High intratumoral CD8+ T-cell infiltration is associated with improved survival in prostate cancer patients undergoing radical prostatectomy.

BACKGROUND: A high density of CD8+ tumor infiltrating lymphocytes (TILs) is associated with improved survival in multiple cancers, but its prognostic role in prostate cancer remains controversial. The aim of our study was to evaluate the prognostic value of CD8+ TILs in prostate cancer patients undergoing radical prostatectomy (RP). We hypothesized that elevated density of CD8+ TILs in the RP specimen would correlate with improved clinical outcomes. This information may be helpful for future immunotherapy clinical trial design and treatment selection. METHODS: Tumor microarrays constructed from 230 patients with localized prostate cancers who underwent RP from 2006 to 2012 at Roswell Park Comprehensive Cancer Center were analyzed retrospectively using immunohistochemistry. CD8+ cell density was evaluated using a computerized scoring system. The cohorts were separated by CD8+ TIL density at the 25th percentile (i.e., low 7 or pT3/4). The median follow-up time was 8.4 years. High CD8+ TIL density was associated with improved 5-year overall survival (98% vs. 91%, p = .01) and prostate cancer-specific survival (99% vs. 95%, p = .04) compared with patients with low CD8+ TIL density. There was a trend toward higher 5-year biochemical recurrence-free survival and metastasis-free survival in the cohort of patients with high CD8+ TIL density (52% vs. 38% and 86% vs. 73%, respectively), although the difference did not reach statistical significance (p = .18 and p = .05, respectively). In a multivariate analysis high CD8+ TIL density was an independent favorable prognostic factor for overall survival (hazards ratio = 0.38; 95% confidence interval: 0.17-0.87; p = .02). In contrast to the prognostic value of CD8+ TIL density, the CD8+ cell density in the matched normal prostate tissue was not associated with any clinical outcomes. CONCLUSION: Intratumoral CD8+ T-cell infiltration in the RP specimen is independently associated with improved survival after RP in this high-risk prostate cancer cohort. Pre-RP immunomodulation that promotes intratumoral CD8+ cytotoxic T-cell infiltration may be beneficial for this population.

Oncologist uptake of comprehensive genomic profile guided targeted therapy.

We describe the extent to which comprehensive genomic profiling (CGP) results were used by oncologists to guide targeted therapy selection in a cohort of solid tumor patients tested as part of standard care at Roswell Park Comprehensive Cancer Center June 2016-June 2017, with adequate follow up through September 2018 (n = 620). Overall, 28.4% of CGP tests advised physicians about targeted therapy use supported by companion diagnostic or practice guideline evidence. Post-test targeted therapy uptake was highest for patients in active treatment at the time of order (86% versus 76% of treatment naïve patients), but also took longer to initiate (median 50 days versus 7 days for treatment naïve patients), with few patients (2.6%) receiving targeted agents prior to testing. 100% of patients with resistance variants did not receive targeted agents. Treatment naïve patients received immunotherapy as the most common alternative. When targeted therapy given off-label or in a trial was the best CGP option, (7%) of patients received it. Our data illustrate the appropriate and heterogeneous use of CGP by oncologists as a longitudinal treatment decision tool based on patient history and treatment needs, and that some patients may benefit from testing prior to initiation of other standard treatments.

Treatment recommendations to cancer patients in the context of FDA guidance for next generation sequencing.

BACKGROUND: Regulatory approval of next generation sequencing (NGS) by the FDA is advancing the use of genomic-based precision medicine for the therapeutic management of cancer as standard care. Recent FDA guidance for the classification of genomic variants based on clinical evidence to aid clinicians in understanding the actionability of identified variants provided by comprehensive NGS panels has also been set forth. In this retrospective analysis, we interpreted and applied the FDA variant classification guidance to comprehensive NGS testing performed for advanced cancer patients and assessed oncologist agreement with NGS test treatment recommendations. METHODS: NGS comprehensive genomic profiling was performed in a CLIA certified lab (657 completed tests for 646 patients treated at Roswell Park Comprehensive Cancer Center) between June 2016 and June 2017. Physician treatment recommendations made within 120 days post-test were gathered from tested patients' medical records and classified as targeted therapy, precision medicine clinical trial, immunotherapy, hormonal therapy, chemotherapy/radiation, surgery, transplant, or non-therapeutic (hospice, surveillance, or palliative care). Agreement between NGS test report targeted therapy recommendations based on the FDA variant classification and physician targeted therapy treatment recommendations were evaluated. RESULTS: Excluding variants contraindicating targeted therapy (i.e., KRAS or NRAS mutations), at least one variant with FDA level 1 companion diagnostic supporting evidence as the most actionable was identified in 14% of tests, with physicians most frequently recommending targeted therapy (48%) for patients with these results. This stands in contrast to physicians recommending targeted therapy based on test results with FDA level 2 (practice guideline) or FDA level 3 (clinical trial or off label) evidence as the most actionable result (11 and 4%, respectively). CONCLUSIONS: We found an appropriate "dose-response" relationship between the strength of clinical evidence supporting biomarker-directed targeted therapy based on application of FDA guidance for NGS test variant classification, and subsequent treatment recommendations made by treating physicians. In view of recent changes at FDA, it is paramount to define regulatory grounds and medical policy coverage for NGS testing based on this guidance.

Adjuvant chemotherapy for stage III colon cancer: relative dose intensity and survival among veterans.

BACKGROUND: Given the paucity of information on dose intensity, the objective of this study is to describe the use of adjuvant chemotherapy for stage III colon cancer, focusing on relative dose intensity (RDI), overall survival (OS) and disease-free survival (DFS). METHODS: Retrospective cohort of 367 patients diagnosed with stage III colon cancer in 2003-2008 and treated at 19 VA medical centers. Kaplan-Meier curves summarize 5-year OS and 3-year DFS by chemotherapy regimen and RDI, and multivariable Cox proportional hazards regression was used to model these associations. RESULTS: 5-fluorouracil/leucovorin (FU/LV) was the most commonly initiated regimen in 2003 (94.4%) and 2004 (62.7%); in 2005-2008, a majority of patients (60%-74%) was started on an oxaliplatin-based regimen. Median RDI was 82.3%. Receipt of >70% RDI was associated with better 5-year OS (p < 0.001) and 3-year DFS (P = 0.009) than was receipt of ≤70% RDI, with 5-year OS rates of 66.3% and 50.5%, respectively and 3-year DFS rates of 66.1% and 52.7%, respectively. In the multivariable analysis of 5-year OS, oxaliplatin + 5-FU/LV (versus 5-FU/LV) (HR = 0.55; 95% CI = 0.34-0.91), >70% RDI at the first year (HR = 0.58; 95% CI = 0.37-0.89) and married status (HR = 0.66; 95% CI = 0.45-0.97) were associated with significantly decreased risk of death, while age ≥75 (versus 55-64) (HR = 2.06; 95% CI = 1.25-3.40), Charlson Comorbidity Index (HR = 1.17; 95% CI = 1.06-1.30), T4 tumor status (versus T1/T2) (HR = 5.88; 95% CI = 2.69-12.9), N2 node status (HR = 1.68; 95% CI = 1.12-2.50) and bowel obstruction (HR = 2.32, 95% CI = 1.36-3.95) were associated with significantly increased risk. Similar associations were observed for DFS. CONCLUSION: Patients with stage III colon cancer who received >70% RDI had improved 5-year OS. The association between RDI and survival needs to be examined in studies of adjuvant chemotherapy for colon cancer outside of the VA.

Cost-Effectiveness Analysis of Adjuvant Stage III Colon Cancer Treatment at Veterans Affairs Medical Centers.

The objective of this study was to evaluate the real-world cost effectiveness of adjuvant stage III colon cancer chemotherapy regimens, given that previous analyses have been based on data from clinical trials. The study was designed using integrated decision tree and Markov model, which was developed to evaluate the cost effectiveness of 5-fluorouracil/leucovorin (5-FU/LV), capecitabine, and the combination of each with oxaliplatin. The analysis was performed from a US Veterans Affairs perspective via retrospectively collected data, over a 5-year model time horizon. Outcome and cost data were used to calculate cost per quality adjusted life year (QALY), and one-way and probabilistic sensitivity analyses were performed. In the base case analysis, capecitabine and capecitabine plus oxaliplatin both cost more and were less effective than other regimens, and 5-FU/LV plus oxaliplatin, compared to 5-FU/LV alone, resulted in a cost of $25,997 per QALY gained. Model results were generally robust to parameter variation. Capecitabine plus oxaliplatin could be economically reasonable if full dosing occurred ≥76% of the time (base case 42%). In a real-world setting, the addition of oxaliplatin to 5-FU/LV is more effective but also more costly than 5-FU/LV alone. If full dosing of capecitabine-containing regimens can be assured, they may also be cost-effective strategies.

Intermittent chemotherapy in patients with metastatic androgen-independent prostate cancer: results from ASCENT, a double-blinded, randomized comparison of high-dose calcitriol plus docetaxel with placebo plus docetaxel.

BACKGROUND: Survival in patients with metastatic, chemotherapy-naive, androgen-independent prostate cancer (AIPC) is improved with 10 to 12 cycles of docetaxel-containing chemotherapy but further management is undefined. In the current study, the authors examined retreatment with the same regimen after a treatment holiday. METHODS: Patients treated with docetaxel at a dose of 36 mg/m(2) plus either high-dose calcitriol (DN-101; 45 mug) or placebo administered weekly for 3 of every 4 weeks could suspend treatment if their serum prostate-specific antigen (PSA) level was reduced >or=50% and reached a level or=50% and was >or=2 ng/mL or when there was other evidence of disease progression. The study was not powered to compare treatment holiday outcomes between the 2 arms. RESULTS: A total of 250 patients were randomized 1:1. Overall, 18% of patients (20% in the high-dose calcitriol group and 16% in the placebo group) entered the intermittent chemotherapy arm. The median duration of the first chemotherapy holiday was 18 weeks (range, 4%70 weeks). On resumption of treatment after the first holiday, 45.5% of evaluable patients responded with a >or=50% reduction in serum PSA from their postholiday baseline, 45.5% met the criteria for stable PSA for at least 12 weeks, and 9.1% of patients developed disease progression. CONCLUSIONS: To the authors' knowledge, the current study is the first report of intermittent chemotherapy in patients with AIPC who were prospectively tested in a large multi-institutional trial. This strategy results in a clinically significant duration of chemotherapy holidays and can be offered to a minority of patients. At the time of retreatment, the majority of patients again respond to treatment or their PSA levels stabilized. Additional studies of intermittent chemotherapy are needed to better characterize the optimal patient population and the optimal approach.

Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators.

PURPOSE: To compare the safety and activity of DN-101, a new high-dose oral formulation of calcitriol designed for cancer therapy, and docetaxel with placebo and docetaxel. PATIENTS AND METHODS: Patients with progressive metastatic androgen-independent prostate cancer and adequate organ function received weekly docetaxel 36 mg/m2 intravenously for 3 weeks of a 4-week cycle combined with either 45 microg DN-101 or placebo taken orally 1 day before docetaxel. The primary end point was prostate-specific antigen (PSA) response within 6 months of enrollment, defined as a 50% reduction confirmed at least 4 weeks later. RESULTS: Two hundred fifty patients were randomly assigned. Baseline characteristics were similar in both arms. Within 6 months, PSA responses were seen in 58% in DN-101 patients and 49% in placebo patients (P = .16). Overall, PSA response rates were 63% (DN-101) and 52% (placebo), P = .07. Patients in the DN-101 group had a hazard ratio for death of 0.67 (P = .04) in a multivariate analysis that included baseline hemoglobin and performance status. Median survival has not been reached for the DN-101 arm and is estimated to be 24.5 months using the hazard ratio, compared with 16.4 months for placebo. Grade 3/4 adverse events occurred in 58% of DN-101 patients and in 70% of placebo-treated patients (P = .07). Most common grade 3/4 toxicities for DN-101 versus placebo were neutropenia (10% v 8%), fatigue (8% v 16%), infection (8% v 13%), and hyperglycemia (6% v 12%). CONCLUSION: This study suggests that DN-101 treatment was associated with improved survival, but this will require confirmation because survival was not a primary end point. The addition of weekly DN-101 did not increase the toxicity of weekly docetaxel.

High dose calcitriol may reduce thrombosis in cancer patients.

The incidence of venous and arterial thrombosis in a placebo-controlled randomised trial of DN-101 (high dose calcitriol) with docetaxel versus docetaxel was compared. Of the 13 thrombotic events observed in the 250 patients enroled in this study, two occurred in DN-101 and 11 in placebo-treated patients (P = 0.01). This difference remained significant after adjustment for baseline history of thrombosis, atrial fibrillation and use of anti-thrombotic agents. In vitro and vitamin D receptor (VDR) knockout mouse studies predict that nanomolar concentrations of calcitriol may act as an antithrombotic agent. We report the first clinical observation that supports this hypothesis in humans.