The effect of nutritional counseling on muscle mass and treatment outcome in patients with metastatic colorectal cancer undergoing chemotherapy: A randomized controlled trial.

BACKGROUND & AIMS: A low muscle mass before start of treatment and loss of muscle mass during chemotherapy is related to adverse outcomes in patients with cancer. In this randomized controlled trial, the effect of nutritional counseling on change in muscle mass and treatment outcome in patients with metastatic colorectal cancer during first-line chemotherapy was studied. METHODS: Patients scheduled for first-line chemotherapy (n = 107) were randomly assigned to individualized nutritional counseling by a dietitian (NC) or usual care (UC). NC was aimed at sufficient protein- and energy intake, supported by oral supplements or enteral feeding if indicated. Furthermore, physical activity was encouraged. Outcomes were assessed at baseline (T0) and the time of the first (T1) and second (T2) regular follow-up computed tomography scans. The proportion of patients with a clinically relevant decrease in skeletal muscle area of ≥6.0 cm2, measured by computed tomography, was the primary outcome. Secondary outcomes included body weight, quality of life, treatment toxicity and progression free and overall survival. RESULTS: A total of 107 patients were enrolled (mean age, 65 years (SD, 11 years), 63% male). Mean change in skeletal muscle area from T0 till T1 was -2.5 (SD, 9.5) cm2, with no difference between NC versus UC (p = 0.891). The proportion of patients with a clinically relevant decrease in skeletal muscle area of ≥6.0 cm2 did not differ (NC 30% versus UC 31%, p = 0.467). NC compared with UC had a significant positive effect on body weight (B coefficient 1.7, p = 0.045), progression free survival (p = 0.039) and overall survival (p = 0.046). CONCLUSIONS: NC of patients undergoing chemotherapy for metastatic colorectal cancer had no effect on muscle mass. However, we found that NC may increase body weight and improve progression free survival and overall survival compared to UC in this group of patients. These findings need further evaluation in future clinical trials. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov NCT01998152; Netherlands Trial Register NTR4223.

Randomized phase 2 study of gemcitabine and cisplatin with or without vitamin supplementation in patients with advanced esophagogastric cancer.

PURPOSE: Preclinical research and prior clinical observations demonstrated reduced toxicity and suggested enhanced efficacy of cisplatin due to folic acid and vitamin B12 suppletion. In this randomized phase 2 trial, we evaluated the addition of folic acid and vitamin B12 to first-line palliative cisplatin and gemcitabine in patients with advanced esophagogastric cancer (AEGC). METHODS: Patients with AEGC were randomized to gemcitabine 1250 mg/m2 (i.v. days 1, 8) and cisplatin 80 mg/m2 (i.v. day 1) q 3 weeks with or without folic acid (450 µg/day p.o.) and vitamin B12 (1000 µg i.m. q 9 weeks). The primary endpoint was response rate (RR). Secondary endpoints included overall survival (OS), time to progression (TTP), toxicity, and exploratory biomarker analyses. Cisplatin sensitivity and intracellular platinum levels were determined in adenocarcinoma cell lines cultured under high and low folate conditions in vitro. RESULTS: Adenocarcinoma cells cultured in medium with high folate levels were more sensitive to cisplatin and this was associated with increased intracellular platinum levels. In the randomized phase 2 clinical trial, which ran from October 2004 to September 2013, treatment was initiated in 78 of 82 randomized pts, 39 in each study arm. The RR was similar; 42.1% for supplemented patients vs. 32.4% for unsupplemented patients; p = 0.4. Median OS and TTP were 10.0 and 5.9 months for supplemented vs. 7.7 and 5.4 months for unsupplemented patients (OS, p = 0.9; TTP, p = 0.9). Plasma homocysteine was lower in the supplemented group [n = 20, 6.9 ± 1.6 (mean ± standard error of mean, SEM) µM; vs. 12.5 ± 4.0 µM; p < 0.001]. There was no significant difference in the Cmax of gemcitabine and cisplatin in the two treatment groups. CONCLUSION: Folic acid and vitamin B12 supplementation do not improve the RR, PFS, or OS of cisplatin and gemcitabine in patients with AEGC.

Photoactivation of lysosomally sequestered sunitinib after angiostatic treatment causes vascular occlusion and enhances tumor growth inhibition.

The angiogenesis inhibitor sunitinib is a tyrosine kinase inhibitor that acts mainly on the VEGF and PDGF pathways. We have previously shown that sunitinib is sequestered in the lysosomes of exposed tumor and endothelial cells. This phenomenon is part of the drug-induced resistance observed in the clinic. Here, we demonstrate that when exposed to light, sequestered sunitinib causes immediate destruction of the lysosomes, resulting in the release of sunitinib and cell death. We hypothesized that this photoactivation of sunitinib could be used as a vaso-occlusive vascular-targeting approach to treating cancer. Spectral properties of sunitinib and its lysosomal accumulation were measured in vitro. The human A2780 ovarian carcinoma transplanted onto the chicken chorioallantoic membrane (CAM) and the Colo-26 colorectal carcinoma model in Balb/c mice were used to test the effects of administrating sunitinib and subsequently exposing tumor tissue to light. Tumors were subsequently resected and subject to immunohistochemical analysis. In A2780 ovarian carcinoma tumors, treatment with sunitinib+light resulted in immediate specific angio-occlusion, leading to a necrotic tumor mass 24 h after treatment. Tumor growth was inhibited by 70% as compared with the control group (**P<0.0001). Similar observations were made in the Colo-26 colorectal carcinoma, where light exposure of the sunitinib-treated mice inhibited tumor growth by 50% as compared with the control and by 25% as compared with sunitinib-only-treated tumors (N≥4; P=0.0002). Histology revealed that photoactivation of sunitinib resulted in a change in tumor vessel architecture. The current results suggest that the spectral properties of sunitinib can be exploited for application against certain cancer indications.

Symptoms from treatment with sunitinib or sorafenib: a multicenter explorative cohort study to explore the influence of patient-reported outcomes on therapy decisions.

PURPOSE: Optimal long-lasting treatment with sunitinib and sorafenib is limited by dose modifications (DMs) due to adverse events (AEs). These AEs may be underrecognized and their influence on health-related quality of life (HRQL) underestimated. Improved insight into the relationship between AEs and therapy decisions is needed. To improve decision making around managing symptoms and reduce DMs, this study was set up to explore the influence of patient-reported symptoms on therapy decisions. METHODS: In this multicenter cohort study, patient characteristics, reasons for and different forms of used dose modifications, and AEs were prospectively obtained from cancer patients on sunitinib/sorafenib treatment. Used instruments to get insight into AEs were the patient-scored Utrecht Symptom Diary (USD) and the professional-scored Common Terminology Criteria for AEs version 3.0. RESULTS: Median total treatment duration in 42 patients was 16 weeks. Median time till dose modification was 10 weeks. DMs occurred mostly due to multiple mild AEs. By using the USD, a higher prevalence of most AEs was found compared to the literature. Sixty percent of the patients experienced a decreased HRQL due to multiple AEs. CONCLUSIONS: Because severe AEs due to sunitinib/sorafenib treatment seldom occur, it is more important to focus on treating and preventing multiple mild AEs with higher impact on HRQL, when trying to avoid dose modifications. Using patient self-reported measurement methods helps to early recognize symptoms and to differentiate among symptom intensities. This systematic approach might help to achieve the optimal dosing, which might improve PFS and OS.

CD133+ circulating haematopoietic progenitor cells predict for response to sorafenib plus erlotinib in non-small cell lung cancer patients.

BACKGROUND: Blood-based biomarkers may be particularly useful for patient selection and prediction of treatment response for angiogenesis inhibitors. Circulating endothelial cells (CECs) and haematopoietic progenitor cells (HPCs) might have a role in tumour angiogenesis and in tumour growth. Measurement of CECs and HPCs in the blood of patients could be a simple, non-invasive way to monitor or predict responses to treatment. METHODS: (VEGFR2(+)) CECs(,) (CD133(+)) HPCs, plasma vascular endothelial growth factor (VEGF) and erythropoietin were measured in blood from 25 non-small cell lung cancer (NSCLC) patients before and during treatment with sorafenib plus erlotinib (SO/ER). In order to assess the drug specificity of changes in CECs and HPCs, 18 patients treated with bevacizumab plus erlotinib (BV/ER) and 10 patients with erlotinib (ER) monotherapy were studied. Response was measured in all patient groups by Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: At day 7, SO/ER-treated patients showed a three-fold increase in CECs (P<0.0001) comparable to BV/ER-treated patients (P<0.01), and the CECs did not change with erlotinib treatment (P=0.8). At day 7, CD133(+)/HPCs decreased with SO/ER treatment (P<0.0001). HPC numbers did not change with either BV/ER or erlotinib. In SO/ER-treated patients pre-treatment CD133(+)/HPCs were significantly lower in responders (P=0.01) and pre-treatment CD133(+)/HPC numbers lower than the median correlated with a longer time-to-progression (TTP) (P=0.037). CONCLUSION: Pre-treatment CD133(+)/HPCs are a promising candidate biomarker to further explore for use in selecting NSCLC patients who might benefit from SO/ER treatment.

Systemic treatment in hepatocellular carcinoma; 'A small step for man...'.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide. In localised disease, orthotopic liver transplantation, surgical resection or local ablations are the mainstay of treatment. In unresectable or metastatic HCC, systemic therapy has unfortunately yielded disappointing results and therefore until recently was generally considered to be ineffective. Most patients with HCC have an underlying liver disease and many drugs may exacerbate the underlying liver disease. Recently, two randomised phase II trials with sorafenib in patients with advanced or metastatic HCC have shown a significant increase in progression free and overall survival of approximately two months, which is an absolute novum for this disease. Sorafenib is therefore now considered a viable treatment option in patients with unresectable or metastatic HCC, a good performance status and Child-Pugh A liver cirrhosis. Despite this very promising result, of major concern is the treatment-related toxicity as observed in these and other trials by sorafenib treatment. However, the important first significant survival benefit by systemic treatment has generated hope for the development of new treatment strategies which will be more efficacious, have favourable toxicity profiles and will further extend survival of this still highly lethal disease.