CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response.

Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response. Inhibiting CXCR4 in an experimental cancer medicine study by 1-wk continuous infusion of the small-molecule inhibitor AMD3100 (plerixafor) induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immune-mediated damage to noninfected tissues: Rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human pancreatic ductal adenocarcinoma and colorectal cancer by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.

Clinicopathological Features of Gastroesophageal Neuroendocrine Neoplasms.

PURPOSE OF REVIEW: Gastroesophageal neuroendocrine neoplasms (NENs) are a rare entity. Recent 2019 WHO classifications reflect our understanding of tumor biology, namely, that distinct molecular characteristics underline tumor behavior and prognosis. Here, we reviewed the evidence for linking molecular findings with the clinicopathological features and treatment of gastroesophageal NENs. RECENT FINDINGS: Degree of differentiation and Ki-67 proliferation index are required for accurate classification of neuroendocrine tumors and carcinomas but not sufficient to distinguish between the two entities. Resection remains the mainstay treatment for early-stage gastroesophageal neuroendocrine tumors. Additional perioperative therapy may benefit mitotically active tumors. There is a role for somatostatin analogues, especially in the setting of metastatic and symptomatic disease. New radiolabeled somatostatin analogues, immunotherapy, and embolization offer multimodality treatments for distant metastases. We need to understand the specific underlying biology of the various subtypes of gastroesophageal NENs to provide tailored treatment.

A phase 2 study of dalantercept, an activin receptor-like kinase-1 ligand trap, in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: Patients with platinum-refractory, recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) have limited options. Activin receptor-like kinase 1 (ALK1) is a type I receptor of the transforming growth factor ß superfamily expressed on activated endothelial cells. Dalantercept is an ALK1 receptor fusion protein that acts as a ligand trap to block signaling through ALK1 and inhibits stages of angiogenesis involved in blood vessel maturation and stabilization. In a phase 1 study, dalantercept demonstrated clinical activity in patients with RM-SCCHN. The objective of the current study was to evaluate the activity of dalantercept in RM-SCCHN. METHODS: Forty-six patients received dalantercept at doses of 80 mg (n = 2), 0.6 mg/kg (n = 13), or 1.2 mg/kg (n = 31) subcutaneously every 3 weeks. The primary endpoint was the overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Secondary endpoints included progression-free survival and overall survival, safety and tolerability, and pharmacokinetic and pharmacodynamic assessments. RESULTS: Forty patients were evaluable for response (13 who received dalantercept 0.6 mg/kg and 27 who received dalantercept 1.2 mg/kg). The overall response rate was 5% (n = 2), and 35% of patients had stable disease; 44% of patients who received 1.2 mg/kg and 30.8% of those who received 0.6 mg/kg achieved disease control (partial response or stable disease). The median progression-fee survival was 1.4 months (95% confidence interval, 1.3-2.2 months), and the median overall survival was 7.1 months (95% confidence interval, 5.5-11.1 months). Drug-related adverse events (>15%) were anemia, fatigue, peripheral edema, headache, and hyponatremia. CONCLUSIONS: In an unselected, heavily pretreated population of patients with RM-SCCHN, dalantercept monotherapy resulted in a favorable safety profile but only modest dose-dependent activity, and it did not meet the primary efficacy objective of the study. Cancer 2016;122:3641-9. © 2016 American Cancer Society.

The role of ¹8F-FDG PET imaging in upper gastrointestinal malignancies.

OPINION STATEMENT: Cancers of the upper gastrointestinal tract form a prevalent and highly morbid group of malignancies. Specifically, median survival for patients with esophagus, gastric, and pancreatic cancers is less than 1 year, and although there has been progress in therapeutic strategies, the vast majority of newly diagnosed patients with these cancers will die of their disease. (18)F-FDG PET ((18)f-fluorodeoxyglucose positron emission tomography) is a useful but underutilized resource for identifying metastatic disease in the upper gastrointestinal tract. While prevalent in the United States, worldwide, (18)F-FDG PET is underutilized especially in countries with a growing emergence of gastroesophageal cancers, despite evidence of clear benefit in cancer staging, and in some cases response assessment and surveillance.

Spectrum of Findings Seen in Patients With IDH1/2-Mutant Cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma-with a growing incidence rate and poor prognosis-is not an aggressive tumor that is not uncommon. Molecular profiling can reveal actionable aberrations in at least a third of the tumors. This is especially so in the case of intrahepatic cholangiocarcinoma (ICC), where mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1/2) make up 15%-20% of these tumors. IDH1/2 mutant ICC is a rare disease that has not been adequately reported. To expand the spectrum of findings seen in these patients, we present a single institution case series. METHODS AND RESULTS: We descriptively characterize the clinical, radiological, and histopathological findings of 12 such patients. IDH1/2 mutant ICC was found in elderly women, with two-thirds of patients having additional co-mutations. Anecdotally, patients who did receive systemic and/or locoregional therapies had long-term durable outcomes. CONCLUSION: Our findings indicate an increasing need to personalize an approach for these patients with specific molecular alterations. With the advent of the IDH1 inhibitor ivosidenib and other inhibitors in this space, IDH1/2 mutation has both prognostic and predictive value. Our series builds upon the patterns and findings seen in these patients.

Met, IGF1R, and other new targets in upper GI malignancies.

OPINION STATEMENT: Upper gastrointestinal (GI) malignancies comprise some of the most aggressive human cancers. Expanding knowledge of molecular mechanisms is finally translating into clinical application, and this has occurred at a relatively rapid rate in the past several years. However, despite recent advances in targeted therapies in upper GI cancers our overall success with targeted therapeutics in this disease area remains dismal. This statement is particularly troubling given some sobering facts: upper GI malignancies are prevalent as well as aggressive with a high morbidity and mortality. Esophagus and gastric cancer combined have an annual global incidence of over 1.2 million new cases annually while median survival is less than 1 year for most patients with metastatic disease. Progress has been limited due to several factors including: disease heterogeneity and variance of phenotype across the globe, clinical trial design strategies that have not yet incorporated selective mechanisms to afford individualized matching of drug to tumor molecular profile and last, a lack of validated predictive markers. Nevertheless there is evidence that many targeted agents can be administered safely at doses that achieve the required effect at the protein level. Several drugs that have negative early trial results can be potentially vital therapeutic agents if patient selection is appropriate.

Neoadjuvant botensilimab plus balstilimab response pattern in locally advanced mismatch repair proficient colorectal cancer.

In patients with locally advanced cancer without distant metastases, the neoadjuvant setting presents a platform to evaluate new drugs. For mismatch repair proficient/microsatellite stable (pMMR/MSS) colon and rectal cancer, immunotherapy has shown limited efficacy. Herein, we report exceptional responses observed with neoadjuvant botensilimab (BOT), an Fc-enhanced next-generation anti-CTLA-4 antibody, alongside balstilimab (BAL; an anti-PD-1 antibody) in two patients with pMMR/MSS colon and rectal cancer. The histological pattern of rapid immune response observed ("inside-out" (serosa-to-mucosa) tumor regression) has not been described previously in this setting. Spatial biology analyses (RareCyte Inc.) reveal mechanisms of actions of BOT, a novel innate-adaptive immune activator. These observations have downstream implications for clinical trial designs using neoadjuvant immunotherapy and potentially sparing patients chemotherapy.

A pilot study treatment of malignant tumors using low-dose 18F-fluorodeoxyglucose (18F-FDG).

Photons, electrons and protons have therapeutic use however positrons have only been used for diagnostic imaging purposes. The energies of positrons (ß+) from F-18 (0.633 MeV) and electrons (ß-) from I-131 (0.606 MeV) are very close and have similar equilibrium dose constants. Since [18F]-fluorodeoxyglucose (18F-FDG) clears rapidly from circulation, administration of 37-74 GBq (1-2 Ci) of 18F-FDG is relatively safe from an internal radiation dosimetry point of view. We initiated a phase I dose escalation study to assess the safety, toxicity, and potential therapeutic utility of administering 100-200 mCi/m2 18F-FDG delivered over a 1 to 5 day period in patients with advanced lymphomas and solid tumors refractory to standard of care treatment (SCT). Here we report the results of the first four patients treated. Four patients with advanced cancers received a single dose of 3.7-7.4 GBq/m2 (100-200 mCi/m2) 18F-FDG. We monitored the patients for adverse effects and for response. No treatment-related toxicities were observed. There was no increased radiation exposure to personnel. Two patients showed decrease in the index lesions' SUVs by 17-33% (Day 1) and 25-31% (Day 30) post treatment. The two other patients showed stable disease on 18F-PET-CT. Interestingly, responses were seen at low radiotherapy doses (below 1 Gy). This exploratory study demonstrated the safety of therapeutic administration of up to 14.2 GBq (385 mCi) 18F-FDG. In patients with 18F-FDG-avid cancers, targeted radionuclide 18F-FDG therapy appears safe and may offer clinical benefit.

Phase I Study of Epigenetic Priming with Azacitidine Prior to Standard Neoadjuvant Chemotherapy for Patients with Resectable Gastric and Esophageal Adenocarcinoma: Evidence of Tumor Hypomethylation as an Indicator of Major Histopathologic Response.

Purpose: Epigenetic silencing of tumor suppressor genes (TSG) is an acquired abnormality observed in cancer and is prototypically linked to DNA methylation. We postulated that pretreatment (priming) with 5-azacitidine would increase the efficacy of chemotherapy by reactivating TSGs. This study was conducted to identify a tolerable dose of 5-azacitidine prior to EOX (epirubicin, oxaliplatin, capecitabine) neoadjuvant chemotherapy in patients with locally advanced esophageal/gastric adenocarcinoma (EGC).Experimental Design: Eligible patients had untreated, locally advanced, resectable EGC, ECOG 0-2, and adequate organ function. 5-Azacitidine (V, 75 mg/m2) was given subcutaneously for 3 (dose level, DL 1) or 5 (DL 2) days prior to each 21-day cycle of EOX (E, 50 mg/m2; O, 130 mg/m2; X, 625 mg/m2 twice daily for 21 days). Standard 3+3 methodology guided V dose escalation. DNA methylation at control and biomarker regions was measured by digital droplet, bisulfite qPCR in tumor samples collected at baseline and at resection.Results: All subjects underwent complete resection of residual tumor (R0). Three of the 12 patients (25%) achieved a surgical complete response and 5 had partial responses. The overall response rate was 67%. The most common toxicities were gastrointestinal and hematologic. Hypomethylation of biomarker genes was observed at all dose levels and trended with therapeutic response.Conclusions: Neoadjuvant VEOX was well-tolerated with significant clinical and epigenetic responses, with preliminary evidence that priming with V prior to chemotherapy may augment chemotherapy efficacy. The recommended phase II trial schedule is 5-azacitidine 75 mg/m2 for 5 days followed by EOX chemotherapy every 21 days. Clin Cancer Res; 23(11); 2673-80. ©2016 AACR.

Chemotherapy dose intensity predicted by baseline nutrition assessment in gastrointestinal malignancies: A multicentre analysis.

BACKGROUND: Malnutrition is prevalent in cancer patients and is associated with inferior outcomes. We examined the association between malnutrition, as measured by the Subjective Global Assessment (SGA), and chemotherapy dose reduction in patients with gastrointestinal malignancies. We hypothesised that malnutrition, defined by a patient's baseline SGA, would be associated with a greater degree of chemotherapy dose-reduction, with the implication of greater chemotherapy related toxicity. DESIGN: We reviewed chemotherapy dosing and treatment related toxicity for patients enrolled in a prospective Gastrointestinal Cancer Registry over their first 8 weeks of treatment. We compared results between well-nourished and malnourished patients. RESULTS: Malnourished patients were more likely than well-nourished patients to have their starting chemotherapy dose reduced from standard published dosing (67% versus 35%, p=0.0001). Despite attenuated initial dosing, malnourished patients received a smaller fraction of planned chemotherapy (mean 80±23% versus 90±15% of cycle 1, p=0.005), primarily due to toxicity-related dose reductions. After controlling for age, gender, Eastern Cooperative Oncology Group performance status (ECOG), albumin, smoking status, body habitus, and weight loss, malnutrition remained the strongest independent predictor of the magnitude of chemotherapy dose reduction (estimate -10.3%, 95% confidence interval -19.0 to -0.1.6%, p=0.020). CONCLUSIONS: Malnutrition is an independent predictor of chemotherapy dose-reduction for toxicity. This study highlights the practical significance of malnutrition in gastrointestinal malignancies and provides a baseline for future nutrition intervention studies to improve chemotherapy tolerability in malnourished patients.

Capecitabine in the treatment of esophageal and gastric cancers.

INTRODUCTION: Fluoropyrimidine therapy has been a mainstay in the treatment of cancers of the esophagus and stomach for nearly half of a century in the form of intravenous 5-fluorouracil. Capecitabine , an oral fluoropyrimidine precursor, was first approved in 2001 for the treatment of metastatic colon cancer and may be used interchangeably with parenteral 5-FU in the treatment of upper gastrointestinal (GI) cancers. AREAS COVERED: In this article, mechanisms of action and synergy with other systemic therapies and radiation are reviewed. A summary of the most important clinical trial results shaping the use of capecitabine in the treatment of cancers of the esophagus and stomach is offered, along with an update of upcoming areas of interest using this agent in these disease types. EXPERT OPINION: Improvements in understanding molecular mechanisms of disease, defining distinct disease subtypes based on histology, genetic background and levels of protein expression as well as signaling pathways may start to clarify the reasons underlying heterogeneous clinical behaviors and different outcomes between patients with seemingly similar tumor types. Capecitabine ushered in the era of oral chemotherapy, providing ease of administration with comparable if not superior efficacy to its older parental counterpart. The best way to fully exploit its potential in gastroesophageal cancers is being actively studied worldwide at all stages of disease management.

Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma.

PURPOSE: To determine the clinical and biologic effects of bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Adults with organ-confined HCC, Eastern Cooperative Oncology Group performance status of 0 to 2, and compensated liver disease were eligible. Patients received bevacizumab 5 mg/kg (n = 12) or 10 mg/kg (n = 34) every 2 weeks until disease progression or treatment-limiting toxicity. The primary objective was to determine whether bevacizumab improved the 6-month progression-free survival (PFS) rate from 40% to 60%. Secondary end points included determining the effects of bevacizumab on arterial enhancement and on plasma cytokine levels and the capacity of patients' plasma to support angiogenesis via an in vitro assay. RESULTS: The study included 46 patients, of whom six had objective responses (13%; 95% CI, 3% to 23%), and 65% were progression free at 6 months. Median PFS time was 6.9 months (95% CI, 6.5 to 9.1 months); overall survival rate was 53% at 1 year, 28% at 2 years, and 23% at 3 years. Grade 3 to 4 adverse events included hypertension (15%) and thrombosis (6%, including 4% with arterial thrombosis). Grade 3 or higher hemorrhage occurred in 11% of patients, including one fatal variceal bleed. Bevacizumab was associated with significant reductions in tumor enhancement by dynamic contrast-enhanced magnetic resonance imaging and reductions in circulating VEGF-A and stromal-derived factor-1 levels. Functional angiogenic activity was associated with VEGF-A levels in patient plasma. CONCLUSION: We observed significant clinical and biologic activity for bevacizumab in nonmetastatic HCC and achieved the primary study end point. Serious bleeding complications occurred in 11% of patients. Further evaluation is warranted in carefully selected patients.

Phase II study of uracil-tegafur with leucovorin in elderly (> or = 75 years old) patients with colorectal cancer: ECOG 1299.

PURPOSE: To evaluate the tolerability and effectiveness of uracil-tegafur (UFT) with leucovorin (LV) in the treatment of elderly patients with advanced colorectal cancer. PATIENTS AND METHODS: Patients > or = 75 years of age with previously untreated colorectal cancer were eligible for this phase II, single-arm, open-label, multicenter cooperative group clinical trial. UFT 100 mg/m2 plus LV 30 mg orally every 8 hours for 28 days every 35 days was administered until progression. RESULTS: Fifty-eight patients were enrolled between June 2000 and July 2001, and 55 were treated. The median age of treated patients was 81 years (range, 75 to 90 years), 26 patients were (47%) women, and 80% had good performance status (0 to 1). The observed overall response rate was 22% (95% CI, 11.8% to 35.0%). The estimated median overall survival time was 13.0 months (95% CI, 9.6 to 17.4 months), and median progression-free survival time was 4.6 months (95% CI, 2.6 to 6.7 months). Among the 56 treated patients (including one ineligible patient), 31 (55%) experienced grade 3 to 4 toxicities, most commonly diarrhea (25%) and GI toxicity (36%), with patients older than 85 years of age at highest risk. CONCLUSION: The results of this trial support the efficacy of oral UFT/LV in elderly patients with colorectal cancer. The regimen is tolerated moderately well overall, particularly as compared with other fluoropyrimidine regimens, although there is increased GI toxicity in the most elderly. These results suggest that studies using newer oral fluoropyrimidine analogs should be investigated in this patient population.