Standards, Options and Recommendations (SOR) for the use of appetite stimulants in oncology. Work group. Federation of the French Cancer Centres (FNCLCC)

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop clinical practice guidelines according to the definitions of the Standards, Options and Recommendations project for the use of appetite stimulants in oncology. METHODS: Data were identified by searching Medline and the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to 55 independent reviewers, and to the medical committees of the 20 French Cancer Centres. RESULTS: The main recommendations for the use of appetite stimulants in oncology are: 1) Corticosteroids and the synthetic progestogens (megestrol acetate and medroxyprogesterone acetate) are appetite stimulants. 2) They can be useful in managing anorexia and weight loss in cancer patients, especially in the palliative setting, despite the potential side-effects of these agents. 3) The most effective way of using these drugs is not known. Inclusion in clinical trials is recommended. 4) Cyproheptadine, metoclopramide, nandrolone and pentoxif line should not be used outside prospective clinical trials. 5) Hydrazine sulfate should not be used.     

Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia.

PURPOSE: Previous double-blind, placebo-controlled, randomized clinical trials have demonstrated that both corticosteroids and progestational agents do partially alleviate cancer anorexia/cachexia. Pilot information suggested that an anabolic corticosteroid might also improve appetite in patients with cancer anorexia/cachexia. The current trial was developed to compare and contrast a progestational agent, a corticosteroid, and an anabolic corticosteroid for the treatment of cancer anorexia/cachexia. PATIENTS AND METHODS: Patients suffering from cancer anorexia/cachexia were randomized to receive either dexamethasone 0. 75 mg qid, megestrol acetate 800 mg orally every day, or fluoxymesterone 10 mg orally bid. Patients were observed at monthly intervals to evaluate weight changes and drug toxicity. Patients also completed questionnaires at baseline and at monthly intervals to evaluate appetite and drug toxicities. RESULTS: Fluoxymesterone resulted in significantly less appetite enhancement and did not have a favorable toxicity profile. Megestrol acetate and dexamethasone caused a similar degree of appetite enhancement and similar changes in nonfluid weight status, with nonsignificant trends favoring megestrol acetate for both of these parameters. Dexamethasone was observed to have more corticosteroid-type toxicity and a higher rate of drug discontinuation because of toxicity and/or patient refusal than megestrol acetate (36% v 25%; P =.03). Megestrol acetate had a higher rate of deep venous thrombosis than dexamethasone (5% v 1%; P =.06). CONCLUSION: Whereas fluoxymesterone clearly seems to be an inferior choice for treating cancer anorexia/cachexia, megestrol acetate and dexamethasone have similar appetite stimulating efficacy but differing toxicity profiles.     

Appetite and cancer-associated anorexia: a review.

Appetite is governed by peripheral hormones and central neurotransmitters that act on the arcuate nucleus of the hypothalamus and nucleus tactus solitarius of the brainstem. Cancer anorexia appears to be the result of an imbalance between neuropeptide-Y and pro-opiomelanocortin signals favoring pro-opiomelanocortin. Many of the appetite stimulants redress this imbalance. Most of our understanding of appetite neurophysiology and tumor-associated anorexia is derived from animals and has not been verified in humans. There have been few clinical trials and very little translational research on anorexia despite its prevalence in cancer.     

Cancer Cachexia: Traditional Therapies and Novel Molecular Mechanism-Based Approaches to Treatment

The complex syndrome of cancer cachexia (CC) that occurs in 50% to 80% cancer patients has been identified as an independent predictor of shorter survival and increased risk of treatment failure and toxicity, contributing to the mortality and morbidity in this population. CC is a pathological state including a symptom cluster of loss of muscle (skeletal and visceral) and fat, manifested in the cardinal feature of emaciation, weakness affecting functional status, impaired immune system, and metabolic dysfunction. The most prominent feature of CC is its non-responsiveness to traditional treatment approaches; randomized clinical trials with appetite stimulants, 5-HT3 antagonists, nutrient supplementation, and Cox-2 inhibitors all have failed to demonstrate success in reversing the metabolic abnormalities seen in CC. Interventions based on a clear understanding of the mechanism of CC, using validated markers relevant to the underlying metabolic abnormalities implicated in CC are much needed. Although the etiopathogenesis of CC is poorly understood, studies have proposed that NFkB is upregulated in CC, modulating immune and inflammatory responses induce the cellular breakdown of muscle, resulting in sarcopenia. Several recent laboratory studies have shown that n-3 fatty acid may attenuate protein degradation, potentially by preventing NFkB accumulation in the nucleus, preventing the degradation of muscle proteins. However, clinical trials to date have produced mixed results potentially attributed to timing of interventions (end stage) and utilizing outcome markers such as weight which is confounded by hydration, cytotoxic therapies, and serum cytokines. We propose that selective targeting of proteasome activity with a standardized dose of omega-3-acid ethyl esters, administered to cancer patients diagnosed with early stage CC, in addition to a standard intervention with nutritionally adequate diet and appetite stimulants, will alter metabolic abnormalities by downregulating NFkB, preventing the breakdown of myofibrillar proteins and resulting in increasing serum protein markers, lean body mass, and functional status.     

Corticosteroids in advanced cancer

Despite the fact that there are only a few controlled trials demonstrating the benefits associated with the use of corticosteroids in specific situations, these agents are administered frequently to patients with advanced cancer. Corticosteroids may be used alone or as adjuvants in combination with other palliative or antineoplastic treatments. For example, corticosteroids may help prevent nausea, vomiting, and hypersensitivity reactions to treatment with chemotherapy or radiation. They are also commonly used as appetite stimulants in patients with advanced cancer. In the adjuvant setting, corticosteroids help to alleviate pain in advanced cancer patients, including specific situations such as back pain related to epidural compression. This article reviews the evidence supporting the use of corticosteroids in a broad range of situations seen in patients with advanced cancer.     

The cancer anorexia-cachexia syndrome

The cancer anorexia-cachexia syndrome is one of the most common causes of death among cancer patients and is present in 80% at death. It is a complex example of metabolic chaos effecting protein, carbohydrate, and fat metabolism. Tumors produce both direct and indirect abnormalities, resulting in anorexia and weight loss. The disease burden does not correlate with the degree of cachexia. Although there is no treatment to control or reverse the process, appetite stimulants may promote increased food intake and enhance quality of life.     

Evidence-based medicine: its effect on treatment recommendations as illustrated by the changing role of postmastectomy irradiation to treat breast cancer

PURPOSE: To illustrate the effect that the quality of evidence has on clinical practice, we examined how the role of radiotherapy in treating breast cancer has changed over the years as the quality of evidence evolved from anecdotal evidence based on expert opinion to randomized clinical trials and meta-analyses. METHODS: We searched the medical literature for key randomized studies and meta-analyses that have influenced the clinical use of postmastectomy irradiation since the first randomized trials in breast cancer in the 1950s. We discuss how clinical practice changed based on the outcomes of these trials, and then discuss the quality of those trials based on the criteria currently used to assess evidence from randomized trials (CONSORT) and meta-analysis (QUORUM). RESULTS: Evidence published from the early trials and meta-analyses on the role of postmastectomy irradiation had a strong effect on clinical practice. Examination of these studies, however, continues to show significant flaws in trial design that, by today's evidence-based standards, would not meet standards of quality. CONCLUSION: The quality of evidence has a strong effect on shaping clinical practice and needs to be continually assessed. Current guidelines developed to critique both individual randomized trials and meta-analyses are helping to establish high standards for trial design and interpretation. Evidence from older trials that were not guided by well-developed guidelines need to be reviewed, particularly when results from those trials are continually updated and used to generate evidence on which to base current clinical practice.     

The syndrome of anorexia-cachexia.

Cancer anorexia/cachexia is a major clinical problem, especially in advanced cancer patients. Its pathogenesis is quite complex. Anorexia plays a central role, but cancer cachexia is more complex than pure chronic starvation. One of the key differences is the preferential mobilization of fat and the sparing of skeletal muscle in simple starvation compared with an equal mobilization of fat and skeletal muscle in cancer patients. An increase in basal energy expenditures seems to play a contributory role in many patients. Cytokines, essentially but not exclusively tumor necrosis factor alpha, play an essential role, and the syndrome can be compared with a low-grade chronic inflammatory state. As it is in most fields in medicine, prevention is more efficacious than treatment, and, to avoid the final and dramatic stages of cancer cachexia, adequate nutritional advice and support must be provided sufficiently early. Parenteral nutrition could facilitate the administration of complete doses of chemotherapy or radiotherapy, but no significant survival benefit or decrease in treatment-induced toxicity have ever been demonstrated in prospective randomized trials. The gut should always be used if at all possible. Percutaneous endoscopic gastrostomy is used increasingly in patients who cannot eat but who have functionally intact gastrointestinal tracts, especially in patients with head and neck cancer. Eight randomized, double-blind, placebo-controlled studies have demonstrated that progestational drugs can somewhat stimulate appetite, food intake, and energy level; increase weight in many patients; and often decrease nausea and vomiting severity; however, pharmacologic treatment of cancer cachexia remains disappointing, and more trials with anticytokine drugs should be conducted.     

The cancer anorexia/weight loss syndrome: Therapeutic challenges

The cancer anorexia/weight loss syndrome is characterized by loss of weight, loss of appetite, overall decline in quality of life, and shortened survival in patients with advanced incurable cancer. It is highly prevalent. To date, treatment options that have been firmly established with good scientific evidence are limited to progestational agents and corticosteroids, both of which have been demonstrated to improve appetite but have otherwise failed to have a favorable impact on some of the other aspects of this syndrome. As the mechanisms behind this syndrome are further elucidated, more effective therapeutic strategies will likely emerge.     

New drugs for the anorexia-cachexia syndrome

Anorexia and cachexia accompany advancing cancer to a greater extent than any other symptom. Cachexia alone causes 22% of cancer deaths. The pathophysiology of cachexia is distinctly different from that of starvation. Resting energy expenditures are elevated, and abnormal intermediary metabolism, proteolysis, and lipolysis occur independently of caloric intake. A facilatative interaction between catecholamines, prostaglandins, and inflammatory cytokines is responsible for cachexia. Successful treatment requires reduction of energy expenditures, reversal of anorexia, and correction of abnormal intermediary metabolism, lipolysis, and proteolysis. Multiple appetite stimulants can be used in combination. Several new potentially useful biologic agents have been tested in animal tumor models. Several of the anticachectic agents have demonstrated in vivo or in vitro antitumor activity. The biologic and clinical activity of each drug is reviewed herein, and potentially useful combinations are listed.     

Medical marijuana for cancer

Answer questions and earn CME/CNE Marijuana has been used for centuries, and interest in its medicinal properties has been increasing in recent years. Investigations into these medicinal properties has led to the development of cannabinoid pharmaceuticals such as dronabinol, nabilone, and nabiximols. Dronabinol is best studied in the treatment of nausea secondary to cancer chemotherapy and anorexia associated with weight loss in patients with acquired immune deficiency syndrome, and is approved by the US Food and Drug Administration for those indications. Nabilone has been best studied for the treatment of nausea secondary to cancer chemotherapy. There are also limited studies of these drugs for other conditions. Nabiximols is only available in the United States through clinical trials, but is used in Canada and the United Kingdom for the treatment of spasticity secondary to multiple sclerosis and pain. Studies of marijuana have concentrated on nausea, appetite, and pain. This article will review the literature regarding the medical use of marijuana and these cannabinoid pharmaceuticals (with emphasis on indications relevant to oncology), as well as available information regarding adverse effects of marijuana use. CA Cancer J Clin 2015;65: 109–122. © 2014 American Cancer Society.     

奥氮平联合醋酸甲地孕酮治疗晚期癌症性厌食症的疗效观察

目的:观察奥氮平联合醋酸甲地孕酮治疗晚期癌症性厌食症的疗效。方法:将85例癌性厌食患者随机分至治疗组（奥氮平联合醋酸甲地孕酮组+营养支持）和对照组（醋酸甲地孕酮组+营养支持）及单纯营养支持组,观察各组治疗前后食欲、体重、卡氏评分和免疫功能的变化并评价不良反应。结果:治疗结束后,治疗组食欲、卡氏评分改善率分别为82.8%、69.0%,对照组分别为65.5%、34.4%,空白组分别为40.7%、33.3%,治疗组改善率明显高于对照组和空白组（P＜0.05）;治疗组在体重、血清白蛋白、免疫功能改善程度方面均优于对照组和空白组（P＜0.05）。未见明显不良反应。结论:奥氮平联合醋酸甲地孕酮能有效改善晚期恶性肿瘤患者厌食症状,是治疗晚期恶性肿瘤患者有效辅助药物,药物不良反应小。     

Review of exercise intervention studies in cancer patients.

PURPOSE: To present an overview of exercise interventions in cancer patients during and after treatment and evaluate dose-training response considering type, frequency, volume, and intensity of training along with expected physiological outcomes. METHODS: The review is divided into studies that incorporated cardiovascular training, combination of cardiovascular, resistance, and flexibility training, and resistance training alone during and after cancer management. Criteria for inclusion were based on studies sourced from electronic and nonelectronic databases and that incorporated preintervention and postintervention assessment with statistical analysis of data. RESULTS: Twenty-six published studies were summarized. The majority of the studies demonstrate physiological and psychological benefits. However, most of these studies suffer limitations because they are not randomized controlled trials and/or use small sample sizes. Predominantly, studies have been conducted with breast cancer patients using cardiovascular training rather than resistance exercise as the exercise modality. Recent evidence supports use of resistance exercise or "anabolic exercise" during cancer management as an exercise mode to counteract side effects of the disease and treatment. CONCLUSION: Evidence underlines the preliminary positive physiological and psychological benefits from exercise when undertaken during or after traditional cancer treatment. As such, other cancer groups, in addition to those with breast cancer, should also be included in clinical trials to address more specifically dose-response training for this population. Contemporary resistance training designs that provide strong anabolic effects for muscle and bone may have an impact on counteracting some of the side effects of cancer management assisting patients to improve physical function and quality of life.     

Rational Second-Generation Antiandrogen Use in Prostate Cancer

The second-generation antiandrogens have achieved an ever-growing list of approvals and indications in subsets of prostate cancer. Here, we provide an overview of second-generation antiandrogen trials and FDA approvals and outline a rational sequencing approach for the use of these agents as they relate to chemotherapy and other available treatment modalities in advanced prostate cancer. All published phase II-III randomized controlled trials reporting outcomes with the use of second-generation antiandrogens in prostate cancer are included as well as all published trials and retrospective studies of second-generation antiandrogen sequencing and/or combinations. Complete tabular and graphical representation of all available evidence is provided regarding the use and sequencing of second-generation antiandrogens in prostate cancer. In metastatic castration-resistant prostate cancer, evidence suggests prioritization of abiraterone before chemotherapy, chemotherapy after second-generation antiandrogen failure, and postchemotherapy enzalutamide in select patients to maximize agent efficacy and tolerability. We conclude that a rational, optimized sequencing of second-generation antiandrogens with other treatment options is feasible with present data.     

Evidence-based use of taxanes in the adjuvant setting of breast cancer. A review of randomized phase III trials

Six major randomized clinical trials evaluating the role of taxanes in the adjuvant setting of breast cancer have demonstrated significant improvements in terms of efficacy in favour of the taxane treatment arm. In all cases, different anthracycline-based regimens were used as the control arm. Nevertheless, many clinicians are still not sufficiently convinced to incorporate the routine use of taxanes in the adjuvant treatment of breast cancer. There are two main objections, first the possible lack of effectiveness of chemotherapy in hormone-receptor positive tumors and second, some of the anthracycline-based control arms used in these trials were not the optimal ones. In this review, we have searched and analyzed all randomized studies that evaluated the role of taxanes in the adjuvant setting of breast cancer patients and have reported results in terms of efficacy or tolerance. The suitability of the control arm, the prospective definition of patient's subgroups and the statistical methodology were taking into account. The objective of this review was to analyze if, at this point in time, there is sufficient evidence to support the routine use of taxanes in the adjuvant setting of breast cancer, and if it is valid for all subgroups including hormone-receptor and Her2/neu positive breast cancer patients. Other objectives of this review were to define the optimal regimen for administration of taxanes, how the tolerability of taxanes may be improved and also, to investigate any potential differences in efficacy or tolerability between docetaxel and paclitaxel.     

Placebo effects in oncology

BACKGROUND: Previous studies have suggested that placebo treatment can have positive effects on a variety of disorders and disease-related symptoms. However, the methodology used to collect and interpret the data may not have been ideal, because the studies were not double-blinded or the endpoints were not properly validated. The purpose of the present study was to determine the probability of improvement in symptoms or quality of life and tumor response in cancer patients treated with placebos in randomized controlled trials. We hypothesized that administration of placebos would improve symptom control and quality of life but would not lead to tumor response. METHODS: We reviewed reports of randomized controlled trials in which there was a placebo arm (37 trials) or a best supportive care (BSC) arm (10 trials). RESULTS: In trials that assessed average responses for patients in the placebo arm, improvements in average levels of pain were reported in two of six trials and in appetite, in one of seven trials. No improvements in average levels of weight gain (six trials), in quality of life (as assessed by patients; 10 trials), or in performance status (as assessed by physicians; nine trials) were reported. In trials that assessed response to a placebo in individual patients, 0%-21% of patients showed reduced pain or decreased analgesic intake, 8%-27% of patients showed appetite improvement, 7%-17% of patients showed weight gain, and 6%-14% of patients showed improvement in performance status. Quality of life for individual patients was not reported in any trial. Tumor response assessed by World Health Organization criteria was observed in 10 (2.7%) of 375 patients (seven trials total). Response as assessed by a serum marker was observed in 1 (1.7%) of 60 patients (two trials total). The probability of symptom improvement in patients receiving BSC was generally similar to that in patients receiving placebo, although no improvement in pain and only one tumor response among 191 patients (five trials) were reported. CONCLUSION: In randomized double-blinded, placebo-controlled trials, presumably with minimum sources of bias, placebos are sometimes associated with improved control of symptoms such as pain and appetite but rarely with positive tumor response. Substantial improvements in symptoms and quality of life are unlikely to be due to placebo effects.     

Evidence-based approaches to other symptoms in advanced cancer

Dyspnea, nausea and vomiting, anorexia, fatigue, and sleep disturbances are common and distressing in advanced cancer. We updated previous systematic reviews of how these symptoms can be alleviated with targeted literature searches. The approach to these symptoms requires comprehensive symptom assessment; treating underlying causes when benefits exceed risks; prioritizing treatment, as patients usually have many symptoms; and addressing psychosocial and spiritual distress. For dyspnea, evidence supports systemic opioids and nonpharmacological treatments such as a fan. The strongest evidence supports metoclopramide for cancer-related nausea and octreotide for bowel obstruction. For anorexia, enteral or parenteral nutrition is indicated with obstruction and expected prognosis of at least 6 weeks. Evidence supports several drugs for appetite affecting quality of life. For fatigue, evidence supports psychosocial interventions and methylphenidate. For insomnia, evidence supports cognitive-behavioral therapy in cancer; no sleep agents have superior effectiveness.     

The use of taxanes in the neoadjuvant treatment of breast cancer: a review of randomized phase II/III trials

This review examines all randomized studies that evaluated the role of taxanes in the neoadjuvant treatment of breast cancer and have reported results in terms of efficacy and tolerance. The primary objective of this review was to evaluate whether, at this point in time, there is sufficient evidence to support the routine use of taxanes in the neoadjuvant treatment of breast cancer. Other objectives were to determine the optimal schedule in which to administer taxanes and anthracyclines and whether the addition of other antitumor drugs improves the efficacy of these anthracycline/taxane-based schedules. A literature search revealed 9 major randomized clinical trials published to date. To facilitate analysis, they were classified according to their protocol design. Five trials evaluated the effect of the addition of a taxane to an anthracycline-based schedule, either concomitantly or sequentially. The remaining 4 trials contained taxanes in both treatment arms in an attempt to optimize the administration schedule of anthracyclines and taxanes, or to improve efficacy by adding a further antitumor drug. This type of analysis has provided the opportunity to draw some conclusions regarding the optimal use of taxanes.     

Pharmacologic therapy for the cancer anorexia/weight loss syndrome: A data-driven, practical approach

The cancer anorexia/weight loss syndrome occurs in over 80% of patients with incurable cancer and is associated with a poor prognosis and negative effects on quality of life. Educating patients and families plays an important role in its management, and caregivers sometimes forget that in select patients who are candidates for it, antineoplastic therapy can occasionally reverse some aspects of this syndrome. Patients may also benefit from appetite stimulants such as corticosteroids and progestational agents,and this review summarizes the benefits of using these agents as well as their contraindications.     

Cancer treatment trials--past failures, current progress and future prospects

Randomized trials are usually too small to provide decisive evidence on the effectiveness of cancer therapy, and most therapeutic developments have been based on studies of tumour response. This approach, together with survival comparisons using historical controls, has led to the development of effective chemotherapy for a few very responsive tumours, but not for most common cancers, where the impact of treatment on survival is quite small. It is difficult to distinguish effective and ineffective innovations in the treatment of such cancers, and consistent progress, in which the more effective treatments are developed and the less effective ones discarded, cannot be achieved without comparisons based on large numbers of randomized patients. The combined evidence on adjuvant therapy for breast cancer and colorectal cancer is reviewed, and a new meta-analysis of published chemotherapy trials in advanced ovarian cancer is presented. The evidence that certain adjuvant regimens can prolong survival is conclusive for breast cancer and quite strong for colorectal cancer, and there is suggestive evidence that cis-platinum prolongs survival in advanced ovarian cancer. Such results illustrate the importance of large randomized trials in evaluating and improving the treatment of common cancers. The major difficulty in achieving large patient entry to randomized studies is the reluctance of many oncologists to participate in collaborative clinical research. The reasons underlying this reluctance, and the way in which such collaboration should be organized to meet these objections, are also discussed.