Antonio Vigano

Prognostic factors in advanced cancer patients: Evidence-based clinical recommendations - A study by the Steering Committee of the European Association for Palliative Care

PURPOSE To offer evidence-based clinical recommendations concerning prognosis in advanced cancer patients. METHODS A Working Group of the Research Network of the European Association for Palliative Care identified clinically significant topics, reviewed the studies, and assigned the level of evidence. A formal meta-analysis was not feasible because of the heterogeneity of published studies and the lack of minimal standards in reporting results. A systematic electronic literature search within the main available medical literature databases was performed for each of the following four areas identified: clinical prediction of survival (CPS), biologic factors, clinical signs and symptoms and psychosocial variables, and prognostic scores. Only studies on patients with advanced cancer and survival < or = 90 days were included. RESULTS A total of 38 studies were evaluated. Level A evidence-based recommendations of prognostic correlation could be formulated for CPS (albeit with a series of limitations of which clinicians must be aware) and prognostic scores. Recommendations on the use of other prognostic factors, such as performance status, symptoms associated with cancer anorexia-cachexia syndrome (weight loss, anorexia, dysphagia, and xerostomia), dyspnea, delirium, and some biologic factors (leukocytosis, lymphocytopenia, and C-reactive protein), reached level B. CONCLUSION Prognostication of life expectancy is a significant clinical commitment for clinicians involved in oncology and palliative care. More accurate prognostication is feasible and can be achieved by combining clinical experience and evidence from the literature. Using and communicating prognostic information should be part of a multidisciplinary palliative care approach.

Quality of life and survival prediction in terminal cancer patients: a multicenter study.

It remains unclear whether health‐related quality of life (HRQoL) measurements from patients and staff can be combined with medical data to predict survival in patients with terminal cancer.

Precision and reliability of strength (Jamar vs. Biodex handgrip) and body composition (dual-energy X-ray absorptiometry vs. bioimpedance analysis) measurements in advanced cancer patients.

Important deteriorations in body composition and strength occur and need to be accurately measured in advanced cancer patients (ACPs). The aim of this study was to establish the relationship between a single-frequency bioimpedance analyzer (BIA) and the dual-energy X-ray absorptiometer (DXA), as well as the Jamar handgrip dynometer and the Biodex handgrip attachment, and to determine the precision of each of these instruments in ACPs. Eighty-one ACPs with non-small-cell lung cancer and gastrointestinal cancer were recruited from the McGill University Health Centre (Montreal, Que.). Consecutive paired measurements, with repositioning between measurements, were obtained for total-body DXA, BIA, Biodex handgrip, and BIA plus Jamar handgrip. The total-body percent coefficient of variation (%CV) for the BIA and DXA were 1.34 and 1.56 for fat mass (FM), respectively, and 0.42 and 0.72 for fat free mass (FFM), respectively. The %CV for the Jamar and Biodex handgrips were 6.3 and 16.7, respectively. Bland-Altman plots were used to characterize the limits of agreement between DXA and BIA for FM (4.60 +/- 7.80 (-3.19 to 12.39) kg) and FFM (-1.87 +/- 7.16 (-9.03 to 5.29) kg). Both DXA and BIA demonstrate good short-term precision in ACPs. However, given its poor accuracy, it remains to be determined if BIA can be used to monitor ACPs for changes in total-body tissue composition as a function of time, whether for observation or response to treatment. Furthermore, because of wide limits of agreement, the DXA and BIA cannot be used interchangeably in research or clinical settings. The Jamar handgrip dynamometer shows more consistency than the Biodex handgrip attachment in ACPs, and should therefore be the preferred measure of changes in strength over time.

Is IL-6 the best pro-inflammatory biomarker of clinical outcomes of cancer cachexia? ☆

BACKGROUND & AIMS Despite the descriptive presence of cancer cachexia (CC) in clinical practice, the underlying mechanisms and diagnostic definition have not been clearly identified. Recent work, attempting to establish diagnostic and staging criteria for CC, has identified IL-6 as a biomarker. This study aimed to investigate the clinical relevance of plasma levels of four pro-inflammatory cytokines (IL-6, IL-1β, IL-8 and TNF-α) in advanced cancer patients (ACP) to further establish their potential in the diagnostic definition of CC. METHODS Blood was obtained from 83 ACP (47 male and 36 female, aged 34-85 years) and analyzed for white blood cells, lymphocytes, C-reactive protein, albumin and cytokines. Subjects completed questionnaires to establish weakness, loss of appetite, fatigue, quality of life and weight loss; completed tests to determine strength, body composition and sarcopenia; and consented to chart review to calculate survival and total days admitted to hospital. RESULTS This study shows that, in ACP, IL-1β is better associated with clinical features of the cachectic condition, such as weakness, loss of appetite, weight loss and sarcopenia, than IL-6. CONCLUSION IL-6 may not best represent the clinical correlates of CC in ACP. Additional cytokines should be considered in the definition of this condition.

Male hypogonadism associated with advanced cancer: a systematic review

Male hypogonadism is commonly diagnosed on the basis of subphysiological concentrations of androgen hormones, and is associated with many symptoms present in advanced cancer. Androgen deficiency might be an important cause of muscle wasting in both cancer cachexia and sarcopenia. We did a systematic review of the clinical association of male hypogonadism in advanced cancer. We searched PubMed, Medline, and Embase for publications on the relation between male hypogonadism and functional status, nutritional status, body composition, symptoms, and quality of life in patients with advanced cancer. Of 381 publications identified, six original articles were included. We found no definitive association between nutritional, functional, or quality-of-life characteristics and male hypogonadism. Possible associations between male hypogonadism and weight loss, low albumin, low-body cell mass index, low-peripheral fat and muscle mass, higher inflammation, higher pain, higher opioid consumption, worse scores for anxiety, depression, and emotional and functional well-being need to be confirmed by better designed studies. There is no clear epidemiological data to indicate whether male hypogonadism is independently associated with clinical and biological sequelae of cancer cachexia, such as higher inflammation, fatigue, and body wasting. Standardised kits sensitive to low concentrations of free-testosterone or bioavailable testosterone are needed to diagnose androgen deficiency in women. A clearer epidemiology of androgen deficiencies in advanced cancer will help determine which patients should receive testosterone-replacement therapy for alleviating cancer cachexia symptoms and improving quality of life.

P‐selectin genotype is associated with the development of cancer cachexia

The variable predisposition to cachexia may, in part, be due to the interaction of host genotype. We analyzed 129 single nucleotide polymorphisms (SNPs) in 80 genes for association with cachexia based on degree of weight loss (>5, >10, >15%) as well as weight loss in the presence of systemic inflammation (C‐reactive protein, >10 mg/l). 775 cancer patients were studied with a validation association study performed on an independently recruited cohort (n = 101) of cancer patients. The C allele (minor allele frequency 10.7%) of the rs6136 (SELP) SNP was found to be associated with weight loss >10% both in the discovery study (odds ratio (OR) 0.52; 95% confidence intervals (CI), 0.29–0.93; p = 0.026) and the validation study (OR 0.09, 95% CI 0.01–0.98, p = 0.035). In separate studies, induction of muscle atrophy gene expression was investigated using qPCR following either tumour‐induced cachexia in rats or intra‐peritoneal injection of lipopolysaccharide in mice. P‐selectin was found to be significantly upregulated in muscle in both models. Identification of P‐selectin as relevant in both animal models and in cachectic cancer patients supports this as a risk factor/potential mediator in cachexia.

Psoas Muscle Area and All-Cause Mortality After Transcatheter Aortic Valve Replacement: The Montreal-Munich Study.

BACKGROUND Psoas muscle area (PMA) is a novel measure of frailty that can be efficiently measured from computed tomography images to help predict risk in older adults referred for transcatheter aortic valve replacement (TAVR). The objective of this study was to determine if PMA would be incrementally predictive of mortality and morbidity after TAVR. METHODS The pre-TAVR computed tomography scans of 208 consecutive patients at 2 hospitals in Montreal and Munich were analyzed to measure the cross-sectional area of the left and right psoas muscles on a single axial slice at the level of L4. The primary outcome was all-cause mortality assessed according to sex-stratified Cox regression models adjusted for the Society of Thoracic Surgeons predicted risk of mortality. RESULTS The mean age was 80.7 ± 6.8 years with 55% women and a total of 57 deaths over a mean follow-up of 504 days. PMA was lower in nonsurvivors compared with survivors among women (12.9 vs 14.5 cm(2); P = 0.047) but not men (21.7 vs 22.4 cm(2); P = 0.50). The association between PMA and all-cause mortality in women persisted after adjustment for Society of Thoracic Surgeons risk (hazard ratio, 0.88 per cm(2); 95% confidence interval, 0.78-0.99). An association between PMA and bleeding complications was seen in men (odds ratio, 0.78; 95% confidence interval, 0.62-0.97). Sensitivity analyses with PMA normalized to body mass index yielded similar results. CONCLUSIONS This study has shown that PMA is a marker of frailty associated with midterm survival in women who undergo TAVR. Further research is warranted to pursue PMA as a prognostic marker and therapeutic target in this vulnerable population.

Relationship Between Angiotensin-Converting Enzyme Gene Polymorphism and Body Composition, Functional Performance, and Blood Biomarkers in Advanced Cancer Patients

Purpose: Nutritional and functional outcome measures have been shown to vary in patients with chronic diseases according to the polymorphic alleles of angiotensin-converting enzyme (ACE), but little is known about the associations between ACE gene polymorphism (ACEGP) and the components of body composition, strength, and selected blood markers in advanced cancer patients (ACP). Experimental Design: Data were collected from an inception cohort of 172 newly diagnosed ACP with gastrointestinal and non–small cell lung cancer. ACEGP status was defined by the presence of one of the following three combinations of alleles: insertion/insertion, insertion/deletion, and deletion/deletion. Body composition measurements using Dual-energy X-ray Absorptiometry comprised of the following: total fat mass, percent body fat, lean body mass, and appendicular lean mass. Body mass index; handgrip force by Jamar dynamometry; subjective recording of nutrition and performance status as per patient-generated subjective global assessment; cell blood count and differential, serum albumin, ACE, and C-reactive protein were also recorded. Results: Multiple regression analysis, controlling for gender, age, diagnosis, treatments (radio/chemo), survival, and medication use (ACE inhibitors, anti-inflammatories, statins) revealed the following significant (P ≤ 0.05) relationships in the insertion/deletion compared with insertion/insertion group: higher hemoglobin (Hb; β, 6.39 g/dl; 95% confidence interval, 0.01-12.78), lower total fat mass (−5.78 kg; −11.62 to 0.07), percent body fat (−6.04%; −12.20 to 0.12), and lean body mass (−3.26 kg; −6.78 to 0.26). When comparing the DD to the II group, higher serum ACE (9.10; 1.96-16.25), Hb (6.25 g/dl; −0.63 to 13.12), and handgrip force by Jamar (6.85 lbs; 0.78-12.93) were found. Conclusion: Of the variables studied, ACEGP seems to be primarily associated with differences in body composition, Hb, and muscle strength in ACP. Further data are needed to determine the clinical effect of ACEGP in cancer cachexia.

MAP3K11/GDF15 axis is a critical driver of cancer cachexia

Cancer associated cachexia affects the majority of cancer patients during the course of the disease and thought to be directly responsible for about a quarter of all cancer deaths. Current evidence suggests that a pro‐inflammatory state may be associated with this syndrome although the molecular mechanisms responsible for the development of cachexia are poorly understood. The purpose of this work was the identification of key drivers of cancer cachexia that could provide a potential point of intervention for the treatment and/or prevention of this syndrome.

Determining the Precision of Dual Energy X-Ray Absorptiometry and Bioelectric Impedance Spectroscopy in the Assessment of Breast Cancer-Related Lymphedema

BACKGROUND The composition of breast cancer-related lymphedema (BCRL) has been shown to evolve from the initial accumulation of fluid to the development of fibrotic lesions and abnormal fat deposition. Therefore, precise and reliable assessments of BCRL are required to develop accurate staging and management. Although dual energy x-ray absorptiometry (DXA) and bioelectric impedance spectroscopy (BIS) have been used to assess BCRL, no study has evaluated the precision of these two modalities in the same cohort. METHODS AND RESULTS We determined the precision of DXA and BIS in lymphedematous (LE) and nonaffected (NA) arms of 24 women with Stage II unilateral BCRL. Precision was calculated from the results of paired bilateral arm measurements obtained from DXA scans measuring fat, lean, and bone mineral masses, BIS measuring extracellular fluid (ECF) and total fluid volume, and circumferential tape measurements (CM) of the arms to calculate the anatomic volume. Precision error was expressed as the root mean square (RMS) of the coefficients of variation (%CV) and standard deviations (SD). RESULTS The precisions of DXA and BIS varied from 1.16% (DXA measurements of LE arm total volume) to 1.86% (BIS LE arm total fluid volume) and from 0.95% (DXA lean mass of NA arm) to 1.72% (DXA BMC of NA arm). Precision of CM measures of arm volume were 1.71% CV for LE arm and 2.51% CV for NA arm. The fat and lean masses of the LE arm exceeded the NA arm by about 15% (p<0.0001). ECF and total fluid volume of LE arm was 22.6% and 19% greater than the NA arm (p<0.0001), respectively. CONCLUSION For BCRL, these findings suggest that DXA and BIS are two measurement instruments that provide acceptable levels of precision for the measurement of arm lean mass, fat mass and ECF volume, respectively.