ROMANA 3: A phase 3 safety extension study of anamorelin in advanced non-small-cell lung cancer (NSCLC) patients with cachexia

© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Background: Cancer anorexia-cachexia is a debilitating condition frequently observed in NSCLC patients, characterized by decreased body weight, reduced food intake, and impaired quality of life. Anamorelin, a novel selective ghrelin receptor agonist, has anabolic and appetite-enhancing activities. Patients and methods: ROMANA 3 was a safety extension study of two phase 3, double-blind studies that assessed safety and efficacy of anamorelin in advanced NSCLC patients with cachexia. Patients with preserved Eastern Cooperative Oncology Group ≤ 2 after completing 12 weeks (w) on the ROMANA 1 or ROMANA 2 trials (0-12 weeks) could enroll in ROMANA 3 and continue to receive anamorelin 100 mg or placebo once daily for an additional 12w (12-24 weeks). The primary endpoint of ROMANA 3 was anamorelin safety/tolerability (12-24 weeks). Secondary endpoints included changes in body weight, handgrip strength (HGS), and symptom burden (0-24 weeks). Results: Of the 703 patients who completed ROMANA 1 and ROMANA 2, 513 patients entered ROMANA 3 (anamorelin, N = 345, mean age 62.0 years; placebo, N = 168; mean age 62.2 years). During ROMANA 3, anamorelin and placebo groups had similar incidences of treatment-emergent adverse events (TEAEs; 52.2% versus 55.7%), grade ≥ 3 TEAEs (22.4% versus 21.6%), and serious TEAEs (12.8% versus 12.6%). There were 36 (10.5%) and 23 (13.8%) deaths in the anamorelin and placebo groups, respectively; none were drug-related. Improvements in body weight and anorexia-cachexia symptoms observed in the original trials were consistently maintained over 12-24 weeks. Anamorelin, versus placebo, significantly increased body weight from baseline of original trials at all time points (P < 0.0001) and improved anorexia-cachexia symptoms at weeks 3, 6, 9, 12, and 16 (P < 0.05). No significant improvement in HGS was seen in either group. Conclusion: During the 12-24 weeks ROMANA 3 trial, anamorelin continued to be well tolerated. Over the entire 0-24w treatment period, body weight and symptom burden were improved with anamorelin

The response of leptin, interleukin-6 and fat oxidation to feeding in weight-losing patients with pancreatic cancer

At baseline, weight-losing pancreatic cancer patients (n=7) had lower leptin (P&#60;0.05) but higher cortisol, interleukin-6, resting energy expenditure and fat oxidation than healthy subjects (n=6, P&lt;0.05). Over a 4 h feeding period, the areas under the curve for glucose, cortisol and interleukin-6 were greater (P&#60;0.05), but less for leptin in the cancer group (P&#60;0.05). Therefore, it would appear that low leptin concentrations, increased fat oxidation and insulin resistance are associated with increased concentrations of cortisol and interleukin-6 in weight-losing patients with pancreatic cancer

The systemic inflammatory response, weight loss, performance status and survival in patients with inoperable non-small cell lung cancer

The relationship between the magnitude of systemic inflammatory response and the nutritional/functional parameters in patients with inoperable non-small cell lung cancer were studied. The extent of weight loss, albumin, C-reactive protein, performance status and quality of life was measured in 106 patients with inoperable non-small cell lung cancer (stages III and IV). Survival analysis was performed using the Cox proportional hazard model. The majority of patients were male and almost 80% had elevated circulating C-reactive protein concentrations (>10 mg l−1). On multivariate analysis, age (P=0.012), tumour type (0.002), weight loss (P=0.056), C-reactive protein (P=0.047), Karnofsky performance status (P=0.002) and fatigue (P=0.046) were independent predictors of survival. The patients were grouped according to the magnitude of the C-reactive protein concentrations (⩽10, 11–100 and >100 mg l−1). An increase in the magnitude of the systemic inflammatory response was associated with increased weight loss (P=0.004), reduced albumin concentrations (P=0.001), reduced performance status (P=0.060), increased fatigue (P=0.011) and reduced survival (HR 1.936 95%CI 1.414–2.650, P<0.001). These results indicate that the majority of patients with inoperable non-small cell lung cancer have evidence of a systemic inflammatory response. Furthermore, an increase in the magnitude of the systemic inflammatory response resulted in greater weight loss, poorer performance status, more fatigue and poorer survival

Functional identity of receptors for proteolysis-inducing factor on human and murine skeletal muscle

Background: Cachexia in both mice and humans is associated with tumour production of a sulphated glycoprotein called proteolysis-inducing factor (PIF). In mice PIF binds with high affinity to a surface receptor in skeletal muscle, but little is known about the human receptor. This study compares the human PIF receptor with the murine. Methods: Human PIF was isolated from the G361 melanoma and murine PIF from the MAC16 colon adenocarcinoma. The human PIF receptor was isolated from human skeletal muscle myotubes. Protein synthesis and degradation induced by human and murine PIF was studied in human and murine skeletal muscle myotubes. Results: Both the human and murine PIF receptors showed the same immunoreactivity and Mr 40 000. Both murine and human PIF inhibited total protein synthesis and stimulated protein degradation in human and murine myotubes to about the same extent, and this was attenuated by a rabbit polyclonal antibody to the murine PIF receptor, but not by a non-specific rabbit antibody. Both murine and human PIF increased the activity of the ubiquitin-proteasome pathway in both human and murine myotubes, as evidenced by an increased 'chymotrypsin-like' enzyme activity, protein expression of the 20S and 19S proteasome subunits, and increased expression of the ubiquitin ligases MuRF1 and MAFbx, and this was also attenuated by the anti-mouse PIF receptor antibody. Conclusions: These results suggest that the murine and human PIF receptors are identical

Is there a genetic cause for cancer cachexia? - a clinical validation study in 1797 patients

Peer reviewedPublisher PD

The presence of the proteolysis-inducing factor in urine does not predict the malignancy of a pancreatic tumour

BACKGROUND: The proteolysis-inducing factor (PIF) was identified as a tumour product in various gastrointestinal cancers. A previous study in pancreatic cancer patients suggested PIF expression as a tumour marker, which is not related to tumour size. We hypothesized that PIF could be a useful marker to exclude benign pancreatic tumors, as chronic pancreatitis with a pancreatic mass. METHODS: Urine of patients with a pancreatic mass of uncertain malignancy was investigated for PIF expression by Western blot. Sufficient urine protein for analysis was available in 59 patients. The diagnosis was established by histology in 54 patients and by follow up in five patients with chronic pancreatitis. In addition, serum CA19-9 was measured. RESULTS: The sensitivity (specifity) for the detection of a malignant pancreatic tumour was 90% (75%) and 54% (71%) for CA19-9 and PIF, respectively. The sensitivity (specifity) for the distinction of pancreatic cancer from chronic pancreatitis was 89% (80%) and 57% (63%) for CA19-9 and PIF, respectively. CONCLUSION: Evaluation of PIF in urine is of no diagnostic value in patients with a pancreatic mass of unknown malignancy

The influence of systemic inflammation, dietary intake and stage of disease on rate of weight loss in patients with gastro-oesophageal cancer

Although weight loss is often a dominant symptom in patients with upper gastrointestinal malignancy, there is a lack of objective evidence describing changes in nutritional status and potential associations between weight loss, food intake, markers of systemic inflammation and stage of disease in such patients. Two hundred and twenty patients diagnosed with gastric/oesophageal cancer were studied. Patients underwent nutritional assessment consisting of calculation of body mass index, measurement of weight loss, dysphagia scoring and estimation of dietary intake. Serum acute-phase protein concentrations were determined by enzyme-linked immunosorbent assay. In all, 182 (83%) patients had lost weight at diagnosis (median loss, 7% body weight). Weight loss was associated with poor performance status, advanced disease stage, dysphagia, reduced dietary intake and elevated serum C-reactive protein (CRP) concentrations. Multiple regression identified dietary intake (estimate of effect, 38%), serum CRP concentrations (estimate of effect, 34%) and stage of disease (estimate of effect, 28%) as independent variables in determining degree of weight loss. Mechanisms other than reduced dietary intake or mechanical obstruction by the tumour appear to be involved in the nutritional decline in patients with gastro-oesophageal malignancy. Recognition that systemic inflammation plays a role in nutritional depletion may inform the development of appropriate therapeutic strategies to ameliorate weight loss, making patients more tolerant of cancer-modifying treatments such as chemotherapy

A randomised, phase II, unblinded trial of an Exercise and Nutrition-based Rehabilitation programme (ENeRgy) versus standard care in patients with cancer: feasibility trial protocol

Acknowledgements - The authors would like to thank Marie Curie and the Chief Scientist Office (UK) for funding this work (MCRGS-07-16-73), as well as acknowledge the support offered from the trial sponsors (ACCORD & NHS Lothian Edinburgh, UK). Also the valued contributions from the Southampton Clinical Trials Unit (UK), the Cicely Saunders Institute of Palliative Care, Policy and Rehabilitation, Kings College London (UK) as well as colleagues from different institutes within Edinburgh University (UK). Thanks to all the St Columba’s staff who helped get the trial set up, or assisted with the administration and the smooth running of the trial. Particular thanks to St Columba’s day therapies team especially Yvonne Whitehouse. Thanks to our dedicated ENeRgy clinic volunteers, Gillian Reid and Tommy Dalgleish for their commitment and helping make our participants feel welcomed and at ease, and for keeping the clinics running smoothly. Thanks to the clinical administration team and both community nurse specialist teams who showed great enthusiasm in identifying potential participants. Thanks to Marie Curie Hospice Edinburgh and the support from Dr. Emma Carduff (Marie Curie Glasgow) for their engagement and assistance with the trial. Thanks also to Abbott Nutrition, for supplying the oral nutritional supplements for the trial (ProSure), also for support from the Abbott team, in particular Dr Anne Voss.Erna Haraldsdottir - ORCID: 0000-0002-6451-1374 https://orcid.org/0000-0002-6451-1374Patients are living longer with incurable cancer [1] such that in many cases, cancer is likened to a chronic disease [2, 3, 4]. This development has wide-ranging implications for both patients and wider society, with increased longevity comes increased morbidity and associated socio-economic burden [5, 6]. Primary cost drivers for patients with advanced cancer are hospitalisation, GP and domiciliary visits [7]. Rehabilitation has been advocated as one such way of optimising the function and quality of life in this group of patients [8]; however, the optimal components of a rehabilitation model for patients with incurable cancer remain to be elucidated...The trial was funded by Marie Curie and the Chief Scientist Office (funding reference MCRGS-07-16-73). The funding bodies specified where changes were required to the design of the trial (including incorporating the impact upon carers and any health-economic impact as outcomes of the trial).4pubpub19

Length of Stay: An Inappropriate Readout of the Success of Enhanced Recovery Programs

BACKGROUND: Enhanced recovery after surgery (ERAS) programs are designed to reduce hospital length of stay by shortening the postoperative recovery period. The intended effect of an accelerated recovery on the length of stay may be frustrated by a delayed discharge. This study was designed to assess the influence of an ERAS program on the proportion, appropriateness, and extent of delay in discharge. METHODS: Patients who enrolled in the ERAS program (n = 121) between 2003 and 2006 were compared with 52 patients who were managed traditionally in 2001. RESULTS: Ninety percent of the pre-ERAS patients and 87% of the ERAS patients were not discharged on the day that discharge criteria were fulfilled. The additional stay of 59% of the pre-ERAS patients and 69% of the ERAS patients was inappropriate. Wound care (15% in the pre-ERAS and 3% of the ERAS group) and observation of any symptoms pointing to an anastomotic leakage (10% in both groups) were the most important reasons for a medical appropriate delay of discharge. The extent of delay in discharge decreased significantly from a median of two days in the pre-ERAS group to a median of 1 day in the ERAS group (p = 0.004). CONCLUSIONS: Reductions in length of stay up to a median of 2 days after start of an enhanced recovery program may relate to changes in organization of care and not to a shorter recovery period. Recovery statistics should replace or at least be added to the length of stay as outcome of enhanced recovery programs. AD - Department of Surgery, University Hospital Maastricht, PO Box 5800, 6202 AZ, Maastricht, the Netherlands. [email protected]