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Biliary tract cancers demonstrate profound therapeutic resistance, and broadly effective therapies for refractory disease are lacking. We conducted a single-arm, second-line phase II trial combining DKN-01, a humanized monoclonal antibody targeting Dickkopf-1 (DKK-1), and nivolumab to treat patients with advanced biliary tract cancer (NCT04057365). No objective responses were seen. To identify mechanisms of treatment failure, we analyzed paired pre-treatment and on-treatment biopsies using scRNA-seq and constructed a detailed molecular classification of malignant and immune cells. We annotated five biliary tract cancer malignant cell states: classical, basal, mesenchymal, neural-like, and endothelial-like. Neural-like and endothelial-like states, which drive therapeutic resistance in other cancers, have not previously been described in BTC. Malignant cell states co-varied with distinct immune cell states, revealing diverse mechanisms of myeloid and T-cell mediated immune suppression, including M2 myeloid and terminally exhausted T cell programs that were induced by DKN-01/nivolumab. Here, we provide the first systematic classification of functionally annotated cell states in biliary tract cancer and provide new insight into resistance mechanisms to an immunotherapy combination that can inform the next generation of trials., Competing Interests: MP has served as a consultant for Third Rock Ventures. LP has served as a consultant for Astellas. DGD has received research funding support from Bayer, Bristol-Myers Squibb, Exelixis and Surface Oncology. NH holds equity in and advises Danger Bio/Related Sciences, is on the scientific advisory board of Repertoire Immune Medicines and CytoReason, owns equity in and has licensed patents to BioNTech and receives research funding from Bristol Myers Squibb and Calico Life Sciences. DTT has received consulting fees from ROME Therapeutics, Sonata Therapeutics, Leica Biosystems Imaging, PanTher Therapeutics, and abrdn. DTT is a founder and has equity in ROME Therapeutics, PanTher Therapeutics and TellBio, Inc., which is not related to this work. DTT is on the advisory board with equity for ImproveBio, Inc. DTT has received honorariums from Astellas, AstraZeneca, Moderna, and Ikena Oncology that are not related to this work. DTT receives research support from ACD-Biotechne, AVA LifeScience GmbH, Incyte Pharmaceuticals, Sanofi, and Astellas which was not used in this work. DTT’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. AM has served a consultant/advisory role for Third Rock Ventures, Asher Biotherapeutics, Abata Therapeutics, ManaT Bio, Flare Therapeutics, venBio Partners, BioNTech, Rheos Medicines and Checkmate Pharmaceuticals, is currently a part-time Entrepreneur in Residence at Third Rock Ventures, is an equity holder in ManaT Bio, Asher Biotherapeutics and Abata Therapeutics, and has received research funding support from Bristol-Myers Squibb. AM’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. All other authors have nothing to disclose.

Objective: The aim of this study was to evaluate the incidence of radiotherapy (RT)-related lymphopenia, its predictors, and association with survival in unresectable intrahepatic cholangiocarcinoma (ICC) treated with hypofractionated-RT (HF-RT)., Methods: Retrospective analysis of 96 patients with unresectable ICC who underwent HF-RT (median 58.05 Gy in 15 fractions) between 2009 and 2022 was performed. Absolute lymphocyte count (ALC) nadir within 12 weeks of RT was analyzed. Primary variable of interest was severe lymphopenia, defined as Grade 3+ (ALC <0.5 k/μL) per CTCAE v5.0. Primary outcome of interest was overall survival (OS) from RT., Results: Median follow-up was 16 months. Fifty-two percent of patients had chemotherapy pre-RT, 23% during RT, and 40% post-RT. Pre-RT, median ALC was 1.1 k/μL and 5% had severe lymphopenia. Post-RT, 68% developed RT-related severe lymphopenia. Patients who developed severe lymphopenia had a significantly lower pre-RT ALC (median 1.1 vs. 1.5 k/μL, P =0.01) and larger target tumor volume (median 125 vs. 62 cm 3 , P =0.02). In our multivariable Cox model, severe lymphopenia was associated with a 1.7-fold increased risk of death ( P =0.04); 1-year OS rates were 63% vs 77% ( P =0.03). Receipt of photon versus proton-based RT (OR=3.50, P =0.02), higher mean liver dose (OR=1.19, P <0.01), and longer RT duration (OR=1.49, P =0.02) predicted severe lymphopenia., Conclusions: HF-RT-related lymphopenia is an independent prognostic factor for survival in patients with unresectable ICC. Patients with lower baseline ALC and larger tumor volume may be at increased risk, and use of proton therapy, minimizing mean liver dose, and avoiding treatment breaks may reduce RT-related lymphopenia., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To evaluate the safety and efficacy of neoadjuvant therapy (NAT), followed by surgical resection in patients with pancreatic ductal adenocarcinoma (PDAC) aged ≥75 years., Background: Whether administration of NAT, followed by surgical resection in elderly patients with PDAC is safe and effective is unknown., Methods: The present study is a three-part comparison of older (≥75 years) versus younger (<75 years) patients in different settings throughout the continuum of PDAC care. The first analysis was a comparison of older versus younger consecutive patients with nonmetastatic PDAC who were initiated on FOLFIRINOX. The second was a comparison of older versus younger patients who underwent NAT, followed by surgical resection, and the third and final analysis was a comparison of older patients who underwent either NAT, followed by surgical resection versus upfront surgical resection. Postoperative complications, overall survival (OS), and time to recurrence (TTR) were compared. Propensity score matching (PSM) analysis was performed to adjust for potential confounders., Results: In the first analysis, a lower proportion of older patients (n = 40) were able to complete the intended neoadjuvant FOLFIRINOX (8) cycles compared with younger patients (n = 214; 65.0% vs 81.4%, P = 0.021). However, older patients were just as likely to undergo surgical exploration as younger patients (77.5% vs 78.5%, P = 0.89), as well as surgical resection (57.5% vs 55.6%, P = 0.70). In the second analysis, PSM was conducted to compare older (n = 54) versus younger patients (n = 54) who underwent NAT, followed by surgical resection. There were no significant differences in postoperative complications between the matched groups. While there was a significant difference in OS between older and younger patients (median OS: 16.43 vs 30.83 months, P = 0.002), importantly, there was no significant difference in TTR (median: 7.65 vs 11.83 months, P = 0.215). In the third analysis, older patients who underwent NAT, followed by surgical resection (n = 48) were compared with similar older patients who underwent upfront surgical resection (n = 48). After PSM, there was a significant difference in OS (median OS: 15.78 months vs 11.51 months, P = 0.037), as well as TTR (median TTR: 8.81 vs 7.10 months, P = 0.046) representing an association with improved outcomes that favored the neoadjuvant approach among older patients alone., Conclusions: This comprehensive three-part study showed that administration of NAT, followed by surgical resection, seems to be safe and effective among patients ≥75 years of age. An aggressive approach should be offered to older adults undergoing multimodal treatment of PDAC., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Portal vein and superior mesenteric vein thrombosis (PVT/SMVT) are potentially morbid complications of radiation dose-escalated local therapy for pancreatic cancer. We retrospectively reviewed records for patients treated with and without intraoperative radiation (IORT) to identify risk factors for PVT/SMVT., Methods: Ninety-six patients with locally advanced or borderline resectable pancreatic adenocarcinoma received neoadjuvant therapy followed by surgical exploration from 2009 to 2014. Patients at risk for close or positive surgical margins received IORT boost to a biologically effective dose (BED10) > 100. Prognostic factors for PVT/SMVT were evaluated using competing risks regression., Results: Median follow-up was 79 months for surviving patients. Fifty-six patients (58%) received IORT. Twenty-nine patients (30%) developed PVT/SMVT at a median time of 18 months. On univariate competing risks regression, operative blood loss and venous repair with a vascular interposition graft, but not IORT dose escalation or diabetes history, were significantly associated with PVT/SMVT. The development of thrombosis in the absence of recurrence was significantly associated with a longstanding diabetes history, post-neoadjuvant treatment CA19-9, and operative blood loss. All 4 patients who underwent both IORT and vascular repair with a graft developed PVT/SMVT. PVT/SMVT in the absence of recurrence is not associated with significantly worsened overall survival but led to frequent medical interventions., Conclusions: Approximately 30% of patients who underwent neoadjuvant chemoradiation for PDAC developed PVT/SMVT a median of 18 months following surgery. This was significantly associated with venous reconstruction with vascular grafts, but not with escalating radiation dose. PVT/SMVT in the absence of recurrence was associated with significant morbidity., (© 2023. The Society for Surgery of the Alimentary Tract.)

Background: FOLFIRINOX is increasingly used in the management of pancreatic ductal adenocarcinoma (PDAC). However, neoadjuvant therapy is associated with toxicity, possible disease progression, and biopsy-related and biliary complications that may preclude operative exploration. Data on the true attrition rate outside of clinical trials or resected surgical series are lacking., Study Design: Patients with nonmetastatic PDAC who initiated FOLFIRINOX from 2015 to 2020 were identified from our institution's pharmacy records. Multivariable regression and Cox proportional hazard models were used for adjusted analyses of categorical and survival outcomes, respectively., Results: Of 254 patients who initiated first-line neoadjuvant FOLFIRINOX, 199 (78.3%) underwent exploration, and 54 (21.3%) did not complete their chemotherapy cycles due to poor tolerability (46.3%), poor response (31.5%), or disease progression (14.8%), among other causes (7.4%). A total of 109 (42.9%) patients experienced grade 3/4 FOLFIRINOX-related toxicity, of whom 73 (28.7%) and 100 (39.4%) required an emergency department visit or inpatient admission, respectively. Finally, not undergoing surgical exploration was associated with impaired overall survival (hazard ratio 7.0; 95% CI 3.8 to 12.8; p < 0.001). Independent predictors of not undergoing exploration were remote history of chemotherapy receipt (odds ratio [OR] 0.06; p = 0.02), inability to complete FOLFIRINOX cycles (OR 0.2, p = 0.003), increase in ECOG score (OR 0.2, p < 0.001), and being single or divorced (OR 0.3, p = 0.018)., Conclusions: Among 254 patients with nonmetastatic PDAC initiated on FOLFIRINOX, of whom 52% were locally advanced, a total of 199 (78.3%) were explored, 142 (71.4%) underwent successful resection, and 129 (90.8%) were resected with negative margins. Despite 109 (42.9)% of patients experiencing significant toxicity, most patients could be managed through treatment-related complications to complete planned neoadjuvant chemotherapy and undergo planned surgical exploration., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To identify disparities in access to NAT for PDAC at the prehospital and intrahospital phases of care., Summary of Background Data: Delivery of NAT in PDAC is susceptible to disparities in access. There are limited data that accurately locate the etiology of disparities at the prehospital and intrahospital phases of care., Methods: Retrospective cohort of patients ≥18 years old with clinical stage I-II PDAC from the 2010-2016 National Cancer Database. Multiple logistic regression was used to assess 2 sequential outcomes: (1) access to an NAT facility (prehospital phase) and (2) receipt of NAT at an NAT facility (intrahospital phase)., Results: A total of 36,208 patients were included for analysis in the prehospital phase of care. Higher education, longer travel distances, being treated at academic/research or integrated network cancer programs, and more recent year of diagnosis were independently associated with receipt of treatment at an NAT facility. All patients treated at NAT facilities (31,099) were included for the second analysis. Higher education level and receiving care at an academic/research facility were independently associated with increased receipt of NAT. NonBlack racial minorities (including American Indian, Asian, Pacific Islanders), being Hispanic, being uninsured, and having Medicaid insurance were associated with decreased receipt of NAT at NAT facilities., Conclusions: Non-Black racial minorities and Hispanic patients were less likely to receive NAT at NAT facilities compared to White and non-Hispanic patients, respectively. Discrepancies in administration of NAT while being treated at NAT facilities exist and warrant urgent further investigation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To compare positron emission tomography (PET)/magnetic resonance imaging (MRI) to the standard of care imaging (SCI) for the diagnosis of peritoneal carcinomatosis (PC) in primary abdominopelvic malignancies., Summary Background Data: Identifying PC impacts prognosis and management of multiple cancer types., Methods: Adult subjects were prospectively and consecutively enrolled from April 2019 to January 2021. Inclusion criteria were: 1) acquisition of whole-body contrast-enhanced (CE) 18F-fluorodeoxyglucose PET/MRI, 2) pathologically confirmed primary abdominopelvic malignancies. Exclusion criteria were: 1) greater than 4 weeks interval between SCI and PET/MRI, 2) unavailable follow-up. SCI consisted of whole-body CE PET/computed tomography (CT) with diagnostic quality CT, and/or CE-CT of the abdomen and pelvis, and/or CE-MRI of the abdomen±pelvis. If available, pathology or surgical findings served as the reference standard, otherwise, imaging followup was used. When SCI and PET/MRI results disagreed, medical records were checked for management changes. Follow-up data were collected until August 2021., Results: One hundred sixty-four subjects were included, 85 (52%) were female, and the median age was 60 years (interquartile range 50-69). At a subject level, PET/MRI had higher sensitivity (0.97, 95% CI 0.86-1.00) than SCI (0.54, 95% CI 0.37-0.71), P < 0.001, without a difference in specificity, of 0.95 (95% CI 0.90-0.98) for PET/MRI and 0.98 (95% CI 0.93-1.00) for SCI, P ¼ 0.250. PET/MRI and SCI results disagreed in 19 cases. In 5/19 (26%) of the discordant cases, PET/MRI findings consistent with PC missed on SCI led to management changes., Conclusion: PET/MRI improves detection of PC compared with SCI which frequently changes management., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: A multimodal approach of surgery and chemotherapy, with or without radiation, is the mainstay of therapy with curative-intent for resectable pancreatic ductal adenocarcinoma (PDAC). This study compared utilization trends and outcomes of upfront surgery with and without adjuvant therapy., Methods: The National Cancer Database was queried for patients with a diagnosis of stage 1 or 2 PDAC who underwent upfront resection. Multivariable regression was applied to identify factors associated with initiation of adjuvant therapy., Results: Of the 39,128 patients in the study, 67% initiated adjuvant therapy after resection, whereas 33% received upfront surgery alone. Receipt of adjuvant multimodal therapy increased from 59% in 2006 to 69% in 2017 (P < 0.0001). Non-white race was associated with lower odds of receiving adjuvant therapy after adjustment for income status, education attainment, and other variables (Hispanic/Spanish [odds ratio {OR}, 0.77; 95% confidence interval {CI}, 0.69-0.86] and non-Hispanic black [OR 0.84; 95% CI 0.78-0.91 vs non-Hispanic white; P < 0.001). The variables that contributed to receipt of adjuvant therapy were place of residence in high versus low education attainment area (OR 1.30; 95% CI 1.18-1.44; P < 0.0001) and lower odds for initiation of adjuvant therapy with increasing distance from the treating facility (> 50 miles [OR 0.51; 95% CI 0.47-0.54] vs <12.5 miles; P < 0.0001). The median unadjusted overall survival (OS) time was 18.2 months (95% CI 17.7-18.8 months) for upfront surgery alone and 25.3 months (95% CI 24.9-25.8 months) for surgery with adjuvant therapy., Conclusions: The patients who underwent upfront surgical resection for PDAC showed wide socioeconomic disparities in the use of adjuvant therapy independent of insurance status, facility type, or travel distance., (© 2022. Society of Surgical Oncology.)

Background: After neoadjuvant therapy, pathologic analysis of rectal cancer resected specimens may show a complete response in the primary tissue cancer with residual tumor in the lymph nodes (ypT0N+)., Objectives: The aim of this study was to describe the 5-year overall survival and factors associated with survival of ypT0N+ patients with rectal cancer who had neoadjuvant therapy followed by surgery and to compare these patients' survival with patients in other pathologic categories., Design: We conducted a retrospective analysis., Settings: We used the National Cancer Database., Patients: We identified patients with rectal adenocarcinoma who underwent total neoadjuvant therapy or neoadjuvant chemoradiation followed by surgery between 2006 and 2016. Besides ypT0N+, 5 pathologic categories were identified: ypT0N0, ypT1-2N0, ypT3-4N0, ypT1-2N+, and ypT3-4N+., Main Outcome Measure: The primary outcome measure was 5-year overall survival., Results: We included 30,751 patients with rectal adenocarcinoma. A total of 342 patients developed ypT0N+, of whom 181 (52.9%) received total neoadjuvant therapy. Among patients who received total neoadjuvant therapy, developing ypT0N+ was associated with a lower 5-year overall survival than ypT0N0 and ypT1-2N0. However, ypT0N+ disease was associated with a higher 5-year overall survival than ypT3-4N+. There were no differences in 5-year overall survival between ypT0N+ and ypT3-4N0 or ypT1-2N+. Similar findings were noticed among patients who received neoadjuvant chemoradiation and adjuvant chemotherapy. For patients with ypT0N+, older age, male gender, and higher number of positive lymph nodes were all associated with a decrease in the overall survival., Limitations: Limitations include the retrospective nature of this study, lack of variables describing the chemotherapy and radiation regimens used, and paucity of data on disease-specific survival or recurrence., Conclusions: Developing ypT0N+ was associated with a lower 5-year overall survival than ypT0N0 and ypT1-2N0. However, it was associated with a higher 5-year overall survival than ypT3-4N+. See Video Abstract at http://links.lww.com/DCR/B863 ., Sobrevida De Los Pacientes Con Yptn Despus De La Terapia Neoadyuvante En El Cncer De Recto: ANTECEDENTES:Después del tratamiento neoadyuvante en el cáncer de recto bajo, el análisis patológico de la pieza operatoria resecada, puede mostrar una respuesta patológica completa del tumor primario pero con tumor residual en los ganglios linfáticos (ypT0N+).OBJETIVOS:Describir la sobrevida general a 5 años y los factores asociados con la sobrevida de los pacientes ypT0N+ con cáncer de recto, que recibieron terapia neoadyuvante seguida de cirugía y comparar la sobrevida de estos pacientes con la de pacientes con otros estadios patológicos.DISEÑO:Realizamos un análisis retrospectivo.AJUSTES:Utilizamos la base de datos nacional del cáncer.PACIENTES:Identificamos pacientes con adenocarcinoma de recto que se sometieron a terapia neoadyuvante total, seguida de cirugía entre 2006 y 2016. Además de ypT0N +, se identificaron 5 categorías patológicas: ypT0N0, ypT1-2N0, ypT3-4N0, ypT1-2N+, e ypT3-4N+.PRINCIPAL MEDIDA DE RESULTADO:La medida de resultado principal fue la supervivencia general a 5 años.RESULTADOS:Se incluyeron 30.751 pacientes con adenocarcinoma de recto. Un total de 342 pacientes desarrollaron ypT0N+, de los cuales 181 (52,9%) recibieron terapia neoadyuvante total. Entre los pacientes que recibieron terapia neoadyuvante total, el desarrollo de ypT0N+ se asoció con una supervivencia general a 5 años más baja que ypT0N0 e ypT1-2N0. Sin embargo, la enfermedad ypT0N+ se asoció con una supervivencia general a 5 años más alta que ypT3-4N+. No hubo diferencias en la supervivencia global a 5 años entre ypT0N+ y ypT3-4N0 o ypT1-2N+. Se observaron hallazgos similares entre los pacientes que recibieron terapia neoadyuvante y quimioterapia adyuvante. Para los pacientes con ypT0N+, la edad avanzada, el sexo masculino y un mayor número de ganglios linfáticos positivos se asociaron con una disminución en la supervivencia general.LIMITACIONES:Las limitaciones incluyen la naturaleza retrospectiva del estudio, la falta de variables que describan los regímenes de quimioterapia y radiación utilizados y la escasez de datos sobre la supervivencia o la recurrencia específicas de la enfermedad.CONCLUSIONES:El desarrollo de ypT0N+ se asoció con una supervivencia general a 5 años más baja que ypT0N0 e ypT1-2N0. Sin embargo, se asoció con una supervivencia global a 5 años más alta que ypT3-4N+. Consulte Video Resumen en http://links.lww.com/DCR/B863 . (Traducción-Dr. Rodrigo Azolas )., (Copyright © The ASCRS 2021.)

Altered RNA expression of repetitive sequences and retrotransposition are frequently seen in colorectal cancer, implicating a functional importance of repeat activity in cancer progression. We show the nucleoside reverse transcriptase inhibitor 3TC targets activities of these repeat elements in colorectal cancer preclinical models with a preferential effect in p53-mutant cell lines linked with direct binding of p53 to repeat elements. We translate these findings to a human phase II trial of single-agent 3TC treatment in metastatic colorectal cancer with demonstration of clinical benefit in 9 of 32 patients. Analysis of 3TC effects on colorectal cancer tumorspheres demonstrates accumulation of immunogenic RNA:DNA hybrids linked with induction of interferon response genes and DNA damage response. Epigenetic and DNA-damaging agents induce repeat RNAs and have enhanced cytotoxicity with 3TC. These findings identify a vulnerability in colorectal cancer by targeting the viral mimicry of repeat elements., Significance: Colorectal cancers express abundant repeat elements that have a viral-like life cycle that can be therapeutically targeted with nucleoside reverse transcriptase inhibitors (NRTI) commonly used for viral diseases. NRTIs induce DNA damage and interferon response that provide a new anticancer therapeutic strategy. This article is highlighted in the In This Issue feature, p. 1397., (©2022 American Association for Cancer Research.)

Background: Coronary vasospasm is a known side effect of 5-FU (fluorouracil) therapy. Beyond switching to non-5FU-based chemotherapy, there are no established treatments for 5-FU associated coronary vasospam. Our objective was to assess the safety and efficacy of re-challenge with 5-FU after pre-treatment with calcium channel blockers (CCBs) and long-acting nitrates among patients 5-FU associated coronary vasospasm., Methods: We conducted a retrospective study of patients with 5-FU coronary vasospasm at a single academic center. By protocol, those referred to cardio-oncology received pre-treatment with either combination [nitrates and CCBs] or single-agent therapy [nitrates or CCBs]) prior to re-challenge with 5-FU. Our primary outcome was overall survival. Other important outcomes included progression-free survival and safety., Results: Among 6,606 patients who received 5-FU from January 2001 to Dec 2020, 115 (1.74%) developed coronary vasospasm. Of these 115 patients, 81 patients continued 5-FU therapy, while 34 stopped. Of the 81 who continued, 78 were referred to cardio-oncology and prescribed CCBs and/or nitrates prior to subsequent 5-FU, while the remaining 3 continued 5-FU without cardiac pre-treatment. Of the 78, 56.4% (44/78) received both nitrates and CCBs, 19.2% (15/78) received CCBs alone, and 24.4% (19/78) received nitrates alone. When compared to patients who stopped 5-FU, those who continued 5-FU after pre-treatment (single or combination therapy) had a decreased risk of death (HR 0.42, P = 0.005 [95% CI 0.23-0.77]) and a trend towards decreased cancer progression (HR 0.60, P = 0.08 [95% CI 0.34-1.06]). No patient in the pre-treatment group had a myocardial infarct after re-challenge; however, chest pain (without myocardial infarction) recurred in 19.2% (15/78) among those who received cardiac pre-treatment vs. 66.7% (2/3) among those who did not (P = 0.048). There was no difference in efficacy or the recurrence of vasospasm among patients who received pre-treatment with a single agent (nitrates or CCBs) or combination therapy (14.7% (5/34) vs. 25.0% (11/44), P = 0.26)., Conclusion: Re-challenge after pre-treatment with CCBs and nitrates guided by a cardio-oncology service was safe and allowed continued 5-FU therapy., Competing Interests: TGN is supported, in part, through a kind gift from Curtis Greer and Pamela Kohlberg. TGN also reports acting as a consultant for Parexel, H3 Biomedicine, Bristol Myers-Squibb, Abbvie and Intrinsic Imaging, unrelated to the current research. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: There are individual variations in neo-adjuvant chemoradiation therapy (nCRT) in patients with locally advanced rectal cancer (LARC). No reliable modality currently exists that can predict the efficacy of nCRT. The purpose of this study is to assess if CT-based fractal dimension and filtration-histogram texture analysis can predict therapeutic response to nCRT in patients with LARC., Methods: In this retrospective study, 215 patients (average age: 57 years (18-87 years)) who received nCRT for LARC between June 2005 and December 2016 and underwent a staging diagnostic portal venous phase CT were identified. The patients were randomly divided into two datasets: a training set (n = 170), and a validation set (n = 45). Tumor heterogeneity was assessed on the CT images using fractal dimension (FD) and filtration-histogram texture analysis. In the training set, the patients with pCR and non-pCR were compared in univariate analysis. Logistic regression analysis was applied to identify the predictive value of efficacy of nCRT and receiver operating characteristic analysis determined optimal cutoff value. Subsequently, the most significant parameter was assessed in the validation set., Results: Out of the 215 patients evaluated, pCR was reached in 20.9% (n = 45/215) patients. In the training set, 7 out of 37 texture parameters showed significant difference comparing between the pCR and non-pCR groups and logistic multivariable regression analysis incorporating clinical and 7 texture parameters showed that only FD was associated with pCR (p = 0.001). The area under the curve of FD was 0.76. In the validation set, we applied FD for predicting pCR and sensitivity, specificity, and accuracy were 60%, 89%, and 82%, respectively., Conclusion: FD on pretreatment CT is a promising parameter for predicting pCR to nCRT in patients with LARC and could be used to help make treatment decisions., Key Points: • Fractal dimension analysis on pretreatment CT was associated with response to neo-adjuvant chemoradiation in patients with locally advanced rectal cancer. • Fractal dimension is a promising biomarker for predicting pCR to nCRT and may potentially select patients for individualized therapy., (© 2021. European Society of Radiology.)

Purpose: Colorectal cancer (CRC) incidence in patients younger than 50 years of age, commonly defined as early-onset (EO-CRC), is rising. EO-CRC often presents with distinct clinicopathologic features. However, data on prognosis are conflicting and outcomes with modern treatment approaches for metastatic disease are still limited., Materials and Methods: We prospectively enrolled patients with metastatic CRC (mCRC) to a biobanking and clinical data collection protocol from 2014 to 2018. We grouped the cohort based on age at initial diagnosis: < 40 years, 40-49 years, and ≥ 50 years. We used regression models to examine associations among age at initial diagnosis, treatments, clinicopathologic features, and survival., Results: We identified 466 patients with mCRC (45 [10%] age < 40 years, 109 [23%] age 40-49 years, and 312 [67%] age ≥ 50 years). Patients < 40 years of age were more likely to have received multiple metastatic resections (odds ratio [OR], 3.533; P = .0066) than their older counterparts. Patients with EO-CRC were more likely to receive triplet therapy than patients > 50 years of age (age < 40 years: OR, 6.738; P = .0002; age 40-49 years: OR, 2.949; P = .0166). Patients 40-49 years of age were more likely to have received anti-EGFR therapy (OR, 2.633; P = .0016). Despite differences in care patterns, age did not predict overall survival., Conclusion: Despite patients with EO-CRC receiving more intensive treatments, survival was similar to the older counterpart. However, EO-CRC had clinical and molecular features associated with worse prognoses. Improved biologic understanding is needed to optimize clinical management of EO-CRC. The cost-benefit ratio of exposing patients with EO-CRC to more intensive treatments has to be carefully evaluated., Competing Interests: Nora K. HorickEmployment: Northwest BiotherapeuticsStock and Other Ownership Interests: Northwest BiotherapeuticsPatents, Royalties, Other Intellectual Property: An immediate family member holds patents, has patents pending, and receives royalties from a technology relating to health or medicine Lawrence S. BlaszkowskyStock and Other Ownership Interests: Pfizer Jeffrey W. ClarkResearch Funding: Pfizer David P. RyanStock and Other Ownership Interests: MPM Capital, Acworth Pharmaceuticals, Thrive Earlier Detection Corp, Exact SciencesHonoraria: UpToDate, Research to PracticeConsulting or Advisory Role: MPM Capital, Oncorus, Gritstone Oncology, Maverick Therapeutics, TCR2 Therapeutics, Twentyeight-Seven TherapeuticsResearch Funding: Stand Up To CancerPatents, Royalties, Other Intellectual Property: McGraw Hill Chapter Royalties, Johns Hopkins University PressExpert Testimony: Boehringer IngelheimOther Relationship: TCR2 Therapeutics Lipika GoyalConsulting or Advisory Role: Debiopharm Group, Alentis Therapeutics, QED Therapeutics, H3 Biomedicine, AstraZeneca, Klus Pharma, Agios, Taiho Pharmaceutical, Incyte, Sirtex Medical, Genentech, ExelixisUncompensated Relationships: Agios, Debiopharm Group, Taiho Pharmaceutical, Merck Joseph FransesStock and Other Ownership Interests: Merck, BiogenConsulting or Advisory Role: Foundation MedicineResearch Funding: Genentech/Roche Samuel J. KlempnerStock and Other Ownership Interests: TP TherapeuticsHonoraria: NateraConsulting or Advisory Role: Lilly, Boston Biomedical, Astellas Pharma, Foundation Medicine, Bristol Myers Squibb, Pieris Pharmaceuticals, Merck, Daiichi Sankyo/UCB JapanSpeakers' Bureau: Foundation MedicineResearch Funding: Leap Therapeutics, BeiGeneOther Relationship: NCCN Eric J. RoelandConsulting or Advisory Role: Napo Pharmaceuticals, AIM Specialty Health, Oragenics, BASF, Vector Oncology, Asahi Kasei, Heron, Pfizer/EMD Serono, Astellas Pharma, Helsinn TherapeuticsExpert Testimony: Regents of the University of California Colin D. WeekesHonoraria: Celgene, Merrimack, Lilly, BayerConsulting or Advisory Role: Celgene, Merrimack, IpsenResearch Funding: Millennium, Celgene, Bayer, Genentech/Roche, AbbVie, Lilly, AstraZeneca, Gilead Sciences, Ipsen, HalozymeTravel, Accommodations, Expenses: Lilly, Celgene, Bayer Theodore S. HongConsulting or Advisory Role: Merck, Synthetic Biologics, Novocure, SyndaxResearch Funding: Novartis, Taiho Pharmaceutical, AstraZeneca, IntraOp, Tesaro, Bristol Myers Squibb, Ipsen Emily E. Van SeventerEmployment: Blueprint MedicinesStock and Other Ownership Interests: Blueprint Medicines Ryan B. CorcoranStock and Other Ownership Interests: Avidity Biosciences, nRichDx, Fount Therapeutics, C4 Therapeutics, Revolution Medicines, Kinnate Biopharma, Remix Therapeutics, Erasca IncConsulting or Advisory Role: Avidity Nanomedicines, Taiho Pharmaceutical, Merrimack, Genentech, N-of-One, Astex Pharmaceuticals, Amgen, Bristol Myers Squibb, Roche, Shire, FOGPharma, Loxo, Roivant, Warp Drive Bio, Spectrum Pharmaceuticals, Symphogen, Array BioPharma, Chugai Pharma, nRichDx, Fount Therapeutics, Novartis, Shionogi, Elicio Therapeutics, C4 Therapeutics, Revolution Medicines, Zikani Therapeutics, Natera, Kinnate Biopharma, Ipsen, AbbVie, Asana Biosciences, Remix TherapeuticsResearch Funding: AstraZeneca, Sanofi, Asana Biosciences, Lilly Aparna R. ParikhConsulting or Advisory Role: PureTech, Foundation Medicine, Lilly, NateraResearch Funding: Plexxikon, Bristol Myers Squibb, Genentech, Guardant Health, Array BioPharma, Lilly, Novartis Pharmaceuticals UK Ltd, TesaroNo other potential conflicts of interest were reported.

Overcoming intrinsic resistance to immune checkpoint blockade for microsatellite stable (MSS) colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) remains challenging. We conducted a single-arm, non-randomized, phase II trial (NCT03104439) combining radiation, ipilimumab and nivolumab to treat patients with metastatic MSS CRC (n = 40) and PDAC (n = 25) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The primary endpoint was disease control rate (DCR) by intention to treat. DCRs were 25% for CRC (ten of 40; 95% confidence interval (CI), 13-41%) and 20% for PDAC (five of 25; 95% CI, 7-41%). In the per-protocol analysis, defined as receipt of radiation, DCR was 37% (ten of 27; 95% CI, 19-58%) in CRC and 29% (five of 17; 95% CI, 10-56%) in PDAC. Pretreatment biopsies revealed low tumor mutational burden for all samples but higher numbers of natural killer (NK) cells and expression of the HERVK repeat RNA in patients with disease control. This study provides proof of concept of combining radiation with immune checkpoint blockade in immunotherapy-resistant cancers., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: Detection of persistent circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who will ultimately recur. Most ctDNA MRD assays require tumor sequencing to identify tumor-derived mutations to facilitate ctDNA detection, requiring tumor and blood. We evaluated a plasma-only ctDNA assay integrating genomic and epigenomic cancer signatures to enable tumor-uninformed MRD detection., Experimental Design: A total of 252 prospective serial plasma specimens from 103 patients with colorectal cancer undergoing curative-intent surgery were analyzed and correlated with recurrence., Results: Of 103 patients, 84 [stage I (9.5%), II (23.8%), III (47.6%), IV (19%)] had evaluable plasma drawn after completion of definitive therapy, defined as surgery only ( n = 39) or completion of adjuvant therapy ( n = 45). In "landmark" plasma drawn 1-month (median, 31.5 days) after definitive therapy and >1 year follow-up, 15 patients had detectable ctDNA, and all 15 recurred [positive predictive value (PPV), 100%; HR, 11.28 ( P < 0.0001)]. Of 49 patients without detectable ctDNA at the landmark timepoint, 12 (24.5%) recurred. Landmark recurrence sensitivity and specificity were 55.6% and 100%. Incorporating serial longitudinal and surveillance (drawn within 4 months of recurrence) samples, sensitivity improved to 69% and 91%. Integrating epigenomic signatures increased sensitivity by 25%-36% versus genomic alterations alone. Notably, standard serum carcinoembryonic antigen levels did not predict recurrence [HR, 1.84 ( P = 0.18); PPV = 53.9%]., Conclusions: Plasma-only MRD detection demonstrated favorable sensitivity and specificity for recurrence, comparable with tumor-informed approaches. Integrating analysis of epigenomic and genomic alterations enhanced sensitivity. These findings support the potential clinical utility of plasma-only ctDNA MRD detection. See related commentary by Bent and Kopetz, p. 5449 ., (©2021 American Association for Cancer Research.)

Objective: The aim of this study was to compare the performance of positron emission tomography (PET)/magnetic resonance (MR) versus stand-alone PET and stand-alone magnetic resonance imaging (MRI) in the detection and characterization of suspected liver metastases., Materials and Methods: This multi-institutional retrospective performance study was approved by the institutional review boards and was Health Insurance Portability and Accountability Act compliant, with waiver of informed consent. Seventy-nine patients with confirmed solid extrahepatic malignancies who underwent upper abdominal PET/MR between February 2017 and June 2018 were included. Where focal hepatic lesions were identified, the likelihood of a diagnosis of a liver metastasis was defined on an ordinal scale for MRI, PET, and PET/MRI by 3 readers: 1 nuclear medicine physician and 2 radiologists. The number of lesions per patient, lesion size, and involved hepatic segments were recorded. Proof of metastases was based on histopathologic correlation or clinical/imaging follow-up. Diagnostic performance was assessed using sensitivity, specificity, positive and negative predictive values, and receiver operator characteristic curve analysis., Results: A total of 79 patients (53 years, interquartile range, 50-68; 43 men) were included. PET/MR had a sensitivity of 95%, specificity of 97%, positive predictive value of 97%, and negative predictive value of 95%. The sensitivity, specificity, positive predictive value, and negative predictive value of MRI were 88%, 98%, 98%, and 90% and for PET were 83%, 97%, 97%, and 86%, respectively. The areas under the curve for PET/MRI, MRI, and PET were 95%, 92%, and 92%, respectively., Conclusions: Contrast-enhanced PET/MR has a higher sensitivity and negative predictive value than either PET or MRI alone in the setting of suspected liver metastases. Fewer lesions were characterized as indeterminate by PET/MR in comparison with PET and MRI. This superior performance could potentially impact treatment and management decisions for patients with suspected liver metastases., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia. NETs are generally subclassified by site of origin, stage, and histologic characteristics. Appropriate diagnosis and treatment of NETs often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine and adrenal tumors and are intended to assist with clinical decision-making. This article is focused on the 2021 NCCN Guidelines principles of genetic risk assessment and counseling and recommendations for well-differentiated grade 3 NETs, poorly differentiated neuroendocrine carcinomas, adrenal tumors, pheochromocytomas, and paragangliomas.

Purpose: Imaging is central to the diagnosis and management of Pancreatic Ductal Adenocarcinoma (PDAC). This study evaluated if positron emission tomography (PET)/magnetic resonance imaging (MRI) elicited treatment modifications in PDAC when compared to standard of care imaging (SCI)., Procedures: This retrospective study included consecutive patients with PDAC who underwent 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]F-FDG) PET/MRI and SCI from May 2017 to January 2019. SCI included abdominal computed tomography (CT), MRI, and/or PET/CT. For patients who had more than one pair of PET/MRI and SCI, each management decision was independently evaluated. Treatment strategies based on each modality were extracted from electronic medical records. Follow-up was evaluated until January 2020., Results: Twenty-five patients underwent 37 PET/MRI's, mean age was 65 ± 9 years and 13 (13/25, 52 %) were men. 49 % (18/37, 95 % CI 33-64 %) of the PET/MRI scans changed clinical management. Whether the SCI included a PET/CT or not did not significantly modify the probability of management change (OR = 0.9, 95 % CI 0.2-4, p = 1). One hundred percent (33/33) of the available follow-up data confirmed PET/MRI findings., Conclusions: PET/MRI significantly changed PDAC management, consistently across the different SCI modalities it was compared to. These findings suggest a role for PET/MRI in the management of PDAC.

Purpose: The role of positron emission tomography/magnetic resonance (PET/MR) in evaluating the local extent of rectal cancer remains uncertain. This study aimed to investigate the possible role of PET/MR versus magnetic resonance (MR) in clinically staging rectal cancer., Methods: This retrospective two-center cohort study of 62 patients with untreated rectal cancer investigated the possible role of baseline staging PET/MR versus stand-alone MR in determination of clinical stage. Two readers reviewed T and N stage, mesorectal fascia involvement, tumor length, distance from the anal verge, sphincter involvement, and extramural vascular invasion (EMVI). Sigmoidoscopy, digital rectal examination, and follow-up imaging, along with surgery when available, served as the reference standard., Results: PET/MR outperformed MR in evaluating tumor size (42.5 ± 21.03 mm per the reference standard, 54 ± 20.45 mm by stand-alone MR, and 44 ± 20 mm by PET/MR, P = 0.004), and in identifying N status (correct by MR in 36/62 patients [58%] and by PET/MR in 49/62 cases [79%]; P = 0.02) and external sphincter infiltration (correct by MR in 6/10 and by PET/MR in 9/10; P = 0.003). No statistically significant differences were observed in relation to any other features., Conclusion: PET/MR provides a more precise assessment of the local extent of rectal cancers in evaluating cancer length, N status, and external sphincter involvement. PET/MR offers the opportunity to improve clinical decision-making, especially when evaluating low rectal tumors with possible external sphincter involvement.

Purpose: This study was designed to assess the ability of perioperative circulating tumor DNA (ctDNA) to predict surgical outcome and recurrence following neoadjuvant chemoradiation for locally advanced rectal cancer (LARC)., Materials and Methods: Twenty-nine patients with newly diagnosed LARC treated between January 2014 and February 2018 were enrolled. Patients received long-course neoadjuvant chemoradiation prior to surgery. Plasma ctDNA was collected at baseline, preoperatively, and postoperatively. Next-generation sequencing was used to identify mutations in the primary tumor, and mutation-specific droplet digital polymerase chain reaction was used to assess mutation fraction in ctDNA., Results: The median age was 54 years. The overall margin-negative, node-negative resection rate was 73% and was significantly higher among patients with undetectable preoperative ctDNA (n = 17, 88%) versus patients with detectable preoperative ctDNA (n = 9, 44%; P = .028). Undetectable ctDNA was also associated with more favorable neoadjuvant rectal scores (univariate linear regression, P = .029). Recurrence-free survival (RFS) was calculated for the subset (n = 19) who both underwent surgery and had postoperative ctDNA available. At a median follow-up of 20 months, patients with detectable postoperative ctDNA experienced poorer RFS (hazard ratio, 11.56; P = .007). All patients (4 of 4) with detectable postoperative ctDNA recurred (positive predictive value = 100%), whereas only 2 of 15 patients with undetectable ctDNA recurred (negative predictive value = 87%)., Conclusion: Among patients treated with neoadjuvant chemoradiation for LARC, patients with undetectable preoperative ctDNA were more likely to have a favorable surgical outcome as measured by the rate of margin-negative, node-negative resections and neoadjuvant rectal score. Furthermore, we have confirmed prior reports indicating that detectable postoperative ctDNA is associated with worse RFS. Future prospective study is needed to assess the potential for ctDNA to assist with personalizing treatment for LARC., (© 2021 by American Society of Clinical Oncology.)

Background: We aimed to identify factors associated with refusal of surgery among patients with colon cancer., Methods: This 2004-2016 NCDB retrospective study identified AJCC stage I-III colon cancer patients who were recommended surgery. Multivariable logistic regression defined adjusted odds ratios of refusing treatment, with sociodemographic and clinical covariates. Treatment propensity-adjusted Cox proportional hazard ratios defined differential survival stratified by clinical stage, controlling for potential confounders., Results: Of 170,594 patients recommended surgery, 1116 refused. Increased rates of surgery refusal were associated with older age, African American race, CDCC>3, and female sex. Decreased rates of surgery refusal were associated with higher income and private insurance. Stratifying by stage, refusal rates among African Americans remained disparately high. Refusal of surgery was associated with worse overall survival., Conclusions: Disparate rates of refusal of surgery for resectable colon cancer by race and other sociodemographic factors highlight potential treatment adherence reinforcement beneficiaries, necessitating further study of shared decision-making., Competing Interests: Declaration of competing interest The authors have no relevant conflicts of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Although treatment-related lymphopenia (TRL) is common and associated with poorer survival in multiple solid malignancies, few data exist for anal cancer. We evaluated TRL and its association with survival in patients with anal cancer treated with chemoradiation (CRT)., Materials and Methods: A retrospective analysis of 140 patients with nonmetastatic anal squamous cell carcinoma (SCC) treated with definitive CRT was performed. Total lymphocyte counts (TLC) at baseline and monthly intervals up to 12 months after initiating CRT were analyzed. Multivariable Cox regression analysis was performed to evaluate the association between overall survival (OS) and TRL, dichotomized by grade (G)4 TRL (<0.2k/μL) 2 months after initiating CRT. Kaplan-Meier and log-rank tests were used to compare OS between patients with versus without G4 TRL., Results: Median time of follow-up was 55 months. Prior to CRT, 95% of patients had a normal TLC (>1k/μL). Two months after initiating CRT, there was a median of 71% reduction in TLC from baseline and 84% of patients had TRL: 11% G1, 31% G2, 34% G3, and 8% G4. On multivariable Cox model, G4 TRL at two months was associated with a 3.7-fold increased risk of death. On log-rank test, the 5-year OS rate was 32% in the cohort with G4 TRL versus 86% in the cohort without G4 TRL., Conclusion: TRL is common and may be another prognostic marker of OS in anal cancer patients treated with CRT. The association between TRL and OS suggests an important role of the host immunity in anal cancer outcomes., Implications for Practice: This is the first detailed report demonstrating that standard chemoradiation (CRT) commonly results in treatment-related lymphopenia (TRL), which may be associated with a poorer overall survival (OS) in patients with anal squamous cell carcinoma. The association between TRL and worse OS observed in this study supports the importance of host immunity in survival among patients with anal cancer. These findings encourage larger, prospective studies to further investigate TRL, its predictors, and its relationship with survival outcomes. Furthermore, the results of this study support ongoing efforts of clinical trials to investigate the potential role of immunotherapy in anal cancer., (© 2020 AlphaMed Press.)

Background: Metastatic esophagogastric cancers (EGCs) have a poor prognosis with an approximately 5% 5-year survival. Additional treatment approaches are needed. c-MET gene-amplified tumors are an uncommon but potentially targetable subset of EGC. Clinical characteristics and outcomes were evaluated in patients with MET-amplified EGC and compared with those without MET amplification to facilitate identification of these patients and possible treatment approaches., Patients and Methods: Patients with locally advanced or metastatic MET-amplified EGC at Massachusetts General Hospital (MGH) were identified using fluorescent in situ hybridization analysis, with a gene-to-control ratio of ≥2.2 defined as positive. Non-MET-amplified patients identified during the same time period who had undergone tumor genotyping and treatment at MGH were evaluated as a comparison group., Results: We identified 233 patients evaluated for MET amplification from 2002 to 2019. MET amplification was seen in 28 (12%) patients versus 205 (88%) patients without amplification. Most MET-amplified tumors occurred in either the distal esophagus (n = 9; 32%) or gastroesophageal junction (n = 10; 36%). Of MET-amplified patients, 16 (57%) had a TP53 mutation, 5(18%) had HER2 co-amplification, 2 (7.0%) had EGFR co-amplification, and 1 (3.5%) had FGFR2 co-amplification. MET-amplified tumors more frequently had poorly differentiated histology (19/28, 68.0% vs. 66/205, 32%; p = .02). Progression-free survival to initial treatment was substantially shorter for all MET-amplified patients (5.6 vs. 8.8 months, p = .026) and for those with metastatic disease at presentation (4.0 vs. 7.6 months, p = .01). Overall, patients with MET amplification had shorter overall survival (19.3 vs. 24.6 months, p = .049). No difference in survival was seen between low MET-amplified tumors (≥2.2 and <25 MET copy number) compared with highly amplified tumors (≥25 MET copy number)., Conclusion: MET-amplified EGC represents a distinct clinical entity characterized by rapid progression and short survival. Ideally, the identification of these patients will provide opportunities to participate in clinical trials in an attempt to improve outcomes., Implications for Practice: This article describes 233 patients who received MET amplification testing and reports (a) a positivity rate of 12%, similar to the rate of HER2 positivity in this data set; (b) the clinical characteristics of poorly differentiated tumors and nodal metastases; and (c) markedly shorter progression-free survival and overall survival in MET-amplified tumors. Favorable outcomes are reported for patients treated with MET inhibitors. Given the lack of published data in MET-amplified esophagogastric cancers and the urgent clinical importance of identifying patients with MET amplification for MET-directed therapy, this large series is a valuable addition to the literature and will have an impact on future practice., (© AlphaMed Press 2020.)

Objective: We hypothesized that differences in resection rates of colorectal liver metastases exist based on socioeconomic status (SES) inequalities., Methods: The NCDB was utilized to study patients of different median household income diagnosed with colon adenocarcinoma from 2010 to 2015., Results: A total of 21,258 patients met inclusion criteria, of whom 3,587 (16.9%) underwent metastasectomy. Patients of the highest income quartile were more likely to undergo metastasectomy compared to the lowest quartile (OR 1.20, CI 1.07-1.37, p = 0.003). Overall, patients in the highest income quartile had a median OS of 17.1 months compared with 13.0 months for the lowest quartile (HR 0.85, CI 0.81-0.90, p < 0.001). While metastasectomy was associated with improved OS across all groups, the disparity by income quartile widened (29.2 vs. 22.0 months, respectively; HR 0.51, CI 0.49-0.54, p < 0.001)., Conclusion: Higher income patients were more likely to undergo metastasectomy compared with lower income patients and were associated with longer OS., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: While the ACOSOG and ALaCaRT trials found that laparoscopic resections for rectal cancer failed to demonstrate non-inferiority of pathologic outcomes when compared with open resections, the COLOR II and COREAN studies demonstrated non-inferiority of clinical outcomes, leading to uncertainty regarding the value of minimally invasive (MIS) techniques in rectal cancer surgery. We analyzed differences in pathologic and clinical outcomes between open versus MIS resections for rectal cancer., Methods: We identified patients who underwent resection for stage II or III rectal adenocarcinoma from the National Cancer Database (2010-2015). Surgical approach was categorized as open or MIS (laparoscopic or robotic). Logistic regression and Cox proportional hazard analysis were used to assess differences in outcomes and survival. Analysis was performed in an intention-to-treat fashion., Results: A total of 31,190 patients who underwent rectal adenocarcinoma resection were identified, of whom 52.8% underwent open resection and 47.2% underwent MIS resection (31.0% laparoscopic, 16.2% robotic). After adjustment for patient, tumor, and institutional characteristics, MIS approaches were associated with significantly decreased risk of positive circumferential resection margins (OR 0.82, 95% CI 0.72-0.94), increased likelihood of harvesting ≥ 12 lymph nodes (OR 1.12, 95% CI 1.04-1.21), shorter length of stay (OR 0.57, 95% CI 0.53-0.62), and improved overall survival (HR 0.90, 95% CI 0.83-0.98)., Conclusions: MIS approaches to rectal cancer resection were associated with improved pathologic and clinical outcomes when compared to the open approach. In this nationwide, facility-based sample of cancer cases in the United States, our data suggest superiority of MIS techniques for rectal cancer treatment.

Objectives: Single-institution studies have shown improved outcomes among patients with a pathologic complete response (pCR) following neoadjuvant therapy. We sought to evaluate the impact of pCR and near-complete response (nCR) on overall survival (OS) using a large national database., Methods: The National Cancer Database was queried for patients given a diagnosis of pancreatic cancer from 2004 to 2014. A pCR was defined as no tumor identified in the pancreas after surgical resection. An nCR was defined as a primary tumor less than 1 cm without lymph node metastases. The primary outcome was OS., Results: A total of 5364 patients underwent neoadjuvant chemotherapy and/or radiation followed by pancreatectomy. Forty-one patients (0.8%) had a pCR, 54 (1%) had an nCR, and the remaining 5266 (98.2%) had an otherwise incomplete response. Patients with pCR had a median OS of 43 months compared with 24 months for nCR and 23 months for incomplete response (P < 0.0001). Only pCR was associated with improved OS on adjusted Cox regression., Conclusions: For patients given a diagnosis of pancreatic cancer who underwent neoadjuvant treatment and surgical resection, achieving a pCR was associated with improved OS compared with those with residual tumor. An association between nCR and improved survival was not observed.

Purpose: Intrahepatic cholangiocarcinoma (ICC) is associated with a poor prognosis with surgical resection offering the best chance for long-term survival and potential cure. However, in up to 36% of patients who undergo surgery, more extensive disease is found at time of operation requiring cancellation of surgery. PET/MR is a novel hybrid technology that might improve local and whole-body staging in ICC patients, potentially influencing clinical management. This study was aimed to investigate the possible management implications of PET/MR, relative to conventional imaging, in patients affected by untreated intrahepatic cholangiocarcinoma., Methods: Retrospective review of the clinicopathologic features of 37 patients with iCCC, who underwent PET/MR between September 2015 and August 2018, was performed to investigate the management implications that PET/MR had exerted on the affected patients, relative to conventional imaging., Results: Of the 37 patients enrolled, median age 63.5 years, 20 (54%) were female. The same day PET/CT was performed in 26 patients. All patients were iCCC-treatment-naïve. Conventional imaging obtained as part of routine clinical care demonstrated early-stage resectable disease for 15 patients and advanced stage disease beyond the scope of surgical resection for 22. PET/MR modified the clinical management of 11/37 (29.7%) patients: for 5 patients (13.5%), the operation was cancelled due to identification of additional disease, while 4 "inoperable" patients (10.8%) underwent an operation. An additional 2 patients (5.4%) had a significant change in their operative plan based on PET/MR., Conclusions: When compared with standard imaging, PET/MR significantly influenced the treatment plan in 29.7% of patients with iCCC., Trial Registration: 2018P001334.

Background/objectives: We sought to identify the reliability of AJCC clinical staging was in comparison to pathologic staging in surgically resected patients with pancreatic cancer., Methods: We used the National Cancer Database Pancreas from 2004 to 2016 and evaluated patients who underwent resection for PDAC with all documented components of clinical and pathologic stage. We first evaluated the distribution of overall clinical stage and pathologic stage and then evaluated for stage migration by assessing the number of patients who shifted from a clinical stage group to a respective pathologic stage group. To further characterize the migratory pattern, we assessed the distribution of clinical and pathologic T-stage and N-stage., Results: In our cohort of 28,338 patients who underwent resection for PDAC, AJCC clinical staging did not reliably predict pathologic stage. Stage migration after resection was responsible for discrepancies between the distribution of overall clinical stage and pathologic stage. The predominant migration was from patients with clinical stage I disease to pathologic stage II disease. Most patients with clinical T1 and T2 disease were upstaged to pathologic T3 disease and over half of patients with clinical N0 disease were upstaged to pathologic N1 disease after resection., Discussion: Clinical staging appears to overrepresent early T1, T2, and N0 disease, and underrepresent T3 and N1 disease., Competing Interests: Declaration of competing interest The National Cancer Data Base (NCDB) is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. The CoC’s NCDB and the hospitals participating in the CoC NCDB are the source of the de-identified data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors. The authors report no conflict of interest related to this work., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Objective: To define short-term and long-term outcomes of IORT for the management of BR/LA PDAC in the era of modern neoadjuvant therapy (NAT)., Background: In the era of neoadjuvant FOLFIRINOX, many patients with borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC) become candidates for surgical exploration with curative intent. IORT may be used to consolidate treatment for successfully resected patients with close or positive margins or administered in unresectable patients without distant metastases., Methods: A retrospective review of 158 patients who received IORT in the setting of biopsy-proven BR/LA PDAC following NAT between 2008 and 2017 was performed. The Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS) of FOLFIRINOX treated patients., Results: Most patients (83%) received FOLFIRINOX, and 95% underwent consolidative chemoradiation therapy (50.4-58.8 Gy). Among FOLFIRINOX-treated patients, 86 underwent combined surgical resection with IORT (10 Gy) while 46 received IORT alone (15-20 Gy). The median PFS and OS were 21.5 and 46.7 months for patients who underwent resection with IORT and 14.7 and 23 months in the IORT alone group. Local progression occurred in 12.7% of patients after resection with IORT, and in 15% of patients who received IORT alone. Major complications occurred in 13% of patients following resection, and 5% of patients after IORT alone, including one death., Conclusion: IORT combined with surgical resection appears to be associated with improved survival and minimal morbidity in patients with positive or close margins. IORT is also associated with improved survival in patients with unresectable, non-metastatic disease.

Purpose: ctDNA offers a promising, noninvasive approach to monitor therapeutic efficacy in real-time. We explored whether the quantitative percent change in ctDNA early after therapy initiation can predict treatment response and progression-free survival (PFS) in patients with metastatic gastrointestinal cancer., Experimental Design: A total of 138 patients with metastatic gastrointestinal cancers and tumor profiling by next-generation sequencing had serial blood draws pretreatment and at scheduled intervals during therapy. ctDNA was assessed using individualized droplet digital PCR measuring the mutant allele fraction in plasma of mutations identified in tumor biopsies. ctDNA changes were correlated with tumor markers and radiographic response., Results: A total of 138 patients enrolled. A total of 101 patients were evaluable for ctDNA and 68 for tumor markers at 4 weeks. Percent change of ctDNA by 4 weeks predicted partial response (PR, P < 0.0001) and clinical benefit [CB: PR and stable disease (SD), P < 0.0001]. ctDNA decreased by 98% (median) and >30% for all PR patients. ctDNA change at 8 weeks, but not 2 weeks, also predicted CB ( P < 0.0001). Four-week change in tumor markers also predicted response ( P = 0.0026) and CB ( P = 0.022). However, at a clinically relevant specificity threshold of 90%, 4-week ctDNA change more effectively predicted CB versus tumor markers, with a sensitivity of 60% versus 24%, respectively ( P = 0.0109). Patients whose 4-week ctDNA decreased beyond this threshold (≥30% decrease) had a median PFS of 175 days versus 59.5 days (HR, 3.29; 95% CI, 1.55-7.00; P < 0.0001)., Conclusions: Serial ctDNA monitoring may provide early indication of response to systemic therapy in patients with metastatic gastrointestinal cancer prior to radiographic assessments and may outperform standard tumor markers, warranting further evaluation., (©2020 American Association for Cancer Research.)

Background: Many studies have demonstrated associations between surgical resections at academic centers and improved outcomes, particularly for complex operations. However, few studies have examined this relationship in intrahepatic cholangiocarcinoma (ICC). The hypothesis of this study was that facility type is associated with improved postoperative outcomes and survival for patients with ICC who undergo resection., Methods: Patients with stages 1 to 3 ICC who underwent hepatectomy were identified using the National Cancer Database (NCDB) (2004-2014). Facilities were categorized as academic or community centers per Commission on Cancer designations. High-volume hospitals were those that performed 11 or more hepatectomies per year. Multilevel logistic mixed-effects models to identify predictors of outcomes and parametric survival-time models were used to determine overall survival (OS)., Results: The study identified 2256 patients. Of these patients, 423 (18.8%) were treated at community centers, and 1833 (81.3%) were treated at academic centers. Nearly all high-volume centers were academic facilities (98.5% academic vs. 1.5% community centers), whereas low-volume centers were mixed (65.5% academic vs. 34.5% community centers) (p < 0.001). Surgery performed at an academic center was an independent predictor of decreased positive margins (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.51-0.98; p = 0.04), a lower 90-day mortality rate (OR, 0.62; 95% CI, 0.39-0.97; p = 0.03), and improved OS (hazard ratio [HR], 0.78; 95% CI, 0.63-0.96; p = 0.02). Facility hepatectomy volume was not independently associated with any short- or long-term outcomes., Conclusions: Treatment at an academic center is associated with fewer positive resection margins, a decreased 90-day mortality rate, and improved OS for patients who undergo ICC resection. Facility surgical volume was not shown to be significantly associated with any postoperative outcomes after adjustment for patient and disease characteristics.

Background: Administration of adjuvant therapy (AT) in patients with intrahepatic cholangiocarcinoma (ICC) remains inconsistent despite recent trial data. This study investigates predictors of receipt of AT and survival., Methods: Patients with ICC who underwent resection were identified using the NCDB (2004-2014). Logistic regression and Cox analysis were used to determine predictors of AT and survival, respectively. "High-risk" was defined as positive margins/nodes or stage III/IVa disease., Results: 2813 patients were identified, of whom 42.3% received AT. Patients with positive margins, positive nodes, and higher stage tended to receive AT (p < 0.001). Black patients and patients with Medicare/Medicaid were less likely to receive AT. In "high-risk" patients, AT was associated with lower mortality (HR 0.66, 95% CI 0.56-0.78, p < 0.001)., Conclusions: AT after ICC resection is associated with improved survival in patients with positive margins, positive nodes, and stage III/IVa disease. There are disparities and regional variations in the receipt of AT., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The primary aim of the present study was to evaluate if PET/MR induced management changes versus standard of care imaging (SCI) in treated colorectal cancer patients. The secondary aim was to assess the staging performance of PET/MR and of SCI versus the final oncologic stage., Methods: Treated CRC patients who underwent PET/MR with 18 F-FDG and SCI between January 2016 and October 2018 were enrolled in this retrospective study. Their medical records were evaluated to ascertain if PET/MR had impacted on their clinical management versus SCI. The final oncologic stage, as reported in the electronic medical record, was considered the true stage of disease., Results: A total of 39 patients who underwent 42 PET/MR studies were included, mean age 56.7 years (range 39-75 years), 26 males, and 13 females. PET/MR changed clinical management 15/42 times (35.7%, standard error ± 7.4%); these 15 changes in management were due to upstaging in 9/42 (21.5%) and downstaging in 6/42 (14.2%). The differences in management prompted by SCI versus PET/MR were statistically significant, and PET/MR outperformed SCI (P value < 0.001; odds ratio = 2.8). In relation to the secondary outcome, PET/MR outperformed the SCI in accuracy of oncologic staging (P value = 0.016; odds ratio = 4.6)., Conclusions: PET/MR is a promising imaging tool in the evaluation of treated CRC and might change the management in these patients. However, multicenter prospective studies with larger patient samples are required in order to confirm these preliminary results.

During cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient 1-3 . Previous case reports and small case series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance 4-8 . However, the effectiveness of cfDNA versus standard single-lesion tumor biopsies has not been directly compared in larger-scale prospective cohorts of patients following progression on targeted therapy. Here, in a prospective cohort of 42 patients with molecularly defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of postprogression cfDNA versus tumor biopsy revealed that cfDNA more frequently identified clinically relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not found in the matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cfDNA, tumor biopsies and rapid autopsy specimens elucidated substantial geographic and evolutionary differences across lesions. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity, and that the emergence of multiple resistance alterations in an individual patient may represent the 'rule' rather than the 'exception'. These findings have profound therapeutic implications and highlight the potential advantages of cfDNA over tissue biopsy in the setting of acquired resistance.

Purpose: Definitive chemoradiation with concurrent 5-fluorouracil (5-FU)/mitomycin C (MMC) is an effective treatment for localized anal cancer, but it is associated with significant acute long-term treatment-related toxicity. Pencil beam scanning proton beam (PBS-PT) radiation therapy may potentially reduce this toxicity. This is a multi-institutional pilot study evaluating the feasibility of definitive concurrent chemoradiation with PBS-PT in combination with 5-FU and MMC for carcinoma of the anal canal., Methods and Materials: Patients were enrolled on a National Cancer Institute-sponsored, prospective, multi-institutional, single-arm pilot study (NCT01858025). Key eligibility criteria included Eastern Cooperative Oncology Group 0 to 2, age ≥18 years, histologically confirmed invasive squamous cell carcinoma of the anal canal, and clinically staged T1-4, N0-3 disease. Patients were treated with PBS-PT per Radiation Therapy Oncology Group 0529 dose schema and concurrent 5-FU/MMC on day 1 and 29. The primary objective of this study was to determine feasibility of PBS-PT with concurrent 5-FU/MMC, defined as grade 3+ dermatologic toxicity less than 48% (reported grade 3+ dermatologic toxicity from Radiation Therapy Oncology Group 98-11). Secondary objectives were to determine the rates of overall grade 3+ toxicities, clinical complete response rate, and disease outcomes., Results: Between February 2014 and April 2017, we enrolled 25 patients into our study, all of whom were analyzed. Twenty-three patients (92%) completed treatment per protocol, and 2 patients died on treatment. Median time to completion of treatment was 42 days (range, 38-49). The grade 3+ radiation dermatitis rate was 24%. Median follow-up is 27 months (range, 21-50) among the 21 patients still alive. The overall rate of clinical complete response was 88%. The 2-year local failure, colostomy-free survival, progression-free survival, and overall survival are 12%, 72%, 80%, and 84%, respectively., Conclusions: In our prospective, multi-institutional pilot study of PBS-PT with concurrent 5-FU/MMC, PBS-PT was found to be feasible. A phase 2 study of proton beam radiation therapy is currently underway., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: Ablative radiation therapy is increasingly being used for hepatocellular carcinoma (HCC) resulting in excellent local control rates; however, patients without evidence of disease progression often die from liver failure. The clinical benefit of proton- over photon-based radiation therapy is unclear. We therefore sought to compare clinical outcomes of proton versus photon ablative radiation therapy in patients with unresectable HCC., Methods and Materials: This is a single-institution retrospective study of patients treated during 2008 to 2017 with nonmetastatic, unresectable HCC not previously treated with liver-directed radiation therapy and who did not receive further liver-directed radiation therapy within 12 months after completion of index treatment. The primary outcome, overall survival (OS), was assessed using Cox regression. Secondary endpoints included incidence of non-classic radiation-induced liver disease (defined as increase in baseline Child-Pugh score by ≥2 points at 3 months posttreatment), assessed using logistic regression, and locoregional recurrence, assessed using Fine-Gray regression for competing risks. All outcomes were measured from radiation start date., Results: The median follow-up was 14 months. Of 133 patients with median age 68 years and 75% male, 49 (37%) were treated with proton radiation therapy. Proton radiation therapy was associated with improved OS (adjusted hazard ratio, 0.47; P = .008; 95% confidence interval [CI], 0.27-0.82). The median OS for proton and photon patients was 31 and 14 months, respectively, and the 24-month OS for proton and photon patients was 59.1% and 28.6%, respectively. Proton radiation therapy was also associated with a decreased risk of non-classic radiation-induced liver disease (odds ratio, 0.26; P = .03; 95% CI, 0.08-0.86). Development of nonclassic RILD at 3 months was associated with worse OS (adjusted hazard ratio, 3.83; P < .001; 95% CI, 2.12-6.92). There was no difference in locoregional recurrence, including local failure, between protons and photons., Conclusions: Proton radiation therapy was associated with improved survival, which may be driven by decreased incidence of posttreatment liver decompensation. Our findings support prospective investigations comparing proton versus photon ablative radiation therapy for HCC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The most appropriate treatment for early-stage hepatocellular carcinoma (HCC) remains unclear. This study compared the association of resection versus ablation with overall survival (OS) in patients with early-stage HCC., Methods: Using the National Cancer Database (NCDB), patients diagnosed with stage I/II HCC between 2004 and 2014 were identified. Cox analysis was used to determine predictors of OS., Results: We identified 53,161 patients, of whom 15.9% underwent ablation and 14.5% underwent resection. Patients with fewer comorbidities, larger tumors, and private insurance were more likely to undergo resection. Resection was associated with significantly improved OS compared to ablation (HR 0.58, 95% CI 0.54-0.61, p < 0.001), at all tumor sizes (p < 0.05) and any degree of liver fibrosis (p < 0.05)., Conclusions: Resection of HCC tumors of all sizes and any degree of underlying fibrosis was associated with significantly improved OS compared with ablation. There was pronounced variability in the use of ablation versus resection for early-stage HCC., Summary: This study found that patients with early-stage hepatocellular carcinoma (HCC) have improved overall survival (OS) after surgical resection, compared to ablation, at all tumor sizes and any extent of liver disease. There were also marked variations in treatment patterns for early-stage HCC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Importance: Patients with locally advanced pancreatic cancer have historically poor outcomes. Evaluation of a total neoadjuvant approach is warranted., Objective: To evaluate the margin-negative (R0) resection rate of neoadjuvant FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) and losartan followed by chemoradiotherapy for locally advanced pancreatic cancer., Design, Setting, and Participants: A single-arm phase 2 clinical trial was conducted at a large academic hospital from August 22, 2013, to May 22, 2018, among 49 patients with previously untreated locally advanced unresectable pancreatic cancer as determined by multidisciplinary review. Patients had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 17.1 months (range, 5.0-53.7) among 27 patients still alive at study completion., Interventions: Patients received FOLFIRINOX and losartan for 8 cycles. Patients with radiographically resectable tumor after chemotherapy received short-course chemoradiotherapy (5 GyE × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy (50.4 Gy with a vascular boost to 58.8 Gy) with fluorouracil or capecitabine., Main Outcomes and Measures: R0 resection rate., Results: Of the 49 patients (26 women and 23 men; median age 63 years [range, 42-78 years]), 39 completed 8 cycles of FOLFIRINOX and losartan; 10 patients had fewer than 8 cycles due to progression (5 patients), losartan intolerance (3 patients), and toxicity (2 patients). Seven patients (16%) had short-course chemoradiotherapy while 38 (84%) had long-course chemoradiotherapy. Forty-two (86%) patients underwent attempted surgery, with R0 resection achieved in 34 of 49 patients (69%; 95% CI, 55%-82%). Overall median progression-free survival was 17.5 months (95% CI: 13.9-22.7) and median overall survival was 31.4 months (95% CI, 18.1-38.5). Among patients who underwent resection, median progression-free survival was 21.3 months (95% CI, 16.6-28.2), and median overall survival was 33.0 months (95% CI, 31.4 to not reached)., Conclusions and Relevance: Total neoadjuvant therapy with FOLFIRINOX, losartan, and chemoradiotherapy provides downstaging of locally advanced pancreatic ductal adenocarcinoma and is associated with an R0 resection rate of 61%., Trial Registration: ClinicalTrials.gov identifier: NCT01821729.

Objectives: Most localized hepatocellular carcinoma (HCC) patients are not surgically operable or transplantation candidates, increasing the role for nonsurgical therapies. Ablative external beam radiotherapy (XRT) and transarterial radioembolization (TARE) are emerging radiotherapeutic treatments for localized HCC. We sought to evaluate their utilization and efficacy in a large nationwide cohort., Materials and Methods: We conducted an observational study of 2685 patients from the National Cancer Database (NCDB) diagnosed with American Joint Committee on Cancer 7th edition clinical stage I to III HCC between 2004 and 2015, treated with definitive-intent XRT delivered in 1 to 15 fractions or TARE. The association between treatment modality (XRT vs. TARE) and overall survival (OS) was defined using propensity score-weighted Kaplan-Meier estimators and propensity score-weighted multivariable Cox regressions., Results: Among 2685 patients, 2007 (74.7%) received TARE and 678 (25.3%) received XRT, with increasing usage for both from 2004 to 2015 (Ptrend<0.001), but with overall greater uptake and absolute usage of TARE. Patients who received TARE were more likely to have elevated alpha fetoprotein and more advanced stage (P<0.05 for all). Median OS was 14.5 months for the entire cohort. XRT was associated with an OS advantage compared with TARE on propensity score-unadjusted analysis (adjusted hazard ratio [AHR], 0.89; 95% confidence interval, 0.79-1.00; P=0.049), but not on propensity score-adjusted analysis (AHR, 0.99; 95% confidence interval, 0.86-1.13; P=0.829)., Conclusions: Our study demonstrates that while both XRT and TARE usage have increased with time, there was greater uptake and absolute use of TARE. We found no difference in survival between XRT and TARE after propensity score adjustment.

Background: Antiangiogenic therapy is a proven therapeutic modality for refractory gastric and gastroesophageal junction adenocarcinoma. This trial assessed whether the addition of a high affinity angiogenesis inhibitor, ziv-aflibercept, could improve the efficacy of first-line mFOLFOX6 (oxaliplatin, leucovorin, and bolus plus infusional 5- fluorouracil) in metastatic esophagogastric adenocarcinoma., Methods: Patients with treatment-naive metastatic esophagogastric adenocarcinoma were randomly assigned (in a 2:1 ratio) in a multicenter, placebo-controlled, double-blind trial to receive first-line mFOLFOX6 with or without ziv-aflibercept (4 mg/kg) every 2 weeks. The primary endpoint was 6-month progression-free survival (PFS)., Results: Sixty-four patients were randomized to receive mFOLFOX6 and ziv-aflibercept (43 patients) or mFOLFOX6 and a placebo (21 patients). There was no difference in the PFS, overall survival, or response rate. Patients treated with mFOLFOX6/ziv-aflibercept tended to be more likely to discontinue study treatment for reasons other than progressive disease (P = .06). The relative dose intensity of oxaliplatin and 5-fluorouracil was lower in the mFOLFOX6/ziv-aflibercept arm during the first 12 and 24 weeks of the trial. There were 2 treatment-related deaths due to cerebral hemorrhage and bowel perforation in the mFOLFOX6/ziv-aflibercept cohort., Conclusions: Ziv-aflibercept did not increase the anti-tumor activity of first-line mFOLFOX6 in metastatic esophagogastric cancer, potentially because of decreased dose intensity of FOLFOX. Further evaluation of ziv-aflibercept in unselected, chemotherapy-naive patients with metastatic esophagogastric adenocarcinoma is not warranted., (© 2019 American Cancer Society.)