Hodgson, David

Abstract Children’s Oncology Group (COG) trial AHOD0431 reduced systemic therapy and used response-adapted involved-field radiotherapy (IFRT) in early-stage pediatric classic Hodgkin lymphoma. We investigated the impact of positron emission tomographic response after 1 cycle (PET1) and on IFRT outcomes and pattern of relapse. Patients in AHOD0431 underwent PET1 response assessment after AVPC (doxorubicin, vincristine, prednisone, and cyclophosphamide). “Rapid early responders” (RERs) had a negative PET1 (PET1−); “slow early responders” (SERs) had a positive PET1 (PET1+). Patients with a partial response by computed tomographic and functional imaging after 3 chemotherapy cycles received 21-Gy IFRT, whereas complete responders had no IFRT. Progression-free survival (PFS) was evaluated for RERs and SERs treated with or without IFRT. Recurrence sites were initial, new, or both. Relapses involving initial sites were characterized as “within the PET1+ site” or “initially involved but outside the PET1+ site.” Median follow-up was 118 months. The 10-year PFS rate among RERs was 96.6% with IFRT and 84.1% without IFRT (P = .10), whereas SERs were 80.9% with IFRT and 64.0% without IFRT (P = .03). Among 90 RERs who did not receive IFRT, all 14 relapses included an initial site. Among 45 SERs receiving no IFRT, 14 of 16 relapses were in the initial site (9 PET1+ site only). Among 58 patients receiving IFRT, 5 of 10 relapses were in the PET1+ site. After 3 cycles of AVPC alone, RERs showed favorable results. Conversely, SERs had unfavorable outcomes with AVPC alone, although they improved with 21-Gy IFRT. RT remains an important component of treatment for SERs. This trial was registered at www.clinicaltrials.gov as #NCT00302003.

7504 Background: The anti-CD30 antibody drug conjugate, Brentuximab vedotin (Bv) is approved for adults with advanced stage HL but its use has not been established in children or adolescents. We compared the efficacy and safety of Bv with doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide (Bv-AVE-PC) to the standard pediatric dose intensive regimen ABVE-PC, inclusive of bleomycin. Methods: This multicenter randomized, open-label phase 3 study enrolled patients 2-21 years (yrs) with previously untreated HL, stages IIB + bulk, IIIB, IVA, IVB. Patients were randomized to 5 cycles of either ABVE-PC or Bv-AVE-PC given every 21 days with granulocyte colony-stimulating factor support. Centrally reviewed PET-CT after 2 cycles (PET2) identified slow responding lesions (SRL) defined as Deauville score > 3. Involved site radiotherapy (ISRT) was given to bulky mediastinal adenopathy and SRL. The primary objective was 3-year EFS; events include relapse/progression, second malignant neoplasm (SMN) or death. Final data cutoff was 31 December 2021. Results: 600 participants were enrolled across 151 institutions from March 2015 to August 2019; 587 were eligible. Median age was 15.6 yrs (range 3.4-21). Patient and disease characteristics were balanced across study arms. Histology was nodular sclerosing in 76.5%. Stage distribution: 20.6% IIB-bulk; 19.3% IIIB; 28.5% IVA; 31.7% IVB. At a median follow-up of 42.1 mos (0.1-80.9), 3-year EFS (95%CI) by intent-to-treat analyses was 82.5% (77.4, 86.5) with ABVE-PC and 92.1% (88.4, 94.7) with Bv-AVE-PC (HR 0.41 (0.25, 0.67), p = 0.0002). Median time to 1st event was 9.4 months for both arms but the range differs by arm (3.6-57.8 ABVE-PC; 1.3, 25.8 Bv-AVE-PC). Relapse rate was 17% following ABVE-PC and 7% with Bv-AVE-PC. One SMN is noted in each arm: thyroid cancer at 57.8 mos and acute myeloid leukemia at 20.3 mos. 3-year overall survival (95%CI) was 98.5% (96.0, 99.4) for ABVE-PC and 99.3% (97.3, 99.8) for Bv-AVE-PC (p = 0.38). PET2 SRL rates were comparable (ABVE-PC 19% vs. Bv-AVE-PC 18%, p = 0.8). As-treated ISRT receipt did not differ (ABVE-PC 55.7% vs. Bv-AVE-PC 52.7%, p = 0.69). No difference in grade 3/4 adverse events was observed; myelosuppression, reflected in a 32% incidence of > grade 3 febrile neutropenia, did not differ by arm (p = 0.67). Only 19% of patients experienced > grade 2 neuropathy by the Balis pediatric neuropathy scale, with no difference between arms (p = 0.86). Conclusions: Brentuximab vedotin with AVE-PC in a dose intensive regimen has superior efficacy to ABVE-PC for pediatric patients with high-risk HL. A 59% risk reduction in EFS was achieved with no increase in toxicity and with fewer patients receiving ISRT compared to prior pediatric trials for high-risk HL. Clinical trial information: 02166463.

Abstract PURPOSE By reducing dose to normal brain tissue, proton radiotherapy (PRT) may lessen neurocognitive risk traditionally associated with photon radiotherapy (XRT). We examined change in neurocognitive scores over time in pediatric medulloblastoma patients treated with PRT versus XRT. METHODS Neurocognitive scores from 79 patients (37 PRT, 42 XRT) were examined. Patients were treated between 2007–2018 on the same treatment protocols that differed only by craniospinal modality (PRT versus XRT). Change in scores over time since diagnosis were compared between groups. RESULTS Groups were similar on most demographic/clinical variables: sex (67.1% male), age at diagnosis (mean 8.6 years), CSI dose (median 23.4 Gy), length of follow-up (mean 4.3 years), and parental education (mean 14.3 years). Boost dose (p<0.001) and margin (p=0.001) differed between groups. Adjusting for covariates, the PRT group exhibited superior outcomes in global IQ, perceptual reasoning, and working memory versus the XRT group (all p<0.05). The XRT group exhibited significant decline in global IQ, working memory, and processing speed (all p<0.05). The PRT group exhibited stable scores in all domains except processing speed (p=0.003). Posterior fossa syndrome imparted risk independent of modality. CONCLUSION This is the first study comparing neurocognitive trajectories between pediatric patients treated for medulloblastoma with PRT versus XRT on comparable, contemporary protocols. PRT was associated with more favorable neurocognitive outcomes in most domains compared to XRT, although processing speed emerged as vulnerable in both groups. This is the strongest evidence to date of an intellectual sparing advantage with PRT in the treatment of pediatric medulloblastoma.

Abstract Purpose: Low-dose tamoxifen reduces breast cancer risk, but remains untested in chest-irradiated cancer survivors—a population with breast cancer risk comparable with BRCA mutation carriers. We hypothesized that low-dose tamoxifen would be safe and efficacious in reducing radiation-related breast cancer risk. Patients and Methods: We conducted an investigator-initiated, randomized, phase IIb, double-blinded, placebo-controlled trial (FDA IND107367) between 2010 and 2016 at 15 U.S. sites. Eligibility included ≥12 Gy of chest radiation by age 40 years and age at enrollment ≥25 years. Patients were randomized 1:1 to low-dose tamoxifen (5 mg/day) or identical placebo tablets for 2 years. The primary endpoint was mammographic dense area at baseline, 1 and 2 years. IGF-1 plays a role in breast carcinogenesis; circulating IGF-1 and IGF-BP3 levels at baseline, 1 and 2 years served as secondary endpoints. Results: Seventy-two participants (low-dose tamoxifen: n = 34, placebo: n = 38) enrolled at a median age of 43.8 years (35–49) were evaluable. They had received chest radiation at a median dose of 30.3 Gy. Compared with the placebo arm, the low-dose tamoxifen arm participants had significantly lower mammographic dense area (P = 0.02) and IGF1 levels (P < 0.0001), and higher IGFBP-3 levels (P = 0.02). There was no difference in toxicity biomarkers (serum bone-specific alkaline phosphatase, lipids, and antithrombin III; urine N-telopeptide cross-links) between the treatment arms. We did not identify any grade 3–4 adverse events related to low-dose tamoxifen. Conclusions: In this randomized trial in chest-irradiated cancer survivors, we find that low-dose tamoxifen is effective in reducing established biomarkers of breast cancer risk and could serve as a risk-reduction strategy.

Background: While HL is a highly curable cancer, patients (pts) with advanced stage disease experience increased risk of relapse. Delineation of prognosis is desired to compare cohorts and outcomes between trials, and to define groups of pts for whom reduction in treatment may be appropriate or where novel therapeutic approaches are needed. The International Prognostic Score (IPS), which was derived from a discovery set of 1,618 HL pts with complete data, was a seminal publication in the field (Hasenclever and Diehl NEJM 1998). However, these data were published >20 years ago with a significant minority of pts having received chemotherapy regimens no longer in clinical use. More contemporary analyses have shown altered utility of the IPS (e.g., Moccia JCO 2012; Diefenbach BJH 2015). In addition, prior studies identified bulk disease as an adverse prognostic factor in advanced stage HL (Laskar JCO 2004; Johnson JCO 2010). Our objective was to leverage individual pt data (IPD) from HoLISTIC (www.hodgkinconsortium.com) to discover a new, robust, and modern prognostication index for advanced-stage HL pts applicable to diverse settings across the world. Methods: We created a data repository of IPD from clinical trials for newly diagnosed HL pts, which includes 4,085 advanced-stage (III or IV) pts treated in 8 large, prospective studies completed in the modern era (ie, IIL HD9601: Gobbi JCO 2005; Italian HD2000: Federico JCO 2009; ECOG 2496: Gordon JCO 2013; SWOG 0816: Press JCO 2016; IIL HD0801: Zinzani JCO 2016; RATHL: Johnson NEJM 2016; GITIL HD0607: Gallamini JCO 2017; and COG AHOD 0831: Kelly BJH 2019) as well as prominent cancer registries (eg, the Mayo/Iowa Molecular Epidemiologic Resource (MER)). The discovery analysis herein included pts from the ECOG 2496, HD0801 IIL, GITIL HD0607, and SWOG 0816 studies. Furthermore, it was restricted to pts (n=1,279) on these trials with complete data for all 9 covariates of interest: age; sex; advanced stage (III vs IV); B symptoms; any bulk; and values of hemoglobin, white blood count (WBC), lymphocyte count, and albumin. Using Cox proportional hazard (PH) models, we evaluated univariate associations between 5-year progression-free survival (PFS) and overall survival (OS) with the aforementioned prognostic variables. Age was categorized based on plots and optimum model fit (c statistic). Lab values were dichotomized using cut-points from the 1998 IPS. Per convention, treatment factors were not included in the model. To identify independent prognostic factors of PFS and OS, a parsimonious Cox PH model was fit using backward selection of all potential risk factors (P<0.05). Hazard ratios (HR) with 95% confidence interval (CI) were reported. Kaplan Meier (KM) plots were also reported for risk factors in the multivariable (MVA) models to visualize differences. Results: Among all pts, characteristics included: median age of 32.9 years (IQR 25.4-44, range 15-83); 55% male; 49% stage IV; 63% B symptoms; 26% bulk >10 cm; 20% hemoglobin <10.5 g/dL; 15% WBC count ≥15,000/mm3; 9% lymphocyte count <600/mm3; and 63% with albumin <4g/dL. For analysis of age, we observed a U-shaped relationship with PFS (Fig A), which helped delineate optimal cut points of 15-24 years (23.1%), 25-49 years (61.4%), and ≥50 years (15.6%). In univariate analysis: age, stage, B symptoms, bulk, anemia, low lymphocyte count, and low albumin were associated with worse survival. In the MVA model, age >50 years, stage IV disease, B symptoms, and bulky disease were associated with worse PFS; and age >50 years, stage IV disease, bulky disease, anemia, and low albumin were associated with worse OS (Fig B). KM plots for age, stage, and bulk are presented in Fig C. Conclusions. In this international, multi-study analysis of advanced stage HL in the modern era, we identified several factors that were associated with both worse PFS and OS on MVA (ie, age, stage IV disease, and bulky disease). The finding of bulky disease as a significant prognostic factor warrants further investigation. In addition, we detected an age-related U-shaped impact on PFS with inferior outcomes for pts ages 15-25 years and ≥50 years, the latter in an increasing linear fashion. Altogether, these data will serve as a training cohort for a modern HL prognostication index that will be augmented and analyzed with a large independent validation cohort (vis-à-vis the remaining HL data in the HoLISTIC consortium), which will be presented at the ASH meeting. Disclosures Parsons: Seattle Genetics: Consultancy. Advani:Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy; Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding. Federico:Spectrum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mundipharma s.r.l.: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon/Teva: Research Funding. Friedberg:Acerta Pharma - A member of the AstraZeneca Group, Bayer HealthCare Pharmaceuticals.: Other; Bayer: Consultancy; Kite Pharmaceuticals: Research Funding; Portola Pharmaceuticals: Consultancy; Roche: Other: Travel expenses; Seattle Genetics: Research Funding; Astellas: Consultancy. Hutchings:Genmab: Research Funding; Janssen: Research Funding; Roche: Consultancy; Genmab: Consultancy; Takeda: Consultancy; Roche: Research Funding; Celgene: Research Funding; Daiichi: Research Funding; Sankyo: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Roche: Honoraria; Genmab: Honoraria; Takeda: Honoraria. Johnson:MorphoSys: Honoraria; Kymera: Honoraria; Kite Pharma: Honoraria; Incyte: Honoraria; Celgene: Honoraria; Epizyme: Consultancy, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Oncimmune: Consultancy; Boehringer Ingelheim: Consultancy; Janssen: Consultancy; Oncimmune: Consultancy; Janssen: Consultancy; Genmab: Honoraria; Bristol-Myers: Honoraria; Epizyme: Consultancy, Research Funding. Radford:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Speakers Bureau; ADCT: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Current equity holder in publicly-traded company, Other: Spouse; AstraZeneca: Current equity holder in publicly-traded company, Other: Spouse; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Zinzani:MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cerhan:NanoString: Research Funding; BMS/Celgene: Research Funding. Evens:Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Mylteni: Consultancy, Honoraria.

607 Background: Women with a history of radiation therapy (RT) for Hodgkin lymphoma (HL) have an elevated risk of breast cancer (BC). The characteristics, treatment and outcomes of these cancers, compared with sporadic breast cancers, are not well described. In particular, rates of synchronous and metachronous bilateral BC may be greater in patients with a history of RT for HL. Methods: Women diagnosed with BC between 1980 and 2006 following RT for HL were identified retrospectively from 8 institutions in North America. Each patient in this cohort was matched with 3 BC patients with no history of HL, from the same institution, by age at BC diagnosis, year of BC diagnosis and race. Information on patient and tumor characteristics, disease recurrence and new contralateral tumors was obtained from medical records. Analysis of metachronous contralateral breast cancer (CBC) was limited to women with a breast at risk, and adjusted hazard ratios (HRs) for CBC were estimated using Cox proportional hazards regression. Results: 253 BC patients with a history of RT for HL were matched with 741 patients with sporadic BC. The median interval between HL and first BC diagnosis was 19 years. Median age at BC diagnosis was 44 years and median follow-up was 5 years from BC diagnosis. Synchronous bilateral BC was diagnosed in 6% of the HL survivors and 2% of the matched patients with sporadic BC. Among women with unilateral disease, 21% of HL survivors and 3% of sporadic BC patients had a bilateral mastectomy. Overall 64 women with a breast at risk developed metachronous CBC. BC patients with a history of RT for HL had a greater rate of metachronous CBC (adjusted hazard ratio 3.3, 95% CI 2.1–5.8), controlling for patient, tumor and treatment characteristics. In addition, those who received chemotherapy for BC were less likely to develop CBC (adjusted HR 0.51, 95% CI 0.31–0.85), and those with a family history of BC in a 1st degree relative were more likely to develop CBC (adjusted HR 1.8, 95% CI 1.1–3.0). Conclusions: Women who develop BC after RT for HL have more than 3 times the risk of CBC than similar women with sporadic BC. Our findings support close follow-up for CBC in BC patients with a history of RT for HL and may inform decisions about prophylactic mastectomy in this population. No significant financial relationships to disclose.

AbstractThis report by the Radiation Oncology Discipline of Children's Oncology Group (COG) describes the practice patterns of pediatric image‐guided radiotherapy (IGRT) based on a member survey and provides practice recommendations accordingly. The survey comprised of 11 vignettes asking clinicians about their recommended treatment modalities, IGRT preferences, and frequency of in‐room verification. Technical questions asked physicists about imaging protocols, dose reduction, setup correction, and adaptive therapy. In this report, the COG Radiation Oncology Discipline provides an IGRT modality/frequency decision tree and the expert guidelines for the practice of ionizing image guidance in pediatric radiotherapy patients.