Efficacy and Safety of Neoadjuvant Gemcitabine Plus Nab-Paclitaxel in Borderline Resectable and Locally Advanced Pancreatic Cancer-A Systematic Review and Meta-Analysis.

Therapy with gemcitabine and nab-paclitaxel (GNP) is the most commonly used palliative chemotherapy, but its advantage in the neoadjuvant setting remains unclear. Accordingly, our aim is to evaluate the impact of first-line neoadjuvant therapy with GNP in patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC). A systematic search for published studies until August 2020 was performed. The primary endpoint included resection and R0 resection rates in the intention-to-treat population. Secondary endpoints were response rate, survival and toxicity. Among 21 studies, 950 patients who received neoadjuvant GNP were evaluated. Treatment with GNP resulted in surgical resection and R0 resection rates as follows: 49% (95% CI 30-68%) and 36% (95% CI 17-58%) for BRPC and 16% (95% CI 7-26%) and 11% (95% CI 5-19%) for LAPC, respectively. The objective response rates and the median overall survival (mOS) ranged from 0 to 67% and 12 to 30 months, respectively. Neutropenia (range 5-77%) and neuropathy (range 0-22%) were the most commonly reported grade 3 to 4 adverse events. Neoadjuvant chemotherapy with GNP can be performed safely and with valuable effects in patients with BRPC and LAPC. The utility of GNP in comparison to FOLFIRINOX in the neoadjuvant setting requires further investigation in prospective randomized trials.

Phase I Study of Docetaxel and Temsirolimus in Refractory Solid Tumors.

INTRODUCTION: The mammalian target of rapamycin (mTOR) is a downstream mediator in the phosphatidylinositol 3-kinase/Akt signaling pathway, and plays a central role in cell proliferation, growth, differentiation, migration, and survival. Temsirolimus (CCI-779), a selective inhibitor of the mTOR, is an ester analog of rapamycin (sirolimus) with improved aqueous solubility and pharmacokinetic (PK) properties. Preclinical studies have confirmed additive and synergistic antitumor activity in cancer cell lines (breast, prostate cancer) with combinations of taxanes and mTOR inhibitors. We conducted a phase I open-label, dose-escalation study to determine the maximal tolerated dose (MTD) of docetaxel in combination with temsirolimus in patients with refractory solid tumors. PATIENTS AND METHODS: Eligible patients had a diagnosis of a refractory solid malignancy, measurable disease, and adequate organ function. Patients were sequentially enrolled in 4 dose level intravenous combinations of docetaxel and temsirolimus. Temsirolimus was administered weekly with docetaxel administered every 3 weeks. Laboratory data for tumor markers and radiologic imaging were conducted prestudy and then after every 2 cycles of the treatment. Radiologic response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Blood samples for PK and pharmacodynamic analysis were planned to be drawn at MTD. Apart from the traditional 3+3 design, we also implemented Bayesian Optimal Interval design which uses isotonic regression method to select MTD. We proceeded with isotonic regression analysis by using 20% dose-limiting toxicity (DLT) rate as target. RESULTS: Twenty-six patients were treated in this study in 4 cohorts and dose levels. Fourteen males and 12 females were enrolled with a median age of 50 years (range of 27 to 72 y) and median Eastern Cooperative Oncology Group performance score of 1. Tumor histologies included pancreas (6), colon (5), rectum (3), gallbladder (2), non-small cell lung (2), endometrium (1), neuroendocrine (1), esophagus (1), stomach (1), pharynx (1), small intestine (1), and duodenum (1). Stable disease was observed in 2/4 (50%), 3/7 (43%), 4/10 (40%), and 3/5 (60%) patients in cohorts 1, 2, 3, and 4, respectively. Dose escalation in cohorts 2, 3, and 4 was complicated by DLTs such as grade 4 neutropenia and grade 3 diarrhea and an inability for patients to tolerate treatments during and beyond cycle 1 without dose reductions. Therefore, we could not determine an MTD or recommended phase II dose using the traditional 3+3 study analysis. Blood samples for PK and pharmacodynamic analysis were not collected since MTD was not determined. By using 20% DLT rate closest to the target, isotonic regression analysis showed identical estimated DLT rates in dose -1 (docetaxel 50 mg/m2 and temsirolimus 15 mg/m2) and dose level 1 (docetaxel 60mg/m2 and temsirolimus 15 mg/m2). CONCLUSIONS: Dose escalation of docetaxel and temsirolimus was limited by severe myelosuppressive toxicity in this phase I study. Most of the DLTs occurred after cycle 1 of therapy hence, we were unable to determine MTD or collect blood samples for PK and pharmacodynamic analysis. Our trial did not meet its objectives due to significant DLTs with this chemotherapy combination. Although our novel use of Bayesian Optimal Interval design using isotonic regression method to select MTD showed identical estimated DLT rates in dose levels 1 and -1, clinically our patients were not able to complete 2 cycles of this regimen without dose reductions due to myelosuppressive toxicity in either of these dose levels, and hence, escaped clinical validity. This combination regimen should not be studied further at the dose levels and schedules tested in our study.

Role of Immunotherapy in Advanced Gastroesophageal Cancer.

PURPOSE OF REVIEW: Immunotherapy and tumor microenvironment have been at the forefront of cancer research over the past several decades. Here, we will review the role of immunotherapy in advanced gastroesophageal cancers including targeted antibodies, immunomodulating agents, vaccines, oncolytic virus therapy, and adoptive immunotherapy, and discuss the future direction for immunotherapy in this population. RECENT FINDINGS: Targeted antibodies are already standard-of-care. An anti-PD-1 monoclonal antibody is currently FDA approved for second-line treatment of locally advanced or metastatic ESCC, as well as beyond second-line treatment of advanced G/GEJ cancers, and recent data suggests it may be considered in first-line treatment of advanced G/GEJ cancers. Combination therapies such as immunotherapy plus chemotherapy and/or radiotherapy, vaccines, oncolytic viral therapy, and adoptive immunotherapy in varying combinations are currently under active investigation. Several trials are ongoing and are hoped to reach more efficacious and individualized treatment options in advanced gastroesophageal cancer, where novel treatment options are desperately needed.

The impact of hypertension on cerebral perfusion and cortical thickness in older adults.

Hypertension may increase risk for dementia possibly because of its association with decreased cortical thickness. Disturbed cerebral autoregulation is one plausible mechanism by which hypertension impacts the cerebral structure, but the associations among hypertension, brain perfusion, and cortical thickness are poorly understood. The current sample consisted of 58 older adults with varying levels of vascular disease. Diagnostic history of hypertension and antihypertensive medication status was ascertained through self-report, and when available, confirmed by medical record review. All participants underwent arterial spin labeling and T1-weighted magnetic resonance imaging to quantify total and regional cortical perfusion and thickness. Analysis of covariance adjusting for medical variables showed that participants with hypertension exhibited reduced temporal and occipital brain perfusion and total and regional cortical thickness relative to those without hypertension. The effects of hypertension on total brain perfusion remained unchanged even after adjustment for age, although no such pattern emerged for cortical thickness. Decreased total brain perfusion predicted reduced thickness of the total brain and of the frontal, temporal, and parietal lobe cortices. Antihypertensive treatment was not associated with total cerebral perfusion or cortical thickness. This study provides initial evidence for the adverse effects of a diagnostic history of hypertension on brain hypoperfusion and reduced cortical thickness. Longitudinal studies are needed to investigate the role of hypertension and its interaction with other contributing factors (e.g., age) in the manifestation of cerebral hypoperfusion and reduced cortical thickness.