Neoadjuvant FOLFOXIRI prior to chemoradiotherapy for high-risk ("ugly") locally advanced rectal cancer: study protocol of a single-arm, multicentre, open-label, phase II trial (MEND-IT).

BACKGROUND: The presence of mesorectal fascia (MRF) invasion, grade 4 extramural venous invasion (EMVI), tumour deposits (TD) or extensive or bilateral extramesorectal (lateral) lymph nodes (LLN) on MRI has been suggested to identify patients with indisputable, extensive locally advanced rectal cancer (LARC), at high risk of treatment failure. The aim of this study is to evaluate whether or not intensified chemotherapy prior to neoadjuvant chemoradiotherapy improves the complete response (CR) rate in these patients. METHODS: This multicentre, single-arm, open-label, phase II trial will include 128 patients with non-metastatic high-risk LARC (hr-LARC), fit for triplet chemotherapy. To ensure a study population with indisputable, unfavourable prognostic characteristics, hr-LARC is defined as LARC with on baseline MRI at least one of the following characteristics; MRF invasion, EMVI grade 4, enlarged bilateral or extensive LLN at high risk of an incomplete resection, or TD. Exclusion criteria are the presence of a homozygous DPD deficiency, distant metastases, any chemotherapy within the past 6 months, previous radiotherapy within the pelvic area precluding standard chemoradiotherapy, and any contraindication for the planned treatment. All patients will be planned for six two-weekly cycles of FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) prior to chemoradiotherapy (25 × 2 Gy or 28 × 1.8 Gy with concomitant capecitabine). A resection will be performed following radiological confirmation of resectable disease after the completion of chemoradiotherapy. A watch and wait strategy is allowed in case of a clinical complete response. The primary endpoint is the CR rate, described as a pathological CR or a sustained clinical CR one year after chemoradiotherapy. The main secondary objectives are long-term oncological outcomes, radiological and pathological response, the number of resections with clear margins, treatment-related toxicity, perioperative complications, health-related costs, and quality of life. DISCUSSION: This trial protocol describes the MEND-IT study. The MEND-IT study aims to evaluate the CR rate after intensified chemotherapy prior to concomitant chemoradiotherapy in a homogeneous group of patients with locally advanced rectal cancer and indisputably unfavourable characteristics, defined as hr-LARC, in order to improve their prognosis. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04838496 , registered on 02-04-2021 Netherlands Trial Register: NL9790. PROTOCOL VERSION: Version 3 dd 11-4-2022.

Trastuzumab and pertuzumab combination therapy for advanced pre-treated HER2 exon 20-mutated non-small cell lung cancer.

INTRODUCTION: In 1-3% of non-small cell lung cancer (NSCLC) human epidermal growth factor 2 (HER2) mutations are identified as a genomic driver. Nevertheless, no HER2-targeted treatment is approved for NSCLC. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort 'trastuzumab/pertuzumab for HER2 exon20 mutation positive (HER2m+) NSCLC'. METHODS: Patients with treatment refractory, advanced HER2m+ NSCLC with measurable disease (RECISTv1.1) were eligible. Treatment with intravenous trastuzumab combined with pertuzumab every 3 weeks was administered. The primary end-point was clinical benefit (CB: either objective response or stable disease ≥ 16 weeks). Patients were enrolled using a Simon-like 2-stage design, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 patient had CB in stage 1. At baseline, a biopsy for biomarker analysis, including whole genome sequencing, was obtained. RESULTS: Twenty-four evaluable patients were enrolled and treated between May 2017 and August 2020. CB was observed in 9 patients (38%); including an objective response rate of 8.3% (2 patients had a partial response) and 7 patients with stable disease ≥ 16 weeks. The most frequently observed HER2 mutation was p.Y772_A775dup (71%, n = 20). Median follow-up was 13 months, median progression-free survival and overall survival 4 (95% CI 3-6) and 10 months (95% CI 4 - not reached), respectively. Whole genome sequencing data (available for 67% of patients) confirmed the inclusion mutation in all cases. No unexpected toxicity was observed. CONCLUSION: Despite the fact that the study did meet its primary end-point, trastuzumab/pertuzumab was only marginally active in a subset of patients with heavily pre-treated HER2m+ NSCLC.

Efficacy and toxicity of vemurafenib and cobimetinib in relation to plasma concentrations, after administration via feeding tube in patients with BRAF-mutated thyroid cancer: a case series and review of literature.

INTRODUCTION: The combination of vemurafenib, a proto-oncogene B-Raf inhibitor (BRAFi) and cobimetinib, an inhibitor of mitogen-activated protein kinase kinase (MEKi) has shown to improve survival in patients with BRAF V600-mutated melanoma. BRAF mutations are also frequently detected driver mutations in other tumor types, including thyroid carcinoma. Since thyroid carcinoma is not a labeled indication for BRAF/MEKi, a cohort for patients with BRAF V600-mutated thyroid carcinoma was opened within the Drug Rediscovery Protocol (DRUP), a national ongoing pan-cancer multi-drug trial, in which patients receive off-label treatment with approved drugs based on their molecular tumor profile. RESULTS: Here, we present two patients with BRAF-mutated thyroid carcinoma, who were successfully treated with vemurafenib/cobimetinib administered via a feeding tube. Plasma concentrations of vemurafenib and cobimetinib were determined. A partial response was observed in both patients, but they experienced significant toxicity. CONCLUSION: Our cases show that vemurafenib/cobimetinib treatment is effective in BRAF V600-mutated thyroid carcinoma, also when administered via a feeding tube. Although serious side effects occurred in both patients, we hypothesize that this was not attributable to the administration route. Therefore, administration of vemurafenib/cobimetinib by feeding tube is feasible and effective. TRIAL REGISTRATION: Clinical trial identification: NCT02925234.

Pre-treatment tumor-infiltrating T cells influence response to neoadjuvant chemoradiotherapy in esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a disease with dismal treatment outcomes. Response to neoadjuvant chemoradiation (CRT) varies greatly. Although the underlying mechanisms of CRT resistance are not identified, accumulating evidence indicates an important role for local antitumor immunity. To explore the immune microenvironment in relation to response to CRT we performed an in-depth analysis using multiplex immunohistochemistry, flow cytometry and mRNA expression analysis (NanoString) to generate a detailed map of the immunological landscape of pretreatment biopsies as well as peripheral blood mononuclear cells (PBMCs) of EAC patients. Response to CRT was assessed by Mandard's tumor regression grade (TRG), disease-free- and overall survival. Tumors with a complete pathological response (TRG 1) to neoadjuvant CRT had significantly higher tumor-infiltrating T cell levels compared to all other response groups (TRG 2-5). These T cells were also in closer proximity to tumor cells in complete responders compared to other response groups. Notably, immune profiles of near-complete responders (TRG 2) showed more resemblance to non-responders (TRG 3-5) than to complete responders. A high CD8:CD163 ratio in the tumor was associated with an improved disease-free survival. Gene expression analyses revealed that T cells in non-responders were Th2-skewed, while complete responders were enriched in cytotoxic immune cells. Finally, complete responders were enriched in circulating memory T cells. preexisting immune activation enhances the chance for a complete pathological response to neoadjuvant CRT. This information can potentially be used for future patient selection, but also fuels the development of immunomodulatory strategies to enhance CRT efficacy.

Correction to: [89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer.

Missing Electronic Supplementary Materials.

Sorafenib administered using a high-dose, pulsatile regimen in patients with advanced solid malignancies: a phase I exposure escalation study.

BACKGROUND: (Pre)clinical evidence is accumulating that intermittent exposure to increased doses of protein kinase inhibitors may improve their treatment benefit. In this phase I trial, the safety of high-dose, pulsatile sorafenib was studied. PATIENTS AND METHODS: High-dose sorafenib was administered once weekly in exposure escalation cohorts according to a 3 + 3 design. Drug monitoring was performed in weeks 1-3 and doses were adjusted to achieve a predefined target plasma area under the curve (AUC)(0-12 h). The effect of low gastric pH on improving sorafenib exposure was investigated by intake of the acidic beverage cola. RESULTS: Seventeen patients with advanced malignancies without standard treatment options were included. Once weekly, high-dose sorafenib exposure was escalated up to a target AUC(0-12 h) of 125-150 mg/L/h, achieving a twofold higher Cmax compared to standard continuous dosing. Dose-limiting toxicity was observed in three patients: grade 3 duodenal perforation (2800 mg sorafenib), grade 5 multiorgan failure (2800 mg sorafenib) and grade 5 biliary tract perforation (3600 mg sorafenib). The mean difference between observed and target AUC(0-12 h) was 45% (SD ± 56%) in week 1 using a fixed starting dose of sorafenib compared to 2% (SD ± 32%) in week 3 as a result of drug monitoring (P = 0.06). Dissolving sorafenib in cola, instead of water, did not improve sorafenib exposure. Clinical benefit with stable disease as the best response was observed in two patients. CONCLUSION: Treatment with high-dose, once weekly sorafenib administration resulted in dose-limiting toxicity precluding dose escalation above the exposure cohort of 125-150 mg/L/h. Drug monitoring was a successful strategy to pursue a target exposure.

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.

[89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer.

PURPOSE: One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [89Zr]Zr-cetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy. PATIENTS AND METHODS: PET/CT imaging of [89Zr]Zr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m2 ≤ 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent [89Zr]Zr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks. RESULTS: Visual tumor uptake on [89Zr]Zr-cetuximab PET/CT was observed in 66% of 35 patients. There was no relationship between PET positivity and treatment benefit (52% versus 80% for PET-negative, P = 0.16), progression-free survival (3.6 versus 5.7 months, P = 0.15), or overall survival (7.1 versus 9.4 months, P = 0.29). However, in 67% of PET-negative patients, cetuximab dose escalation (750-1250 mg/m2) was applied, potentially influencing outcome in this group. None of the second [89Zr]Zr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making [89Zr]Zr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUVpeak did not correlate to changes in tumor size on CT (P = 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit. BRAF mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab. CONCLUSION: Tumor uptake on [89Zr]Zr-cetuximab PET/CT failed to predict treatment benefit in patients with RAS wild-type mCRC receiving cetuximab monotherapy. BRAF mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.

The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs.

The large-scale genetic profiling of tumours can identify potentially actionable molecular variants for which approved anticancer drugs are available1-3. However, when patients with such variants are treated with drugs outside of their approved label, successes and failures of targeted therapy are not systematically collected or shared. We therefore initiated the Drug Rediscovery protocol, an adaptive, precision-oncology trial that aims to identify signals of activity in cohorts of patients, with defined tumour types and molecular variants, who are being treated with anticancer drugs outside of their approved label. To be eligible for the trial, patients have to have exhausted or declined standard therapies, and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. Here we show an overall rate of clinical benefit-defined as complete or partial response, or as stable disease beyond 16 weeks-of 34% in 215 treated patients, comprising 136 patients who received targeted therapies and 79 patients who received immunotherapy. The overall median duration of clinical benefit was 9 months (95% confidence interval of 8-11 months), including 26 patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy. The Drug Rediscovery protocol facilitates the defined use of approved drugs beyond their labels in rare subgroups of cancer, identifies early signals of activity in these subgroups, accelerates the clinical translation of new insights into the use of anticancer drugs outside of their approved label, and creates a publicly available repository of knowledge for future decision-making.

Are patient-reported outcomes of physical function a valid substitute for objective measurements?

Background: Physical function is important for defining treatment strategies in patients with cancer and can be estimated using patient-reported outcomes (pros). Although pros are subjective, physical activity and fitness can be tested objectively with adequate, but more labour-intensive methods that are rarely used in daily clinical practice. To determine whether pros for physical function (pro-pf) accurately predict physical function, we studied their interrelationships with objective measures of physical activity and fitness in patients with cancer who had completed cancer treatment, including adjuvant or neoadjuvant chemotherapy or autologous stem-cell transplantation. Methods: Baseline data from the react (Resistance and Endurance Exercise After Chemotherapy) and exist (Exercise Intervention After Stem-Cell Transplantation) studies were evaluated. In those studies, the effects of an exercise intervention on physical fitness, fatigue, and health-related quality of life in patients with cancer shortly after completion of chemotherapy or stem-cell transplantation were studied. Interrelationships between pro-pf (physical function subscale of the European Organisation for Research and Treatment of Cancer 30-question core Quality of Life Questionnaire), physical activity (accelerometer), and cardiorespiratory fitness (peak oxygen uptake) were assessed using univariable and multivariable multilevel linear mixed-model analyses. Results: After adjustment for age, sex, and body mass index, the pro-pf was significantly associated with physical activity (ß = 1.75; 95% confidence interval: 1.08 to 2.42) and cardiorespiratory fitness (ß = 0.10; 95% confidence interval: 0.06 to 0.13). Standardized coefficients were 0.28 and 0.26 respectively, indicating a weak association. Conclusions: The pro-pf is only weakly associated with objective physical activity and fitness evaluation in patients after curative treatment for cancer. The pro-pf cannot, therefore, be used in clinical practice as a substitute for objective measures of physical function.

Radiomics analysis of pre-treatment [18F]FDG PET/CT for patients with metastatic colorectal cancer undergoing palliative systemic treatment.

BACKGROUND: The aim of this study was to assess radiomics features on pre-treatment [18F]FDG positron emission tomography (PET) as potential biomarkers for response and survival in patients with metastatic colorectal cancer (mCRC). METHODS: Patients with mCRC underwent [18F]FDG PET/computed tomography (CT) prior to first- or third-line palliative systemic treatment. Tumour lesions were semiautomatically delineated and standard uptake value (SUV), metabolically active tumour volume (MATV), total lesion glycolysis (TLG), entropy, area under the curve of the cumulative SUV-volume histogram (AUC-CSH), compactness and sphericity were obtained. RESULTS: Lesions of 47 patients receiving third-line systemic treatment had higher SUVmax, SUVpeak, SUVmean, MATV and TLG, and lower AUC-CSH, compactness and sphericity compared to 52 patients receiving first-line systemic treatment. Therefore, first- and third-line groups were evaluated separately. In the first-line group, anatomical changes on CT correlated negatively with TLG (ρ = 0.31) and MATV (ρ = 0.36), and positively with compactness (ρ = -0.27) and sphericity (ρ = -0.27). Patients without benefit had higher mean entropy (p = 0.021). Progression-free survival (PFS) and overall survival (OS) were worse with a decreased mean AUC [hazard ratio (HR) 0.86, HR 0.77] and increase in mean MATV (HR 1.15, HR 1.22), sum MATV (HR 1.14, HR 1.19), mean TLG (HR 1.16, HR 1.22) and sum TLG (HT1.12, HR1.18). In the third-line group, AUC-CSH correlated negatively with anatomical change (ρ = 0.21). PFS and OS were worse with an increased mean MATV (HR 1.27, HR 1.68), sum MATV (HR 1.35, HR 2.04), mean TLG (HR 1.29, HR 1.52) and sum TLG (HT 1.27, HR 1.80). SUVmax and SUVpeak negatively correlated with OS (HR 1.19, HR 1.21). Cluster analysis of the 10 radiomics features demonstrated no complementary value in identifying aggressively growing lesions or patients with impaired survival. CONCLUSION: We demonstrated an association between improved clinical outcome and pre-treatment low tumour volume and heterogeneity as well as high sphericity on [18F]FDG PET. Future PET imaging research should include radiomics features that incorporate tumour volume and heterogeneity when correlating PET data with clinical outcome.

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.

Insight in taste alterations during treatment with protein kinase inhibitors.

The role of Protein Kinase Inhibitors (PKI) in the treatment of various types of cancer is increasingly prominent. Their clinical application is accompanied by the development of side effects, among which patient-reported taste alterations. These alterations are missed frequently, but impair nutritional intake, are associated with weight loss and often result in significant morbidity, especially in the context of chronic administration. Accurate reporting of taste alterations is hampered by lack of modules for symptom objectification and inadequate understanding on the underlying mechanisms. In this review we initially describe the physiology of taste and smell and the mechanism of action of PKIs. We proceed to summarize taste related side effects as reported in major clinical trials and describe possible causal factors. Lastly, an in-depth analysis is given on potential molecular pathways responsible for the PKI-induced taste alterations. Objectification of patient-reported symptoms and universal reporting, along with a better understanding of the underlying mechanisms, will lead to early recognition and optimized treatment, ultimately improving patient adherence and quality of life.

Optimal use of anti-EGFR monoclonal antibodies for patients with advanced colorectal cancer: a meta-analysis.

This meta-analysis was performed to determine the optimal use of anti-EGFR mAb in the treatment of metastasized colorectal cancer (mCRC). Seventeen randomized clinical trials were included, all evaluating the added value of anti-EGFR mAb to standard treatment line in patients with KRAS wild-type mCRC. Hazard and odds ratios were pooled using a random effect model, weighted according to cohort size. Pooled data of six first- and two second-line studies demonstrated a significantly improved ORR (OR 1.62, CI 1.27-2.04; OR 4.78, CI 3.39-6.75, respectively) and PFS (HR 0.79, CI 0.67-0.94; HR 0.80, CI 0.71-0.91, respectively) with the addition of anti-EGFR mAb to chemotherapy, while OS remained similar. Two third-line anti-EGFR mAb monotherapy studies revealed an improved PFS and OS (HR 0.44, CI 0.35-0.52; HR 0.55, CI 0.41-0.74). Addition of anti-EGFR versus anti-VEGF mAb to first-line chemotherapy was evaluated in three studies; ORR and PFS were comparable, while OS was improved (HR 0.8, CI 0.65-0.97). The influence of the chemotherapy backbone on anti-EGFR mAb efficacy, evaluated with meta-regression, indicated a higher ORR with irinotecan-based versus oxaliplatin-based regimens, but comparable PFS and OS. Reported toxicity (≥3 grade) increased ~20% in all treatment lines with the addition of anti-EGFR mAb. Anti-EGFR treatment significantly improves response and survival outcome of patients with (K)RAS wild-type mCRC, regardless of treatment line or chemotherapeutic backbone. Saving anti-EGFR mAb as third-line monotherapy is a valid and effective option to prevent high treatment burden caused by combination therapy. Combination treatment with anti-EGFR mAb to achieve radical resection of metastases needs further investigation.

Does severe toxicity affect global quality of life in patients with metastatic colorectal cancer during palliative systemic treatment? A systematic review.

Background: New palliative systemic treatment regimens in patients with metastatic colorectal cancer (mCRC) have significantly improved overall survival and prognosis. These treatment regimens are often accompanied by increased toxicity, which may impair patients' quality of life (QOL). We systematically reviewed whether severe toxicity affects global QOL in patients with mCRC receiving palliative systemic treatment in recent published randomized controlled trials (RCTs). Materials and methods: Phase III RCTs evaluating palliative systemic treatments in patients with mCRC and published between 2004 and 2016 were considered. Studies were evaluated on the basis of global QOL scores, toxicity during treatment (assessed by scoring relevant adverse events) and primary outcomes (POs). Results: A total of 30 studies were identified in which 19863 patients were included. In 25 out of these 30 trials (83%), no difference in global QOL between treatment arms was observed. In contrast, 22 out of 30 trials (73%) showed increased toxicity during treatment in the experimental arm as compared with the control arm. In 19 out of 22 trials with higher toxicity (86%) global QOL outcomes remained unaffected or improved. In ten out of eleven studies with a better PO, no improvement in global QOL was seen. Conclusion: Global QOL of patients with mCRC included in phase III RCTs evaluating palliative systemic treatment did not differ across treatment arms despite consistently higher toxicity during treatment of the experimental compared with the standard treatment arms. Based on these findings we conclude that the use of global QOL for comparing treatment arms in RCTs for patients with mCRC does not provide information of clinical relevance. Further consideration of how to better assess the net effect of new agents on patients' QOL is urgently needed.

The assessment of anorexia in patients with cancer: cut-off values for the FAACT-A/CS and the VAS for appetite.

PURPOSE: Anorexia is a frequently observed symptom in patients with cancer and is associated with limited food intake and decreased quality of life. Diagnostic instruments such as the Anorexia/Cachexia Subscale (A/CS) of the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire and the visual analog scale (VAS) for appetite have been recommended in the assessment of anorexia, but validated cut-off values are lacking. This study aimed to obtain cut-off values of these instruments for the assessment of anorexia in patients with cancer. METHODS: The FAACT-A/CS and the VAS for appetite were administered to patients with cancer before start of chemotherapy. As reference standard for anorexia, two external criteria were used: (1) a cut-off value of ≥2 on the anorexia symptom scale of the EORTC QLQ C-30 and (2) the question "Do you experience a decreased appetite?" (yes/no). ROC curves were used to examine the optimal cut-off values for the FAACT-A/CS and VAS. RESULTS: A total of 273 patients (58 % male; 64.0 ± 10.6 years) were included. The median score on the FAACT-A/CS was 38 (IQR 32-42) points and 77 (IQR 47-93) points on the VAS. Considering both external criteria, the optimal cut-off value for the FAACT-A/CS was ≤37 (sensitivity (se) 80 %, specificity (sp) 81 %, positive predictive value (PV(+)) 79 %, negative predictive value (PV(-)) 82 %) and for the VAS was ≤70 (se 76 %, sp 83 %, PV(+) 80 %, PV(-) 79 %). CONCLUSIONS: For the assessment of anorexia in patients with cancer, our study suggests cut-off values of ≤37 for the FAACT-A/CS and ≤70 for the VAS. Future studies should confirm our findings in other patient samples.

What is the benefit of treatment with multiple lines of chemotherapy for patients with metastatic breast cancer? A retrospective cohort study.

BACKGROUND: Despite the extensive clinical experience, it is still under debate to what extent patients with metastatic breast cancer (MBC) benefit from multiple lines of chemotherapy beyond standard first or second line treatment. Selection of patients with MBC who will benefit from treatment is crucial to improve outcome and reduce unnecessary toxicity. In this retrospective study, systemic treatment outcome for patients with metastatic MBC is being evaluated. We evaluated to what extent the clinical benefit of prior chemotherapy can predict the success of a subsequent treatment line. METHODS: Ninety-one patients treated with chemotherapy for MBC between January 2005 and January 2009 were included in this study. Clinical characteristics of patients, choices of chemotherapy and response at first evaluation of every treatment line was evaluated based on radiologic and clinical data. RESULTS: Patients received multiple systemic cytotoxic and biological (combination) therapies. 30% of these patients received more than five consecutive systemic (combination) treatments. First line chemotherapy was mostly anthracycline-based, followed by taxanes, capecitabine and vinorelbine. The response rate (RR, complete response plus partial response according to RECIST 1.1) decreased from 20% (95% CI 11-28%) upon first line of treatment to 0% upon the fourth line. The clinical benefit rate (combining RR and stable disease) decreased from 85% (95% CI 78-93%) in the first to 54% (95% CI 26-67) upon the fourth line. 24% of the patients with clinical benefit at first evaluation did not receive a subsequent line of treatment when progressive disease occurred, while sixty-one percent of the patients with progressive disease at first evaluation of a treatment did not receive a subsequent line of chemotherapy. When applied, the efficacy of a subsequent line of treatment was similar for patients independent of previous treatment benefit. CONCLUSION: The clinical benefit at first evaluation from systemic treatment in MBC does not predict for subsequent treatment benefit in this retrospective analysis. The fact that 61% of patients did not receive subsequent treatment after previous treatment failure suggests that either clinical judgement is of critical value in selection of patients to prevent them from unnecessary toxicity or, alternatively indicates that based on the assumption that prior treatment failure predicts for lack of benefit undertreatment of patients occurs. Therefore, a more adequate clinical judgement tool or predictive biomarkers for response are urgently needed to improve treatment outcome.