Current and Emerging Therapeutic Targets for the Treatment of Cholangiocarcinoma: An Updated Review.

Cholangiocarcinoma is a malignancy of the bile ducts that is often associated with late diagnosis, poor overall survival, and limited treatment options. The standard of care therapy for cholangiocarcinoma has been cytotoxic chemotherapy with modest improvements in overall survival with the addition of immune checkpoint inhibitors. The discovery of actionable mutations has led to the advent of targeted therapies against FGFR and IDH-1, which has expanded the treatment landscape for this patient population. Significant efforts have been made in the pre-clinical space to explore novel immunotherapeutic approaches, as well as antibody-drug conjugates. This review provides an overview of the current landscape of treatment options, as well as promising future therapeutic targets.

Recurrence patterns and associated factors of locoregional failure following neoadjuvant chemoradiation and surgery for esophageal cancer.

BACKGROUND: Despite neoadjuvant chemoradiation (nCRT) followed by esophagectomy for locally advanced esophageal cancer, locoregional recurrence (LRR) is common and factors associated with LRR have not been clearly identified. METHODS: Patients were identified from a single institution, prospectively maintained database (1996-2013). Patterns of recurrence were described and associated factors of LRR were analyzed using competing risks regression models. RESULTS: Of the 456 patients treated with nCRT and surgery, 167 patients developed recurrence. Locoregional and distant recurrences were observed in 69 (15.1%) and 140 (30.9%) patients, respectively. Time to recurrence (13.6 vs 10.4 months, P = 0.20) and median overall survival (29.3 vs 19.1 months, P = 0.12) were no different among the 27 patients (6%) who developed a solitary LRR compared to patients who developed distant recurrence. Univariable analysis identified lymphovascular invasion (HR 1.46, P = 0.07), lymph node ratio >0.5 (HR 2.16, P = 0.02), positive margin (HR 1.95, P = 0.05), lack of response to neoadjuvant therapy (HR 1.99, P < 0.01), clinical T stage (HR 2.62, P < 0.01) and final T3/4 stage (HR 2.06, P < 0.01) as factors significantly associated with LRR. Clinical T stage and response to neoadjuvant treatment were independently associated with LRR on multivariable analysis. CONCLUSIONS: Although aggressive tumor biology plays a significant role in LRR, optimizing neoadjuvant treatments to obtain a complete pathologic response may lead to improved locoregional control.

Phase II study of the antibody-drug conjugate TAK-264 (MLN0264) in patients with metastatic or recurrent adenocarcinoma of the stomach or gastroesophageal junction expressing guanylyl cyclase C.

Background The first-in-class antibody-drug conjugate TAK-264 (formerly MLN0264) consists of an antibody targeting guanylyl cyclase C (GCC) conjugated to monomethyl auristatin E (MMAE) via a peptide linker. This phase II study evaluated the efficacy and safety of TAK-264 in patients with adenocarcinoma of the stomach or gastroesophageal junction expressing GCC, who had progressed on ≥1 line of prior therapy. Methods This study used a two-stage design, with an interim analysis conducted after stage I to determine whether to continue to stage II or discontinue on the grounds of futility. Adult patients with gastric and gastroesophageal junction adenocarcinoma expressing low, intermediate, or high GCC levels received TAK-264 1.8 mg/kg as a 30-min intravenous infusion once every 21 days, for up to 1 year. The primary endpoint was objective response rate. Radiographic assessments of tumor burden were performed every 2 cycles (6 weeks). Results A total of 38 patients participated in the study. Patients received a median of 2 (range 1-14) cycles; 8 (21%) received at least 6 cycles. The most common adverse events were nausea (53%), fatigue (32%), and decreased appetite (29%). Grade ≥3 events including anemia, diarrhea, and neutropenia were seen in 14 (37%) patients. Systemic exposure to TAK-264 was maintained throughout each treatment cycle. Two patients (6%) with intermediate GCC expression had objective responses. Conclusions TAK-264 demonstrated a manageable safety profile in this patient population. The stage I interim analysis did not support continuation to stage II of the study.

A phase II study of antibody-drug conjugate, TAK-264 (MLN0264) in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C.

Background This phase II open-label, multicenter study evaluated the efficacy, safety, and tolerability of TAK-264 in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C (GCC). Methods Patients with advanced or metastatic pancreatic adenocarcinoma expressing GCC (H-score ≥ 10) received TAK-264 1.8 mg/kg on day 1 of a 21-day cycle as a 30-min intravenous infusion for up to 1 year or until disease progression or unacceptable toxicity. The primary objective was overall response rate (ORR [complete response + partial response (PR)]). Secondary objectives included evaluations of the safety and pharmacokinetic profile of TAK-264 (NCT02202785). Results 43 patients were enrolled and treated with 1.8 mg/kg TAK-264: 11, 15, and 17 patients with low, intermediate, and high GCC expression, respectively. Median number of treatment cycles received was two (range 1-10). The ORR was 3%, including one patient with intermediate GCC expression who achieved a PR. All patients experienced ≥1 adverse events (AE). The majority of patients experienced grade 1/2 AEs affecting the gastrointestinal tract. Fifteen (35%) patients experienced ≥grade 3 drug-related AEs; five (12%) patients had a serious AE. The most common (≥10% of patients) all-grade drug-related AEs were nausea (33%), fatigue (28%), neutropenia (23%), decreased appetite (23%), vomiting (16%), asthenia (16%), and alopecia (14%). Conclusions TAK-264 demonstrated a manageable safety profile; however, the low efficacy of TAK-264 observed in this study did not support further clinical investigation.

Effect of body mass index on operative outcome after robotic-assisted Ivor-Lewis esophagectomy: retrospective analysis of 129 cases at a single high-volume tertiary care center.

The impact of body weight on outcomes after robotic-assisted esophageal surgery for cancer has not been studied. We examined the short-term operative outcomes in patients according to their body mass index following robotic-assisted Ivor-Lewis esophagectomy at a high-volume tertiary-care referral cancer center and evaluated the safety of robotic surgery in patients with an elevated body mass index. A retrospective review of all patients who underwent robotic-assisted Ivor-Lewis esophagectomy between April 2010 and June 2013 for pathologically confirmed distal esophageal cancer was conducted. Patient demographics, clinicopathologic data, and operative outcomes were collected. We stratified body mass index at admission for surgery according to World Health Organization criteria; normal range is defined as a body mass index range of 18.5-24.9 kg/m2. Overweight is defined as a body mass index range of 25.0-29.9 kg/m2 and obesity is defined as a body mass index of 30 kg/m2 and above. Statistics were calculated using Pearson's Chi-square and Pearson's correlation coefficient tests with a P-value of 0.05 or less for significance. One hundred and twenty-nine patients (103 men, 26 women) with median age of 67 (30-84) years were included. The majority of patients, 76% (N = 98) received neoadjuvant therapy. When stratified by body mass index, 28 (22%) were normal weight, 56 (43%) were overweight, and 45 (35%) were obese. All patients had R0 resection. Median operating room time was 407 (239-694) minutes. When stratified by body mass index, medians of operating room time across the normal weight, overweight and obese groups were 387 (254-660) minutes, 395 (310-645) minutes and 445 (239-694), respectively. Median estimated blood loss (EBL) was 150 (25-600) cc. When stratified by body mass index, medians of EBL across the normal weight, overweight and obese groups were 100 (50-500) cc, 150 (25-600) cc and 150 (25-600), respectively. Obesity significantly correlated with longer operating room time (P = 0.05) but without significant increased EBL (P = 0.348). Among the three body mass index groups there was no difference in postoperative complications including thrombotic events (pulmonary embolism and deep venous thrombosis) (P = 0.266), pneumonia (P = 0.189), anastomotic leak (P = 0.090), wound infection (P = 0.390), any cardiac events (P = 0.793) or 30 days mortality (P = 0.414). Our data study demonstrates that patients with esophageal cancer and an elevated body mass index undergoing robotic-assisted Ivor-Lewis esophagectomy have increased operative times but no significantly increased EBL during the procedure. Other potential morbidities did not differ with the robotic approach.

Timing of Adjuvant Chemotherapy and Impact on Survival for Resected Gastric Cancer.

BACKGROUND: Because postoperative convalescence often prolongs the interval between surgery and chemotherapy in patients undergoing treatment for advanced gastric cancer, this study assesses the survival impact of timing of adjuvant chemotherapy (AC) in patients undergoing curative resection for gastric cancer. METHODS: The 2003-2012 ACS NCDB was analyzed for patients treated with gastrectomy for stages 1-3 gastric cancer. Treatment groups were stratified by time to initiation of AC: initiation of chemotherapy within 8 weeks postoperatively, between 8 and 12 weeks postoperatively, after 12 weeks postoperatively, and no chemotherapy. Univariate and multivariate analyses were performed. RESULTS: Of 7942 patients undergoing gastrectomy, 29 % received AC. Of those who received AC, 58 % initiated AC within 8 weeks, 28 % initiated AC between 8 and 12 weeks, and 14 % received AC after 12 weeks. Among patients who received AC, median survival was not significantly different between time cohorts, even when stratified by pathologic stage. Median survival was longer for chemotherapy cohorts when compared with the no chemotherapy cohort, specifically in patients with pathologic stages 2 and 3 disease. In multivariable analysis, patients who received AC had a 27-29 % lower hazard of death (p < .0001), with administration of AC at any time, compared with patients who did not receive AC, but had no difference in hazard when comparing delayed AC to earlier administration of AC. CONCLUSIONS: Time to initiation of AC does not impact survival. With improved survival over patients who did not receive AC, even delayed initiation of chemotherapy should be offered, when appropriate.

Gastric Cancer, Version 3.2016, NCCN Clinical Practice Guidelines in Oncology.

Gastric cancer is the fifth most frequently diagnosed cancer and the third leading cause of death from cancer in the world. Several advances have been made in the staging procedures, imaging techniques, and treatment approaches. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer provide an evidence- and consensus-based treatment approach for the management of patients with gastric cancer. This manuscript discusses the recommendations outlined in the NCCN Guidelines for staging, assessment of HER2 overexpression, systemic therapy for locally advanced or metastatic disease, and best supportive care for the prevention and management of symptoms due to advanced disease.

Phase I trial of combination of FOLFIRI and pasireotide, a somatostatin analogue, in advanced gastrointestinal malignancies.

INTRODUCTION: Pasireotide (SOM230) is a somatostatin analog with high binding affinity for somatostatin receptors including sst1, 2, 3 and 5 and inhibit insulin like growth factor-1. Blocking of IGF-1 receptor (IGF-1R) in combination with cytotoxic chemotherapy has demonstrated additive or synergistic activity in pre-clinical models. This study aimed to evaluate the maximum tolerated dose (MTD) of pasireotide in combination with standard FOLFIRI (5-fluorouracil, leucovorin and irinotecan) regimen in patients with gastrointestinal malignancies. METHODS: This was a phase 1, 3 + 3 design, open-label dose escalation study conducted in sequential cohorts to determine the MTD of pasireotide in combination with FOLFIRI. All patients had gastrointestinal malignancies and were previously treated. Sixteen patients enrolled in five dose cohorts at pasireotide doses of 40, 60, 80, 100 and 120 mg were evaluated for safety and tolerability of the combination. RESULTS: The tumor types of the enrolled subjects included esophageal (n = 5), biliary tract (n = 3), colon (n = 3), gastric (n = 2), pancreatic (n = 1), anal (n = 1) and small bowel (n = 1). No dose limiting toxicities were observed. The most common adverse events related to the study treatment included hyperglycemia (81 %), neutropenia (62 %), thrombocytopenia (44 %), anorexia (44 %), dehydration (25 %) and elevated alkaline phosphatase (25 %). Two patients had partial response and 7 patients had stable disease. Plasma levels of IGF-1 and IGFBP-3 were significantly reduced after treatment with pasireotide. DISCUSSION: Combination of pasireotide and FOLFIRI has manageable safety profile and is feasible in patients with gastrointestinal malignancies. Preliminary signals of activity were observed. Larger phase II trials are warranted.

Esophageal and esophagogastric junction cancers, version 1.2015.

Esophageal cancer is the sixth most common cause of cancer deaths worldwide. Adenocarcinoma is more common in North America and Western European countries, originating mostly in the lower third of the esophagus, which often involves the esophagogastric junction (EGJ). Recent randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival in patients with resectable cancer. Targeted therapies with trastuzumab and ramucirumab have produced encouraging results in the treatment of advanced or metastatic EGJ adenocarcinomas. Multidisciplinary team management is essential for patients with esophageal and EGJ cancers. This portion of the NCCN Guidelines for Esophageal and EGJ Cancers discusses management of locally advanced adenocarcinoma of the esophagus and EGJ.

The prognostic value of residual nodal disease following neoadjuvant chemoradiation for esophageal cancer in patients with complete primary tumor response.

BACKGROUND: The prognostic significance of residual nodal disease in otherwise complete pathologic responders (ypT0N+) to neoadjuvant chemoradiation (nCRT) for esophageal cancer is unknown. METHODS: ypT0N+ responders were identified from a single institution database of esophageal cancer patients undergoing esophagectomy and were compared to patients without locoregional disease (ypT0N0) and to non-complete responders (ypT+). RESULTS: Out of 487 patients, 196 ypT0N0 and 14 ypT0N+ patients were identified. Pre-treatment stage was similar between ypT0N0 and ypT0N+ patients: 66% versus 73% of patients had uT3 disease (P = 0.50) and 76% versus 55% had nodal involvement (P = 0.49), respectively. Locoregional recurrence (43%) was more common in ypT0N+ patients. Median overall survival (OS) was worse in ypT0N+ patients (14.8 months) compared to ypT0N0 patients (92.2 months) and ypT+ patients (38.0 months, P < 0.001). Median OS of ypT0N+ patients was similar to ypT+ stage II (29.6 months, P = 0.84) and stage III (27.5 months, P = 0.95) disease. No difference in median OS existed in patients with residual nodal disease (n = 163) based on local response (14.8 months in ypT0N+ and 22.5 months in ypT+N+ patients, P = 0.55). CONCLUSIONS: Residual nodal disease in esophageal cancer patients with complete response in the primary tumor following nCRT portends a poor prognosis and behaves similar to pathologic stage II/III disease.

Single-institution retrospective comparison of preoperative versus definitive chemoradiotherapy for adenocarcinoma of the esophagus.

PURPOSE: We sought to determine the impact of esophagectomy on survival in patients with adenocarcinoma of the esophagus cancer after chemoradiotherapy (CRT). METHODS: A database of esophageal cancer was queried for nonmetastatic patients with adenocarcinoma treated between 2000 and 2011 with CRT. Overall survival (OS) and recurrence-free survival (RFS) curves were calculated according to the Kaplan-Meier method and log-rank analysis. Multivariate analysis was performed by the Cox proportional hazard model. RESULTS: We identified 154 patients (60 without surgery; 94 with surgery) who were included in the analysis. The only differences between the 2 groups were more advanced disease stage, improved performance status, and younger age in the surgery group. Patients undergoing surgery had significantly higher survival. Median and 5-year OS for surgical patients were 4.1 years and 43.6 %, versus 1.9 years and 35.6 % for nonsurgical patients (p = 0.007). Multivariate analysis for OS and RFS revealed that factors associated with increased survival were surgical resection, tumor length < 5 cm, male gender, and lower stage. Age, tumor location, radiation dose/technique, and induction chemotherapy were not prognostic. There was a trend toward improved survival on univariate analysis (p = 0.10) and multivariate analysis (p = 0.063) for surgical patients compared to nonsurgical patients who were healthy enough for surgery before CRT (n = 38), and no difference in OS in nonsurgical patients healthy enough for surgery after CRT (n = 22). CONCLUSION: Esophagectomy after CRT is associated with improved survival in patients with adenocarcinoma after CRT. Trimodal therapy should continue to remain the standard of care for esophageal adenocarcinoma.

Is every psychiatrist an oncology psychiatrist?-Special needs for special populations: a scoping review.

BACKGROUND: The evolution of psychiatric care for patients with cancer has played out over the last century. The first collaboration of psychiatry, oncology surgery, and radiation-oncology occurred in the mid-1950s and represented the early seeds of psycho-oncology. The role of a psychiatrist specializing in treating patients with cancer, a psychosocial oncologist or psycho-oncologist, spans the care continuum from prevention to end of life. The specific needs of patients with gastrointestinal (GI) malignancies range from management of anxiety and depression to focused management for adjustment to an ostomy to sexual dysfunction to treatment in the face of a neuroendocrine tumor (NET). METHODS: This is a scoping review; we compiled and summarized psychiatric illnesses commonly encountered in care of patients with cancer in addition to unique GI oncology-related issues. We conducted an electronic PubMed search between 1990-2022. We are presenting the data and providing our insight into psychosocial oncology care for this special population. RESULTS: The field of psycho-oncology is relatively new. We failed to identify any randomized prospective studies, the majority of the studies were retrospective or longitudinal. The majority of the publications were in the form of review. We reviewed the GI literature to identify the psychological impact of ostomies, sexual impairment and metabolically active NETs. We provide suggested treatment interventions targeting the biological, psychological, and social aspects of patient and family lives. CONCLUSIONS: The role of a psychosocial oncologist as part of the collaborative multidisciplinary treatment team provides nuanced care with attention to unique cancer-related issues that arise during the disease course. The psycho-oncologist brings expertise in combining targeted therapeutic strategies with pharmacologic interventions to address the multi-dimensional symptomatology patients experience. Using a layered approach, patients with mild symptoms can be supported by the general team, while those with moderate to severe symptoms require specialty psychiatric consultation.

Palliative care for patients with gastroesophageal cancer at all stages: a narrative review.

BACKGROUND AND OBJECTIVE: Gastroesophageal junction (GEJ) cancer is a highly morbid disease with a poor prognosis. While uncommon in the United States, globally it is ranked as the sixth or seventh most common cancer depending on survey tool. GEJ cancer presents a unique and challenging symptom profile for patients at all disease stages, regardless of histology. Even patients with early stage disease experience debilitating cancer-related symptoms and treatment side effects. The heavy symptom burden associated with this disease includes dysphagia, nausea and vomiting, pain, anxiety, depression and malnutrition. These symptoms require a multidisciplinary approach involving local therapies including radiation and stent placement, systemic cancer-directed therapy, nutritional support, and supportive medical management. This review aims to examine the unique symptom burden experienced by patients with GEJ cancer and provide an updated overview of symptom management techniques. METHODS: A PubMed search was conducted using the terms "gastroesophageal junction cancer AND palliative care". Articles published from 2008 to 2022 with a primary focus on supportive care for patients with GEJ cancers were reviewed. KEY CONTENT AND FINDINGS: A total of 119 articles were identified and screened in our database search. Of these, 22 full text articles met inclusion criteria and were reviewed. Seventeen articles addressed technical interventions for the alleviation of dysphagia, 1 article focused on nutrition, 1 article described the impact of multidisciplinary tumor boards, 1 article presented the effect of home nurse visits, 1 article described the use of antiemetics, and 1 article was a narrative review of supportive care. CONCLUSIONS: In this narrative review, we examine specific supportive care needs in the GEJ cancer population. While the predominant symptom addressed in the literature is dysphagia, patients with GEJ cancer carry a complex symptom burden from diagnosis, through cancer-directed therapy to end-of-life care. Early referral to specialty palliative care should be considered for all patients with GEJ cancer to foster symptom management and delivery of goal concordant care.

Palliative care tumor board: a narrative review and presentation of a novel conference to enhance collaboration and coordination of pain and symptom management for patients with advanced cancer.

BACKGROUND AND OBJECTIVE: The World Health Organization endorses that palliative care has a significant impact on the outcomes of patients with cancer. Integration of palliative care into standard oncology practice has been shown to improve a variety of patient outcomes. In this article, we present our experience with the development of a palliative care tumor board. METHODS: Starting in June 2021, we implemented a multidisciplinary palliative care and oncology tumor board focused on pain and symptom management. Complex cases were presented bimonthly. We retrospectively reviewed our experience. Data were collected on the attendees, the case presented, and the resultant therapeutic decisions made. KEY CONTENT AND FINDINGS: Between June 2021 and September 2022, tumor board meetings were conducted in person and virtually. An average of twelve people attended, including physicians and nurse practitioners from the palliative care, oncology, interventional radiology, radiation oncology, psychiatry, pediatric palliative care, and physical medicine and rehab disciplines. There were 68 patients presented with the most frequently discussed cancer being breast cancer, followed by lung cancer. A total of 18 patients (26%) were referred for procedure, including 7 patients (10%) for radiation and 11 patients (16%) for interventional procedures, and 34 patients (50%) had medication changes as outcomes of the meeting. CONCLUSIONS: The development of a biweekly palliative care conference modeled after traditional oncologic tumor board meetings allows patients to be discussed in a multidisciplinary setting and commonly results in changes in the management for pain and other cancer-related symptoms.

Characterizing after-hours hematology/oncology clinic calls.

BACKGROUND: After-hour calls can be resource intensive and remain a significant challenge to medical practices, though they have historically been poorly or non-reimbursable services. This study reviews after-hour calls from hematology/oncology patients at a cancer center to characterize after-hour care needs, identify care gaps, and look for opportunities to improve outpatient healthcare delivery. METHODS: This descriptive, retrospective Institutional Review Board-approved study analyzed patient calls between June 2015 to February 2021 in an academic hematology/oncology practice. Data from 500 calls were reviewed and cataloged into a database including patient demographics, clinical history, and information surrounding the call (e.g., primary reason for the call, outcome of the call). Calls were also categorized as being urgent or not from a patient or provider's perspective. RESULTS: Among 500 calls, representing 398 unique patients, the average patient was 62 years old and 52% of calls were from females. Most calls were made to report symptoms (65%), followed by calls to follow-up on labs, tests, or imaging (13%), and clarifying treatment plans (10%). Oncology patients represented 67% of calls and hematology (malignant and benign) patients represented 33%. More specifically, patients with gastrointestinal cancer (25%), hematologic malignancies (24%), and thoracic cancer (13%) represented the diagnoses with the highest call volume. CONCLUSIONS: This study explores the complexity and variety of after-hour cancer patient calls. By systematically exploring patient calls, this data can provide insight into patients' needs outside of regular clinic times and help practices develop strategies to anticipate these needs, reduce after-hour call burden, and improve overall quality of care.

Nivolumab plus ONC201 plus in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients: a Brown University Oncology Research Group phase Ib/II study (BrUOG379).

Background: Immune checkpoint inhibitors alone, or in combination with chemotherapy failed to provide meaningful clinical activity for patients with microsatellite stable (MSS) colorectal cancer (CRC). ONC201 is a small molecule that inactivates AKT and ERK signaling and actives the TRAIL pathway. Preclinical studies indicated potential benefits of combining ONC201 with checkpoint inhibitors. This is a phase Ib/II trial of ONC201 plus nivolumab for patient with MSS CRC who progressed on standard treatment. Methods: Enrolled patients received ONC201 plus nivolumab in a dose de-escalation fashion to determine the maximum tolerated dose (MTD). Additional patients were enrolled in the dose-expansion cohort. ONC201 at a dose of 625 mg was given orally at day -7 of cycle 1, followed by weekly dosing. Nivolumab was given every 2 weeks at 240 mg IV starting on day 1 of every cycle (cycle =28 days). The primary end point was dose-limiting toxicity (DLT) during the observation window (run-in dose day -7, cycle 1 to assessment pre-dosing cycle 2). The plan was to enroll 28 additional patients at the MTD so that a total of 34 patients would be treated at the MTD. Pharmacokinetics (PKs) and tumor biopsies were collected at several time points per study protocol. Results: A total of 13 patients (8 patients in the dose escalation *6 evaluable*) were enrolled between December 4, 2019 and March 2021. All patients had received ≥2 previous lines of chemotherapy and had confirmed microsatellite stability or mismatch repair-proficient tumors. No DLTs were observed with 625 mg ONC201 in the first three patients. Three additional patients were enrolled at the same dose to confirm safety. Two patients progressed during the DLT period and had to be replaced. During the dose-expansion part, five patients were enrolled and none required dose reduction or modification. No objective tumor response was observed in the 13 treated patients. Disease progression was confirmed at the time of the first imaging evaluation at 8 weeks following cycle 2. Post discussion at the Data and Safety Monitoring Board (DSMB) on May 25, 2021, the principal investigator (PI) and Committee voted to close the study to new patient enrollment prior to reaching accrual of 34 patients, secondary to lack of efficacy. Conclusions: In this study of patients with advanced MSS CRC, combination ONC201/nivolumab was well-tolerated; objective responses to ONC201/nivolumab were not observed.

Selection of Germline Genetic Testing Panels in Patients With Cancer: ASCO Guideline.

PURPOSE: To guide use of multigene panels for germline genetic testing for patients with cancer. METHODS: An ASCO Expert Panel convened to develop recommendations on the basis of a systematic review of guidelines, consensus statements, and studies of germline and somatic genetic testing. RESULTS: Fifty-two guidelines and consensus statements met eligibility criteria for the primary search; 14 studies were identified for Clinical Question 4. RECOMMENDATIONS: Patients should have a family history taken and recorded that includes details of cancers in first- and second-degree relatives and the patient's ethnicity. When more than one gene is relevant based on personal and/or family history, multigene panel testing should be offered. When considering what genes to include in the panel, the minimal panel should include the more strongly recommended genes from Table 1 and may include those less strongly recommended. A broader panel may be ordered when the potential benefits are clearly identified, and the potential harms from uncertain results should be mitigated. Patients who meet criteria for germline genetic testing should be offered germline testing regardless of results from tumor testing. Patients who would not normally be offered germline genetic testing based on personal and/or family history criteria but who have a pathogenic or likely pathogenic variant identified by tumor testing in a gene listed in Table 2 under the outlined circumstances should be offered germline testing.Additional information is available at www.asco.org/molecular-testing-and-biomarkers-guidelines.

Increased survival associated with surgery and radiation therapy in metastatic gastric cancer: a Surveillance, Epidemiology, and End Results database analysis.

BACKGROUND: Patients with metastatic gastric cancer have poor survival. The purpose of this study was to compare outcomes of metastatic gastric cancer patients stratified by surgery and radiation therapy. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was accessed to identify patients with AJCC M1 stage IV gastric cancer (based on the American Joint Committee on Cancer Cancer Staging Manual, 6th edition) between 2004 thru 2008. Patients were divided into 4 groups: group 1, no surgery or radiation; group 2, radiation alone; group 3, surgery alone; group 4, surgery and radiation. Survival analysis was determined by Kaplan-Meier and log-rank analysis. Multivariate analysis (MVA) was analyzed by the Cox proportional hazard ratio model. RESULTS: A total of 5072 patients were identified. Surgery and/or radiation were associated with a survival benefit. Median and 2-year survival for groups 1, 2, 3, and 4 was 7 months and 8.2%, 8 months and 8.9%, 10 months and 18.2%, and 16 months and 31.7%, respectively (P < .00001). MVA for all patients revealed that surgery and radiation were associated with decreased mortality whereas T-stage, N-stage, age, signet ring histology, and peritoneal metastases were associated with increased mortality. In patients treated with surgery, MVA showed that radiation was associated with decreased mortality, whereas T-stage, N-stage, age, removal of < 15 lymph nodes, signet ring histology, and peritoneal metastases was associated with increased mortality. Age was the only prognostic factor in patients who did not undergo surgery. CONCLUSIONS: Surgery and radiation are associated with increased survival in a subset of patients with metastatic gastric cancer. Prospective trials will be needed to address the role and sequence of surgery and radiation in metastatic gastric cancer.

Outcomes associated with surgery for T4 esophageal cancer.

BACKGROUND: T4 esophageal cancer often portends a dismal prognosis even after surgical resection. Historical incomplete resections and poor survival rates often make surgery palliative rather than curative. METHODS: Using a comprehensive esophageal cancer database, we identified patients who underwent an esophagectomy for T4 tumors between 1994 and 2011. Neoadjuvant treatment (NT) and pathologic response variables were recorded, and response was denoted as complete response (pCR), partial response (pPR), and nonresponse (NR). Clinical and pathologic data were compared. Survival was calculated using Kaplan-Meier curves with log-rank tests for significance. RESULTS: We identified 45 patients with T4 tumors all who underwent NT. The median age was 60 years (range, 31-79 years) with a median follow-up of 27 months (range, 0-122 months). There were 19 pCR (42 %), 22 pPR (49 %), and 4 NR (9 %). R0 resections were accomplished in 43 (96 %). There were 18 recurrences (40 %) with a median time to recurrence of 13.5 months (2.2-71 months). In this group pCR represented 7 (38.9 %), whereas pPR and NR represented 10 (55.5 %), and 1 (5.5 %) respectively. The overall and disease-free survival for all patients with T4 tumors were 35 and 36 %, respectively. Patients achieving a pCR had a 5 year overall and disease-free survival of 53 and 54 %, compared with pPR 23 and 28 %, while there were no 5 year survivors in the NR cohort. CONCLUSION: We have demonstrated that neoadjuvant therapy and downstaging of T4 tumors leads to increased R0 resections and improvements in overall and disease-free survival.

Lymph node harvest in esophageal cancer after neoadjuvant chemoradiotherapy.

BACKGROUND: This study was designed to determine the effects of lymph node (LN) harvest on survival in esophageal cancer after neoadjuvant chemoradiation (nCRT). METHODS: An analysis of surgically resected esophageal cancer patients after nCRT was performed to determine an association between the number of LNs resected and survival. Overall survival (OS) and disease-free survival (DFS) curves were calculated according to the Kaplan-Meier method and log-rank analysis. Multivariate analysis (MVA) was performed by the Cox proportional hazard model. RESULTS: We identified 358 patients with a mean follow-up of 27.3 months. The number of LN removed was not impacted by the type of surgical procedure. The number of LNs removed (<10 vs. ≥10, <12 vs. ≥12, and <15 vs. ≥15) did not impact OS or DFS. We found a significant difference in OS and DFS by pathologic response. The median and 5-year OS for patients with complete, partial, and no response was 65.6 months and 52.7%, 29.7 months and 30.4%, and 17.7 months and 25.4% (p=0.0002). However, the number of LN harvested did not impact OS and DFS when patients were stratified by pathologic response. MVA also revealed that the number of lymph nodes removed was not prognostic for OS or DFS. Higher age, higher stage, and less than a complete response were associated with a decreased OS. Higher stage and less than a complete response were prognostic for worse DFS. CONCLUSIONS: The number of LNs harvested during esophagectomy does not impact survival after nCRT. Stage and pathologic response continue to be the strongest prognostic factors for survival in esophageal cancer after nCRT.