Delta tocotrienol as a supplement to FOLFOXIRI in first-line treatment of metastatic colorectal cancer. A randomized, double-blind, placebo-controlled phase II study.

PURPOSE: Triplet chemotherapy might be more effective than doublet chemotherapy in metastatic colorectal cancer (mCRC), but it may also be marked by increased toxicity. To investigate whether δ-tocotrienol, a vitamin E analogue, with possible neuroprotective and anti-inflammatory effects, reduces the toxicity of triplet chemotherapy, we conducted a randomized, double-blind, placebo-controlled trial in mCRC patients receiving first-line 5-fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI). MATERIAL AND METHODS: Seventy patients with mCRC were randomly assigned (1:1) to receive FOLFOXIRI plus either δ-tocotrienol or placebo at the Department of Oncology, Vejle Hospital, Denmark. Eligibility criteria were adenocarcinoma in the colon or rectum, age 18-75 years and ECOG performance status 0-1. FOLFOXIRI was given in eight cycles followed by four cycles of 5-fluorouracil. δ-tocotrienol 300 mg or placebo × 3 daily was added during chemotherapy and for a maximum of two years. The primary endpoint was time to hospitalization or death during treatment with chemotherapy. RESULTS: Median time to first hospitalization or death was 3.7 months in the placebo group (95% CI 1.93-not reached (NR)), and was NR in the δ-tocotrienol group (95% CI 1.87-NR) with a hazard ratio of 0.70 (95% CI 0.36-1.36). Grade 3-4 toxicities were uncommon in both groups, except for neutropenia, which occurred in 19 patients (58%) in the placebo group and 17 patients (50%) in the δ-tocotrienol group. There were no grade 3 or 4 peripheral sensory neuropathy. In the placebo group, 24 patients (71%) had oxaliplatin dose reductions compared to 17 patients (47%) in the δ-tocotrienol group (p = 0.047). CONCLUSION: The addition of δ-tocotrienol to FOLFOXIRI did not statistically significant prolong the time to first hospitalization or death compared to FOLFOXIRI plus placebo. Toxicity was manageable and not statistically different. There was a statistically significant difference in dose reductions of oxaliplatin pointing to a possible neuroprotective effect of δ-tocotrienol.

Prognostic impact of early ctDNA dynamics during chemotherapy of metastatic cancer.

Aim: Clinical utility of the dynamics of ctDNA is sparse. This study aimed at evaluating the prognostic impact of early ctDNA dynamics in patients with metastatic cancer treated with chemotherapy. Materials & methods: The ctDNA dynamics were evaluated in 595 patients with metastatic cancer using droplet digital PCR. Results: Patients with an increase in ctDNA after one treatment cycle (n = 73; 12.2%) had an overall survival of 5.6 months compared with 8.6 months in patients with stable or decreasing ctDNA (n = 328; 55.1%) and 21.0 months in patients with undetectable ctDNA (p < 0.001; hazard ratio: 0.47; 95% CI: 0.41-0.53). Conclusion: Early ctDNA dynamics hold important prognostic information and have great implications for evaluation with the perspective of a more individualized treatment strategy.

The Clinical Impact of Methylated Homeobox A9 ctDNA in Patients with Non-Resectable Biliary Tract Cancer Treated with Erlotinib and Bevacizumab.

Methylated homeobox A9 (meth-HOXA9) is tumor specific and has been suggested as a prognostic biomarker in several types of cancer. ctDNA measured as meth-HOXA9 may be a valuable biomarker in the decision-making process about last-line treatment of biliary tract cancer (BTC). The aim of the study was to investigate the clinical impact of meth-HOXA9 in plasma from patients receiving erlotinib and bevacizumab for late-stage BTC and to investigate the treatment effect and adverse events. Droplet digital PCR was applied to detect meth-HOXA9 in 39 patients. Response rates were registered according to RECIST (1.1) and adverse events according to Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE (4.0)). Endpoints were progression-free survival (PFS), overall survival (OS), response rate, and toxicity. A significant difference in PFS and OS between patients with increasing and non-increasing meth-HOXA9 was detected after one treatment cycle, hazard ratio (HR) 12.4 (p < 0.0001) and HR 2.75 (p = 0.04), respectively. The most common adverse events of erlotinib were fatigue, pain, and rash, and those of bevacizumab were bleeding and wounds. This study found meth-HOXA9 to be negatively associated with survival in patients with late-stage BTC. Hence, meth-HOXA9 may guide early discontinuation of ineffective treatment.

NPY Gene Methylation in Circulating Tumor DNA as an Early Biomarker for Treatment Effect in Metastatic Colorectal Cancer.

Despite several limitations, the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) are still the gold standard in response evaluation of metastatic colorectal cancer (mCRC). The aim of the present study was to investigate hypermethylated neuropeptide Y circulating tumor DNA (meth-NPY) as an early biomarker for treatment effect and monitoring in 70 mCRC patients receiving first-line treatment in the FOLFOXIRI-Toco trial. Meth-NPY was analyzed using droplet digital PCR, and the response rate was defined as the fraction of patients converting from a baseline detectable level to an undetectable level after the first treatment cycle (responders). A significant increase in meth-NPY was defined as a value with no overlap between the 95% CI of the current and preceding measurement. Progression-free survival (PFS) was significantly longer in meth-NPY responders compared to non-responders, 10.1 and 7.6 months, respectively (p = 0.02, HR = 0.43). Patients with response according to RECIST 1.1 had a PFS of 10.1 compared to 7.3 months for non-responders (p = 0.17, HR = 0.65). A significant increase in meth-NPY was found with a median of 49 days before radiological progression. In conclusion, early meth-NPY response proved superior to response according to RECIST 1.1 with respect to predicting improved PFS. Meth-NPY is an early indicator of progression, allowing treatment reorientation at an earlier timepoint.

Correlation Between Natural Killer Cell Activity and Treatment Effect in Patients with Disseminated Cancer.

INTRODUCTION: The aim of the present study was to analyze the possible correlation between Natural Killer (NK) cell activity as measured by the NK Vue assay and treatment efficacy in patients with disseminated cancer. MATERIALS AND METHODS: The study included four trials encompassing palliative treatment, i.e. one trial on prostate- and ovarian cancer, respectively, and two trials on colorectal cancer. The current results are based on 93 patients with mature data on treatment effect. Blood samples were collected at baseline and prior to each treatment cycle into NK Vue. Following 24 hours of stimulation the level of interferon-gamma (IFNγ) in the plasma was measured as a surrogate for NK cell activity. RESULTS: The relationship between NK cell activity and treatment response was similar across tumor types and treatment. The IFNγ either remained at or dropped to an abnormal level (<200 pg/mL) during treatment in group 1 (n = 35). In group 2 (n = 30) the level remained within a normal range (>200 pg/mL), while in group 3 (n = 28) it increased from an abnormal to a normal level. The response rate was 14%, 47%, and 82%, respectively, P < .001. The median progression free survival was 2.6 months (95% confidence interval (CI) 2.1-3.9), 10.0 months (95% CI 6.5-11.1), and 8.3 months (95% CI 6.5-8.7), respectively, P < .001 (log-rank). CONCLUSION: Patients lacking the ability to mount an immune response during the first 2 months of treatment have a poor prognosis, and their clinical benefit of the treatment is questionable.

[Immunotherapy is cancer treatment with a novel side-effect profile].

Within the last few years we have treated still more types of cancer with immune checkpoint inhibitors - anti-cytotoxic T-lymphocyte-associated-4 antibodies and anti-program-med cell death 1/anti-programmed cell death ligand 1 antibodies. A unique set of side effects called immune related adverse events irAEs may occur during treatment. Although severe irAEs remain rare they can become life-threatening. Early detection of irAEs and initiation of relevant treatment are therefore crucial to reduce the risk of long-term seque-lae. We provide a detailed overview of irAEs and recommendations for treatment according to established guidelines.

[Imaging of hepatic angiosarcoma]. / Hepatisk angiosarkom som billeddiagnostisk differentialdiagnose til atypisk hæmangiom.

Primary hepatic angiosarcoma (PHA) is a very rare malignant tumour with imaging characteristics that can mimic atypical haemangioma (HA). This is a case report of a 47-year-old male with PHA. Contrast-enhanced ultrasound (CEUS) has shown to be effective in differentiating PHA from HA, CT has more variable findings, in MRI PHA can mimic HA, arteriovenous malformations and cystic metastases, and PET/CT can be used to verify the diagnosis. In this case CEUS was supplied with a contrast CT, MRI and PET/CT. An elevated fluorodeoxyglucose uptake within the left liver lobe was shown on PET/CT.