Tumor growth and progression are characterized by specific alterations of energy and nutrient intake and metabolism, which result in the cancer cachexia syndrome.1 This syndrome is complex and is characterized by anorexia, early satiety, severe weight loss, weakness, immunodepression, anemia, edema, and depression.2–4 It can result in death. Tumor growth and the host immune-specific activation are responsible for these processes.5 Chemotherapy treatment often compounds the problem. Current guidelines for protocols of nutritional management of ovarian and other cancer patients are often lacking in evidence and are based on expert opinion.6 Although intestinal obstruction, which affects up to 30% of ovarian cancer patients, is a significant complication, it has been well described elsewhere.7–9 This review focuses on the nutritional challenges faced by patients with ovarian cancer and the limited evidence for noninvasive nutritional intervention. We refer to current practice in the United Kingdom and suggest possible future research in oral nutrition intervention in this patient population.
The Problem of Malnutrition in Ovarian Cancer
The location of the ovarian tumor deep in the abdomen limits the possibility of a precise early diagnosis. Late diagnosis is associated with advanced disease, which in turn is associated with worsening nutritional and performance outcomes. These are caused by (1) reduced ability to eat (feeling too full too quickly, nausea and vomiting), (2) bowel obstruction, and sometimes (3) diarrhea, the consequences of which may cause patients to stop eating. The psychological impact of a disease arising in a reproductive organ consequently reduces appetite and nutritional intake.10 As with other cancers, derived systemic and metabolic disturbances, which lead to specific humoral and inflammatory responses,3 result in detrimental metabolic alterations. In addition, cancer treatments, particularly chemotherapy, often cause complications that compound the nutritional problem.
Pathways that result in cancer cachexia are well documented3 and involve inadequate food intake, metabolic alterations, and specific humoral and inflammatory responses. These pathways and those involving some hormones such as ghrelin, insulin, and leptin; neuropeptides; and neurotransmitters that play a role in the metabolism of nutrients and maintenance of homeostatic functions have since become better understood. Manipulation of these may be significant in the management of cancer malnutrition. The dynamics of individual contributors evolve during the course of the disease, such that malnutrition should be viewed as a continuum that requires regular reassessment.3 Factors that lead to cancer cachexia in ovarian cancer are summarized in Figure 1.
Malnutrition compromises both treatment and recovery, resulting in worse overall outcomes and increased resource utilization. One of the challenges so far has been to provide evidence for the place of nutritional care in the treatment pathway. The negligible response of cachexia to available pharmacological and nutritional interventions has led a general view that nothing can be done, and palliation of the worst effects of this complex metabolic picture is all that can be achieved.11 Further challenges have been caused by lack of criterion-standard methods of determining nutritional status, universally accepted clinical definitions of key terms such as malnutrition and cachexia, and assessment parameters being affected by illness and injury leading to inability to isolate the effect of malnutrition from the influence of disease.12,13
Progress is being made, and international groups are working together to provide universally acceptable and clinically relevant definitions of key terms and consensus statements.11,14 Disease-related malnutrition has recently been defined as the point at which the severity or persistence of inflammation results in a decrease in lean body mass associated with functional impairment and at least partially attributable to a decrease in nutrient intake, but also tightly linked to the effect of the inflammatory state on intermediary metabolism.14 There is emerging evidence indicating that those mechanisms ultimately leading to the severe wasting of cachexia are operating early during the natural history of disease11 and increased muscle proteolysis suggestive of cachexia being detectable in cancer patients even in the absence of weight loss.15 This and the fact that anorexia is one of the most common symptoms prompting women to see their general practitioner highlight the need for effective early intervention in cancers where malnutrition and cachexia are highly prevalent.
The detrimental effects of reduced intake due to disease effect or treatment are unquestionable. Currently, there are marked variations in clinical practice.16 Literature and advice on nutritional management of patients undergoing treatment for ovarian cancer are not clear, and recommendations made by advisory bodies in Europe, United States, and Australia for cancer patients lack evidence and are largely based on expert opinion.6 In bowel obstruction, for instance, it has not been clearly identified which patients should be treated aggressively and what mode of therapy should be pursued.7 The lack of clarity is also reflected in often contradictory information given to patients. Patients themselves tend to seek out information and have been shown to reduce consumption of some types of food such as fat, sugar, and red meat and increase consumption of fruit and vegetables with the hope of aiding cure of their disease.17 Patients may see the tumor as a reason to eat “healthy food” and may thus compromise themselves at a time when they need high energy-dense intakes.
There is also some evidence that suggests that restricted calorific intake increases longevity in multiple species and slows several age-related biological functions, including decreased immune function and tumorigenesis.18–20 The biological mechanisms of this process are neither clearly understood nor have been demonstrated unequivocally. However, suggesting that deprivation rather than supplementation may be part of the answer to malnutrition and tumor progression seems counterintuitive. There is a need for further research with key carcinogenesis and/or energy balance pathways to provide important understanding of the calorie-cancer relationship.21
Even though nutritional intake has been shown to be substantially reduced in patients with cancer experiencing weight loss,22 it is not always diminished. Once a critical point is reached, the complex interplay between underlying disease, metabolic alterations, and reduced availability of nutrients will eventually and inevitably cause death.11 Adequate intake often fails to reverse the cachectic process where inflammation is present.
Metabolic and Inflammatory Pathways
The metabolic and immune changes in cancer are well documented and are not necessarily cancer-specific. They are thought to be mediated by the pathophysiological process, that is, tumor, or host-derived chemical factors, for example, peptides, neurotransmitters, cytokines, and lipid-mobilizing factors, and are associated with hypertriacylglycerolemia, lipolysis, and acceleration of protein turnover.23 Host and tumor-derived factors seem to interact with intracellular signaling mechanisms to disrupt skeletal muscle protein balance.24 Tumor cells increase nutrient uptake and angiogenesis to support the up-regulation of metabolism necessary for unrestricted growth, and they have a high degree of anaerobic glycolysis and produce large amounts of lactate and a net uptake of amino acids.23
Significant research has been carried out on metabolic pathways and the role of the inflammation on malnutrition and cachexia. These include efforts to understand the role of cytokines as inflammatory mediators that can influence a change in the cognitive and autonomic processing that governs the initiation and cessation of ingestion,25 strategies with molecules able to block cytokine production by either destabilizing their mRNA or inhibiting their synthesis or to interfere with cytokine-receptor interaction,26 and exploration of anticytokine strategies combined with oral supplements and treatments aiming to modulate inflammatory processes associated with cachexia.6 There has also been work on analysis and understanding of DNA sequences, RNA transcripts, and metabolism, which may in the future allow for the identification of specific genotypes and phenotypes that may help with metabolic profiling and lead to individualized dietary therapies,27 although this needs further exploration.
In the last decade, there was a surge in interest in hormones that influence metabolic homeostasis including insulin, leptin, and ghrelin and neuropeptides. They are involved in the metabolism of nutrients and maintenance of homeostatic functions.28–36 It is thought that there are relatively normal insulin secretion in cancer and reduced insulin sensitivity (peripheral insulin resistance), resulting in inefficient metabolism and availability of carbohydrates to the body. The other hormones and neuropeptides are implicated in energy control, feeding behavior, and accretion of fat. Understanding their roles presents research opportunities, where manipulating them to stimulate food intake or prevent breakdown of body reserves potentially improving patient outcomes seems a real potential.
Importance of Adequate Nourishment in the Face of Disease and Treatment
Up to 40% of all cancer patients die of the effects of malnutrition rather than of the malignancy itself.37 It has been said that the chance of surviving ovarian cancer mainly depends on (1) patient characteristics, (2) tumor biology, and (3) the quality of treatment.38,39 Whereas the first 2 are nonmodifiable, the latter can be. Nutrition is an important aspect of quality of treatment that could potentially impact on patient outcomes38; hence, strategies that support and ensure maintenance of adequate nutrient intake and utilization in the presence of symptoms and through treatment need to be found.
Malnutrition alters cellular physiology and organ function, affecting surgical outcome and postoperative morbidity and mortality.40–42 The feasibility of complete cytoreduction is related to tumor volume and location, it is also related to a patient’s ability to withstand a long operation (age, performance status, nutritional status).43 Malnourished patients undergoing surgery are more likely to have complications such as increased blood loss, poor wound healing, infections, and admissions to intensive care units,44,45 while those undergoing adjuvant chemotherapy show a decreased response to the treatment, increased risk of chemotherapy-induced toxicity, and increased risk of complications and death during the course of treatment.46 Failure to complete intended chemotherapy regimen is also common. Comorbidities such as chest infections due to decreased immunity and electrolyte imbalance with implications for lung function and cardiac complications are also common.
Quality of Life
A diagnosis of ovarian cancer, pain, anxiety, anger, fear, and difficult treatments affect all aspects of a woman’s life including her sexuality,47,48 resulting in reduced quality of life. Low quality of life in turn contributes to psychological distress, which feeds into the vicious cycle of aggravated nutritional intake and weight loss, further plunging quality of life. This cycle is exacerbated by relapse or disease progression, which occurs in the majority of patients within 18 months of diagnosis.
Evidence Base for Current Clinical Practice
We sought to determine what clinical trials or other studies of noninvasive nutrition intervention in ovarian cancer patients had been carried out by searching MEDLINE and the Cochrane databases. The findings were unexpected; no randomized controlled trials were identified that evaluated the impact of additional oral nutrients or other interventions such as diet counseling. Gupta et al39 evaluated the impact of nutrition on survival in a cohort of women diagnosed with ovarian. Interpretation of their results is complicated by the fact that their baseline assessment includes patients who had received treatment and those who had not. The other 7 studies identified (Table 1) evaluated the efficacy and safety of early postoperative feeding compared with delayed feeding. Even so, only 1 study55 focused on only ovarian and peritoneal cancer patients, the rest (6 studies) included all gynecological cancers with one (Schilder et al 51) including noncancer patients. Health outcomes related to surgical protocols were the primary outcome for all the studies. They showed that the former was safe and well tolerated by patients and also that there was reduction in postoperative complications such as infection and length of stay. This evidence supports the postoperative Enhanced Recovery Programme (oral intake as soon as possible after surgery)56–58 currently practiced in many surgical settings in the UK National Health Service. Gupta et al39 followed up patients in the medium term. Although they found that patients who were well nourished at baseline or whose nutritional status improved at 3 months had significantly better survival than those whose nutritional status deteriorated, the challenge remained in that the baseline was not clearly defined.
The majority of patients treated for ovarian cancer in the United Kingdom do not receive a nutritional management package at the onset. There are exceptions where nutritional problems interfere with planned treatment and patients are referred to a dietitian for intervention. Patients’ weight and height are assessed at first contact and before treatment. Comprehensive nutritional screening is often carried out only at the time of admission to a ward. Even so, there are questions of how well applied the assessment outcomes are to daily patient care. Nutritional support tends to be more robust where there are complications or in end stages where enteral and parenteral routes are preferred and usually as part of the palliation. There is no clear evidence of what type of nutrients could be used effectively to slow down or reverse cachexia and what doses and conditions would enable this to happen. Moreover, researchers often focus on very specific and usually short periods (around treatment) for assessment and intervention, whereas we know that the processes that lead to cachexia precede any signs or symptoms.
It is possible that the limited number and scope of nutrition intervention research highlight the challenges of working with patients diagnosed with this low-incidence but deadly disease. There needs to be clear evidence of the categorical changes in nutritional status of patients in relation to survival or death. The understanding of these changes and how they relate to tumor characteristics (histopathology, stage, grade, etc) and patient characteristics (age, weight, activity level, etc) can move forward attempts to provide targeted and individually tailored nutritional intervention. Prospective cohorts assessing nutritional status over a number of years could be a good starting point. Evidence from such cohorts can be used to design randomized controlled trials to establish whether nutrition intervention at any stage in the disease trajectory will achieve improvement beyond short-term indices such as quality of life, recurrence, prognosis, and survival. So far, only short-term benefits such as length of hospital stay, early return to oral diet, and a reduction in complications and infection rates have been demonstrated. Also, questions need to be answered about which particular nutrients linked to the causation of cachexia can be used effectively to slow down or reverse this condition and what doses and conditions would enable this to happen.
Guidelines for nutritional management of ovarian cancer patients are largely based on expert opinion. There is a need for a clear, objective, comprehensive, and long-term assessment of nutritional status of patients with ovarian cancer, how this changes at different stages of the cancer trajectory, and how the changes impact health and nutritional outcomes, disease recurrence, quality of life, and survival. This would provide a basis for well-designed randomized controlled trials with specific and controlled nutrients/counseling targeted at identified specific needs.
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