Cachexia and Dietetic Interventions in Patients With Esophagogastric Cancer: A Multicenter Cohort Study.

BACKGROUND: Cachexia is common in patients with esophagogastric cancer and is associated with increased mortality. Nutritional screening and dietetic interventions can be helpful in preventing evolvement of cachexia. Our aim was to study the real-world prevalence and prognostic value of pretreatment cachexia on overall survival (OS) using patient-reported weight loss, and to explore dietetic interventions in esophagogastric cancer. MATERIALS AND METHODS: Patients with esophagogastric cancer (2015-2018), regardless of disease stage, who participated in the Prospective Observational Cohort Study of Esophageal-Gastric Cancer Patients (POCOP) and completed patient-reported outcome measures were included. Data on weight loss and dietetic interventions were retrieved from questionnaires before start of treatment (baseline) and 3 months thereafter. Additional patient data were obtained from the Netherlands Cancer Registry. Cachexia was defined as self-reported >5% half-year body weight loss at baseline or >2% in patients with a body mass index (BMI) <20 kg/m2 according to the Fearon criteria. The association between cachexia and OS was analyzed using multivariable Cox proportional hazard analyses adjusted for sex, age, performance status, comorbidities, primary tumor location, disease stage, histology, and treatment strategy. RESULTS: Of 406 included patients, 48% had pretreatment cachexia, of whom 65% were referred for dietetic consultation at baseline. The proportion of patients with cachexia was the highest among those who received palliative chemotherapy (59%) or best supportive care (67%). Cachexia was associated with decreased OS (hazard ratio, 1.52; 95% CI, 1.11-2.09). Median weight loss after 3-month follow-up was lower in patients with cachexia who were referred to a dietician at baseline compared with those who were not (0% vs 2%; P=.047). CONCLUSIONS: Nearly half of patients with esophagogastric cancer have pretreatment cachexia. Dietetic consultation at baseline was not reported in more than one-third of the patients with cachexia. Because cachexia was independently associated with decreased survival, improving nutritional screening and referral for dietetic consultation are warranted to prevent further deterioration of malnutrition and mortality.

TOXview: a novel graphical presentation of cancer treatment toxicity profiles.

Background: Toxicity profiles play a crucial role in the choice between specific palliative chemotherapy regimens. To optimize the quality of life for cancer patients, patients should be adequately informed about potential toxicities before undergoing chemotherapy. Therefore, we constructed TOXviews, a novel graphical presentation and overview of toxicity profiles to improve information provision about adverse events. As an example, we analyzed first-line chemotherapy regimens for advanced esophagogastric cancer (AEGC). Methods: We searched PubMed, EMBASE, CENTRAL, ASCO and ESMO for prospective phase II or III randomized controlled trials (RCTs) on palliative first-line systemic treatment for AEGC until February 2017. We extracted proportions of Common Terminology Criteria for Adverse Events grade 1-2 (mild) and 3-4 (severe) adverse events from each chemotherapy arm and pooled these by using single-arm meta-analysis. Toxicity profiles per chemotherapy regimen were visualized in bidirectional bar charts with pooled proportions plus 95% confidence intervals. For comparative analysis, chemotherapy regimens were grouped in singlets, doublets and triplets. Results: We included 92 RCTs with a total of 16,963 patients. TOXviews for 3 fluoropyrimidine singlets, 5 cisplatin-containing doublets (C-doublets), 10 fluoropyrimidine non-cisplatin containing doublets (F-doublets), 4 anthracycline-containing triplets (A-triplets) and 5 taxane-containing triplets (T-triplets) were constructed. C-doublets, A-triplets and T-triplets all showed an increased incidence of grade 3-4 adverse events and clinically relevant grade 1-2 adverse events compared to F-doublets. Conclusion: TOXview provides a new graphical presentation and overview of chemotherapy toxicities. TOXviews can be used to educate physicians about the incidences of AEs of systemic therapy and improve informed decision-making.

Reporting of health-related quality of life in randomized controlled trials involving palliative systemic therapy for esophagogastric cancer: a systematic review.

BACKGROUND: Health-related quality of life (HRQoL) assessments are increasingly incorporated into oncological randomized controlled trials (RCTs). The quality of HRQoL reporting in RCTs concerning palliative systemic treatment for advanced esophagogastric cancer is currently unknown. Therefore, we conducted a systematic review to investigate the quality of HRQoL reporting over time. METHODS: PubMed, CENTRAL and EMBASE were searched for RCTs concerning systemic treatment for advanced esophagogastric cancer up to February 2017. The Minimum Standard Checklist for Evaluating HRQoL Outcomes in Cancer Clinical Trials was used to rate the quality of HRQoL reporting. Univariate and multivariate generalized linear regression analysis was used to investigate factors affecting the quality of reporting over time. RESULTS: In total, 37 original RCTs (N = 10,887 patients) were included. The quality of reporting was classified as 'very limited' in 4 studies (11%), 'limited' in 24 studies (65%), and 'probably robust' in 9 studies (24%). HRQoL reporting did not improve over time, and it did not improve following the publication of the CONSORT-PRO statement in 2013. The publication of HRQoL findings in a separate article and second-line treatment were associated with better reporting. CONCLUSIONS: HRQoL reporting in RCTs concerning palliative systemic therapy for advanced esophagogastric cancer is limited and has not improved over time. This systematic review provides specific recommendations for authors to improve HRQoL reporting: formulate hypotheses a priori, clearly describe instrument administration, and handle missing data and interpret findings appropriately.

Quality of Life During Palliative Systemic Therapy for Esophagogastric Cancer: Systematic Review and Meta-Analysis.

BACKGROUND: Palliative systemic therapy can prolong life and reduce tumor-related symptoms for patients with advanced esophagogastric cancer. However, side effects of treatment could negatively affect health-related quality of life (HRQoL). Our aim was to review the literature and conduct a meta-analysis to examine the effect of palliative systemic therapy on HRQoL. METHODS: EMBASE, Medline, and Central were searched for phase II/III randomized controlled trials until April 2018 investigating palliative systemic therapy and HRQoL. Meta-analysis was performed on baseline and follow-up summary values of global health status (GHS) and other European Organisation for Research and Treatment of Cancer scales. A clinically relevant change and difference of 10 points (scale 0-100) was set to assess the course of HRQoL over time within treatment arms as well as between arms. RESULTS: We included 43 randomized controlled trials (N = 13 727 patients). In the first-line and beyond first-line treatment setting, pooled baseline GHS mean estimates were 54.6 (95% confidence interval = 51.9 to 57.3) and 57.9 (95% confidence interval = 55.7 to 60.1), respectively. Thirty-nine (81.3%) treatment arms showed a stable GHS over the course of time. Anthracycline-based triplets, fluoropyrimidine-based doublets without cisplatin, and the addition of trastuzumab to chemotherapy were found to have favorable HRQoL outcomes. HRQoL benefit was observed for taxane monotherapy and several targeted agents over best supportive care beyond first line. CONCLUSIONS: Patients reported impaired GHS at baseline and generally remained stable over time. Anthracycline-based triplets and fluoropyrimidine-based doublets without cisplatin may be preferable first-line treatment options regarding HRQoL for HER2-negative disease. Taxanes and targeted agents could provide HRQoL benefit beyond first line compared with best supportive care.

Phase I Dose Escalation Study with Expansion Cohort of the Addition of Nab-Paclitaxel to Capecitabine and Oxaliplatin (CapOx) as First-Line Treatment of Metastatic Esophagogastric Adenocarcinoma (ACTION Study).

First-line triplet chemotherapy including a taxane may prolong survival in patients with metastatic esophagogastric cancer. The added toxicity of the taxane might be minimized by using nab-paclitaxel. The aim of this phase I study was to determine the feasibility of combining nab-paclitaxel with the standard of care in the Netherlands, capecitabine and oxaliplatin (CapOx). Patients with metastatic esophagogastric adenocarcinoma received oxaliplatin 65 mg/m2 on days 1 and 8, and capecitabine 1000 mg/m2 bid on days 1-14 in a 21-day cycle, with nab-paclitaxel on days 1 and 8 at four dose levels (60, 80, 100, and 120 mg/m2, respectively), using a standard 3 + 3 dose escalation phase, followed by a safety expansion cohort. Baseline tissue and serum markers for activated tumor stroma were assessed as biomarkers for response and survival. Twenty-six patients were included. The first two dose-limiting toxicities (i.e., diarrhea and dehydration) occurred at dose level 3. The resulting maximum tolerable dose (MTD) of 80 mg/m2 was used in the expansion cohort, but was reduced to 60 mg/m2 after three out of eight patients experienced diarrhea grade 3. The objective response rate was 54%. The median progression-free (PFS) and overall survival were 8.0 and 12.8 months, respectively. High baseline serum ADAM12 was associated with a significantly shorter PFS (p = 0.011). In conclusion, albeit that the addition of nab-paclitaxel 60 mg/m2 to CapOx may be better tolerated than other taxane triplets, relevant toxicity was observed. There is a rationale for preserving taxanes for later-line treatment. ADAM12 is a potential biomarker to predict survival, and warrants further investigation.

SOURCE: A Registry-Based Prediction Model for Overall Survival in Patients with Metastatic Oesophageal or Gastric Cancer.

Prediction models are only sparsely available for metastatic oesophagogastric cancer. Because treatment in this setting is often preference-based, decision-making with the aid of a prediction model is wanted. The aim of this study is to construct a prediction model, called SOURCE, for the overall survival in patients with metastatic oesophagogastric cancer. Data from patients with metastatic oesophageal (n = 8010) or gastric (n = 4763) cancer diagnosed during 2005⁻2015 were retrieved from the nationwide Netherlands cancer registry. A multivariate Cox regression model was created to predict overall survival for various treatments. Predictor selection was performed via the Akaike Information Criterion and a Delphi consensus among experts in palliative oesophagogastric cancer. Validation was performed according to a temporal internal-external scheme. The predictive quality was assessed with the concordance-index (c-index) and calibration. The model c-indices showed consistent discriminative ability during validation: 0.71 for oesophageal cancer and 0.68 for gastric cancer. The calibration showed an average slope of 1.0 and intercept of 0.0 for both tumour locations, indicating a close agreement between predicted and observed survival. With a fair c-index and good calibration, SOURCE provides a solid foundation for further investigation in clinical practice to determine its added value in shared decision making.

Prognostic and predictive factors for overall survival in metastatic oesophagogastric cancer: A systematic review and meta-analysis.

BACKGROUND: Consistent evidence on prognostic and predictive factors for advanced oesophagogastric cancer is lacking. Therefore, we performed a systematic review and meta-analysis. METHODS: We searched PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) databases for phase II/III randomised controlled trials (RCTs) until February 2017 on palliative systemic therapy for advanced oesophagogastric cancer that reported prognostic or predictive factors for overall survival (PROSPERO-CRD42014015177). Prognostic factors were identified from multivariate regression analyses in study reports. Factors were considered potentially clinically relevant if statistically significant (P ≤ 0.05) in multivariate analysis in ≥50% of the total number of patients in the pooled sample of the RCTs and were reported with a pooled sample size of ≥600 patients in the first-line or ≥300 patients in the beyond first-line setting. Predictive factors were identified from time-to-event stratified treatment comparisons and deemed potentially clinically relevant if the P-value for interaction between subgroups was ≤0.20 and the hazard ratio in one of the subgroups was significant (P ≤ 0.05). RESULTS: Forty-six original RCTs were included (n = 15,392 patients) reporting on first-line (n = 33) and beyond first-line therapy (n = 13). Seventeen prognostic factors for overall survival in the first-line and four in the beyond first-line treatment setting were potentially clinically relevant. Twenty-one predictive factors in first-line and nine in beyond first-line treatment setting were potentially relevant regarding treatment efficacy. CONCLUSIONS: The prognostic and predictive factors identified in this systematic review can be used to characterise patients in clinical practice, be included in future trial designs, enrich prognostic tools and generate hypotheses to be tested in future research to promote patient-centred treatment.