Clinical outcomes for previously treated patients with advanced biliary tract cancer: a meta-analysis.

Aim: A systematic review and meta-analysis were performed to evaluate the efficacy of treatments for previously treated advanced biliary tract cancer (BTC) patients. Materials & methods: Databases were searched for studies evaluating treatments for advanced (unresectable and/or metastatic) BTC patients who progressed on prior therapy. Pooled estimates of objective response rate (ORR), median overall survival (OS) and median progression-free survival (PFS) were calculated using random effects meta-analysis. Results: Across 31 studies evaluating chemotherapy or targeted treatment regimens in an unselected advanced BTC patient population, pooled ORR was 6.9%, median OS was 6.6 months and median PFS was 3.2 months. Conclusion: The efficacy of conventional treatments for previously treated advanced BTC patients is poor and could be improved by novel therapies.

What is this article about? Most patients with biliary tract cancer are identified with advanced disease, and almost all go through a worsening of the disease after their first treatment. For patients who go on to receive their next treatment, current guidelines are unclear regarding the best treatment choice. Therefore, we examined the available medical literature and performed an analysis of multiple studies to calculate overall estimates of the clinical value of standard treatments for these patients. Our goal was to develop a benchmark against which to compare the clinical value of new treatments that are currently being assessed in clinical trials. What were the results? We identified 31 studies assessing standard treatments (involving chemotherapy or molecularly targeted treatments) in previously treated advanced biliary tract cancer patients. Across these studies, the objective tumor response rate was 6.9%, median overall survival was 6.6 months and median progression-free survival was 3.2 months. What do the results of the study mean? These results indicate that there is limited clinical value of standard treatments for patients with advanced biliary tract cancer whose disease worsened after first treatment. This medical need could potentially be met by new treatments, such as immunotherapies that restore the immune system's ability to attack cancer cells and thereby prolong patient survival.

Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. METHODS: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. FINDINGS: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7-30·4). Median overall survival was 12·7 months (95% CI 11·5-13·6) in the pembrolizumab group versus 10·9 months (9·9-11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72-0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. INTERPRETATION: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

ALBI score and outcomes in patients with hepatocellular carcinoma: post hoc analysis of the randomized controlled trial KEYNOTE-240.

AIMS: This post hoc analysis evaluated albumin/bilirubin (ALBI) score, an objective measure of liver function, in patients receiving pembrolizumab plus best supportive care (BSC) compared with placebo plus BSC in the KEYNOTE-240 study. METHODS: Patients with confirmed hepatocellular carcinoma (HCC) and progression after/intolerance to sorafenib, Child-Pugh class A liver function, and Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned 2:1 to pembrolizumab 200 mg or placebo intravenously every 3 weeks plus BSC for ⩽35 cycles or until confirmed progression/unacceptable toxicity. Outcomes were assessed by ALBI grade. RESULTS: Of 413 patients, at baseline 116 had an ALBI grade 1 score (pembrolizumab, n = 74; placebo, n = 42) and 279 had an ALBI grade 2 score (n = 193; n = 86). Change from baseline in ALBI score to the end of treatment was similar in both arms [difference in least squares mean, -0.039; 95% confidence interval (CI): -0.169 to 0.091]. Time to ALBI grade increase was similar in both arms [median for pembrolizumab versus placebo: 7.8 versus 6.9 months; hazard ratio (HR) = 0.863 (95% CI: 0.625-1.192)]. Regardless of baseline ALBI grade, a trend toward improved overall survival was observed with pembrolizumab [grade 1: HR = 0.725 (95% CI: 0.454-1.158); grade 2: HR = 0.827 (95% CI: 0.612-1.119)]. CONCLUSION: Pembrolizumab did not adversely impact liver function compared with placebo in patients with HCC, as measured by changes in ALBI scores. A trend toward improved overall survival was observed with pembrolizumab in both ALBI grade groups. ClinicalTrials.gov identifier: NCT02702401.

Pralatrexate in Combination with Oxaliplatin in Advanced Esophagogastric Cancer: A Phase II Trial with Predictive Molecular Correlates.

The purpose of our study was to evaluate the efficacy of a combination of pralatrexate plus oxaliplatin in advanced esophagogastric cancer (EGC), analyze the impact of polymorphisms in folate metabolism pathway genes on toxicity and efficacy of pralatrexate, and to evaluate microRNA profile of tumor epithelium as a predictive biomarker. This was a two-stage trial with a safety lead in cohort and a primary endpoint of overall response rate (ORR). Patients received biweekly intravenous oxaliplatin (85 mg/m2) and pralatrexate (Dose level 1 [D1], 120 mg/m2; dose level-1 [D-1] 100 mg/m2). Single-nucleotide polymorphisms (SNP) in genes encoding proteins involved in pralatrexate metabolism were evaluated in germline DNA. microRNA profiling of the tumor epithelium was performed. ORR was 26%. Dose-limiting toxicities were observed in 2 of 4 patients at D1 and none at D-1. The T>C polymorphism in DHFR rs11951910 was significantly associated with lower progression-free survival (PFS; P ≤ 0.01), whereas the presence of the SLC19A1 rs2838957 G>A polymorphism was associated with improved PFS (P = 0.02). Presence of the GGH rs3780130 A>T and SLC19A1 rs1051266 G>A polymorphisms were significantly associated with better overall survival (OS; P = 0.01), whereas GGH rs7010484 T>C polymorphism was associated significantly with reduced OS (P = 0.04). There was no correlation between epithelial microRNA expression profile with disease progression or response. We conclude that the combination of oxaliplatin and pralatrexate is safe, is well tolerated, and has modest efficacy in advanced EGC. Pharmacogenomic analysis may be relevant to the use of pralatrexate in combination with platinum agents.

Rethinking the Role of Radiation Therapy in the Treatment of Unresectable Hepatocellular Carcinoma: A Data Driven Treatment Algorithm for Optimizing Outcomes.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide, with a majority of HCC patients not suitable for curative therapies. Approximately 70% of initially diagnosed patients cannot undergo surgical resection or transplantation due to locally advanced disease, poor liver function/underlying cirrhosis, or additional comorbidities. Local therapeutic options for patients with unresectable HCC, who are not suitable for thermal ablation, include transarterial embolization (bland, chemoembolization, radioembolization) and/or external beam radiation therapy (EBRT). Regarding EBRT specifically, technological advancements provide a means for safe and effective radiotherapy delivery in a wide spectrum of HCC patients. In multiple prospective studies, EBRT delivery in a variety of different fractionation schemes or in combination with transcatheter arterial chemoembolization (TACE) demonstrate improved outcomes, particularly with combination therapy. The Barcelona Clinic Liver Cancer classification provides a framework for treatment selection; however, given the growing complexity of treatment strategies, this classification system tends to simplify decision-making. In this review, we discuss the current literature regarding unresectable HCC and propose a modified treatment algorithm that emphasizes the role of radiation therapy for Child-Pugh score A or B patients with ≤3 nodules measuring >3 cm, multinodular disease or portal venous thrombosis.

Vertebral body irradiation during chemoradiation therapy for esophageal cancer contributes to acute bone marrow toxicity.

BACKGROUND: Hematologic toxicity (HT) commonly occurs during chemoradiation therapy (CRT) for esophageal cancer. We sought to determine radiation doses that correlate with declines in blood counts due to vertebral body (VB) irradiation during CRT. METHODS: We analyzed 53 esophageal cancer patients who were treated with weekly neoadjuvant carboplatin, paclitaxel and RT with weekly complete blood counts (CBC) available during treatment. HTs were graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Dose volume histogram (DVH) parameters of Vx, defined as percentage of entire bony vertebra (body, pedicles, laminae, processes) receiving at least x Gy of radiation, were collected for VB V5 (VBV5), VBV10-VBV60 in increments of 10, and mean vertebral dose (MVD). Linear and logistic regressions were performed to identify associations between leukopenia nadirs and DVH parameters. Receiver operator curves identified thresholds to avoid grade ≥3 leukopenia. RESULTS: A proportion of 32.1% of patients (n=17) developed grade 3 leukopenia and 5.7% (n=3) developed grade 4 leukopenia. VBV5, VBV10, VBV20, VBV30, and MVD were significantly associated with worsening leukopenia on univariate and multivariate analysis. Associations with leukopenia were not seen with VBV40 and VBV50 DVH values. Thresholds to avoid grade ≥3 leukopenia were VBV10 <49.1%, VBV20 <45.6%, and MVD <17.2 Gy. CONCLUSIONS: VBV5, VBV10, VBV20, VBV30 associate with leukopenia during CRT for esophageal cancer patients. Improved radiation sparing of the VB may decrease HT and may improve tolerability of concurrent chemotherapy and allow for intensification of systemic therapy during RT.

Safety and enhanced immunostimulatory activity of the DRD2 antagonist ONC201 in advanced solid tumor patients with weekly oral administration.

BACKGROUND: ONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The first-in-human trial of ONC201 previously established a recommended phase II dose (RP2D) of 625 mg once every three weeks. Here, we report the results of a phase I study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of weekly ONC201. METHODS: Patients ≥ 18 years old with an advanced solid tumor refractory to standard treatment were enrolled. Dose escalation proceeded with a 3 + 3 design from 375 mg to 625 mg of ONC201. One cycle, also the dose-limiting toxicity (DLT) window, was 21 days. The primary endpoint was to determine the RP2D of weekly ONC201, which was confirmed in an 11-patient dose expansion cohort. RESULTS: Twenty patients were enrolled: three at 375 mg and 17 at 625 mg of ONC201. The RP2D was defined as 625 mg with no DLT, treatment discontinuation, or dose modifications due to drug-related toxicity. PK profiles were consistent with every-three-week dosing and similar between the first and fourth dose. Serum prolactin and caspase-cleaved cytokeratin-18 induction were detected, along with intratumoral integrated stress response activation and infiltration of granzyme B+ Natural Killer cells. Induction of immune cytokines and effectors was higher in patients who received ONC201 once weekly versus once every three weeks. Stable disease of > 6 months was observed in several prostate and endometrial cancer patients. CONCLUSIONS: Weekly, oral ONC201 is well-tolerated and results in enhanced immunostimulatory activity that warrants further investigation. TRIAL REGISTRATION: NCT02250781 (Oral ONC201 in Treating Patients With Advanced Solid Tumors), NCT02324621 (Continuation of Oral ONC201 in Treating Patients With Advanced Solid Tumors).

Multiple primary malignancies in patients with anal squamous cell carcinoma.

Prior studies examining the risk of second primary malignancy (SPM) after a first primary cancer generally have used large datasets such as the Surveillance, Epidemiology, and End Results (SEER) registry and excluded survivors of previous primaries and developers of synchronous primaries. The goal of this study was to provide a more complete representation of multiple cancer risk in squamous cell carcinoma of the anus (SCCA) patients. A single-institution retrospective study of 46 patients treated definitively for SCCA between January 2006 and July 2017 was conducted. Of the 46 patients, 18 (39%) had either a primary malignancy before SCCA (n=9) or SPM after an index SCCA (n=9). Six patients had ≥3 total malignancies. In our cohort, patients without SPMs tended to die from SCCA recurrence, while patients with SPMs were more likely to die from their SPM than from SCCA. Our study suggests that patients with SCCA are often either survivors of previous cancers or develop later malignancies. Several risk factors may play a role including HPV infection, HPV-related or treatment-related immunosuppression, somatic mutations due to chemotherapy, and genetic factors. Patients with SCCA require lifelong surveillance given their elevated risk of malignancy. Future work should focus on identifying genomic or immunologic factors that may predispose SCCA patients to develop multiple primary malignancies.

Phase Ib Results of the Rational Combination of Selumetinib and Cyclosporin A in Advanced Solid Tumors with an Expansion Cohort in Metastatic Colorectal Cancer.

MEK inhibition is of interest in cancer drug development, but clinical activity in metastatic colorectal cancer (mCRC) has been limited. Preclinical studies demonstrated Wnt pathway overexpression in KRAS-mutant cell lines resistant to the MEK inhibitor, selumetinib. The combination of selumetinib and cyclosporin A, a noncanonical Wnt pathway modulator, demonstrated antitumor activity in mCRC patient-derived xenografts. To translate these results, we conducted a NCI Cancer Therapy Evaluation Program-approved multicenter phase I/IB trial (NCT02188264) of the combination of selumetinib and cyclosporin A. Patients with advanced solid malignancies were treated with the combination of oral selumetinib and cyclosporin A in the dose escalation phase, followed by an expansion cohort of irinotecan and oxaliplatin-refractory mCRC. The expansion cohort utilized a single-agent selumetinib "run-in" to evaluate FZD2 biomarker upregulation and KRAS-WT and KRAS-MT stratification to identify any potential predictors of efficacy. Twenty and 19 patients were enrolled in dose escalation and expansion phases, respectively. The most common adverse events and grade 3/4 toxicities were rash, hypertension, and edema. Three dose-limiting toxicities (grade 3 hypertension, rash, and increased creatinine) were reported. The MTD was selumetinib 75 mg twice daily and cyclosporin A 2 mg/kg twice daily on a 28-day cycle. KRAS stratification did not identify any differences in response between KRAS-WT and KRAS-MT cancers. Two partial responses, 18 stable disease, and 10 progressive disease responses were observed. Combination selumetinib and cyclosporin A is well tolerated, with evidence of activity in mCRC. Future strategies for concept development include identifying better predictors of efficacy and improved Wnt pathway modulation.Significance: These findings translate preclinical studies combining selumetinib and cyclosporin into a phase I first-in-human clinical trial of such a combination in patients with advanced solid malignancies. Cancer Res; 78(18); 5398-407. ©2018 AACR.

Management of locally advanced rectal cancer in the elderly: a critical review and algorithm.

Colorectal cancer incidence and death rates have been declining over the past 10 years. However, it remains the second leading cause of death in men ages 60-79 and the third leading cause of death in men over 80 and in women over 60 years old. However, there is little data specific to the treatment of the elder patient, since few of these patients are included in trials. With the advent of improved therapies, there are many alternative options available. Still, no definitive consensus or guidelines have been defined for this particular patient population. The goal of this study is to review the literature on the management of rectal cancer in the elderly and to propose treatment algorithms to help the oncology team in treatment decision-making.

Decision-Making Strategy for Rectal Cancer Management Using Radiation Therapy for Elderly or Comorbid Patients.

Rectal cancer predominantly affects patients older than 70 years, with peak incidence at age 80 to 85 years. However, the standard treatment paradigm for rectal cancer oftentimes cannot be feasibly applied to these patients owing to frailty or comorbid conditions. There are currently little information and no treatment guidelines to help direct therapy for patients who are elderly and/or have significant comorbidities, because most are not included or specifically studied in clinical trials. More recently various alternative treatment options have been brought to light that may potentially be utilized in this group of patients. This critical review examines the available literature on alternative therapies for rectal cancer and proposes a treatment algorithm to help guide clinicians in treatment decision making for elderly and comorbid patients.

A Multicenter Phase II Study of Gemcitabine, Capecitabine, and Bevacizumab for Locally Advanced or Metastatic Biliary Tract Cancer.

OBJECTIVES: Vascular endothelial growth factor overexpression, seen in 42% to 76% of biliary tract cancers (BTCs), correlates with poor survival. We explored the safety/efficacy and potential biomarkers for bevacizumab in combination with gemcitabine-capecitabine in advanced BTCs. PATIENTS AND METHODS: Inoperable stage III/IV BTC patients in our prospective study were given 1000 mg/m of gemcitabine (on days 1, 8), 650 mg/m of capecitabine (on days 1 to 14), and 15 mg/kg of bevacizumab (on day 1) in 21-day cycles. Circulating tumor cells and quality of life were assessed at baseline and before cycle 2 and 3. RESULTS: In total, 50 patients with gallbladder cancer (22%), intrahepatic (58%), and extrahepatic (20%) cholangiocarcinoma, received a median of 8 treatment cycles for median treatment duration of 5.8 months. Common grade 3/4 toxicities were neutropenia (36%), thrombocytopenia (16%), fatigue (20%), infections (14%), and hand-foot syndrome (10%). There were 12 partial response (24%), 24 stable disease (48%) with clinical benefit rate of 72%. Median progression-free survival was 8.1 months (95% confidence interval, 5.3-9.9). Median overall survival was 10.2 months (95% confidence interval, 7.5-13.7). Circulating tumor cells were identified at baseline in 21/46 patients (46%), who had lower median overall survival compared with those without (9.4 vs. 13.7 mo; P=0.29). Patients with quality of life scores greater than the group median by the end of first cycle of treatment had improved survival compared with those who did not (13.3 vs. 9.4 mo; P=0.39). CONCLUSIONS: Addition of bevacizumab to gemcitabine/capecitabine did not improve outcome in an unselected group of patients with advanced BTC compared with historical controls. The selective benefit of vascular endothelial growth factor inhibition in BTC remains to be explored.

Adjuvant therapeutic strategies for resectable pancreatic adenocarcinoma.

Of all patients diagnosed with pancreatic adenocarcinoma, only 15-20% present with resectable disease. Despite curative-intent resection, the prognosis remains poor with the majority of patients recurring, prompting the need for adjuvant therapy. Historical data support the use of adjuvant 5-fluorouracil (5-FU) or gemcitabine, but recent data suggest either gemcitabine plus capecitabine or modified FOLFIRINOX can improve overall survival when compared to gemcitabine alone. The use of adjuvant chemoradiation therapy remains controversial, primarily due to limitations in study design and mixed results of historical trials. The ongoing Radiation Therapy Oncology Group (RTOG)-0848 trial hopes to further define the role of adjuvant chemoradiation therapy. Intraoperative radiation therapy (IORT) and adjuvant immunotherapy represent additional possibilities to improve outcomes, but evidence supporting their use is limited. This article reviews adjuvant therapeutic strategies for resectable pancreatic adenocarcinoma, including chemotherapy, chemoradiation therapy, IORT and immunotherapy.

Clinical characteristics of adenosquamous esophageal carcinoma.

BACKGROUND: Current published information of adenosquamous carcinoma (ASC) of the esophagus in the United States is limited to isolated case reports. We sought to study the clinical characteristics of this tumor using the Surveillance, Epidemiology and End Results (SEER) database. METHODS: Relevant data of all patients with esophageal cancer in the SEER database diagnosed from 1998-2010 was obtained. Demographic, grade, stage, treatment and survival characteristics of patients with ASC were summarized and compared to those patients with adenocarcinoma (ACA) and squamous cell carcinoma (SqCC). Univariate analyses across comparison groups were performed using Wilcoxon rank sum test for continuous covariates and the Pearson Chi-square test for categorical covariates. To evaluate the association of selected covariates to survival by histology, unadjusted and adjusted proportional hazards models were generated for the entire study population. To further control for the difference in covariates among the histology groups, propensity weighted Cox regression modeling was performed using the inverse propensity to treat weighting (IPTW) approach. RESULTS: Of 29,890 patients with the histological subgroups, only 284 patients had ASC (1%). Patients with ACA had a higher grade (72.9% with grade III/IV) and presented with advanced stage (48.2% distant disease) than their comparison group. Patients with ASC had worse overall survival compared to ACA but not SqCC in both univariate and multivariate analyses (OR =0.76; P<0.05 and OR =0.86; P<0.05 respectively). These results were further confirmed by the propensity weighted Cox regression analysis. Analysis of the ASC population alone demonstrated that decreasing stage, radiation therapy (OR =0.59; P<0.001) and surgery (OR =0.86; P<0.001) were associated with better overall survival, but grade was not. CONCLUSIONS: ASC of the esophagus is a rare histological variant comprising 1% of esophageal ACA in the Unites States. This histological subtype presents in later stages, at a higher grade and portends a poorer survival than the more common ACA. Radiation therapy and surgical resection of appropriate stage patients provide the best chance of survival.

Pathologic Complete Response Is an Independent Predictor of Improved Survival Following Neoadjuvant Chemoradiation for Esophageal Adenocarcinoma.

INTRODUCTION: Reports of improved survival in patients with pathologic complete response (pCR) to neoadjuvant therapy for esophageal and gastroesophageal junction (GEJ) adenocarcinoma is extrapolated from heterogeneous studies that include squamous cell histology. We sought to determine if pCR is associated with a survival advantage in a homogenous group of patients with esophageal adenocarcinoma. METHODS: This is a single institution analysis of all patients with T2-T4 or node positive esophageal adenocarcinoma treated with neoadjuvant chemoradiotherapy and esophagectomy between 2004 and 2014. Patients were divided into two groups based on pathological response, pCR vs. incomplete pathological response (iPR). Survival outcomes were evaluated using standard Kaplan-Meier methods and multivariable Cox regression models. RESULTS: A total of 205 patients were included in the study: 38 (19 %) patients with pCR and 167 patients (81 %) with iPR. The two groups were similar with respect to clinical stage, age, gender, comorbid conditions, ECOG status, smoking, and alcohol use. Patients in the pCR group had a higher percentage of tumors located in middle third of esophagus (11 vs. 2 %, p = 0.04) while tumor grade was similar in both groups. Median follow-up was 50 months, range 2-109 months. The 3-year overall (OS) and recurrence-free survival (RFS) for iPR was 48 and 39 %, respectively, vs. 86 and 80 % for pCR group, respectively. CONCLUSION: This analysis of a cohort of homogeneous patients with esophageal adenocarcinoma undergoing multimodality therapy showed that pCR is an independent predictor of improved RFS and OS. This data contributes to a growing body of evidence highlighting the benefits of neoadjuvant therapy specific to esophageal adenocarcinoma particularly when pCR is achieved.

Association Between Clinically Staged Node-Negative Esophageal Adenocarcinoma and Overall Survival Benefit From Neoadjuvant Chemoradiation.

IMPORTANCE: While neoadjuvant chemoradiation for esophageal cancer improves oncologic outcomes for a broad group of patients with locally advanced and/or node-positive tumors, it is less clear which specific subset of patients derives most benefit in terms of overall survival (OS). OBJECTIVE: To determine whether neoadjuvant chemoradiation based on esophageal adenocarcinoma histology has similar oncologic outcomes for patients treated with surgery alone when stratified by clinical nodal status. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis using the American College of Surgeons National Cancer Database from 1998 to 2006. Patients with esophageal adenocarcinoma histology and clinical stage T1bN1-N3 or T2-T4aN-/+M0 were divided into 2 treatment groups: (1) neoadjuvant chemoradiation followed by surgery and (2) surgery alone. Subset analysis within each treatment group was performed for clinically node-negative patients (cN-) vs node-positive patients (cN+) in conjunction with pathological nodal status. A propensity score-adjusted analysis, which included patient demographics, comorbidity status, and clinical T stage, was also performed. MAIN OUTCOME AND MEASURES: The primary outcome was 3-year OS. Secondary outcomes included margin status, postoperative length of stay, unplanned readmission rate, and 30-day mortality. RESULTS: A total of 1309 patients were identified, of whom 539 received neoadjuvant chemoradiation followed by surgery and 770 received surgery alone. Of the 1309 patients, 41.2% (n = 539) received neoadjuvant chemoradiation and 47.2% (n = 618) were cN+. Median follow-up for the entire cohort was 73.3 months (interquartile range, 64.1-93.5 months). The 3-year OS was better for neoadjuvant chemoradiation followed by surgery compared with surgery alone (49% vs 38%, respectively; P < .001). Stratifying based on clinical nodal status, the propensity score-adjusted OS was significantly better for cN+ patients who received neoadjuvant chemoradiation (hazard ratio, 0.52; 95% CI, 0.42-0.66; P < .001). In contrast, there was no difference in OS for cN- patients based on treatment (hazard ratio, 0.84; 95% CI, 0.65-1.10; P = .22). CONCLUSIONS AND RELEVANCE: Patients with cN+ esophageal adenocarcinoma benefit significantly from neoadjuvant chemoradiation. However, patients with cN- tumors treated with neoadjuvant chemoradiation plus surgery do not derive a significant OS benefit compared with surgery alone. This finding may have significant implications on the use of neoadjuvant chemoradiation in patients with cN- disease.

Baseline circulating IL-17 predicts toxicity while TGF-ß1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma.

BACKGROUND: We evaluated candidate circulating serum cytokines, chemokines and growth factors in patients with locally/regionally advanced melanoma receiving neoadjuvant ipilimumab with toxicity and clinical outcome. METHODS: Patients were treated with ipilimumab (10 mg/kg IV every 3 weeks, 2 doses) before and after surgery. xMAP multiplex serum testing for 36 functionally selected cytokines and chemokines was performed at baseline and at six weeks (following ipilimumab). Based on our prior data, the association of IL-17 and immune related colitis was tested. Serum cytokines were divided into functional groups (Th1, Th2, Regulatory, Proinflammatory) and were assessed at baseline and week 6 using sparse-group Lasso modeling to assess the association of various cytokine groups with progression free survival (PFS). The linear combination of the cytokines/chemokines in this model was then used as a risk score and a Kaplan-Meier curve was generated to examine the association of the dichotomized score and PFS. RESULTS: Thirty-five patients were enrolled whose staging was: IIIB (3; N2b), IIIC (30; N2c, N3), IV (2). Median follow-up was 18 months. Among 33 evaluable patients, median PFS was 11 months (95 % CI = 6.2-19.2). IL-17 was found to correlate significantly with the incidence of grade 3 diarrhea/colitis when measured at baseline (p = 0.02) with a trend towards significance at 6 weeks (p = 0.06). In the modeling analysis, at baseline, the linear combination of 2 regulatory cytokines [TGF- ß1 (ρ = 0.19) and IL-10 (ρ = -0.34)] was significantly associated with PFS (HR 2.66; p = 0.035). No significant correlations with clinical outcomes were found in examining the week 6 cytokines. CONCLUSIONS: Baseline IL-17 level was significantly associated with the later development of severe diarrhea/colitis while the combination of baseline TGF- ß1 and IL-10 levels were associated with therapeutic clinical outcome after neoadjuvant ipilimumab. These findings warrant further investigation and validation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00972933.

Role of Repeat 18F-Fluorodeoxyglucose Positron Emission Tomography Examination in Predicting Pathologic Response Following Neoadjuvant Chemoradiotherapy for Esophageal Adenocarcinoma.

IMPORTANCE: Predicting complete pathologic response (CPR) preoperatively can significantly affect surgical decision making. There are conflicting data regarding positron emission tomography computed tomography (PET CT) characteristics and the ability of PET CT to predict pathologic response following neoadjuvant chemoradiotherapy in esophageal adenocarcinoma because most existing studies that include squamous histology have limited numbers and use nonstandardized PET CT imaging. OBJECTIVE: To determine if PET CT characteristics are associated with CPR in patients undergoing trimodality treatment for esophageal adenocarcinoma. DESIGN, SETTING, AND PARTICIPANTS: A retrospective medical record review was conducted at a large tertiary cancer center from a prospectively maintained database from January 1, 2005, to December 31, 2012. Inclusion criteria were patients undergoing esophagectomy for locally advanced esophageal adenocarcinoma post-neoadjuvant chemoradiotherapy with 2 standardized PET CT studies done at our institution (pre-neoadjuvant chemoradiotherapy and post-neoadjuvant chemoradiotherapy) for review. Data collected included clinical, pathologic, imaging, and treatment characteristics. MAIN OUTCOME AND MEASURE: The primary study outcome was the association of PET CT characteristics with histologic confirmed pathologic response. RESULTS: Of the total participants, 77 patients met the inclusion criteria. Twenty-two patients (28.6%) had CPR vs 55 patients (71.4%) who had incomplete pathologic response. The 2 groups were similar in age, sex, race/ethnicity, comorbid conditions, Eastern Cooperative Oncology Group status, tumor grade, chemotherapy, and radiation regimen and days between the 2 PET CTs. The mean prestandardized uptake variable (SUV; 14.5 vs 11.2; P = .05), δ SUV (10.3 vs 5.4; P = .02), and relative δ SUV (0.6 vs 0.4; P = .02) were significantly higher in those with CPR vs incomplete pathologic response. Using the Youden Index, a δ SUV value less than 45% was predictive of residual disease with a positive predictive value of 91.7% (95% CI, 73-99; P < .05). CONCLUSIONS AND RELEVANCE: To our knowledge, this is the largest study examining the role of PET CT characteristics in esophageal adenocarcinoma for patients undergoing neoadjuvant chemoradiotherapy that demonstrates that δ SUV of less than 45% is associated with patients with residual disease but not CPR. Based on the findings from our study, the current recommendation is still surgical resection regardless of the posttherapy PET SUV in the primary tumor. However, our study highlights the ability to detect patients with residual disease and the need to critically evaluate these patients for consideration of additional therapies.

Evaluation of a 4-protein serum biomarker panel-biglycan, annexin-A6, myeloperoxidase, and protein S100-A9 (B-AMP)-for the detection of esophageal adenocarcinoma.

BACKGROUND: Esophageal adenocarcinoma (EAC) is associated with a dismal prognosis. The identification of cancer biomarkers can advance the possibility for early detection and better monitoring of tumor progression and/or response to therapy. The authors present results from the development of a serum-based, 4-protein (biglycan, myeloperoxidase, annexin-A6, and protein S100-A9) biomarker panel for EAC. METHODS: A vertically integrated, proteomics-based biomarker discovery approach was used to identify candidate serum biomarkers for the detection of EAC. Liquid chromatography-tandem mass spectrometry analysis was performed on formalin-fixed, paraffin-embedded tissue samples that were collected from across the Barrett esophagus (BE)-EAC disease spectrum. The mass spectrometry-based spectral count data were used to guide the selection of candidate serum biomarkers. Then, the serum enzyme-linked immunosorbent assay data were validated in an independent cohort and were used to develop a multiparametric risk-assessment model to predict the presence of disease. RESULTS: With a minimum threshold of 10 spectral counts, 351 proteins were identified as differentially abundant along the spectrum of Barrett esophagus, high-grade dysplasia, and EAC (P<.05). Eleven proteins from this data set were then tested using enzyme-linked immunosorbent assays in serum samples, of which 5 proteins were significantly elevated in abundance among patients who had EAC compared with normal controls, which mirrored trends across the disease spectrum present in the tissue data. By using serum data, a Bayesian rule-learning predictive model with 4 biomarkers was developed to accurately classify disease class; the cross-validation results for the merged data set yielded accuracy of 87% and an area under the receiver operating characteristic curve of 93%. CONCLUSIONS: Serum biomarkers hold significant promise for the early, noninvasive detection of EAC.

Breast cancer resistance protein (BCRP) and excision repair cross complement-1 (ERCC1) expression in esophageal cancers and response to cisplatin and irinotecan based chemotherapy.

BACKGROUND: Esophageal cancer patients face a dismal outcome despite tri-modality management and median survival remains 15-18 months. Breast cancer resistance protein (BCRP) is an ATP-dependent efflux protein associated with chemotherapy resistance. The role of BCRP expression in esophageal cancer and normal esophageal cells is not known. Excision repair cross complement-1 (ERCC1) overexpression has been correlated with poorer response to cisplatin based chemotherapy. We examined the expression of BCRP and ERCC1 in patients with esophageal cancer and correlated it with survival in patients receiving irinotecan and cisplatin based chemotherapy. METHODS: With IRB approval, 40 cases of esophageal cancer diagnosed from 2004-2008, were stained for BCRP and ERCC1 expression by immunohistochemistry and scored by a pathologist blinded to clinical data. Baseline demographics, therapy given and survival data were collected and correlated with BCRP and ERCC1 expression. Fisher's exact test was used to determine association between BCRP and ERCC1 expression and demographics. Cox proportional hazards model was used for association of BCRP and ERCC1 with survival. RESULTS: On immunohistochemistry, 30/40 cancers (75%) expressed BCRP. Interestingly, down-regulation of BCRP expression in tumor compared with normal cells was seen in 40% of patients. ERCC1 positivity was seen in 15/30 cases (50%). Median overall survival (OS) was 19 months with no difference in survival between BCRP positive and negative patients (P=0.13) or ERCC1 positive and negative patients (P=0.85). Estimated hazard ratio (HR) of death for BRCP positive patients was 2.29 (95% CI: 0.79-6.64) and for ERCC1 positive patients was 1.09 (95% CI: 0.46-2.56). There was no association of BCRP and ERCC1 expression with disease stage, age, gender or histology. For patients who received cisplatin and irinotecan as first line chemotherapy, there was no difference in survival based on BCRP or ERCC1 status. CONCLUSIONS: BCRP expression is seen in a majority of esophageal cancers and normal esophageal mucosa. ERCC1 expression is seen in about half of the patients with esophageal cancer. Irinotecan based studies with esophageal and gastric cancer suggest response rates of 14-65%. Whether the 40% of tumors in our study found with down regulation of BCRP expression, constitute a majority of these responders needs to be prospectively validated in a larger data set. It should include markers such as ERCC1 predicting response to 5-fluorouracil and platinum based chemotherapy, to enable individualizing therapy for this cancer.