Diagnostic criteria for cancer cachexia: reduced food intake and inflammation predict weight loss and survival in an international, multi-cohort analysis.

BACKGROUND: Cancer-associated weight loss (WL) associates with increased mortality. International consensus suggests that WL is driven by a variable combination of reduced food intake and/or altered metabolism, the latter often represented by the inflammatory biomarker C-reactive protein (CRP). We aggregated data from Canadian and European research studies to evaluate the associations of reduced food intake and CRP with cancer-associated WL (primary endpoint) and overall survival (OS, secondary endpoint). METHODS: The data set included a total of 12,253 patients at risk for cancer-associated WL. Patient-reported WL history (% in 6 months) and food intake (normal, moderately, or severely reduced) were measured in all patients; CRP (mg/L) and OS were measured in N = 4960 and N = 9952 patients, respectively. All measures were from a baseline assessment. Clinical variables potentially associated with WL and overall survival (OS) including age, sex, cancer diagnosis, disease stage, and performance status were evaluated using multinomial logistic regression MLR and Cox proportional hazards models, respectively. RESULTS: Patients had a mean weight change of -7.3% (±7.1), which was categorized as: ±2.4% (stable weight; 30.4%), 2.5-5.9% (19.7%), 6.0-10.0% (23.2%), 11.0-14.9% (12.0%), ≥15.0% (14.6%). Normal food intake, moderately, and severely reduced food intake occurred in 37.9%, 42.8%, and 19.4%, respectively. In MLR, severe WL (≥15%) (vs. stable weight) was more likely (P < 0.0001) if food intake was moderately [OR 6.28, 95% confidence interval (CI 5.28-7.47)] or severely reduced [OR 18.98 (95% CI 15.30-23.56)]. In subset analysis, adjusted for food intake, CRP was independently associated (P < 0.0001) with ≥15% WL [CRP 10-100 mg/L: OR 2.00, (95% CI 1.58-2.53)] and [CRP > 100 mg/L: OR 2.30 (95% CI 1.62-3.26)]. Diagnosis, stage, and performance status, but not age or sex, were significantly associated with WL. Median OS was 9.9 months (95% CI 9.5-10.3), with median follow-up of 39.7 months (95% CI 38.8-40.6). Moderately and severely reduced food intake and CRP independently predicted OS (P < 0.0001). CONCLUSIONS: Modelling WL as the dependent variable is an approach that can help to identify clinical features and biomarkers associated with WL. Here, we identify criterion values for food intake impairment and CRP that may improve the diagnosis and classification of cancer-associated cachexia.

Laparoscopically assisted versus open oesophagectomy for patients with oesophageal cancer-the Randomised Oesophagectomy: Minimally Invasive or Open (ROMIO) study: protocol for a randomised controlled trial (RCT).

INTRODUCTION: Surgery (oesophagectomy), with neoadjuvant chemo(radio)therapy, is the main curative treatment for patients with oesophageal cancer. Several surgical approaches can be used to remove an oesophageal tumour. The Ivor Lewis (two-phase procedure) is usually used in the UK. This can be performed as an open oesophagectomy (OO), a laparoscopically assisted oesophagectomy (LAO) or a totally minimally invasive oesophagectomy (TMIO). All three are performed in the National Health Service, with LAO and OO the most common. However, there is limited evidence about which surgical approach is best for patients in terms of survival and postoperative health-related quality of life. METHODS AND ANALYSIS: We will undertake a UK multicentre randomised controlled trial to compare LAO with OO in adult patients with oesophageal cancer. The primary outcome is patient-reported physical function at 3 and 6 weeks postoperatively and 3 months after randomisation. Secondary outcomes include: postoperative complications, survival, disease recurrence, other measures of quality of life, spirometry, success of patient blinding and quality assurance measures. A cost-effectiveness analysis will be performed comparing LAO with OO. We will embed a randomised substudy to evaluate the safety and evolution of the TMIO procedure and a qualitative recruitment intervention to optimise patient recruitment. We will analyse the primary outcome using a multi-level regression model. Patients will be monitored for up to 3 years after their surgery. ETHICS AND DISSEMINATION: This study received ethical approval from the South-West Franchay Research Ethics Committee. We will submit the results for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ISRCTN10386621.

Diagnostic criteria for the classification of cancer-associated weight loss.

PURPOSE: Existing definitions of clinically important weight loss (WL) in patients with cancer are unclear and heterogeneous and do not consider current trends toward obesity. METHODS: Canadian and European patients with cancer (n = 8,160) formed a population-based data set. Body mass index (BMI) and percent WL (%WL) were recorded, and patients were observed prospectively until death. Data were entered into a multivariable analysis controlling for age, sex, cancer site, stage, and performance status. Relationships for BMI and %WL to overall survival were examined to develop a grading system. RESULTS: Mean overall %WL was -9.7% ± 8.4% and BMI was 24.4 ± 5.1 kg/m(2), and both %WL and BMI independently predicted survival (P < .01). Differences in survival were observed across five categories of BMI (< 20.0, 20.0 to 21.9, 22.0 to 24.9, 25.0 to 27.9, and ≥ 28.0 kg/m(2); P < .001) and five categories of %WL (-2.5% to -5.9%, -6.0% to -10.9%, -11.0% to -14.9%, ≥ -15.0%, and weight stable (± 2.4%); P < .001). A 5 × 5 matrix representing the five %WL categories within each of the five BMI categories was graded based on median survival and prognostic significance. Weight-stable patients with BMI ≥ 25.0 kg/m(2) (grade 0) had the longest survival (20.9 months; 95% CI, 17.9 to 23.9 months), and %WL values associated with lowered categories of BMI were related to shorter survival (P < .001), as follows: grade 1, 14.6 months (95% CI, 12.9 to 16.2 months); grade 2, 10.8 months (95% CI, 9.7 to 11.9 months); grade 3, 7.6 months (95% CI, 7.0 to 8.2 months); and grade 4, 4.3 months (95% CI, 4.1 to 4.6 months). Survival discrimination by grade was observed within specific cancers, stages, ages, and performance status and in an independent validation sample (n = 2,963). CONCLUSION: A robust grading system incorporating the independent prognostic significance of both BMI and %WL was developed.

Cancer of the gastric cardia is rising in incidence in an Asian population and is associated with adverse outcome.

BACKGROUND: Tumors arising from the esophagogastric junction (OGJ) are increasing in incidence in the west, but data from Asian populations are conflicting. Singapore has a mixed-Asian population with an international lifestyle. This study was designed to examine the changing trends in incidence of gastric cardia cancer (type III) within this population and to compare the clinicopathological characteristics and outcome of these tumors with gastric tumors. METHODS: Trends in cancer incidence were obtained from the Singapore Cancer Registry. Clinicopathological data were prospectively collected from patients undergoing surgery for gastric cancer who presented to the National University Hospital between 2000 and 2005. Patients underwent surgery with or without (neo)adjuvant therapy. Survival duration was analyzed. RESULTS: The incidence of cardia tumors has increased each decade since 1968 (1968-1982, 6.3%; 1983-1992, 7.6%; 1993-1997, 8.4%; 1998-2002, 9.1%; 2003-2007, 16.2%). Among the study population (n = 159) cardia tumors were associated with male sex (p < 0.01) and dysphagia (p < 0.01). Although R0 resection rates were similar, systemic recurrence rates were higher among patients with cardia cancer (p = 0.031) and survival was reduced compared with patients with non-cardia gastric cancer (median survival 26 vs. 69 months; p < 0.001). Cardia location of the tumor and metastatic lymph node ratio were identified as independent adverse prognostic indicators on multivariate analysis. CONCLUSIONS: Similar to western societies, the incidence of proximal gastric cancer is increasing in Singapore. Cardia tumors are associated with poorer outcomes, suggesting that cardia cancer is a distinct disease from true gastric cancer requiring different management strategies to improve the outcome for these patients.

Apoptosis is present in skeletal muscle of cachectic gastro-intestinal cancer patients.

BACKGROUND & AIMS: Previous studies of our research group have shown that apoptosis is present in skeletal muscle of tumour-bearing animals subject to cachexia. For this reason we decided to investigate the apoptosis in skeletal muscle of cancer patients. METHODS AND RESULTS: In the present study, muscle biopsies from weight-losing patients with upper gastro-intestinal cancer showed a significant increase in muscle DNA fragmentation (three-fold), as compared with control subjects. The increase in DNA laddering was associated with an increase in poly(ADP-ribose) polymerase (PARP) cleavage (four-fold) as measured by western blotting. These two events indicate the presence of muscle apoptosis. These changes were associated with a decrease in MyoD protein content, suggesting important alterations in skeletal muscle physiology. CONCLUSIONS: The results presented therefore confirm that apoptosis is also present in human subjects undergoing cancer cachexia.

Host cytokine genotype is related to adverse prognosis and systemic inflammation in gastro-oesophageal cancer.

BACKGROUND: Systemic inflammation has been linked with reduced survival in cancer, however, the role of the host cytokine genotype versus tumour phenotype in the generation of this response is not clearly established. This study examined the relationship between cytokine polymorphisms (IL-1beta 511, IL-6 174, IL-10 1082, TNFalpha 308 and LTalpha +252) and serum cytokine concentrations, serum CRP concentration and survival duration in patients with gastro-oesophageal malignancy. METHODS: Two hundred and three newly diagnosed patients with gastric or oesophageal cancer had serum CRP and cytokine concentrations determined by ELISA. SNP genotyping was performed by Taqman allelic discrimination genotyping and compared with the genotype observed in 266 healthy volunteers. Clinico-pathological information was collected prospectively and survival duration was recorded. RESULTS: Distribution of the cytokine genotypes was similar between patients and controls. The IL-6 174 CC and IL-10 1082 GG genotypes were associated with elevated serum CRP (P = .03, P = .01, respectively; Mann-Whitney U test) and sTNF-R (P = .015, P = .02) concentrations. These genotypes were also associated with reduced survival duration (P = .01, P = .047; log-rank test). TNFalpha AA genotype was also associated with reduced survival duration on univariate (P = .032) and multivariate analysis (P = .006, multivariate model), but not with inflammatory markers. No other cytokine polymorphisms were associated with systemic inflammatory markers or prognosis. CONCLUSIONS: There is a pro-inflammatory cytokine haplotype (IL-6 CC, IL-10 GG, TNFalpha AA) that is associated with adverse prognosis that may act, at least in part, through an inflammatory mediated mechanism. Determining patients' cytokine haplotype may improve prognostication and allow stratification for intervention studies.

Serum parathyroid hormone-related peptide is associated with systemic inflammation and adverse prognosis in gastroesophageal carcinoma.

BACKGROUND: Parathyroid hormone-related peptide (PTHrP) is a tumor-derived circulating factor that has been associated with hypercalcemia of malignancy. The role of PTHrP as a prognostic indicator remains unclear. Studies suggest that it may function as a growth factor; and, recently, the ability of PTHrP to induce cytokine expression has been described. PTHrP also has been proposed as a procachectic factor. In this study, the authors investigated the prognostic value of PTHrP in patients who had gastroesophageal carcinoma without hypercalcemia and determined whether PTHrP was associated with systemic inflammation and adverse nutritional status. METHODS: Patients were recruited at the time of diagnosis. Serum was collected for determination of c-terminal fragment PTHrP (cPTHrP) levels (by radioimmunoassay) and calcium levels as well as levels of serum cytokines and acute-phase proteins (with an enzyme-linked immunosorbent assay). Nutritional assessment of patients was undertaken at the same time as serum collection. Patients underwent routine staging, and survival duration was recorded. RESULTS: One hundred fifty-one patients with esophagogastric carcinoma were recruited. Six of 151 patients (4.0%) patients were hypercalcemic, and 26 patients (17.2%) had elevated serum cPTHrP levels. There was no association between the cPTHrP level and either serum calcium concentrations (P = 0.72) or adverse nutritional status. Elevated cPTHrP, however, was associated with significantly higher serum levels of soluble tumor necrosis factor receptor (P = 0.008) and with significantly lower levels of transferrin (P = 0.009) and albumin (P = 0.02). There was also a weak association with C-related protein levels (P = 0.06). Elevated cPTHrP levels also were associated with an adverse prognosis, as determined by reduced survival duration, on univariate analysis (P = 0.038), but not on multivariate analysis (P = 0.15). CONCLUSIONS: Elevated serum cPTHrP levels were present in approximately 17% of patients with gastroesophageal carcinoma in the absence of hypercalcemia and was associated with markers of systemic inflammation and with an adverse prognosis.

A comparison of computerised tomography, laparoscopic ultrasound and endoscopic ultrasound in the preoperative staging of oesophago-gastric carcinoma.

INTRODUCTION AND OBJECTIVE: Oesophago-gastric carcinoma is associated with a poor prognosis despite advances in diagnosis and treatment. Accurate preoperative staging of gastro-oesophageal carcinoma is, therefore, essential in order to determine patient selection for potentially curative resection. The aim of this study was to evaluate and compare the role of computerised tomography (CT), laparoscopic ultrasound (LapUS) and endoscopic ultrasound (EUS) in the staging of oesophago-gastric carcinoma. METHODS AND PATIENTS: Thirty-six patients with histologically proven carcinoma of the oesophagus or stomach who were considered fit for surgical resection were identified from a prospectively collected database. All patients underwent spiral CT, LapUS and EUS as part of their preoperative staging investigations. RESULTS from the staging modalities were compared retrospectively with final histopathology where available and to intraoperative findings where the tumour was irresectable. RESULTS: Locally advanced tumours (T3/T4) were accurately identified by CT in 15/16 (94%) and by EUS in 14/16 (88%). LapUS was unable to detect 11 tumours (of which five were T3/T4) because they were above the diaphragm, but in the locally advanced cases where the tumour could be seen the accuracy was 10/12 (83%). EUS was the best modality for assessing early tumours and locoregional nodal involvement with accuracies of 8/13 (62%) and 21/29 (72%), respectively. EUS accuracies rose to 64, 92 and 83% for T1/T2, T3/T4 and N staging with the exclusion of those patients (n=6) in whom strictures prevented full assessment. LapUS had a specificity of 100%, compared to 90% for CT and was more accurate than CT for assessing distant metastases (accuracy of 26/32 (81%) compared to 23/32 (72%) for CT). CONCLUSIONS: Although this study is small it has confirmed that CT, EUS and LapUS act in a complimentary manner to provide the most complete preoperative staging for patients with oesophago-gastric cancer.