Dorth, Jennifer A.

Abstract Background NRG/RTOG 1010 evaluated trastuzumab added to trimodality therapy for HER2+ localized esophageal adenocarcinoma (EAC) management. Secondary PRO objectives assessed improvement in the FACT‐Esophageal Cancer Subscale (ECS), version 4, with trastuzumab, and if improved ECS correlated with pathologic complete response (pCR). Methods Patients were randomized to weekly paclitaxel/carboplatin/radiation (chemoradiation, CRT) followed by surgery ± trastuzumab (CRT + Tras). Disease‐free survival (DFS) was the primary end point. The projected PRO sample size of 158 patients, based on an 80% participation rate of the DFS primary endpoint sample size of 197 HER2+ patients, would provide ≥ 89% power to detect ≥25% increase in the proportion of CRT + Tras patients with ECS improvement from baseline to 6–8 weeks post‐CRT; one‐sided α = 0.05, using a χ 2 test. Improvement in ECS and its swallowing index (SI) and eating index (EI) was defined as 5‐, 2‐, and 2‐point increases, respectively, from baseline to 6–8 weeks post‐CRT. Univariate logistic regression was assessed if pCR was associated with improved ECS. Results From 2010 to 2015, 203 HER2+ patients were randomized and 194 were eligible. Of 171 PRO consenting patients, the ECS was completed by 162 (95%) at baseline, 108 (64%) 6–8 weeks, 82 (49%) 1 year, and 55 (33%) at 2 years. The proportion of patients with an improvement in 6–8 weeks ECS was higher on the CRT + Tras arm (46% vs. 38%), although not significantly different ( p = .39). There was no correlation between pCR and ECS scores at 1 year, with 39% and 37% of pCR and non‐pCR patients, respectively, having improved 1‐year ECS scores. Conclusions The addition of trastuzumab to CRT for localized HER2+ EAC did not improve PROs.

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgement. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature and is not intended as a statement of the standard-of-care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only). PURPOSE To provide evidence-based guidance for clinicians who treat patients with stage I-III anal cancer. METHODS A systematic review of the literature conducted by the Minnesota Evidence-based Practice Center provided the evidence base for this guideline. An ASCO Expert Panel reviewed this evidence and came to consensus on a set of evidence-based recommendations. RESULTS The systematic review contained three randomized controlled trials and three nonrandomized studies of interventions that were relevant to the guideline topic and informed the recommendations. RECOMMENDATIONS Mitomycin-C (MMC) with a fluoropyrimidine (fluorouracil [FU] or capecitabine) is recommended as the radiosensitizing component of chemoradiation (CRT) for anal cancer; the Expert Panel recognizes that capecitabine is often used as an orally administered alternative to FU and is currently being used in ongoing clinical trials. Cisplatin with FU is an additional chemotherapy combination that may be recommended as radiosensitizing chemotherapy. Because of the myelosuppression associated with MMC, the preferable regimen for patients with immunosuppression is cisplatin and FU. Cisplatin is not recommended for patients with renal dysfunction, significant neuropathy, or hearing loss, and there is no evidence to recommend substituting carboplatin for cisplatin. Dose and schedule options for recommended chemotherapy agents are included within the full text of the guideline. Routine induction chemotherapy before CRT and additional chemotherapy after CRT are not recommended for patients with localized anal cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

PURPOSE Total neoadjuvant therapy (TNT) is a newly established standard treatment for rectal adenocarcinoma. Current methods to communicate magnitudes of regression during TNT are subjective and imprecise. Magnetic resonance tumor regression grade (MR-TRG) is an existing, but rarely used, regression grading system. Prospective validation of MR-TRG correlation with pathologic response in patients undergoing TNT is lacking. Utility of adding diffusion-weighted imaging to MR-TRG is also unknown. METHODS We conducted a multi-institutional prospective imaging substudy within NRG-GI002 (ClinicalTrials.gov identifier: NCT02921256 ) examining the ability of MR-based imaging to predict pathologic complete response (pCR) and correlate MR-TRG with the pathologic neoadjuvant response score (NAR). Serial MRIs were needed from 110 patients. Three radiologists independently, then collectively, reviewed each MRI for complete response (mriCR), which was tested for positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity with pCR. MR-TRG was examined for association with the pathologic NAR score. All team members were blinded to pathologic data. RESULTS A total of 121 patients from 71 institutions met criteria: 28% were female (n = 34), 84% White (n = 101), and median age was 55 (24-78 years). Kappa scores for T- and N-stage after TNT were 0.38 and 0.88, reflecting fair agreement and near-perfect agreement, respectively. Calling an mriCR resulted in a kappa score of 0.82 after chemotherapy and 0.56 after TNT reflected near-perfect agreement and moderate agreement, respectively. MR-TRG scores were associated with pCR ( P < .01) and NAR ( P < .0001), PPV for pCR was 40% (95% CI, 26 to 53), and NPV was 84% (95% CI, 75 to 94). CONCLUSION MRI alone is a poor tool to distinguish pCR in rectal adenocarcinoma undergoing TNT. However, the MR-TRG score presents a now validated method, correlated with pathologic NAR, which can objectively measure regression magnitude during TNT.

489 Background: To determine if SBRT followed by sorafenib (SBRT/S) improves overall survival (OS), progression free survival (PFS) and quality of life (QOL) vs. sorafenib alone (S), in patients (pts) with HCC. Methods: Eligible pts had new or recurrent HCC, unsuitable for surgery, ablation or TACE, with Zubrod performance status (PS) 0-2, Child-Pugh (CP) A, BCLC stage B or C, ≤ 5 HCCs, sum of hepatic HCCs ≤ 20 cm, and distant metastases ≤ 3 cm. Pts were randomized 1:1 to S 400 mg BID vs. SBRT (27.5-50 Gy in 5 fractions) followed by S 200 mg BID, increased to 400 mg BID after 28 days. Primary endpoint was OS; reported secondary endpoints - PFS, adverse events (AEs - CTCAEv4), and QOL (improvement in FACT-Hep score by ≥ 5 points from baseline to 6 months). Planned sample size was 292 pts (238 OS events, HR=0.72, 80% power, 1-sided α=0.05). Accrual closed early, due to a change in HCC standard of care. Statistics were amended to report as of 7/1/2022, projecting 155 OS events, with 65% power and the same α. OS and PFS were estimated by Kaplan-Meier and arms compared using log-rank test. Cox proportional hazards models were used to analyze treatment effect. Secondary endpoints were tested with 2-sided α=0.05. Results: Of 193 pts accrued from April 2013 to March 2021 from 23 sites, 177 eligible pts were randomized to S (n=92) vs. SBRT/S (n=85). Median age was 66 yrs (27-84); 41% had Hep. C; 19% had Hep. B or B/C. 82% were BCLC stage C. 74% had macrovascular invasion (MVI), 63% with VP3 or VP4 MVI. 4% had metastases. Median sum of max diameter of HCCs was 8.2 cm for S and 6.7 cm for SBRT/S; 40% had a single HCC. Median follow-up for all and alive pts was 13.2 and 33.7 mo. 22% of S pts received SBRT after discontinuing S. With 153 OS events, median OS was improved from 12.3 mo. (90% CI 10.6, 14.3) with S to 15.8 mo. (90% CI 11.4-19.2) with SBRT/S (HR=0.77, 1-sided p=0.0554). After adjusting for PS, M stage, CP A5 vs. 6, and degree of MVI, OS was statistically significantly improved for SBRT/S (HR=0.72, 95% CI 0.52-0.99, 2-sided Cox p=0.042). Median PFS was improved from 5.5 mo. (95% CI 3.4-6.3) with S to 9.2 months (95% CI 7.5-11.9) with SBRT/S (HR=0.55, 95% CI 0.40-0.75, 2-sided p=0.0001). 8 grade (G) 3+ bleeds were seen: 5 in S arm (1 G3 variceal, 2 G3 upper GI, 1 G3 hepatic, and 1 G4 abdominal) and 3 post SBRT/S (2 G3 upper GI, 1 G3 lower GI). Treatment-related G3+ AEs were not significantly different (S - 42%; SBRT/S - 47%; p=0.52), with 3 G5 AEs (S - 1 hepatic failure, 1 death NOS; SBRT/S - 1 lung infection). 83 (47%) pts consented to QoL. Of 20 S and 17 SBRT/S pts with QoL assessments at baseline and 6 months, 10% on S improved in FACT-Hep score vs 35% on SBRT/S. Conclusions: Compared to S alone, SBRT improved OS & PFS in patients with HCC, with no observed increase in AEs, and a strong suggestion for QOL benefit at 6 months. Supported by U10CA180868 (NRG Onc. Op., U10CA180822 (NRG Onc. SDMC), UG1CA189867 (NCORP), and U24CA180803 (IROC) from the NCI. Clinical trial information: NCT01730937 .