for Regimen A and 22.2% for Regimen B. Based on the significance level of 0.081 (for the second efficacy analysis with overall one-sided significance level of 0.20, power of 0.80, and O’Brien-Fleming-type cumulative error spending function), the 83.8% confidence interval for the difference was between 16.5% and 55.8%. At this predetermined interim analysis, the efficacy bound was crossed indicating that Regimen A is more efficacious than Regimen B. Given these findings, enrollment was stopped. Grade 3/4 toxicities were 73.8% for Regimen A and 29% for Regimen B with neutropenia, thrombocytopenia and febrile neutropenia being the most common toxicities. Conclusions: The rate of near complete pathologic response was significantly greater with the addition of pazopanib to preoperative chemoradiation in children and adults with intermediate/high risk NRSTS. The comparison of survival outcomes requires longer follow-up. Clinical trial information: NCT02180867.

11011 Background: Beyond KRAS status, there are no validated markers for anti-EGFR therapy in mCRC. While expression of genes within the EGF signaling axis has been reported to correlate with benefit, most reports used data from non-randomized trials which cannot distinguish between general prognostic markers and markers that predict for benefit from C. CALGB 80203 was a 238-patient (pt), 4-arm, randomized phase II study of FOLFOX or FOLFIRI +/- C in mCRC pts. Formalin-fixed, paraffin-embedded (FFPE) tumor samples from CALGB 80203 were analyzed for gene expression of HER family ligands, receptors and regulators. Methods: FFPE tumor samples from consenting pts were analyzed for AREG, BTC, CD73, DUSP4, EGF, EGFR, EPGN, EREG, HB-EGF, HER2, HER3, HER4, PHLDA1 and TGFa by RT-qPCR. Interaction between baseline gene expression levels and treatment (C) with respect to progression-free survival (PFS) and overall survival (OS) was modeled using a multiplicative Cox proportional hazards model. Results: Baseline tumor tissue was available from 103 pts; 55% of tumors were KRAS wild type (WT). Two prognostic markers were identified; higher tumor mRNA levels of HER2 (HR=0.64, p=0.002) and EREG (HR=0.89, p=0.016) were associated with longer PFS across all pts. Potential predictive markers of benefit for C were identified. In KRAS WT tumors, lower HER3 expression was associated with longer OS from C treatment while higher HER3 expression was associated with shorter OS from C treatment (chemo + C: HR=1.15; chemo only: HR=0.48, interaction p=0.029). No association was observed for HER3 and outcome in KRAS mutant (MT) tumors. Interestingly, higher CD73 expression was associated with longer PFS in C-treated pts in both KRASWT (chemo + C: HR=0.91; chemo only: HR=1.57, interaction p=0.026) and MT tumors (chemo + C: HR=0.80; chemo only: HR=1.29, p=0.025). Conclusions: In one of the first reports using data from a randomized study, gene expression of HER3 and CD73 were identified as potential predictive markers for C. These data implicate not only HER axis signaling but also immune modulation as potential mechanisms of C action and sensitivity, and warrant confirmation in other large randomized trials.

9525 Background: Determine if prophylactic tadalafil maintains spontaneous (off-drug) erectile function (EF) compared to placebo in patients (pts) treated with radiotherapy (RT) for prostate cancer. Methods: Double-blind 1:1 randomization to tadalafil 5mg daily for 6 mos vs placebo starting with RT. Primary outcomes measured by International Index of Erectile Function (IIEF). Eligibility included pre-RT IIEF Question [Q] 1 response “sometimes/most times/always” able to get an erection. Ps treated with hormones were excluded. Primary outcome was response to IIEF Q1 at 30 wks (6 wks off drug). Pts were stratified by RT modality (external vs. brachytherapy) and age (≤65 vs. >65 years). 182 pts were needed in an intent-to-treat analysis to show a difference from 20% responders with placebo to 40% with tadalafil based on a 2-sided Fishers exact test with α=0.05 and 80% power. Results: We report on 155/222 analyzable/eligible pts. Median age was 63 years, white (73%), and external RT (63%). Mean total dose for external RT was 77.23 Gy and 136.74 Gy for brachytherapy with penile bulb D50 of 24.46 Gy and 31.24 Gy respectively. Most pts completed treatment per protocol (84% tadalafil, 70% placebo). Spontaneous EF at 30 wks from drug start was not different (p=0.99) between arms based on IIEF Q1 response, total IIEF score (52.5 drug vs 52.8 placebo), or score change from baseline (-8.0 drug vs -8.8 placebo). No difference in these outcomes was noted at 1 year. Non-responders at 30 wks were likely to be older (age≥65; p=0.432), but there were no significant predictors at 1 year. About 80% of pts maintained spontaneous EF in both arms. Conclusions: Low-dose daily tadalafil did not preserve EF within the first year of RT for prostate cancer. If tadalafil positively influences delayed RT-induced vasogenic injury, additional time may be needed to observe a benefit to tadalafil as a preventive agent. Alternatively, tadalafil dose modification or altered dosing schedules may be needed to demonstrate a protective effect of this agent when used with RT. Clinical trial information: NCT00951184.

7034 Background: Reduced intensity (RIC) conditioning regimens have allowed older patients and those with comorbidities to receive hematopoietic cell transplantation (HCT). Methods: We analyzed medical costs from the beginning of conditioning to 100 days after HCT for 484 patients who underwent a RIC allogeneic HCT at Fred Hutchinson Cancer Research Center (FHCRC; n=147) and Dana Farber Cancer Institute (DFCI; n=337) from 1/2008 to 12/2010. Costs up to 2 years after HCT were analyzed for DFCI (n=311) as most patients receive their post-transplant care there. Multiple linear regression was used to analyze the association between clinical variables and costs. Results: Disease distribution and transplant characteristics were comparable between the two sites, though significant differences were seen in age distribution (88% FHCRC patients ≥ 50 years vs. 80% at DFCI, p=0.04) and pre-transplant performance scores (63% patients with Karnofsky score≥ 90 at FHCRC vs. 47% at DFCI; p=0.006). Median costs for first 100 days in 2010 $ at FHCRC and DFCI were $129 000 (range 31,000-352,000) and $96,000 (3,000-614,000) respectively, p=0.0002, but differences were not significant in multivariate analysis. Inpatient costs accounted for 42% of early costs at FHCRC and 87% at DFCI.Significant predictors for early costs included a diagnosis of lymphoma/ myeloma (17% decrease in costs; p=0.01), donors other than matched related (50 -100% increase; p<0.001), relapse (17% increase, p=0.04) and ≥ grade II acute GVHD (37% increase; p<0.001). Median costs between d100 and 2 years were $39,000 (0-976,000) at DFCI. 39% of the 2 year costs occurred after first 100 days. There was no association of late costs with pre-transplant variables, and only death was associated with higher costs (138% increase; p=0.005). Conclusions: After adjustment for pre and post HCT variables, the overall costs of the RIC allogeneic transplants were similar between the two institutions despite different management approaches (inpatient vs. outpatient conditioning) and accounting methodologies. Use of unrelated/ alternative donors, relapse and acute GVHD were predictors for higher early costs while only death was associated with higher late costs.

4565 Background: The efficient delivery of adjuvant therapy after radical prostatectomy (RP) in patients with prostate cancer is limited by the lack of biomarkers, beyond clinicopathologic factors, that are able to assess the risk of clinically significant disease progression. Previously, routine FFPE patient specimens from the Mayo Clinic Radical Prostatectomy Registry with long term follow-up were selected to develop a genomic classifier (GC) to predict clinical progression. Here, we present the validation of a GC in a cohort of patients at high risk of disease progression. Methods: A case-cohort study of high-risk RP patients from the Mayo Clinic (N=219) was used to validate the genomic classifier (GC) for predicting clinical progression (defined by positive bone or CT scan post-RP). Its performance was compared to a multivariable clinical classifier (CC) and a genomic-clinical classifier (GCC) which combines GC with established clinicopathologic variables. Concordance index, Cox modeling and decision curve analysis were used to compare the different models. Results: GC and GCC were predictive of clinical progression in the high-risk cohort with c-indices of 0.79 and 0.82, respectively, compared to the clinical classifier (0.70). Multivariable survival analysis showed that the majority of prognostic information of GCC came from the GC with a minor contribution from Gleason score. Decision curve analysis showed that GCC had a higher overall net benefit compared to CC over a wide range of ‘decision-to-treat’ thresholds for the risk of progression. Conclusions: In this high-risk cohort, GC and GCC classifiers showed improved performance over CC in prediction of clinical progression. GC is an independent prognostic factor in this cohort and captures the majority of prognostic information. GC and GCC’s prognostic performance and their usefulness in guiding decision-making in the adjuvant setting after RP need further testing in studies of additional prostate cancer risk groups.

OBJECTIVEFactors associated with syrinx size in pediatric patients undergoing posterior fossa decompression (PFD) or PFD with duraplasty (PFDD) for Chiari malformation type I (CM-I) with syringomyelia (SM; CM-I+SM) are not well established.METHODSUsing the Park-Reeves Syringomyelia Research Consortium registry, the authors analyzed variables associated with syrinx radiological outcomes in patients (< 20 years old at the time of surgery) with CM-I+SM undergoing PFD or PFDD. Syrinx resolution was defined as an anteroposterior (AP) diameter of ≤ 2 mm or ≤ 3 mm or a reduction in AP diameter of ≥ 50%. Syrinx regression or progression was defined using 1) change in syrinx AP diameter (≥ 1 mm), or 2) change in syrinx length (craniocaudal, ≥ 1 vertebral level). Syrinx stability was defined as a < 1-mm change in syrinx AP diameter and no change in syrinx length.RESULTSThe authors identified 380 patients with CM-I+SM who underwent PFD or PFDD. Cox proportional hazards modeling revealed younger age at surgery and PFDD as being independently associated with syrinx resolution, defined as a ≤ 2-mm or ≤ 3-mm AP diameter or ≥ 50% reduction in AP diameter. Radiological syrinx resolution was associated with improvement in headache (p < 0.005) and neck pain (p < 0.011) after PFD or PFDD. Next, PFDD (p = 0.005), scoliosis (p = 0.007), and syrinx location across multiple spinal segments (p = 0.001) were associated with syrinx diameter regression, whereas increased preoperative frontal-occipital horn ratio (FOHR; p = 0.007) and syrinx location spanning multiple spinal segments (p = 0.04) were associated with syrinx length regression. Scoliosis (HR 0.38 [95% CI 0.16–0.91], p = 0.03) and smaller syrinx diameter (5.82 ± 3.38 vs 7.86 ± 3.05 mm; HR 0.60 [95% CI 0.34–1.03], p = 0.002) were associated with syrinx diameter stability, whereas shorter preoperative syrinx length (5.75 ± 4.01 vs 9.65 ± 4.31 levels; HR 0.21 [95% CI 0.12–0.38], p = 0.0001) and smaller pB-C2 distance (6.86 ± 1.27 vs 7.18 ± 1.38 mm; HR 1.44 [95% CI 1.02–2.05], p = 0.04) were associated with syrinx length stability. Finally, younger age at surgery (8.19 ± 5.02 vs 10.29 ± 4.25 years; HR 1.89 [95% CI 1.31–3.04], p = 0.01) was associated with syrinx diameter progression, whereas increased postoperative syrinx diameter (6.73 ± 3.64 vs 3.97 ± 3.07 mm; HR 3.10 [95% CI 1.67–5.76], p = 0.003), was associated with syrinx length progression. PFD versus PFDD was not associated with syrinx progression or reoperation rate.CONCLUSIONSThese data suggest that PFDD and age are independently associated with radiological syrinx improvement, although forthcoming results from the PFDD versus PFD randomized controlled trial (NCT02669836, clinicaltrials.gov) will best answer this question.

The NCCN Guidelines for Management of Immunotherapy-Related Toxicities provide interdisciplinary guidance on the management of immune-related adverse events (irAEs) resulting from cancer immunotherapy. These NCCN Guidelines Insights describe symptoms that may be caused by an irAE and should trigger further investigation, and summarize the NCCN Management of Immunotherapy-Related Toxicities Panel discussions for the 2020 update to the guidelines regarding immune checkpoint inhibitor–related diarrhea/colitis and cardiovascular irAEs.

PURPOSE Primary endocrine therapy for ductal carcinoma in situ (DCIS) as a potential alternative to surgery has been understudied. This trial explored the feasibility of a short-term course of letrozole and sought to determine whether treatment results in measurable radiographic and biologic changes in estrogen receptor (ER)–positive DCIS. PATIENTS AND METHODS A phase II single-arm multicenter cooperative-group trial was conducted in postmenopausal patients diagnosed with ER-positive DCIS without invasion. Patients were treated with letrozole 2.5 mg per day for 6 months before surgery. Breast magnetic resonance imaging (MRI) was obtained at baseline, 3 months, and 6 months. The primary end point was change in 6-month MRI enhancement volume compared with baseline. RESULTS Overall, 79 patients were enrolled and 70 completed 6 months of letrozole. Of these, 67 patients had MRI data available for each timepoint. Baseline MRI volumes ranged from 0.004 to 26.3 cm 3 . Median reductions from baseline MRI volume (1.4 cm 3 ) were 0.6 cm 3 (61.0%) at 3 months ( P < .001) and 0.8 cm 3 (71.7%) at 6 months ( P < .001). Consistent reductions were seen in median baseline ER H-score (228; median reduction, 15.0; P = .005), progesterone receptor H-score (15; median reduction, 85.0; P < .001), and Ki67 score (12%; median reduction, 6.3%; P = .007). Of the 59 patients who underwent surgery per study protocol, persistent DCIS remained in 50 patients (85%), invasive cancer was detected in six patients (10%), and no residual DCIS or invasive cancer was seen in nine patients (15%). CONCLUSIONS In a cohort of postmenopausal women with ER-positive DCIS, preoperative letrozole resulted in significant imaging and biomarker changes. These findings support future trials of extended endocrine therapy as primary nonoperative treatment of some DCIS.