Citations

Malignant melanoma of the lacrimal sac is an exceptionally rare tumor with a poor prognosis. We report two cases of malignant melanoma of the lacrimal sac: a 73 year-old female treated with primary surgical resection and a 75 year-old male treated with surgical resection, adjuvant proton beam radiotherapy, and adjuvant immunotherapy. We discuss the role of post-operative proton beam therapy and recent advancements in immunotherapy. These cases highlight the importance of early diagnosis and multi-modality treatment in this aggressive malignancy.

Background: The prognosis for patients (pts) with relapsed T-ALL and T-LL is dismal; the primary goal of T-ALL/T-LL treatment is to prevent relapse. AALL1231 was a COG phase 3 clinical trial that randomized children and young adults (age 1-30 years) to a modified augmented BFM (aBFM) backbone +/- the proteasome inhibitor bortezomib during induction and delayed intensification (DI) (1.3mg/m2 x 4 doses per block). Bortezomib was tested in frontline therapy based on strong preclinical data and data in relapse on COG AALL07P1. Pts were stratified as standard (SR), intermediate (IR), or very high risk (VHR), primarily based on disease response: morphologic and minimal residual disease (MRD) at end induction and end consolidation (T-ALL) and radiographic response (T-LL). To eliminate cranial radiation (CXRT) in all pts, (except VHR: Day 29 M3 marrow or EOC MRD >0.1% or pts with overt CNS leukemia at diagnosis, CNS3), the aBFM backbone was modified to use dexamethasone (dex) as the sole corticosteroid and an extra pegaspargase dose was added in both induction and DI, following the MRC strategy. IR pts received a second interim maintenance (IM) phase (one Capizzi MTX; one HD-MTX). Following consolidation, VHR pts received 3 BFM high-risk intensification blocks in lieu of IM. Results: AALL1231 accrued 847 patients (824 eligible and evaluable) of 1400 anticipated from 2014 until early closure in 2017 when COG AALL0434 established that nelarabine (NEL) improved DFS in T-ALL (AALL1231 did not include NEL). The 3-year EFS for Arm A (no bortezomib) vs Arm B (bortezomib) were 81.7±2.4% and 85.1±2.2 % (HR=0.782, p=0.074) (3/31/20 data cut-off; see Table 1 for additional outcomes). SR and IR pts, who account for 95% of pts, had significantly improved EFS on Arm B as compared with Arm A. Yet, VHR patients had improved EFS on Arm A. Patients with T-LL had improved EFS and OS with bortezomib: 3-year EFS (76.5±5.9% vs 88.3±4.5%; p = 0.01); 3-year OS (78.0±5.8% vs 89.5±4.2%, p = 0.007). A similar improvement in EFS and OS was not seen in T-ALL; however, with longer follow-up this may change. No excess toxicity was seen on Arm B. A dex-based Induction did result in lower MRD rates; more T-ALL pts on AALL1231 had Day 29 MRD <0.1% as compared with AALL0434 which used a prednisone-based Induction (AALL1231 Arm A: 69.6%; Arm B: 72.2%; AALL0434: 64.6%; p = 0.02). However, this did not translate into improved survival. Indeed OS, but not EFS was worse on AALL1231 than AALL0434. On-going analyses are investigating the increased mortality on AALL1231, but preliminary analyses suggest a combination of increased toxic deaths and overall poor outcome in the VHR group. On AALL0434, 90.8% of T-ALL pts received CXRT. On AALL1231, 9.5% of subjects were scheduled to receive CXRT (CNS3 T-ALL/T-LL: 5.7%; VHR T-ALL: 4.1%). A comparison of AALL0434 pts that received CXRT with similar AALL1231 pts not receiving CXRT on AALL1231 demonstrated similar EFS (p = 0.14) and OS (p = 0.42) (Table 2). CNS relapse rates were higher in these pts on AALL1231 (4.5%) as compared with AALL0434 (1.7%), but overall relapse rates were the same (6.5% vs 6.4%). Notably the benefit of NEL in AALL0434 was due to reduction of CNS relapses. 128 AALL1231 pts came off protocol therapy after the study was closed for physician or patient/parent choice. Data collection is underway to understand the reasons for removal, including if it was to receive NEL. Conclusions: Outcomes for SR and IR pts with T-ALL and T-LL treated with bortezomib were excellent despite the elimination of prophylactic CXRT. Bortezomib significantly improved 3-year EFS for these groups, comprising ~95% of pts. Outcomes for VHR pts were dismal and worse on the bortezomib arm. T-LL pts had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. This is the first trial to demonstrate an OS benefit for de novo pediatric T-LL with a new agent; however, longer follow-up is needed. Therapy intensification allowed elimination of CXRT in the majority of pts without excessive relapse. These results should be interpreted cautiously as the 3-yr OS on AALL1231 was inferior to AALL0434. Nevertheless, incorporating bortezomib into standard therapy for de novo T-LL appears advantageous. Future COG T-ALL/T-LLy trials will build on the positive findings from AALL0434 and AALL1231, balancing intensity while mitigating toxicity to maintain high cure rates without routine cranial radiation. (MLL, SPH, EAR contributed equally) Disclosures Teachey: Amgen: Consultancy; Janssen: Consultancy; La Roche: Consultancy; Sobi: Consultancy. Dunsmore:Dexcom: Current equity holder in publicly-traded company. Galardy:Abbott: Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company. Harker-Murray:Regerenon Pharmaceuticals: Consultancy. Hermiston:Sobi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Shimano:Novartis: Research Funding; Daiichi Sankyo: Research Funding; Pfizer: Research Funding; Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. McKay:Immunogen: Current Employment. Bollard:Mana Therapeutics: Other: IP. Loh:Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Institutional Research Funding. Hunger:Novartis: Consultancy; Amgen Inc.: Current equity holder in publicly-traded company, Honoraria. Raetz:Celgene/BMS: Other; Pfizer: Research Funding. OffLabel Disclosure: Bortezomib for the treatment of acute lymphoblastic leukemia under an IND

AbstractBackgroundAggressive dose de‐escalated adjuvant radiation therapy (RT) in patients with human papillomavirus–associated oropharyngeal squamous cell carcinoma (HPV(+)OPSCC).MethodsPatients with HPV(+)OPSCC on a phase II clinical trial of primary surgery and neck dissection followed by dose de‐escalated RT (N = 79) were compared with a cohort of patients who received standard adjuvant therapy (N = 115). Local recurrence‐free, regional recurrence‐free, distant metastases‐free survival, and progression‐free survival (PFS) were assessed.ResultsOf 194 patients, 23 experienced progression at a median of 1.1 years following surgery (interquartile range [IQR] 0.7‐2.0; range 0.3‐5.4); 10 patients in the de‐escalated cohort and 13 patients in the standard cohort. The 3‐year PFS rate for the de‐escalated cohort was 87%, and in the standard cohort was 90% (hazard ratio [HR] 1.18, 95% confidence interval (CI) [0.50‐2.75]).ConclusionPatients with HPV(+)OPSCC who undergo surgical resection and neck dissection and meet criteria for adjuvant therapy can undergo aggressive dose de‐escalation of RT without increasing risk of progression locally, regionally or at distant sites.

Many American Indian (AI) and Alaska native (AN) patients do not complete guideline-concordant cancer care for the 4 most common cancers. Our aim was to better understand AI/AN attitudes toward radiation therapy (RT). Patients eligible for this survey study were AI/AN patients with cancer at the Phoenix Indian Medical Center who either received previous RT or were recommended to receive RT. An 18-item questionnaire was administered to each of the 50 participants from October 1, 2018, through February 15, 2019. Willingness to travel for RT was compared to respondent characteristics, concerns regarding RT, and obstacles to obtain RT. Duration of RT was important to 78% of patients: 24% would consider traveling 25 miles or more for a standard course, and 48% would travel that distance for a shorter course ( P < .001). The top-ranked barriers to RT were transportation, cost of treatment, and insurance compatibility. The top-ranked concerns about RT were adverse effects, cost of treatment, and fear of RT. Concerns about adverse effects were associated with the radiation team’s inability to explain the treatment ( P = .05). Transportation concerns were significantly associated with accessibility ( P = .02), communication with the RT team ( P = .02), and fear of RT ( P = .04). AI/AN patients are concerned about the adverse effects of RT and the logistics of treatment, particularly costs, transportation, and insurance compatibility. Use of culturally specific education and hypofractionation regimens may increase acceptance of RT for AI/AN patients with cancer, and this hypothesis will be tested in a future educational intervention-based study.

e13617 Background: Breast cancer (BC) is the most prevalent cancer of women in the United States (US). The incidence rates for BC among American Indian and Alaska Native (AI/AN) women vary across the US. A novel application of Bayesian disease mapping was applied to quantify potential inequities in 10-year BC incidence in New Mexico (NM) in order to better inform health equity initiatives within the AI/AN at-risk population. Methods: Surveillance, Epidemiology, and End Results Program (SEER) data from 2005 to 2014 were used to identify new cases of BC within the 33 counties in NM. Initially, a Poisson-gamma model was applied to quantify the reduction in risk of BC within the at-risk AI/AN population compared with the general at-risk population. To account for spatial variation and to address the small area estimation problem inherent in these data by borrowing strength globally and locally in NM, we applied Bayesian disease mapping to the counts of county-level BC cases. We quantified the disparity effect, as measured by the rate ratio (95% credible interval [CI]), comparing the incidence of BC between at-risk AI/AN and non-AI/AN women, and assessed if the rate ratio differed between counties. Markov chain Monte Carlo sampling was used to estimate posterior quantities and the deviance information criterion was used for model selection. Results: In 2010, 1,041,758 women were at-risk for BC of which 107,656 (10.3%) were AI/AN women. During the 10-year study period, 12,974 new BC cases were recorded in the general at-risk population. In the at-risk AI/AN population, the expected number of new cases during the 10-year study period, therefore, was 1,340.74; however, 597 incidence cases of BC were diagnosed in the at-risk AI/AN population resulting in a posterior mean for the true relative risk of 0.445 (95% CI: 0.410, 0.482). Based on the selected model that accounted for over dispersion and spatial correlation among the 33 counties, the posterior mean of the overall adjusted rate ratio was 0.405 (95% CI: 0.336, 0.478). The adjusted rate of BC in AI/AN women was 0.40 times the corresponding adjusted rate for women who were non-AI/AN. Further, the adjusted rate ratios were similar for each county. Conclusions: The novel application of Bayesian disease mapping to these data provided substantial evidence of a significant overall disparity effect in BC incidence within NM between at-risk AI/AN and non-AI/AN women, which was more marked than previous reports. Targeted state-wide health equity initiatives may lead to reducing disparities in BC incidence in AI/AN at-risk women.

Objectives: To report long-term outcomes of nonmelanoma skin cancer (NMSC) in immunosuppressed cardiac and liver transplant recipients (CLTR). Materials and Methods: The authors reviewed CLTR at the Mayo Clinic in Arizona from 1986 to 2013. Patient and tumor characteristics were recorded. Survival rates were calculated using the Kaplan-Meier method. Patient-specific and lesion-specific analyses were performed. Univariate and multivariate cox regressions were performed for comparisons. Results: Seven-hundred and forty-seven patients underwent cardiac (138) or liver (609) transplantation and of these, 97 patients (13%) developed 382 invasive NMSC. The median follow-up was 11 (range, 3 to 27) years for surviving patients. Primary treatment was mainly surgery alone. At 10 years, the local recurrence (LR) rate was 20% (95% confidence interval, 15%-28%), and 14% of patients had multiple LRs. At 10 years, LR rates were higher for T3/T4 tumors when compared with T1/T2 tumors (32.5% vs. 20%, P=0.05). At 10 years, overall survival was 79% (95% confidence interval, 64%-88%). On multivariate analysis, age 61 years and more demonstrated inferior overall survival (P<0.01). Conclusions: This is the first study describing the AJCC 8th edition stage-based patterns of recurrence and long-term outcomes of surgically managed NMSC in a large cohort of immunosuppressed CLTRs. T3 and T4 tumors recur more often than early stage tumors. Further study is required to identify factors related to recurrence and guide upfront treatment intensification in this high-risk population.

PurposeThe dose‐averaged linear energy transfer (LETd) for intensity‐modulated proton therapy (IMPT) calculated by one‐dimensional (1D) analytical models deviates from more accurate but time‐consuming Monte Carlo (MC) simulations. We developed a fast hybrid three‐dimensional (3D) analytical LETd calculation that is more accurate than 1D analytical model.MethodsWe used the Geant4 MC code to generate 3D LETd distributions of monoenergetic proton beams in water for all energies and used a customized error function to fit the LETd lateral profiles at various depths to the MC simulation. The 3D LETd calculation kernel was a lookup table of these fitted coefficients, and LETd was determined directly from spot energies and voxel coordinates during analytical dose calculations. We validated our new method by comparing the calculated LETd distributions to MC results using 3D Gamma index analysis with 3%/2 mm criteria in 12 patient geometries. The significance of the improvement in Gamma index analysis passing rates over the 1D analytical model was determined using the Wilcoxon rank‐sum test.ResultsThe passing rate of 3D Gamma analysis comparing LETd distributions from the hybrid 3D method and the 1D method to MC simulations was significantly improved from 94.0% ± 2.5% to 98.0% ± 1.0% (P = 0.0003). The typical time to calculate dose and LETd simultaneously using an Intel Xeon E5‐2680 2.50 GHz workstation was approximately 2.5 min.ConclusionsOur new method significantly improved the LETd calculation accuracy compared to the 1D method while maintaining significantly shorter calculation time even comparing with the GPU‐based fast MC code.

PURPOSE The purpose of this study was to determine if dose de-escalation from 60 to 66 Gy to 30 to 36 Gy of adjuvant radiotherapy (RT) for selected patients with human papillomavirus–associated oropharyngeal squamous cell carcinoma could maintain historical rates for disease control while reducing toxicity and preserving swallow function and quality of life (QOL). PATIENTS AND METHODS MC1273 was a single-arm phase II trial testing an aggressive course of RT de-escalation after surgery. Eligibility criteria included patients with p16-positive oropharyngeal squamous cell carcinoma, smoking history of 10 pack-years or less, and negative margins. Cohort A (intermediate risk) received 30 Gy delivered in 1.5-Gy fractions twice per day over 2 weeks along with 15 mg/m 2 docetaxel once per week. Cohort B included patients with extranodal extension who received the same treatment plus a simultaneous integrated boost to nodal levels with extranodal extension to 36 Gy in 1.8-Gy fractions twice per day. The primary end point was locoregional tumor control at 2 years. Secondary end points included 2-year progression-free survival, overall survival, toxicity, swallow function, and patient-reported QOL. RESULTS Accrual was from September 2013 to June 2016 (N = 80; cohort A, n = 37; cohort B, n = 43). Median follow-up was 36 months, with a minimum follow-up of 25 months. The 2-year locoregional tumor control rate was 96.2%, with progression-free survival of 91.1% and overall survival of 98.7%. Rates of grade 3 or worse toxicity at pre-RT and 1 and 2 years post-RT were 2.5%, 0%, and 0%. Swallowing function improved slightly between pre-RT and 12 months post-RT, with one patient requiring temporary feeding tube placement. CONCLUSION Aggressive RT de-escalation resulted in locoregional tumor control rates comparable to historical controls, low toxicity, and little decrement in swallowing function or QOL.