Therapy with pembrolizumab in treatment-naïve patients with nonmetastatic, mismatch repair deficient colorectal cancer.

Therapy with immune checkpoint inhibitors (ICI) is effective in patients with metastatic mismatch-repair deficient (dMMR) colorectal cancer (CRC); however, data on treatment with neoadjuvant ICI in patients with locally advanced CRC are limited. From March 2019 to June 2020, five Danish oncological centers treated 10 patients with a treatment-naïve dMMR CRC with preoperative pembrolizumab, 9 with a nonmetastatic, unresectable colon cancer and 1 with a locally advanced rectum cancer. All 10 patients were evaluated regularly at a multidisciplinary team (MDT) meeting, and they all had a radical resection after a median of 8 cycles (range 2-13) of pembrolizumab. A microscopic evaluation of the resected tumors revealed no remaining tumor cells in five patients, while five still had tumor cells present. The patients were given no additional therapy. No recurrences were reported after a median follow-up of 26 months (range 23-38.5 months). Biopsies from Danish patients with CRC are routinely screened for dMMR proteins. In 2017, data from the Danish Colorectal Cancer Group showed that 19% (565/3000) of the patients with colon cancer and 1.5% (19/1279) of those with rectum cancer had an dMMR tumor. Among the patients with MMR determination, 26% (99/384) patients had a T4 dMMR colon cancer; thus, the 10 patients treated with neoadjuvant pembrolizumab comprised about 9% of the patients with a T4 dMMR colon cancer (9/99) and 5% of patients with dMMR rectal cancer (1/19). Therapy with pembrolizumab was feasible and effective. Larger prospective trials are needed to confirm our findings.

Preoperative plasma vitamin D in patients with localized colorectal cancer: Age-dependent association with inflammation, postoperative complications, and survival.

INTRODUCTION: Aging is often associated with low-grade chronic inflammation and a senescent immune system. Vitamin D is a regulator of immune function, and low plasma vitamin D is associated with poor health. The association between plasma vitamin D and inflammatory biomarkers and risk of postoperative complications and survival in patients with colorectal cancer (CRC) is unknown. Our aim was to investigate these associations and how they are influenced by age. MATERIALS AND METHODS: Circulating vitamin D and the inflammatory biomarkers C-reactive protein (CRP), interleukin (IL)-6, and YKL-40 were measured in 398 patients with stage I-III CRC preoperatively. Older patients (≥70 years, n = 208) were compared to younger patients (<70 years, n = 190). The relation between vitamin D and complications and high inflammatory biomarker levels was presented by odds ratios ([OR], 95% confidence interval [CI]). Associations with survival were presented with hazard ratios ([HR], 95% CI). RESULTS: Plasma vitamin D was higher in older patients than in younger patients (75 vs. 67 nmol/L, P = 0.001). High vitamin D was associated with low plasma CRP in younger patients (OR = 0.35, 95% CI 0.17-0.76), but not in older patients (OR = 0.93, 0.49-1.76). High vitamin D in older patients with CRC was associated with reduced risk of major complications (OR = 0.52, 0.28-0.95). This was not found in younger patients (OR = 1.47, 0.70-3.11). Deficient vitamin D (<25 nmol/L) was associated with short overall survival compared to sufficient (>50 nmol/L) irrespective of age (HR = 3.39, 1.27-9.37, P = 0.02). CONCLUSION: For patients with localized CRC, high vitamin D levels before resection were associated with reduced risk of high inflammatory biomarkers for younger patients and reduced risk of major postoperative complications for older patients. Vitamin D deficiency was associated with reduced survival regardless of age.

Patterns of Palliative Chemotherapy and Survival in Patients With Pancreatic Cancer Focusing on Age: A Nationwide Real-World Danish Registry Study.

OBJECTIVES: The aim of this study was to identify patterns of palliative chemotherapy (CTh) and the associated overall survival (OS) in patients with pancreatic cancer, with specific focus on age. METHODS: Between May 1, 2011, and April 30, 2016, 4260 patients were registered in the Danish Pancreatic Cancer Database. The 1715 patients receiving palliative CTh were retrieved. Age was grouped into less than 70, 70 to less than 75, and 75 years or more. RESULTS: Of the 1715 patients receiving first-line CTh, 586 (34%) underwent second-line CTh and 151 (9%) third-line CTh. First-line gemcitabine resulted in a significant worse survival compared with combination CTh, hazard ratio 1.51. For combination CTh, OS differed between the age groups, P < 0.01. The median OS in the less than 70 years (n = 547), 70 to less than 75 years (n = 163), and 75 years or more (n = 67) groups were 9.3, 9.6, and 7.2 months, respectively. No differences in survival were observed among patients receiving first-line gemcitabine (P = 0.35). CONCLUSIONS: Our findings are useful in treatment-related decision making in patients with pancreatic cancer. A significant survival benefit was observed for all patients after first-line combination CTh. The effect of combination CTh was most prominent among patients aged less than 75 years. By age, no differences in survival were observed in those receiving gemcitabine.

Initial treatment and survival in 4163 Danish patients with pancreatic cancer: A nationwide unselected real-world register study.

BACKGROUND: Nationwide register data on the effect of primary treatment on survival in an unselected population of patients with pancreatic cancer (PC) have not been reported before. The study aim was to investigate the overall survival (OS) related to initial treatment with resection, chemotherapy, or best supportive care (BSC) in all patients diagnosed with PC in Denmark from 2011 to 2016. METHODS: From 1 May 2011 to 30 April 2016, 4260 patients with PC were identified in the Danish Pancreatic Cancer Database. Ninety-seven patients (2%) were excluded, 56 because of treatment with preoperative chemotherapy, 39 because of incorrect registration of diagnosis or treatment, and 2 because of loss to follow-up; thus, 4163 patients were included. RESULTS: The 718 patients (17%) receiving resection had a median overall survival (mOS) of 21.9 months (range 20.0-24.2). In the chemotherapy group of 1746 patients (42%), those treated with FOLFIRINOX had the longest mOS of 10.0 months (9.2-11.0), whereas those treated with gemcitabine had the shortest mOS of 5.1 months (4.8-5.6). The 1697 patients (41%) receiving BSC had a mOS of only 1.6 months (1.5-1.7). CONCLUSIONS: The resected PC cohort had an OS comparable with that reported in randomised controlled trials (RCTs). The mOS of the chemotherapy-treated patients was slightly shorter compared with the results from RCTs and reflects the unselected population in this study. During the last decade, a larger fraction of patients received anticancer treatment, but the BSC group was still large and showed extremely poor OS.

A systematic review of observational studies of trifluridine/tipiracil (TAS-102) for metastatic colorectal cancer.

Background: The treatment options for patients with therapy refractory metastatic colorectal cancer (mCRC) are sparse. TAS-102 (FTD/TPI) is a new oral anti-tumour agent composed of a nucleoside analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil, indicated for patients with mCRC who are refractory to standard therapies. This study summarizes published and unpublished experience with FTD/TPI in clinical practice settings. Patients and methods: The Medline/PubMed, Embase and Cochrane Library databases were searched to identify observational studies on FTD/TPI monotherapy for mCRC. Papers describing use of FTD/TPI monotherapy outside clinical trials in series of patients evaluable for effectiveness were eligible. The outcomes of interest were median progression free survival (mPFS), median overall survival (mOS) as well as mean PFS time restricted to six months (PFS6m) and mean OS time restricted to one year (OS1y). Results of the pooled analyses of observational studies were compared to the results of the Japanese phase II trial and the two phase III trials, RECOURSE and TERRA. Results: Seven published and two unpublished studies with 1008 patients from 64 centres were included for analysis. The pooled mPFS was 2.2 months (95% CI 2.1 to 2.3 months), and the pooled mOS was 6.6 months (95% CI 6.1 to 7.1 months). PFS6m was 2.9 months (95% CI 2.6 to 3.1 months) and OS1y was 6.8 (95% CI 6.0 to 7.5) months. While these results all reflect RECOURSE, the pooled mOS is lower than in the phase II trial and the OS1y is inferior to both the phase II trial and TERRA. Conclusion: This systematic review and a meta-analysis indicates that in real life settings, the survival benefit of FTD/TPI monotherapy in patients with therapy refractory mCRC reflects the outcomes in RECOURSE but is inferior to outcomes in the two Asian efficacy trials. What is already known TAS 102 (Lonsurf) is an oral fixed dose combination of trifluridine (FTD) and tipiracil (TPI) indicated as salvage-line treatment in patients with therapy refractory metastatic colorectal cancer (mCRC). A Japanese phase II trial and two phase III trials, RECOURSE and TERRA, demonstrated that FTD/TPI prolonged overall survival. What this study adds This systematic review and meta-analysis of real life data from 64 sites indicates that the effectiveness in daily clinical practice settings of FTD/TPI monotherapy in late stage mCRC reflects the outcomes in RECOURCE but is inferior to the outcomes in the Japanese phase II trial and TERRA.

Tissue microRNAs as predictors of outcome in patients with metastatic colorectal cancer treated with first line Capecitabine and Oxaliplatin with or without Bevacizumab.

PURPOSE: We tested the hypothesis that expression of microRNAs (miRNAs) in cancer tissue can predict effectiveness of bevacizumab added to capecitabine and oxaliplatin (CAPEOX) in patients with metastatic colorectal cancer (mCRC). EXPERIMENTAL DESIGN: Patients with mCRC treated with first line CAPEOX and bevacizumab (CAPEOXBEV): screening (n = 212) and validation (n = 121) cohorts, or CAPEOX alone: control cohort (n = 127), were identified retrospectively and archival primary tumor samples were collected. Expression of 754 miRNAs was analyzed in the screening cohort using polymerase chain reaction (PCR) arrays and expression levels were related to time to disease progression (TTP) and overall survival (OS). Significant miRNAs from the screening study were analyzed in all three cohorts using custom PCR arrays. In situ hybridization (ISH) was done for selected miRNAs. RESULTS: In the screening study, 26 miRNAs were significantly correlated with outcome in multivariate analyses. Twenty-two miRNAs were selected for further study. Higher miR-664-3p expression and lower miR-455-5p expression were predictive of improved outcome in the CAPEOXBEV cohorts and showed a significant interaction with bevacizumab effectiveness. The effects were strongest for OS. Both miRNAs showed high expression in stromal cells. Higher expression of miR-196b-5p and miR-592 predicted improved outcome regardless of bevacizumab treatment, with similar effect estimates in all three cohorts. CONCLUSIONS: We have identified potentially predictive miRNAs for bevacizumab effectiveness and additional miRNAs that could be related to chemotherapy effectiveness or prognosis in patients with mCRC. Our findings need further validation in large cohorts, preferably from completed randomized trials.