Haddock, Michael G.

BACKGROUND: Intraoperative frozen-section analysis provides real-time margin resection status that can guide intraoperative decisions made by the surgeon and radiation oncologist. For patients with locally recurrent rectal cancer undergoing surgery and intraoperative radiation therapy, intraoperative re-resection of positive margins to achieve negative margins is common practice. OBJECTIVE: This study aimed to assess whether re-resection of positive margins found on intraoperative frozen-section analysis improves oncologic outcomes. DESIGN: This is a retrospective cohort study. SETTINGS: This study was an analysis of a prospectively maintained multicenter database. PATIENTS: All patients who underwent surgical resection of locally recurrent rectal cancer with intraoperative radiation therapy between 2000 and 2015 were included and followed for 5 years. Three groups were compared: initial R0 resection, initial R1 converted to R0 after re-resection, and initial R1 that remained R1 after re-resection. Grossly positive margin resections (R2) were excluded. MAIN OUTCOME MEASURES: The primary outcome measures were 5-year overall survival, recurrence-free survival, and local re-recurrence. RESULTS: A total of 267 patients were analyzed (initial R0 resection, n = 94; initial R1 converted to R0 after re-resection, n = 95; initial R1 that remained R1 after re-resection, n = 78). Overall survival was 4.4 years for initial R0 resection, 2.7 years for initial R1 converted to R0 after re-resection, and 2.9 years for initial R1 that remained R1 after re-resection (p = 0.01). Recurrence-free survival was 3.0 years for initial R0 resection and 1.8 years for both initial R1 converted to R0 after re-resection and initial R1 that remained R1 after re-resection (p ≤ 0.01). Overall survival did not differ for patients with R1 and re-resection R1 or R0 (p = 0.62). Recurrence-free survival and freedom from local re-recurrence did not differ between groups. LIMITATIONS: This study was limited by the heterogeneous patient population restricted to those receiving intraoperative radiation therapy. CONCLUSIONS: Re-resection of microscopically positive margins to obtain R0 status does not appear to provide a significant survival advantage or prevent local re-recurrence in patients undergoing surgery and intraoperative radiation therapy for locally recurrent rectal cancer. See Video Abstract at http://links.lww.com/DCR/B886. LA RE-RESECCIÓN DE LOS MÁRGENES MICROSCÓPICAMENTE POSITIVOS ENCONTRADOS DE MANERA INTRAOPERATORIA MEDIANTE LA TÉCNICA DE CRIOSECCIÓN, NO DA COMO RESULTADO UN BENEFICIO DE SUPERVIVENCIA EN PACIENTES SOMETIDOS A CIRUGÍA Y RADIOTERAPIA INTRAOPERATORIA PARA EL CÁNCER RECTAL LOCALMENTE RECIDIVANTE ANTECEDENTES: El análisis de la ténica de criosección para los margenes positivos encontrados de manera intraoperatoria proporciona el estado de la resección del margen en tiempo real que puede guiar las decisiones intraoperatorias tomadas por el cirujano y el oncólogo radioterapeuta. Para los pacientes con cáncer de recto localmente recurrente que se someten a cirugía y radioterapia intraoperatoria, la re-resección intraoperatoria de los márgenes positivos para lograr márgenes negativos es una práctica común. OBJETIVO: Evaluar si la re-resección de los márgenes positivos encontrados en el análisis de la ténica por criosecciónde manera intraoperatorios mejora los resultados oncológicos. DISEÑO: Estudio de cohorte retrospectivo. AJUSTES: Análisis de una base de datos multicéntrica mantenida de forma prospectiva. POBLACIÓN: Todos los pacientes que se sometieron a resección quirúrgica de cáncer de recto localmente recurrente con radioterapia intraoperatoria entre 2000 y 2015 fueron incluidos y seguidos durante 5 años. Se compararon tres grupos: resección inicial R0, R1 inicial convertido en R0 después de la re-resección y R1 inicial que permaneció como R1 después de la re-resección. Se excluyeron las resecciones de márgenes macroscópicamente positivos (R2). PRINCIPALES MEDIDAS DE RESULTADO: Supervivencia global a cinco años, supervivencia sin recidiva y recidiva local. RESULTADOS: Se analizaron un total de 267 pacientes (resección inicial R0 n = 94, R1 inicial convertido en R0 después de la re-resección n = 95, R1 inicial que permaneció como R1 después de la re-resección n = 78). La supervivencia global fue de 4,4 años para la resección inicial R0, 2,7 años para la R1 inicial convertida en R0 después de la re-resección y 2,9 años para la R1 inicial que permaneció como R1 después de la re-resección (p = 0,01). La supervivencia libre de recurrencia fue de 3,0 años para la resección inicial R0 y de 1,8 años para el R1 inicial convertido en R0 después de la re-resección y el R1 inicial que permaneció como R1 después de la re-resección (p ≤ 0,01). La supervivencia global no difirió para los pacientes con R1 y re-resección R1 o R0 (p = 0,62). La supervivencia libre de recurrencia y la ausencia de recurrencia local no difirieron entre los grupos. LIMITACIONES: Población de pacientes heterogénea, restringida a aquellos que reciben radioterapia intraoperatoria. CONCLUSIONES: La re-resección de los márgenes microscópicamente positivos para obtener el estado R0 no parece proporcionar una ventaja de supervivencia significativa o prevenir la recurrencia local en pacientes sometidos a cirugía y radioterapia intraoperatoria para el cáncer de recto localmente recurrente. Consulte Video Resumen en http://links.lww.com/DCR/B886. (Traducción—Dr. Daniel Guerra)

Objectives We evaluated the outcomes of metastatic pancreatic cancer (MPC) patients who underwent liver metastases (LMs)–directed ablative radiotherapy (RT) and sought to characterize patients with more favorable prognosis. Methods A retrospective analysis of 76 MPC patients who underwent ablative RT (median dose, 50 Gy) to LM at 3 academic centers between 2008 and 2018 was performed. Endpoints were local control (LC), progression-free survival, and overall survival (OS) since RT. Results Median follow-up was 10.9 months. Liver metastases were metachronous in 68%. Before RT, LM was responsive/stable on chemotherapy (CTX) in 36% whereas progressive in 43%. Median carbohydrate antigen 19-9 (CA 19-9) at RT was 334 U/mL. After RT, 32% had ≥6 months of CTX break. Twelve-month outcomes were: LC, 66%; progression-free survival, 7%; and OS, 38%. On multivariable analysis, Eastern Cooperative Oncology Group 2–3 (hazard ratio [HR], 13.49; P < 0.01), progressive LM on CTX (HR, 3.26; P < 0.01), and higher CA 19-9 (log 10 scale; HR, 1.39; P < 0.01) at RT predicted worse OS. Conclusions Ablative RT to LM in setting of MPC may offer LC of systemic disease and thus quality time off CTX. Selected patients with good performance status, stable/responsive LM on CTX, and lower CA 19-9 have more favorable prognosis.

239 Background: After trastuzumab (T) approval for advanced HER2-positive E/GEJ-AC, HER2 testing has increased in patients (pts) with resectable disease. Neoadjuvant carboplatin/paclitaxel chemoradiation (nCP-CRT) is a common therapy approach. We performed the largest evaluation, to our knowledge, of the prognostic impact of HER2 in E/GEJ-AC pts treated with nCP-CRT. Methods: We retrospectively reviewed medical records of all trimodality-eligible (T2+ or N+) pts with E/GEJ-AC who started nCP-CRT (usually 50.4 Gy) with planned surgery at Mayo Clinic (2014-2019). HER2 was tested using standard criteria for HER2 positivity (ie, immunohistochemistry 3+ or amplification by in situ hybridization). Clinicopathologic data and time to recurrence (TTR), disease free survival (DFS), overall survival (OS), survival after recurrence (SAR), and pathologic complete response (pCR – ie, no residual tumor in primary or nodes) were collected. Kaplan Meier and multivariate Cox analysis were used. Results: Of 161 consecutive eligible pts, HER2 status was available in 107 pts (HER2-positive n=26, HER2-negative n=81) of whom n=82 had surgery and n=19 had pCR. Most tumors were clinical T3 (80%) or N+ (81%), histologic grade 3 of 3 (62%). HER2 positivity was significantly associated with lower grade, but not with age, clinical T or N, or ECOG performance status (PS). A similar proportion of HER2-positive ( vs negative) pts had surgery. Among pts who had surgery, pCR rates were lower in HER2-positive ( vs negative) pts (11% [2/19] vs 27% [17/63]). After a median follow up of 23 mo, DFS and TTR were significantly shorter in HER2 positive ( vs negative) pts, independent of other pretreatment covariables (Table). Yet OS was comparable. Lung recurrence was enriched in HER2 positive ( vs negative) pts. Among pts with recurrence, SAR was longer in HER2-positive vs -negative pts. A total of 53% (10/19) of previously HER2-positive pts received T-based therapy after recurrence, and these pts were the drivers of favorable SAR (median 22 mo in n=10 HER2-positive pts who received T vs 11 mo in n=9 HER2-positive pts who did not receive T vs 11 mo in n=40 HER2-negative pts; P log-rank=.01). Conclusions: HER2 positivity ( vs negativity) is independently associated with shorter TTR and DFS, but more comparable OS. The adverse association of HER2 on tumor response and TTR may have been largely overcome through enhanced survival after recurrence, although OS data are maturing. These data may have implications for the design of endpoints in future curative-intent anti-HER2 trials. [Table: see text]

AbstractAlthough the development of effective combined chemoradiation regimens for esophageal cancers has resulted in statistically significant survival benefits, the majority of patients treated with curative intent develop locoregional and/or distant relapse. Further improvements in disease control and survival will require the development of individualized therapy based on the knowledge of host and tumor genomics and potentially harnessing the host immune system. Although there are a number of gene targets that are amplified and proteins that are overexpressed in esophageal cancers, attempts to target several of these have not proven successful in unselected patients. Herein, we review our current state of knowledge regarding the molecular pathways implicated in esophageal carcinoma, and the available agents for targeting these pathways that may rationally be combined with standard chemoradiation, with the hope that this commentary will guide future efforts of novel combinations of therapy.

Abstract Pancreatic cancer is the fourth most common cause of cancer-related morality worldwide, and the prognosis remains poor despite aggressive therapy. Carbon ion radiotherapy has favorable radiobiological and physical characteristics in the treatment, including a higher linear energy transfer and higher relative biological effectiveness, which increase the cell kill while potentially reducing toxicities to nearby normal tissues. Although small, early clinical studies have shown promise in both the resectable and unresectable settings to improve local control and overall survival while minimizing toxicities. Currently, there are several trials, including 2 sponsored by institutions in the United States, investigating the role of carbon ion radiotherapy for the treatment of locally advanced pancreatic cancer.

4500 Background: Trastuzumab is a monoclonal antibody against human epidermal growth factor receptor 2 (HER2). The primary objective of RTOG 1010 was to determine if trastuzumab increases disease-free survival (DFS) when combined with trimodality treatment for patients with HER2 overexpressing esophageal adenocarcinoma. Methods: This open label, randomized phase III trial included patients with newly diagnosed stage T1N1-2, T2-3N0-2 adenocarcinoma of the esophagus involving the mid, distal, or esophagogastric junction and up to 5cm of the stomach. All patients received chemotherapy (C) of paclitaxel, 50mg/m2 and carboplatin AUC = 2, weekly for 6 weeks, with radiation (XRT: 3D-CRT or IMRT, 50.4 Gy in 28 fractions) followed by surgery. Patients were randomized 1:1 to receive weekly trastuzumab 4mg/kg week 1 then 2mg/kg/weekly x 5 during CXRT then 6 mg/kg for 1 dose prior to surgery and 6mg/kg every 3 weeks for 13 treatments after surgery. HER2 status was determined by IHC and gene amplification by FISH. With a 2-sided alpha of 0.05, 162 DFS events provide 90% power to detect a signal for an increase in median DFS from 15 to 25 months. DFS and overall survival (OS) were estimated by the Kaplan-Meier method. and arms were compared using the log rank test. The Cox proportional hazards model was used to analyze treatment effect. Results: 571 patients were entered for assessment of HER2 expression, 203 HER2+ patients randomized. The median follow-up for alive patients is 5.0 years. The estimated 2, 3, and 4-year DFS (95% CI) for the CXRT +trastuzumab arm were 41.8% (31.8%, 51.7%), 34.3% (24.7%, 43.9%), and 33.1% (23.6%, 42.7%), respectively, and for the CXRT arm were 40.0% (30.0%, 49.9%), 33.4% (23.8%, 43.0%), and 30.1% (20.7%, 39.4%), respectively; log-rank p = 0.85. The median DFS time is 19.6 months (13.5-26.2) for the CXRT +trastuzumab arm compared to 14.2 months (10.5-23.0) for the CXRT arm. The hazard ratio (95% CI) comparing the DFS of CXRT+trastuzumab arm to the CXRT arm was 0.97 (0.69, 1.36). The median OS time was 38.5 months (26.2-70.4) for the CXRT+trastuzumab arm compared to 38.9 months (29.0-64.5) for the CXRT arm, hazard ratio (95% CI): 1.01 (0.69, 1.47). There was no statistically significant increase in treatment-related toxicities with the addition of trastuzumab including no increase in cardiac events. Conclusions: The addition of trastuzumab to trimodality treatment did not improve DFS for patients with HER2 overexpressing esophageal adenocarcinoma. Supported by NCI grants U10CA180868, UG1CA189867, U10CA180822 and Genentech. Clinical trial information: NCT01196390 .

4009 Background: An ∼65% 5-year disease-free-survival (DFS) rate from 5-FU/mitomycin/radiation for anal carcinoma needs improvement. Methods: A phase III randomized trial compared 5-FU (1,000mg/m2 days 1–4 and 29–32) plus mitomycin (10mg/m2 days 1 and 29) and radiation (45 to 59 Gy) (Arm A) to 5-FU (1,000mg/m2 days 1–4, 29–32, 57–60 and 85–88) plus cisplatin (75mg/m2 on days 1, 29, 57 and 85) and radiation (45 to 59 Gy; start day=57) (Arm B) in anal carcinoma patients. Stratification included gender, clinical N status and tumor diameter. Primary endpoint was DFS. Statistical power was 80% with two-sided test to detect 10% DFS increase for Arm B. Results: Of 682 patients accrued, 598 were analyzable. Most unanalyzed patients’ data are early. Patient characteristics were balanced. Median age was 55 years, women predominated (69%), 27.5% had >5 cm tumor diameter and 26% had clinically N+ cancer. Preliminary 5-year estimated DFS was 56% for Arm A and 48% for Arm B (p=0.28) and 5-year estimated overall survival was 69% for both arms (p=0.24). Men(p=0.04), clinically N+ cancer (p<0.0001) and tumor diameter >5 cm (p=0.005) independently prognosticated DFS in a multivariate analysis. 5-year colostomy rate was 10% for Arm A and 20% for arm B(p=0.12). Grade 3/4 toxicity rates: non-hematologic=76% for Arm A and 75% for Arm B but hematologic=67% for Arm A and 47% for Arm B(p=0.0004). Conclusions: In Intergroup-98–11, induction 5-FU/cisplatin followed by 5-FU/cisplatin/radiation failed to improve DFS compared to the standard treatment, 5-FU/mitomycin/radiation. Supported by RTOG U10 CA21661, CCOP U10 CA37422, Stat U10 CA32115. No significant financial relationships to disclose.

Purpose: NRG/RTOG 0848 was designed to determine whether adjuvant radiation with fluoropyrimidine sensitization improved survival following gemcitabine-based adjuvant chemotherapy for patients with resected pancreatic head adenocarcinoma. In step 1 of this protocol, patients were randomized to adjuvant gemcitabine versus the combination of gemcitabine and erlotinib. This manuscript reports the final analysis of these step 1 data. Methods: Eligibility—within 10 weeks of curative intent pancreaticoduodenectomy with postoperative CA19-9<180. Gemcitabine arm—6 cycles of gemcitabine. Gemcitabine+erlotinib arm—gemcitabine and erlotinib 100 mg/d. Two hundred deaths provided 90% power (1-sided α=0.15) to detect the hypothesized OS signal (hazard ratio=0.72) in favor of the arm 2. Results: From November 17, 2009 to February 28, 2014, 163 patients were randomized and evaluable for arm 1 and 159 for arm 2. Median age was 63 (39 to 86) years. CA19-9 ≤90 in 93%. Arm 1: 32 patients (20%) grade 4 and 2 (1%) grade 5 adverse events; arm 2, 27 (17%) grade 4 and 3 (2%) grade 5. GI adverse events, arm 1: 22% grade ≥3 and arm 2: 28%, ( P =0.22). The median follow-up (surviving patients) was 42.5 months (min-max: <1 to 75). With 203 deaths, the median and 3-year OS (95% confidence interval) are 29.9 months (21.7, 33.4) and 39% (30, 45) for arm 1 and 28.1 months (20.7, 30.9) and 39% (31, 47) for arm 2 (log-rank P =0.62). Hazard ratio (95% confidence interval) comparing OS of arm 2 to arm 1 is 1.04 (0.79, 1.38). Conclusions: The addition of adjuvant erlotinib to gemcitabine did not provide a signal for increased OS in this trial.

AbstractBackgroundSeveral registry-based analyses suggested a survival advantage for married versus single patients with pancreatic cancer. The mechanisms underlying the association of marital status and survival are likely multiple and complex and, therefore, may be obscured in analyses generated from large population-based databases. The goal of this research was to characterize this potential association of marital status with outcomes in patients with resected pancreatic cancer who underwent combined modality adjuvant therapy on a prospective clinical trial.Materials and MethodsThis is an ancillary analysis of 367 patients with known marital status treated on NRG Oncology/RTOG 97-04. Survival analysis was performed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model.ResultsOf 367 patients, 271 (74%) were married or partnered and 96 (26%) were single. Married or partnered patients were more likely to be male. There was no association between marital status and overall survival (OS) or disease-free survival (DFS) on univariate (hazard ratio [HR], 1.09 and 1.01, respectively) or multivariate analyses (HR, 1.05 and 0.98, respectively). Married or partnered male patients did not have improved survival compared with female or single patients.ConclusionAncillary analysis of data from NRG Oncology/RTOG 97-04 demonstrated no association between marital and/or partner status and OS or DFS in patients with resected pancreatic cancer who received adjuvant postoperative chemotherapy followed by concurrent external beam radiation therapy and chemotherapy. Clinical trial identification number. NCT00003216.

147 Background: Lymphopenia during radiation therapy (RT) has been associated with worse oncologic outcomes in a number of malignancies, including esophageal cancer (EC). No studies to date have investigated specific dosimetric parameters associated with this lymphopenia in EC. We performed an analysis of RT dose to multiple organs at risk (OARs) to investigate associations with grade 4 lymphopenia (G4L). Methods: Consecutive EC patients receiving curative intent chemoradiotherapy +/- surgery between July of 2015 and December of 2017 were included. Lymphocyte nadir was defined as the lowest lymphocyte count during RT. G4L was defined as absolute lymphocyte count <200/mm3. Dose to OARs including aorta, body, bone marrow, heart, liver, lung, and spleen were calculated. Univariate logistic regression analyses were performed for each OAR at the 1, 5, 10, 15, 20, 30, 35, 40, and 50 Gy levels with volume receiving dose ‘x’(VxGy) analyzed as a continuous variable per 10% increase. Clinical tumor volume (CTV) and RT modality (photon vs. proton) as well clinical factors including sex, stage (I/II vs. III/IV), age (per 10 year increase), and BMI (per 5 unit increase) were also analyzed. Results: One hundred forty-four pts were identified for inclusion. Seventy-nine pts received photon RT and 65 proton RT. Chemotherapy was weekly carbotaxol (99%). G4L at nadir was 40% overall (56% photon, 22% proton). By organ, body V1-V30Gy (OR 1.45-8.18, p<0.01), heart V1-V30Gy (OR 1.24-1.49, p<0.01), liver V1-V35Gy (OR 1.23-2.75, p<0.01), lung V1-V30Gy (OR 1.26-5.73 p<0.01), and spleen V1-V40Gy (OR 1.26-1.49 p<0.01) were highly associated with G4L whereas dose to aorta and bone marrow were not. Advanced stage (OR, 3.92 p<0.01), photon vs. proton (OR 4.58 p<0.01), and CTV (per 100 cc’s (OR=1.21, p<0.01)) were also associated with G4L. Sex, age, and BMI were not associated with G4L. Conclusions: Low to intermediate dose volumes to OARs including body, spleen, liver, lungs, and heart were associated with G4L. These findings provide rational for the differences seen in rates of G4L for photon versus proton RT.