Cancer Anorexia-cachexia Syndrome Research Articles

Anamorelin for the Treatment of Cancer Anorexia-Cachexia in Nsclc: Results from the Phase 3 Studies Romana 1 and 2

ABSTRACT Background: Cancer anorexia-cachexia syndrome is a common debilitating condition, characterized by decreased body weight, mainly lean body mass (LBM) and negatively impacts quality of life and prognosis. Anamorelin HCl (ANAM) is a novel selective ghrelin receptor agonist with appetite-enhancing and anabolic activity. Methods: These were two international, double-blind, Phase 3 trials assessing ANAM efficacy and safety in patients with unresectable Stage III/IV NSCLC, ECOG 0-2 and cachexia (≥5% weight loss within prior 6 months or BMI Results: There were no within-study population differences for ROMANA 1 (N = 484) and ROMANA 2 (N = 495). Over 12 weeks, ANAM significantly increased LBM vs placebo (p Conclusions: In two global, large-scale Phase 3 studies, ANAM for 12 weeks was well tolerated, and significantly improved LBM, body weight, and anorexia-cachexia symptoms/concerns in advanced NSCLC patients with cachexia. Disclosure: K. Fearon: has received research funding from Helsinn; L. Gleich: is an employee of Medpace, Inc. Y. Yan and J. Friend: is an employee of Helsinn Therapeutics (US), Inc.; A. Abernethy: Received research funding from DARA, Celgene, Helsinn, Bristol-Myers Squibb (BMS), Dendreon, GSK, Pfizer; has consulting agreements with BMS and ACORN Research; is on the Board of Directors of athenahealth (a health information technology company).All other authors have declared no conflicts of interest.

Correlation between the international consensus definition of the cancer anorexia cachexia syndrome (CACS) and patient outcomes in advanced non-small cell lung cancer (NSCLC).

e19042 Background: CACS is a problematic clinical syndrome, difficult to objectively define. A consensus-derived, weight-based definition has been proposed. An observational study was analyzed to e...

Relationship of guarana (Paullinia cupana) on anorexia in patients with advanced cancer.

e20532 Background: Anorexia is prevalent in cancer patients with advanced disease. There are currently some treatments for cancer anorexia-cachexia syndrome (CACS), including corticosteroids, progestogens, cannabinoids and anabolic steroids. However, none of these treatments alone increases appetite and weight with few side effects. In this pilot phase II, open label, non-randomized trial, we evaluated the efficacy and safety of guarana (Paullinia cupana) in patients with cancer and weight loss. Methods: We included advanced cancer patients with decreased appetite and weight loss of more than 5% from their baseline in the past 6 months. All of the patients received 50 mg of the crude dry extract of guarana twice a day for 4 weeks. The trial was designed in 2 phases (Simon model). We considered a positive response in the first phase to be at least 5% weight gain or a 3-point improvement in the appetite scale in at least 3 of the first 18 evaluable patients. Results: Of the 34 eligible patients, 30 were included and 18 completed the protocol. Only 1 patient abandoned the protocol due to toxicity (grade II arthralgia). There were no grade 3 or 4 toxicities. There were no significant differences in nausea, weight loss and quality of life (FACT-G). Only 2 of the 18 patients who completed the study had weight gain above 5% from their baseline, whereas 6 patients had at least a 3-point improvement in the visual appetite scale. The M.D. Anderson Symptom Inventory (MDASI) was used to evaluate several symptoms, and we observed a significant decrease in lack of appetite (p=0.02) and in somnolence (p=0.0142). Conclusions: We concluded that the weight stabilization and increased appetite we observed in this study justify further studies of guarana in this patient population. Clinical trial information: NCT01540019.

Clinical nutrition impact in cancer patients

The clinical nutrition plays major role in many aspects of cancer development, progression and treatment. The tumor growth is associated with profound metabolic and neurochemical alterations, which can lead to the onset of cancer anorexia-cachexia syndrome (CACS). Cancer anorexia-cachexia describes a syndrome of progressive weight loss, anorexia, and persistent erosion of host body cell mass in response to a malignant growth. CACS affects a majority of cancer patients and has a considerable negative impact on quality of life, physical function, anticancer treatment response and survival. Cachexia is estimated to be the immediate cause of death in 20% to 40% of cancer patients. Weight loss has been identified as an indicator of poor prognosis in our 333 cancer patients. We found that at the time of diagnosis, 72% of patients with gastrointestinal cancer, 60% of patients with head-neck, prostate cancer and 55% of patients with lung cancer have already experienced a significant weight loss.

Anamorelin Hydrochloride in the Treatment of Cancer Anorexia-Cachexia Syndrome

Anamorelin hydrochloride is an orally active ghrelin receptor agonist in development by Helsinn, for the treatment of non-small-cell lung cancer (NSCLC) cachexia. In preclinical and clinical studies, the potent affinity of anamorelin for the ghrelin receptor is associated with significant appetite-enhancing activity and resultant improvements in body weight, lean body mass, and handgrip strength compared with placebo. The accompanying stimulatory effects on growth hormone and IGF-1 are not associated with tumor growth, and overall survival in patients with cancer is not compromised. Anamorelin is well tolerated with no dose-limiting toxicities identified to date. The findings of ongoing Phase III studies are needed to confirm the significant potential of anamorelin to treat NSCLC cachexia.

Clinical development of ghrelin axis-derived molecules for cancer cachexia treatment

Cachexia is a devastating complication of cancer for which there is no approved treatment. Here we review the clinical development of ghrelin and ghrelin mimetics (also known as growth hormone secretagogues or GHS) for cancer cachexia treatment. Ghrelin, a novel hormone known to increase appetite, lean and fat mass, and growth hormone secretion, is being developed as a therapeutic option for cancer anorexia-cachexia syndrome (CACS). Recent animal studies suggest that it may also decrease inflammation and that some of its effects may be independent of its only known receptor, the GHS receptor-1a.Clinical studies recently have shown that administration of ghrelin or GHS improves appetite and quality of life as assessed by questionnaires. Weight gain, increased food intake and better tolerance to chemotherapy have also been reported. This treatment appears to be safe and well tolerated. Ghrelin and GHS have the potential to effectively prevent or reverse CACS. Preliminary studies show improvements in weight stabilization and appetite with short-term usage. Further studies are required to fully characterize the role of ghrelin and GHS for the treatment of CACS and to establish the safety of this approach.

Cancer anorexia-cachexia syndrome in advanced lung cancer: An exploratory analysis of patient-reported outcomes data.

e17521 Background: The cancer anorexia-cachexia syndrome (CACS) is a debilitating syndrome of involuntary weight loss, anorexia, declining function, muscle catabolism, and inflammation. It affects many patients with cancer, especially those with advanced disease. We aimed to describe the experience of a group of patients with advanced lung cancer who meet published weight-based criteria for CACS. Methods: Tablet computers were used to collect patient-reported outcomes data from 97 patients with advanced non-small cell lung cancer, using the Patient Care Monitor v2.0 and the FACIT family of questionnaires. 25 patients met published weight criteria for CACS (>=5% weight loss in the past 6 months). 51 patients with stable weights were used as a comparison group; those lacking weight data were excluded. Statistical comparisons were made between these groups to explore differences in symptoms, quality of life, and survival. Results: Patients meeting weight criteria for CACS had lower serum albumins (median 3.7 vs. 3.9, p=0.006) and worse performance status by Karnofsky and ECOG (70 vs. 80, p=0.004, and 2 vs. 1, p=0.027). CACS patients had worse FAACT anorexia-cachexia subscale scores (34.5 vs. 38.5, p=0.018) but were not statistically more likely to be prescribed CACS therapies; only 17% of patients in the CACS group were on medication for this (N=4). FACIT fatigue subscale scores were not statistically different between groups, nor was quality of life by FACT-G. Grip strength and 6-minute walk distance were also not statistically different. Patients in the CACS group had a significantly shorter survival (HR 2.066 [95% CI=1.229,3.474], p=0.005). Conclusions: Patients with advanced non-small cell lung cancer who meet standard weight-based criteria for CACS have inferior survival compared to a similar population without weight loss. Though traditional descriptions of CACS presume a general impairment in quality of life, we did not find statistical differences here aside from the anorexia-cachexia subscale score of FAACT. Few patients were prescribed medication to address symptomatic anorexia/cachexia, suggesting it may be an unmet need in patients with advanced lung cancer.

Erlotinib Plus Parenteral Nutrition

This case study details the poor performance status of a patient with non-small cell lung cancer and cancer anorexia-cachexia syndrome got through the hardest days of high tumor burden and malnutrition, by using a combined therapy of lung cancer-targeted therapy drug and parenteral nutrition. The related literatures were reviewed.

Protocolo diagnóstico y terapéutico del síndrome de anorexia y caquexia tumoral

The cancer anorexia-cachexia syndrome consists of appetite loss and a series of metabolic alterations such as loss of proteins from the muscle compartment and body fat that leads the patients to a situation of extreme malnutrition. Loss of skeletal musculature limits basic mobility and functionality and limits active treatments against the disease. It is a cause of death due to the derived complications.Treatment of this syndrome is based on adequate support treatment of the possible situations associated to lack of sufficient food and assimilation of the nutrients produced by the side effects of the cancer treatments (chemotherapy, radiotherapy and surgery) such as nauseas, vomits, diarrhea or mucositis. There are appetite stimulating and weight gain treatments with demonstrated efficacy. Megestrol is the drug of first choice in these patients. Corticosteroids have a similar efficacy but more in the short term.

The Potential of Ghrelin in Cancer Anorexia–Cachexia

The cancer anorexia–cachexia syndrome (CACS) is often seen in patients with incurable malignancies and is associated with increased mortality, decreased efficacy of anticancer treatments and poor quality of life. However, there are currently no effective therapies for CACS. Since CACS is a multifactorial syndrome with a complex pathophysiology, therapeutic interventions for CACS might potentially include anabolic agents as well as anti-inflammatory effects. Ghrelin affects numerous key pathways in the regulation of body weight and body composition through increased appetite and growth hormone (GH) secretion. Preliminary clinical data indicate that the administration of ghrelin and ghrelin receptor agonist such as anamorelin have beneficial effects on appetite and body weight in patients with CACS. Anamorelin is currently in phase III clinical trials.

Reviews The role of the dietetary nutrition in the stomach cancer

Stomach cancer mortality still represents a significant proportion of all cancer deaths. The majority of patients with advanced cancer experience cancer anorexia-cachexia syndrome with weight loss, reduced appetite, fatigue, and weakness. Neoplastic cachexia is a very common clinical manifestation of upper gastrointestinal (GI) tract cancer and is generally assumed to be secondary to the mechanical effects of the tumor on the upper digestive tract. The main reasons are obstruction to swallowing, early satiety, nausea and vomiting. Another reason for weight loss is the co-existence of systemic inflammation. Nutritional treatment in the group of patients with gastric cancer is still used too rarely and the knowledge about it is still very limited. Nutritional support should be given for patients both in the pre- and postoperative period. Nutrition should also be used in palliative treatment in patients with unresectable stomach cancer. The main principles of nutritional support and its influence are presented in this publication.

ROLE OF ANGIOTENSIN-CONVERTING ENZYME AND VITAMIN D RECEPTOR GENE POLYMORPHISMS IN CANCER ANOREXIA-CACHEXIA SYNDROME

The ubiquitin-proteasome pathway is a crucial conne ction between aberrant immune system activation, systemic inflammation and Cancer Anorexia-Cachexia Syndrome (CACS), a syndrome that culminates in hyper-activation of the ubiquitin-proteasome pathwa y. Angiotensin directly up-regulates this pathway, while vitamin D down-regulates it indirectly through the insulin-like growth factor-1 pathway. We investigat ed the genetic predisposition towards CACS in a cancer population, examining Insertion/Deletion (I/D) polymorphism of angiotensin-converting enzyme gene and FokI and BsmI polymorphisms of vitamin D receptor gene. Sixty-two cancer patients were recru ited and divided into three groups: primary cachect ic (C1, n = 14; dysmetabolic body weight loss ≥5% in 6 months); secondary cachectic (C2, n = 34; similar weight loss, mechanic or iatrogenic origin); and non-cachectic ( NC, n = 16). C2+NC were merged in the control group. The three groups showed significant differences in average prognostic inflammatory nutritional index ( C1: 26.4±23.4; C2: 5.4±5.6; NC: 0.37±0.5), C-reactive protein serum levels (C1: 6.6±2.1; C2: 2.4±2.2; NC: 1.0±2.0 mg/dl), albumin serum levels (C1: 3.1±0.6; C2: 3.5±0.4; NC 3.7±0.6 g/dl), weight loss (C1: 22±8; C2: 1 5±6.7; NC 5±6%) and life expectancy (C1: 6.4±3.3; C2: 25±28; NC: 45±25 months). However, none of the chosen polymorphisms showed any statistically significant correlation with CACS. The complexity of the changes of the immune system in the chronic inflammation state associated with CACS is far greater than expected and further studies are required to identify genetic independen t markers of progression toward CACS.

Improved Fertility Preservation Care for Male Patients With Cancer After Establishment of Formalized Oncofertility Program

Survival to reproductive age among men with cancer has steadily increased and yet cancer therapy and cancer itself may carry the risk of infertility. Since 2006, we have used a formalized fertility preservation program with expedited fertility care at our institution. We assessed the impact of this program by comparing the frequency of sperm cryopreservation and patient characteristics before and after its implementation. Men 18 to 55 years old diagnosed with cancer at our institution from 2002 to 2010 were included in our study. We retrospectively reviewed patient charts to identify those who were offered and subsequently used fertility preservation services before and after program formalization. From 2002 to 2010 at our institution 4,818 men 18 to 55 years old were diagnosed with cancer, of whom 411 were offered fertility preservation consultation and 249 underwent sperm cryopreservation. Since program implementation, the annual number of men receiving fertility preservation consultation and undergoing sperm cryopreservation increased by 2.4 and 2.7-fold, respectively, while the total number diagnosed with cancer remained fairly constant. Upon substratifying patients into the more conventional reproductive age range of 18 to 40 years 23.4% of all men with cancer in this group were offered consultation before formalization vs 43.3% after formalization (p <0.05). The overall sperm use and discard rates were 8.4% and 14.8%, respectively. A formalized institutional fertility preservation program significantly increased the overall number and percent of male patients with cancer who received fertility preservation consultation and pursued sperm cryopreservation. These increases were seen in men with all types of cancer and across all demographics assessed at our institution.

Impact of Nutritional Support in Patients with Gastrointestinal Malignancies - A Review

Cancer Cachexia-Anorexia Syndrome (CACS) is a common and often underdiagnosed syndrome in cancer population. If undiagnosed, this initially reversible syndrome leads to deterioration and is direct cause of death in 20% of cancer patients. Oppositely, with timely diagnosis, nutritional counseling can help to slow the progression and positively influence on quality of life, tolerance to chemotherapy with ultimate goal of prolonging patient’s life. Colorectal and pancreatic cancers are very common tumors type worldwide. The prognosis for the survival in pancreatic cancer is poor as in colorectal after disease progression. Cancer anorexia-cachexia syndrome is highly prevalent among patients with colorectal and pancreatic cancer, and has a large impact on morbidity and mortality, and on patient quality of life. The etiology of primary CACS appears to be related to the pathological loss of inhibitory control of catabolic pathways, whose increased activities are not counterbalanced by the increased central and peripheral anabolic drive. Secondary CACS (related to gastrointestinal obstruction, vomiting due to chemotherapy etc.) is contributing to bad patient’s condition. As a result of being complex and influencing a great number of metabolic pathways, cancer cachexia can be treated in multimodal manner. In this review we are presenting most promising targets and current opinions in ways to treat cachexia and our results with nutritional supplementation in colorectal and pancreatic cancer patients.

Carnitine Administration Reduces Cytokine Levels, Improves Food Intake, and Ameliorates Body Composition in Tumor-Bearing Rats

Increased cytokine expression contributes to the pathogenesis of cancer anorexia–cachexia syndrome. Carnitine may reduce inflammation in chronic diseases. We tested the effects of L-propionylcarnitine (PC group) or saline (C group) on food intake (FI), body composition, and inflammatory status of MCA-sarcoma-bearing rats. On tumor appearance, rats were randomly assigned to daily i.p. injection of L-propionylcarnitine (250 mg/kgBW/d; n = 8) or saline (equal volume; n = 8). FI and fat-free mass wasting improved in PC rats only (p < .01 vs. controls). Cytokines’ levels decreased in PC rats vs. controls (p < .02). Results suggest that carnitine may ameliorate cancer anorexia–cachexia, via reduction of the inflammatory status.

Chronic inflammatory states: their relationship to cancer prognosis and symptoms

A chronic inflammatory state (CIS) commonly accompanies advanced cancers. Elements of a CIS include aberrant immune system activity and changes in hypothalamic-neuroendocrine control mechanisms. The end result is stimulation of tumour growth and metastases. In addition to tumour stimulation, cancer symptoms may be enhanced. While for most symptoms correlation with a CIS remains tenuous, clearly a CIS is linked to the aetiology of the cancer anorexia-cachexia syndrome. To date clinical studies aimed at a CIS are modest, but the increased understanding of the partnership of a CIS, cancer progression and anorexia-cachexia must lead to targeting a CIS in concert with conventional efforts to directly destroy tumour tissue.

Potentiation of ghrelin signaling attenuates cancer anorexia–cachexia and prolongs survival

Cancer anorexia–cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut–brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia–cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, α-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia–cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia–cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia–cachexia.

Stimulation of the Nicotine Antiinflammatory Pathway Improves Food Intake and Body Composition in Tumor-Bearing Rats

Inflammation contributes to the pathogenesis of cancer anorexia-cachexia syndrome. Nicotine administration reduces cytokine levels and mortality during sepsis. Therefore, nicotine administration may result in improved anorexia-cachexia. Sixteen male Fischer rats inoculated with MCA sarcoma were assigned to random injections of nicotine (NIC; 200 mg/kg BW/d) or saline (C). Food intake (FI), body weight, body composition, interleukin (IL)-1, IL-6 levels were evaluated. Data were analyzed via Student's t-test for paired and unpaired data and ANOVA. FI started declining 12 days after tumor inoculation both in C and NIC rats, but the decline was significantly attenuated by nicotine administration. At the end of the study, lean body mass wasting was more severe in C rats than in NIC rats (P < 0.05), whereas a trend toward attenuation of fat mass depletion was observed. IL-1 circulating levels were significantly lower in NIC rats than in C rats (114 ± 21 pg/mL vs. 190 ± 35 pg/mL, respectively; P < 0.01), whereas the reduction of IL-6 levels in NIC rats was only marginally not significant when compared to C rats (555 ± 174 pg/mL vs. 721 ± 160 pg/mL, respectively; P = 0.06). Our data suggest that the nicotinic antiinflammatory pathway may represent an interesting and possibly effective therapy for anorexia-cachexia syndrome.

Interviewing Those Who Just Lost Their Loved Ones: An Innovative Method to Introduce Palliative Medicine to Medical Students (704)

Objectives 1. Discuss a pilot study of taste changes amongst hospice in-patients with advanced cancer. 2. Review the frequency of both subjective and objective taste changes and the relationship between them. 3. Assess the influence of taste changes on dietary intake. Background. Alterations in taste sensation may cause poor dietary intake and malnutrition which likely reduce quality of life (QOL). Identifying different taste abnormalities can help us understand eating difficulties. Research objectives. We conducted a pilot survey study of taste changes amongst hospice inpatients with advanced cancer. We examined the frequency of both subjective and objective taste changes and the relationship between them. We also assessed the influence of taste changes on dietary intake. Methods. We recruited 15 consecutive hospice in-patients. On Day 1, patients were questioned about subjective taste changes, food preferences, and daily dietary intake using a structured questionnaire. A 27food item checklist provided food preferences based on the four basic taste senses. On Day 2, a forced choice 3-stimulus drop test was performed for objective taste evaluation. Pearson’s correlation test identified the association between subjective and objective taste changes. Results. There were seven males and eight females; median age 68 years (range 49e84). Changes in taste and food preference were common. None had received either radiation or chemotherapy recently. Ten reported subjective taste changes in response to direct questions. Most had weight loss and anorexia, which suggested a possible role of taste changes in the cancer anorexia-cachexia syndrome. Meat aversion was found mostly in females. Median energy intake for all was 1,475 kcal/d (range: 224e2,137). Amongst those with subjective taste changes most also had objective changes on formal testing. Subjective and objective taste changes correlated well. Hypogeusia for sweet and salt, and dysgeusia for sour were common specific taste changes. Conclusion. Subjective and objective taste changes in advanced cancer were common. Hypogeusia for sweet and salt, and dysgeusia for sour were predominant. Implications for research, policy, or practice. Awareness of individual food preferences helps plan diets with pleasurable meals, overcome anorexia, maintain adequate nutrition, and increase QOL.

Taste Changes Amongst Hospice Patients with Advanced Cancer (703)

1.Discuss a pilot study of taste changes amongst hospice in-patients with advanced cancer.2.Review the frequency of both subjective and objective taste changes and the relationship between them.3.Assess the influence of taste changes on dietary intake. Background. Alterations in taste sensation may cause poor dietary intake and malnutrition which likely reduce quality of life (QOL). Identifying different taste abnormalities can help us understand eating difficulties. Research objectives. We conducted a pilot survey study of taste changes amongst hospice inpatients with advanced cancer. We examined the frequency of both subjective and objective taste changes and the relationship between them. We also assessed the influence of taste changes on dietary intake. Methods. We recruited 15 consecutive hospice in-patients. On Day 1, patients were questioned about subjective taste changes, food preferences, and daily dietary intake using a structured questionnaire. A 27- food item checklist provided food preferences based on the four basic taste senses. On Day 2, a forced choice 3-stimulus drop test was performed for objective taste evaluation. Pearson's correlation test identified the association between subjective and objective taste changes. Results. There were seven males and eight females; median age 68 years (range 49–84). Changes in taste and food preference were common. None had received either radiation or chemotherapy recently. Ten reported subjective taste changes in response to direct questions. Most had weight loss and anorexia, which suggested a possible role of taste changes in the cancer anorexia-cachexia syndrome. Meat aversion was found mostly in females. Median energy intake for all was 1,475 kcal/d (range: 224–2,137). Amongst those with subjective taste changes most also had objective changes on formal testing. Subjective and objective taste changes correlated well. Hypogeusia for sweet and salt, and dysgeusia for sour were common specific taste changes. Conclusion. Subjective and objective taste changes in advanced cancer were common. Hypogeusia for sweet and salt, and dysgeusia for sour were predominant. Implications for research, policy, or practice. Awareness of individual food preferences helps plan diets with pleasurable meals, overcome anorexia, maintain adequate nutrition, and increase QOL.