The need for dietary intervention in cancer patients. Considerations of intake of concentrated nutrients during antitumor treatment
Hristov*, G. Dimitrov*, Y. Popova, Y. Milusheva, K. Vasileva, S. Katov, V, Borisova, M. Atanasova, P. Troyanova
Department of Medical Oncology, Queen Giovanma University Multiprofile Hospital for Active Treatment, Sofia
*The two principal authors contributed equally to the writing of this work
A healthy diet as prevention against cancer
A healthy lifestyle is crucial to reaching peak body health. It represents a heterogeneous combination of healthy eating habits (complete, balanced and varied diet), intake of sufficient amount of fluids, vitamins and minerals, physical activity, absence of unhealthy habits (alcohol, drugs, smoking), healthy circadian rhythm, mental and emotional health, etc.
The increased Human Development Index (HDI) is directly related to cancer incidence (Fig. 1).(1) Hectic and at the same time sedentary lifestyle of modern times, mental and emotional distress, lack of healthy dietary and physical culture, polluted environment and difficulty in accessing quality food products have determined the statistical boom of cancer diseases in the 21st century, highly dependent on both genetic and epigenetic factors.
Statistical analyses of cancer incidence in different countries show the strong correlation of the incidence of newly diagnosed cancers per capita with the healthy eating habits of their inhabitants. There is a fourfold difference in cancer incidence rates in Western countries (such as Australia) compared to Middle Eastern and Mediterranean countries (such as the United Arab Emirates).(2)
There are obvious differences in the daily lifestyle of the average members of these territories, including healthy eating habits, such as increased intake of fruits and vegetables and reduced intake of trans fats, red meat, processed meat products and alcohol.(3) There are also huge statistical differences in the percentage of the population observing some form of diet, eating and fasting regimen or religious fasting. Taking also into account the fact that the lower cancer incidence in the Middle Eastern countries is in the presence of additional negative factors, such as higher smoking rate (4), higher obesity rate (5), lower healthcare budget (6), higher average age (7) and higher index of polluted environment (8), the importance of healthy food, low alcohol use and good dietary culture is further emphasized as cancer prevention.
The Western diet is characterized by consumption of higher amounts of processed and refined foods rich in salt, added sugar, fats added through frying and breading, increased use of alcohol, sweets and desserts, processed meat products and red meat, and lower amounts of a variety of products in their natural form such as nuts, fruits and vegetables, natural spices, fish and seafood. This dietary pattern has been associated with development and exacerbation of many chronic diseases – obesity, cardiovascular diseases, oncological diseases, endocrine diseases, autoimmune diseases, etc.(9) The Mediterranean diet is considered one of the most healthy diets in the world and represents the absolute opposite of the Western dietary pattern (Fig. 2).
Data from multiple clinical studies show that the Mediterranean diet is associated with a reduced risk of cardiovascular diseases and metabolic syndrome, a reduced risk of type 2 diabetes and dyslipidemia, reduction in inflammatory markers and a reduced risk of cancer death compared to other diets.(10) Its health effect is attributed to the increased intake of healthy nutrients such as:
1. Complex carbohydrates rich in plant polyphenolic molecules with proven antioxidant, anti-inflammatory and prebiotic effects.(11) A high daily intake of polyphenols from a variety of foods (over 900 mg/d) is associated with a healthy gut microbiome function and reduction of the risk of a chronic disease and death.(12)
2. High intake of marine-derived biologically active Omega-3 unsaturated fatty acids – eicosapentaenoic and docosahexaenoic acids (EPA and DHA)
As a result of following this diet the overall ratio between consumption of Omega-3 and Omega 6/9 fatty acids is improved, excessive consumption of saturated fatty acids of animal origin is reduced and intake of unhealthy trans fats is highly limited. This improved balance of dietary fats is associated with reduced production of inflammatory signaling molecules (prostaglandins, interleukins and leukotrienes) and an improved lipid profile, resulting in reduction in the risk of multiple chronic and inflammatory diseases.(13)
3. High-protein foods
There are no good and bad proteins, there are good and bad protein sources. After consumption all ingested proteins are broken down in the gastrointestinal tract into some of the 20 nonessential and essential amino acids, di- and tripeptides, which are absorbed by the gastrointestinal mucosa and satisfy the demands of all tissues, organs and systems of the body. When unprocessed high-protein foods (chicken breast, shrimps, fish, turkey, beef sirloin) are consumed the risk of intake of additional food groups, such as simple carbohydrates, saturated fatty acids and trans fats, is reduced. The diet restricts consumption of foods lower in protein and higher in unhealthy nutrients (smoked salami, salted cold meats, some dairy products), thereby reaching as clean protein intake at mealtimes as possible.(14)
4. Vitamins and minerals
Vitamins and minerals play an essential role in maintaining normal cell functions and growth and development processes. They are required for many enzymatic processes, electrolyte balance, nerve impulse generation, bone matrix formation, hormone regulation, wound healing and many other physiological processes. This diet promotes nutritional diversity with intake of many unprocessed foods of plant and animal origin, sources of all necessary vitamins and minerals, thus preventing the development of their deficiencies in the body.(15)
Dietary intervention in cancer patients
The nutritional status of cancer patients may vary both before diagnosis and during the active phase of disease treatment. Malnutrition, cachexia, anorexia and sarcopenia are common conditions in cancer patients both due to adverse drug reactions of the treatments administered and a patient’s cancer progression and mental and emotional state. Data from studies report malnutrition in 30 to 85% of cancer patients.(16) Malnutrition increased toxicity of medical therapies, decreased quality of life and increased mortality in these patients (Fig. 3).
Dietary adjustment intervention by the primary doctor is recommended before patients enter severe malnutrition, at the first sign of weight loss or inadequate calorie intake (e.g., less than 50% of what is needed for more than a week or less than 100% of what is needed for more than two weeks).(17)
In dietary counseling, it is necessary to encourage intake of energy-dense foods rich in nutrients (especially proteins) and plenty of fluids in an attempt to manage symptoms, correct various nutritional deficiencies and improve nutritional status. Additional use of dietary supplements and concentrated nutrients is recommended when an enriched diet is not effective in reaching nutritional goals.
It is recommended to switch to enteral tube feeding if oral feeding remains inadequate despite attempted dietary intervention (dietary counselling and intake of concentrated nutrients) and parenteral feeding if enteral feeding is insufficient or cannot take place (Fig. 4).(18) Additional considerations may possibly be necessary in the special population of patients with head and neck cancers and GIT tumors (e.g., liquid/mushy diet, perform gastrostomy or add enzymes to the diet).
The Mediterranean diet with different variations in daily calorie intake and macronutrients (e.g. increased protein intake) may be an appropriate healthy and balanced diet that, together with healthy levels of physical activity, may improve the nutritional status and the general well-being and reduce the intensity of adverse drug reactions of the antitumor therapies administered.
Data from various clinical studies support the use of the Mediterranean diet during active treatment of cancer patients to reduce cancer-related fatigue (19) and improve overall quality of life (QoL) manifested with increased physical activity, reduction of pain, dyspnea and insomnia.(20)
Considerations of concentrated nutrient use during antitumor treatment
The use of alternative medicine and dietary supplements is extremely popular among cancer patients. A European study published in Annals of Oncology revealed that the percentage of patients using alternative medicine and dietary supplements can be as high as 73.1%. This phenomenon is a consequence of a normal and expected mental and emotional reaction in a patient in an attempt to regain sense of control over their own health. Obviously, regardless of the beliefs and skepticism of healthcare professionals patients will continue to be interested in and use alternative approaches.
It is a huge problem that patients can easily be misled by people of no medical education offering false healing practices or magic substances of unclear origin, which not only carry a risk of adverse events during antitumor therapy, but may also encourage a patient to completely avoid conventional medical approaches.
The study cited recommended the need for healthcare professionals to improve their qualifications on the use of dietary supplements and alternative approaches in cancer patients. In the light of limited data they should get as informed as possible about potentially helpful substances and approaches, reject those for which evidence of effectiveness is lacking and thus work towards an integrated model of their implementation in the setting of conventional healthcare. (21) Supplementation with concentrated nutrients without medical supervision carries backfiring risks if improperly done. Substances may engage liver enzymes and transport proteins that are required for the metabolism and transport of antitumor drugs, thereby reducing their effectiveness. Overdose of substances with high antioxidant potential may reduce the effectiveness of drugs that rely on oxidative stress to reach their cytotoxic effect (especially when coadministered). Multiple considerations are needed when selecting a dietary supplement during antitumor therapy.
• First of all, there should be no evidence that supplementation with a substance stimulates cancer development (Primum non nocere!).
• It is necessary to consider the recommended daily dose whereby avoiding improper intake (overdose or intake of low and ineffective doses).(22)
• It is necessary to anticipate the cycling of intake according to the half-life of substances and antitumor treatments to avoid potential cross-reactions.
• Consideration should be given to the duration of intake in order to avoid, as far as possible, continuous and prolonged exposure, which may cause adverse effects due to overaccumulation of substances.
SWOG S0221 observational study analyzed breast cancer patients having to undergo postoperative chemotherapy who had taken various dietary supplements for a prolonged period of time. It found a discrete trend for reduced DFS and OS (overall survival) in patients who took antioxidants for a prolonged period of time simultaneously before diagnosis and during the postoperative chemotherapy being administered (adjusted hazard ratio – adjHR, 1.41; 95% CI, 0.98-2.04; P=0.06). No similar trend was found in patients who took antioxidant supple¬men¬tation only before diagnosis or only during therapy. (23) The following is a good model of behavior if the primary doctor decides to include oral dietary supplementation:
• Schedule intake on the days between chemotherapy cycles (Fig. 5).
• The duration of intake should be no longer than 3 to 4 months, after which a 1-month off should be initiated.
• During administration of daily oral antitumor therapies concentrated nutrients should be taken at a maximum time apart from the drug after checking for cross-reactions and benefit-risk assessment by the primary doctor.
When dietary supplements are used during antitumor therapy it is appropriate to assess whether the quantitative intake of a substance contributes to improvement in nutritional status. Many commonly advertised dietary supplements offer ineffectively low doses. It is necessary to consider the substance potential to produce a beneficial and desirable (antiemetic, antioxidant, etc.) effect in a patient who is experiencing therapy-typical toxicities. It is important to consider supplementation as an addition to a diet aimed at adjusting the nutritional status and reducing toxicity of conventional therapies, rather than as cancer treatment.
Proper dietary supplementation done under medical supervision in a clinical study setting demonstrated positive effects with improvement in quality of life and reduction in toxicity. The most prominent representatives for such substances are the following:
1. Omega-3 fatty acids
Data from a meta-analysis for cachectic patients with lung cancer show a statistically significant contribution of Omega-3 (EPA and DHA) fatty acid supplementation to cachexia reduction versus placebo (MD: 1.22, 95% CI: 1.05-1.38, p<0.01) and quality of life (QoL) improvement (MD: 14.40, 95% CI: 9.22-19.59, p<0.01).(24)
A double-blind placebo-controlled statistically significant clinical study in colorectal cancer patients demonstrated that Omega-3 fatty acid supplementation was associated with reduction in neurotoxicity induced by chemotherapy (Oxaliplatin, Capecitabine) and quality of life improvement (52.22% vs. 69.66% in favor of the Omega-3 fatty acid supplementation group; P=0.017).(25)
2. Plant polyphenolic extracts
Data from a double-blind, placebo-controlled study conducted show that crocin (saffron polyphenol) is effective in alleviating symptoms of chemotherapy-induced peripheral neuropathy (CIPN) in cancer patients on antitumor therapy – neuropathic pain was significantly reduced in the crocin group compared to placebo (P < 0.05) (26).
A double-blind placebo-controlled study showed high effectiveness of ginger polyphenol concentrate (6-gingerol) intake in prevention and management of chemotherapy-related nausea and vomiting (CINV) during active treatment with a highly emetogenic chemotherapy – overall CR rate was significantly higher in the 6-gingerol group compared to the placebo group (77 vs. 32%; P < 0.001).(27) A double-blind placebo-controlled study conducted at Mayo Clinic showed that ginseng extract intake during active chemotherapy statistically significantly improved cancer-related fatigue (CRF) and increased quality of life, respectively, of patients in an 8-week QoL index follow-up – 20 vs. 10.3 improvement versus the placebo group (P=0.003).(28) Data from other double-blind placebo-controlled studies show that ginseng extract intake may improve immune function and white blood cell lienage laboratory parameters: after 8 weeks there has been an increase in CD4 and CD8 T cells (p <0.0191), B cells (p <0.0004), WBCs (p <0.0490) (29); stimulate gut microbiome normal function and diversity (30), improve liver parameters and reduce fatigue. Ginseng effectively improves liver enzymes and fatigue score by modulating the gut microbiota in patients with fatty liver disease compared to placebo (p < 0.05).(31)
3. Proteins and amino acids
A meta-analysis demonstrated that dietary supplementation enriched with whey protein and Omega-3 fatty acids reduced muscle wasting and improved quality of life in patients undergoing radiation therapy with chemotherapy (+1.89 kg, 95% CI 0.51-3.27, P=0.02; Q=3.1 P=0.37).(32) Another placebo-controlled study demonstrated that combination supplementation of whey protein, Vitamin D and Vitamin E in older patients with sarcopenia (muscle wasting) statistically significantly improved muscle strength, increased muscle volume and improved quality of life (vs. placebo group: muscle mass MD: 0.18 kg/m2, 95% CI: 0.01-0.35, P= 0.040; handgrip strength MD: 2.68 kg, 95% CI: 0.71-4.65, P=0.009; mental component summary MD: 11.26, 95%CI: 3.86-18.65, P=0.004).(33) A meta-analysis showed that supplementation with the amino acid glutamine resulted in reduction in oral mucositis risk in patients undergoing radiation therapy or chemotherapy – it significantly reduced the incidence of grade 3 and 4 oral mucositis compared to placebo (RR, 0.53; 95% CI, 0.32-0.88).(34)
4. Vitamins and minerals
Vitamin D supplementation in Vitamin D-deficient patients with early non-small cell lung cancer after radical treatment administered showed statistically significant improvement in general condition and quality of life and reduction in the risk of recurrence – Vitamin D therapy showed significantly better 5-year RFS (86% vs. 50%, P=0.04) and OS (91% vs. 48%, P=0.02) in the early-stage adenocarcinoma subgroup versus the placebo group.(35)
Administration of Vitamin E alone or in combination with other antioxidant agents may result in improved oxidative stress markers and reduction in the typical toxicities related to cisplatin application.(36)
5. Probiotics
Gut microbiome has a key role in a number of physiological processes that are important to the host’s health, including gut homeostasis, metabolism, healthy gastrointestinal mucosa function, regulation of inflammatory reactions, immunological activity, etc.
Double-blind studies and meta-analyses demonstrate that supplementation with high microbial count multistrain probiotics may statistically significantly reduce the risk of chemotherapy-induced diarrhea and oral mucositis in patients on active chemotherapy – oral administration of probiotics reduces the risk of chemotherapy-induced diarrhea (≥1 grade) (RR = 0.70; 95% Cl: 0.56, 0.88; P=0.002) and oral mucositis (≥1 grade) (RR: 0.84; 95% Cl: 0.78, 0.91; P < 0.00001).(37)
In conclusion, we would like to summarize that a healthy diet and a good nutritional status of cancer patients play a key role for the general condition, quality of life and outcome of antitumor treatments. Due to the lack of sufficiently qualified oncodietitians in Bulgaria the responsibility for proper and timely dietary intervention in patients falls on the primary medical oncologist. Intake of concentrated nutrients is recommended after attempting to control adverse events with an enriched diet. Multiple considerations regarding the type, quality, amount, duration, and cyclicity of intake of concentrated nutrients are needed so that their positive effects on the body are reached and adverse events and cross reactions are avoided as much as possible during administration of antitumor treatment.
