Nutrigenomics and Integrative Medicine: Shaping the Future of Cancer Management

Abstract

Studies have shown that the treatment incidence of onset cancers significantly rose worldwide after the 90s decade. Multidisciplinary cancer care teams are challenged to keep a survivor’s group’s physical and psychological well-being that presents a long-life perspective. In this way, there is a rise in the search for integrative medicine as complementary or alternative cancer treatments. Although the general information around these subjects is plentiful and diverse, scientific literature still explores the evidence for establishing the possible benefits of nutraceuticals’ bioactive molecules as cancer alternative interventions. Usually, complementary therapy is used to relieve the treatment’s side effects in cancer patients. In addition to conventional treatment, mind-body interventions support patients’ spiritual, emotional, and mental health. Over the last few years, there have been a growing number of studies with significant results on natural products that protect against oral mucositis progression. This narrative review surveys what is known about global patient healthcare as an integrative part of oncologic therapy. The goal is to elucidate the importance of supporting patients and families through complementary therapy with conventional cancer treatments. As a result, these strategies are to soften the impact of the side effects, improve well-being and strengthen the psychological outlook. Ultimately, clinicians and patients must work together to select the best treatment options based on each case’s benefits.

1. Introduction

The integrative medicine idea emerged from the theory that the human body keeps homeostasis. It must maintain a stable balance between the external and internal environment through the body’s physical response [1]. Thus, biopsychosocial-spiritual dimensions of suppressing a somatic disease directly relate to the individual’s well-being [2, 3]. Integrative medicine aims to enhance the bodys innate healing capacity by combining conventional and complementary methods. Integrating the patient and multidisciplinary team would facilitate understanding how health, psychological wellness, and disease influence the cure [4, 5]. This approach is essential to support the oncological patient and their families once the main principle contributes to global health promotion, managing the symptoms and adverse effects of cancer or its treatment [6, 7].

Several civilisations used the beneficial effects of natural products to promote health and avoid illness status. Based on the concept propagated from Hippocrates’ ideas that ‘Let food be thy medicine and medicine be thy food’, the utilisation of natural products emerged as medicine. The term nutraceuticals is a combination of the words ‘nutrition’ and ‘pharmaceutics’. It is a bioactive compound isolated from natural resources to improve health, delay ageing, prevent chronic diseases, and prolong life expectancy [8]. The research in nutraceuticals has improved and risen in the last decades. In vitro and in vivo research and clinical trials have proven some nutritional benefits and therapeutic effects. However, the side effects and synergies of the long-term use of nutraceuticals must be investigated and better described [9].

This chapter aims to underscore the essential role of integrative medicine in supporting cancer patients by minimising the side effects of therapeutic treatments, enhancing overall well-being, and fortifying the immune system. It highlights the relationship between dietary biomarkers that monitor cancer progression and prevention and nutraceuticals that offer therapeutic benefits from natural sources. Additionally, lifestyle modifications, mind-body therapies, photonic stimulation, and natural products in conjunction with conventional cancer treatments to improve patient care will be discussed. The section sustains the relevance of cancer cures with conventional surgery, radiotherapy, systemic chemotherapy, and new therapies such as gene therapy and immune-mediated biological therapy. However, combinatorial strategies could raise health promotion and manage symptoms and adverse effects in the treatment journey. A multidisciplinary team must be involved in the final decision about the therapeutic combination to achieve the ideal interaction between patients’ physical, psychological, social, and spiritual needs during cancer treatment.

2. Integrative oncology as support for cancer treatment

Cancer is a health condition inherent to human life. With the increment in life expectancy globally, there is a rise in cancer numbers worldwide. Additionally, the health system brings advances in the treatment and prevention of cancer. Nowadays, cancer therapies are more effective in cancer control, so it is possible to find more cancer survivors. More related symptoms and side effects of conventional therapy occur long after the treatment [9, 10]. In addition to these factors, the new survivors psychologically experience emotional adjustment in the survivorship period. It is a common occurrence of depression, anxiety, and various aspects of cancer-related distress [11].

The concept of a global patient healthcare system arises to minimise the issues related to cancer therapy. Conventional cancer care and complementary and alternative medicine (CAM) interventions have increased in specialised hospitals and centres. This modality optimises the treatment, reduces the short- and long-term side effects, reinforces the immune system, and keeps the mental health balance [10]. Integrative oncology is a concept of patient-centred care based on a change in lifestyle, mind-body practices, natural products, and alternative therapies with scientific evidence-informed. These tools are used together with conventional treatments to engage patients and families as part of cancer care [7, 12].

A meta-analysis published in 2019 shows the demographic profiles, prevalence, and reasons for using complementary medicine in cancer patients [13]. They related that 51% of cancer patients adopt some of the modalities of these therapies. Usually, the user’s profile is a younger female with higher education, higher income, and previous CAM use. They report that the prevalence of head and neck (HN) cancer patients who used some modality was around 20%, primarily treating therapeutic cancer complications and raising the immune system against the illness [13].

However, most cancer patients using CAM do not receive this recommendation from the physician. A multi-professional team should plan CAM counselling in combination with cancer therapy to conduct an optimised and safe treatment, bringing benefits and avoiding synergistic effects that could compromise the effectiveness of conventional cancer care. Oncology healthcare professionals have failed to guide patients as they seek to use CAM as a cancer treatment support in some countries. The use of ‘miracle’ natural products without scientifically proven effectiveness and therapies that act against conventional treatments or unsafe is commonly noticed, resulting in the patients’ lack of trust in physicians [10, 14]. In addition to evaluating, integrative oncology uses holistic, patient-centred approaches to improve the effectiveness of conventional cancer treatments.

2.1 Lifestyle modifications

In the past two centuries, the world’s population passed a revolution in healthcare and, consequently, living standards. It is possible to note a decrease in the mortality rates, an increase in the average global population, more control of the burden of infection and communicable diseases, and effective treatment and control of illness [15, 16] The long-life expectancy at birth in several countries brings significant challenges to the healthcare system due to the increase in chronic diseases related to poor diet, stress, and no physical activities.

Several studies demonstrated that cancer incidence and mortality have significant range reductions in populations that have adhered to the guidelines for cancer prevention. Usually, the protocol recommends controlling a healthy weight and incorporating a physically active lifestyle: avoiding processed food, increasing plant-based foods, and decreasing alcohol intake [17]. Golubić et al. confirmed the finding and demonstrated that patients with a past cancer diagnosis could present clinically relevant health and quality-of-life benefits with lifestyle modifications. They suggest a program with nutrition, culinary medicine, physical activity, and stress relief components. The recommendation is to use based nutrition in practising mindful eating, stimulating the Mediterranean diet, consuming unrefined, whole plant foods, decreasing meats and animal fats, and avoiding red and processed meats. They also included physical activity and stress relief modules [18].

Adopting a healthy diet does not mean patients must pursue popular diets as curative regimens for cancer. Restrictive diets, in any way, can be hazardous to the patient and could bring nutritional deficiencies, negative calorie balance, and weight loss during cancer treatment. The nutritionist in the integrative oncologist team can recommend a specialised diet that improves health maintenance during and after cancer care, supporting recovery, preventing recurrence, and boosting survival [7, 14, 19]. In general, the overall analysis of the randomised trials demonstrated that most dietary interventions tend to alter the disease prognosis directly or indirectly, modifying the cancer survivors’ quality of life. Physical activity is also recommended during oncological therapy alongside dietary changes. It enhances the quality of life and well-being, reduces cancer-related fatigue, alleviates depression and anxiety symptoms, encourages lymphedema, and improves cardiovascular fitness caused by chemotherapy [7, 14].

2.2 Mind-Body therapies

Mind-body interventions are complementary and integrative health, focusing on integrating mind, body, and behaviour. These techniques can promote relaxation through the mind-body connection and support overall health and well-being [20, 21]. Cancer patients have found some success with treatments such as acupuncture, massage therapy, meditation, relaxation techniques, spinal manipulation, tai chi, and yoga. Psychological and physical well-being among cancer survivors and patients have been shown to be equilibrated by these practices [7, 14, 20].

Acupuncture and acupressure are traditional therapies that originated from traditional Chinese medicine. They have shown efficacy in the side effects control for several cancers. There are reports of control of hot flashes in breast cancer patients, pain in some cancer-related pain and fatigue, nausea, and vomiting during chemotherapy. Acupuncture has been demonstrated to help manage chemotherapy-induced peripheral neuropathy in several trials [14, 22]. To prove the advantage of treating xerostomia in patients with HN cancer, O’Sullivan and Higginson conducted a systematic review. The data collected do not show strong evidence to support that acupuncture avoids radiation-induced xerostomia [23].

Some randomised studies show evidence that yoga, tai chi, massage, and mindfulness-based interventions, such as meditation, can effectively manage pain, nausea, fatigue, and psychological distress (depression, anxiety, and fear of recurrence) among cancer patients. The research shows improvements in sleep, quality of life, psychosocial adjustment during cancer treatment, and a reduction in long-term side effects [7, 14, 21].

A pilot study demonstrated that mind-body therapeutic protocol could reduce several pro-inflammatory cytokines and chemokines involved in the mechanisms of drug resistance and cancer progression in breast cancer. According to their study, there is a relationship between protocol implementation and modulation of inflammatory pathways in acute and long-term cancer therapy, which could decrease the recurrence rate in these patients [24].

On the other hand, the summary of several randomised trials that analysed mind-body approaches to managing the fear of cancer recurrences and calculated their pooled effects showed significant results. According to these authors, immune system function can be altered by dysregulating psychological states, worsening physical symptoms, and increasing recurrence risk. Mind-body interventions have been found to impact neuroendocrine and immune function markers. However, the precise mechanisms through which the discharge of fear could enhance physiological health in cancer patients remain unclear. Researchers found that the intervention reduced the fear of recurrence in the patients. However, more mind-body skills could be tested among these patients to determine which subgroups would benefit from the intervention [22].

2.3 Natural health products

Natural products have shaped the history of anticancer drug discovery. Natural anticancer therapeutics include irinotecan, vincristine, etoposide, and paclitaxel from plants, actinomycin D and mitomycin C from bacteria, and marine-derived bleomycin. Cancer therapy will continue to be dominated by some of these compounds for a considerable time [25]. Despite the advances in cancer treatments, the treatment’s toxic effects still contribute to decreased wellness and poor psychological status among cancer patients.

Many aggressive side effects associated with cancer therapy have been identified, including oral mucositis, gastrointestinal toxicity, hepatotoxicity, nephrotoxicity, haematopoietic system injury, cardiotoxicity, and neurotoxicity. It is common for these side effects to reduce a person’s quality of life and interfere with their treatment. Thus, a greater emphasis is being placed on the study of crude extracts, bioactive components-enriched fractions, pure compounds derived from herbs, and herbal formulas that may be beneficial in managing cancer and decreasing the toxicity of the traditional treatment [26]. Natural products are perceived as safe by patients. The utilisation of natural products to alter cancer outcomes presents a lack of evidence. Usually, studies report evidence of positive effects in alleviating symptoms, though there is an increase in the number of patients who expect a cure with their regular employment [7, 27]. Scientific literature assumes that vitamins, minerals, and foods could avoid or prevent cancer development. Meanwhile, many clinical trials fail to show that natural products are effective as chemo-preventive agents [27].

Using natural products by cancer survivors and those undergoing active treatment could promote harmful effects. A decrease in the efficacy of radiation or chemotherapy effects may happen due to antioxidant products while utilising these products. It could also present detrimental effects in thrombocytopenia patients using anticoagulant herbs. The patients could present a loss of efficacy in hormonal therapies or influences on hormone-sensitive cancers through phyto estrogenic herbs and immunomodulatory natural products to promote alteration in the immunosuppressive therapy [7]. According to the Society for Integrative Oncology and ASCO guidelines, some natural products can improve a patient’s quality of life and well-being. However, a multi-professional integrative team must give the right and individual orientation to avoid potential interactions and maximise the benefits of these products [14].

According to the last ASCO guideline that appraises randomised controlled clinical trials, systematic reviews (SRs), and meta-analyses, the effective treatments of integrative medicine in patients with a cancer diagnosis are acupuncture reflexology or acupressure for general cancer pain or musculoskeletal pain and recommended for reducing chemotherapy-induced nausea and vomiting [28]. ASCO recommends acupuncture, reflexology, acupressure, and hypnosis for managing pain in adult cancer patients receiving palliative or hospice care [28]. They also consider regular aerobic and resistance exercise during active treatment with curative intent [29]. Since 2017, the ASCO Expert Panel has recommended music therapy, meditation, stress management, and yoga for anxiety/stress reduction, depression/mood disorder, and better quality of life [30]. Considering an intermediate level of evidence and with a moderate level of recommendation, they do not suggest using other mind-body interventions or natural pain relief products [28]. Neither the dietary and weight loss interventions nor neutropenic diets prevent infection during active cancer treatment [29]. Neither is the use of ingested dietary supplements to manage breast cancer treatment-related adverse effects [30].

To conclude, clinicians and patients must work together to choose the best approaches based on each case’s benefits. Implementing ASCO guidelines is intended to facilitate the multi-professional team’s selection of appropriate resources for integrative medicine.

3. The approach of nutraceuticals in the medicine

Understanding ‘nutraceutical’ terminology is essential to its medical study. This terminology arose in 1989 by De Felice and the Foundation for Innovation in Medicine as a combination of ‘nutrition and pharmaceutical’ terminologies [31]. In recent years, nutraceuticals have been defined as supplements that contain a concentrated bioactive agent from an ailment, e.g. plant, animal, or marine sources. They are produced in several dietary manners to enhance and improve health status. Usually, these supplements present the bioactive compounds in a dosage higher than the total obtained in a usual food intake [31, 32, 33]. The nutraceutical market explores the advantages of these products as the difference in drug utilisation. They highlight the extended half-life period, immediate activity upon intake, ready availability, and few side effects [34].

On the other hand, there is an increase in the search to consume natural foods that reduce the risk of lifestyle-related disorders by achieving physiological functions beyond nutritional effects. However, it is essential to emphasise that nutraceuticals differ from ‘functional foods’. Functional foods provide the necessary amount of essential nutrients to balance health. Nutraceuticals could be used to prevent or treat some medical conditions once these products are expected to have positive therapeutic effects [35].

Globally, there is a considerable increase in the intake of natural products as pharmaceutical tools. However, the regulation and control of these dietary supplements do not have similar regulations as pharmaceutical substances. International regulation of one standarlisation could ensure the safety and effectiveness of products with low-quality or ineffective ingredients [9, 32]. Moreover, the manufacturers do not have to prove the product’s efficacy to particular conditions. Also, they need to do more profound research that evaluates the safety dose, significance testing, appropriate outcomes, effect sizes, biomarkers of effect, and the differences between statistical and clinical significance [9, 20]. According to Bergamin et al., there needs to be more information about long-term studies to support nutraceuticals’ effectiveness in handling disease risk factors or disease cures. They report that most of the studies present high levels of heterogeneity and bias in characteristics of individuals, study duration, nutraceutical dose, and chemical composition [36].

Once the susceptibility to diseases depends on factors such as genetic predisposition and lifestyle disorders, it is also possible to consider that the response to the natural bioactive compound presents a similar perspective. For this reason, active ingredients with physiological or pharmacological effects could promote side effects and drug interactions in individuals with a more susceptible medical condition. Usually, dietary supplements are safe, but they are associated with risks. Considering this, monitoring the administration of nutraceuticals and supplements is essential to avoid severe undesirable effects in individuals [9, 20].

Usually, chronic diseases present a similar spectrum of risk factors, a connection of imbalance in the immune system, and the development of an inflammation/angiogenic environment. These effects compromise the body’s natural stability and trigger the development and progression of this group of diseases [37]. In a chronic inflammatory environment, higher levels of C-reactive protein (CRP), IL-6 and TNFa exist. Stimulating systemic inflammatory indicators for a long time promotes deleterious health outcomes. Moreover, it is possible to note an increase in the leucocyte and elevated neutrophil levels [38]. The accumulation of inflammatory cells creates a pro-angiogenic environment due to the functional switch of immune cells [37]. Also, the altered environment supports the cancer progression once it favours the tumour angiogenesis, decreases the immune response through the tumour, and creates conditions for cancer cells to grow [39].

Nutraceuticals have been used in medicine to have health-promoting effects, normalising body functions. The bioactive compounds of natural products could be preventive and nutritive and boost the immune system [40]. Further, recent studies have reported evidence of significant effects in managing chronic diseases and adverse effects of drugs when they are used as adjuncts to pharmaceuticals [36]. In this point of view, the medical choice to use nutraceuticals is usually to control or regulate chronic disease risk factors (obesity, hyperglycaemia, hypertension, hypercholesterolemia) associated with lifestyle modification. The shift of these factors impacts the quality of life. It decreases the effects of life-long diseases such as cancer, type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and inflammatory-based diseases such as rheumatoid arthritis, osteoarthritis, vascular dementia, and Crohn’s disease [36, 40].

4. Nutrigenomic and the regulation of cancer biomarkers

Nutrigenomics, a field merging nutrition and genomics, explores how nutrients interact with our molecular environment, influencing the metabolic pathways that maintain our body’s balance. These nutrients act as signals, directing specific gene expression, protein production, and metabolite formation. Different dietary patterns induce distinct sets of these responses, often called ‘signature dietary patterns’ [41, 42]. Nutrigenomics has the potential to revolutionise personalised medicine by tailoring treatments to an individual’s unique genetic and nutritional makeup, enhancing patient care [42].

Extensive research supports the idea that specific foods can prevent and treat various cancers by impacting and altering cancer cells. The relationship between diet and cancer, including breast, prostate, liver, colon, and lung cancers, has been the focus of in-depth studies [41, 43]. Clinical and biomolecular studies have reported links between dietary components and genetic pathways, suggesting potential benefits, although further research is needed to strengthen these connections [41].

Bioactive components from natural sources are screened as potential protective agents against epigenetic changes in cells, which can alter their genetic makeup. These components hold promise for protecting against various stages of cancer development and other conditions, including obesity, type-2 diabetes, autism, cardiovascular diseases, and cancer, where epigenetic modifications play a significant role [41, 43].

Several bioactive components, such as calcium, zinc, selenium, folate, vitamins C, D, and E, carotenoids, flavonoids, indoles, allyl sulphur compounds, conjugated linoleic acid, and N-3 fatty acids, have the potential to influence various physiological processes, including carcinogen detoxification, intercellular communication, cell cycle regulation, apoptosis, hormonal balance, and angiogenesis [41].

4.1 Nutrigenetics and personalised diet in cancer prevention

Nutrigenomics, a powerful tool for studying nutrition and the human genome, delves into the complex relationship between diet and genetics. It uncovers how nutrient-gene interactions influence disease risks, particularly in the early stages of diet-related conditions [44]. By investigating the impact of genetic variations on an individual’s response to dietary intake and metabolic status, nutritional genetics paves the way for personalised health interventions. Studies on population variations in single nucleotide polymorphisms (SNPs) highlight the significant genetic contribution to disease risk, emphasising the role of diet [41, 44].

Cancer prevention research underscores the pivotal role of nutrients in crucial signalling pathways that influence various types of cancer. These pathways include carcinogen metabolism, DNA repair, and cell regulation. Bioactive components in fruits and vegetables can thwart cancer by enhancing detoxification and inhibiting harmful activations [41].

In vitro and preclinical investigations demonstrate that plant-based dietary components effectively regulate detoxification enzymes and activate essential signalling pathways. Additionally, specific dietary elements, such as flavonoids and vitamins B12, E, and C, are known for their ability to repair oxidative DNA damage [45, 46, 47, 48, 49].

Furthermore, some dietary compounds, like genistein and epigallocatechin-3-gallate, can halt the cell cycle [50, 51, 52]. Isothiocyanates regulate cell proliferation by impacting the expression of p21 and blocking cell progression at the G2-M checkpoint in the cell cycle [53]. Several dietary compounds, including selenium, epigallocatechin-3-gallate, phenylethyl isothiocyanate, retinoic acid, sulforaphane, curcumin, apigenin, quercetin, and resveratrol, prevent cancer by impeding apoptosis [54, 55]. These elements actively interfere with programmed cell death, underscoring their significance in cancer prevention.

Dietary components also influence inflammation and angiogenesis, vital cancer development and progression processes. Studies show that certain dietary components, including conjugated linoleic acid, long-chain omega-3 fatty acids found in fish oil, butyrate, epigallocatechin-3-gallate, curcumin, resveratrol, genistein, luteolin, quercetin, and vitamins A and D, can affect these processes that provide essential nutrients and oxygen to malignant cells [41, 56, 57].

Personalised nutrition, informed by genetics, is crucial in customising dietary interventions based on an individual’s genetic profile. This approach highlights the significance of a multidisciplinary approach to disease prevention and management, considering genetic and environmental factors. Nutraceuticals also emerge as a promising solution for preventing and treating various diseases.

4.2 Biomarkers of nutrition and health

The core objective of nutrition is to maintain and enhance optimal health, emphasising the importance of identifying biomarkers for early changes that can precede disease onset, serving as preventive and health indicators. These pre-disease physiological alterations are associated with disruptions in the body’s equilibrium when faced with environmental or nutritional influences, offering a fresh approach to preserving overall physiological well-being [58].

Nutritional biomarkers evaluate dietary intake and metabolism through biochemical, functional, or clinical indicators. These biomarkers serve as the cornerstone for research on the impact of nutrition on health and disease. Nutritionally regulated health biomarkers are the primary focus, as they measure dietary intake based on the biological responses elicited [58, 59, 60].

These biomarkers can identify specific dietary components and their effects on cancer risk and growth. As discussed, identifying these markers can lead to tailored dietary recommendations, lifestyle modifications, and personalised interventions to reduce cancer risk or slow its progression. By examining these associations, it is possible to comprehend the role of nutraceuticals in oncogenesis better, facilitating dietary choices for cancer prevention and management [61].

4.2.1 Vitamins

The connection between vitamin A and cancer is multifaceted, supported by animal models and epidemiological studies showing its potential in preventing cancer. Vitamin A influences immune cells, cellular membrane structure, protein glycosylation, cell adhesion regulation, RNA transcription, and DNA replication. Its role in binding to transcription factors and histone acetyltransferases underscores its significance in maintaining proper cellular differentiation, highlighting its potential in cancer prevention and management [61].

Studies findings suggest that blood concentrations of carotenes and retinol in cancer patients do not consistently differ from those in healthy controls; however, varying associations between specific micronutrients like vitamin A and retinol and cancer risk are observed, indicating the potential role of these substances in cancer development and progression [62, 63, 64, 65].

Folate deficiency can disrupt DNA stability, heightening the risk of genetic mutations and cancer. Antifolate drugs intentionally induce DNA damage as part of cancer therapy, underscoring folate’s role in preserving chromosomal integrity. A shortage of vitamin B9 leads to extensive DNA demethylation, potentially fostering oncogenesis by activating dormant oncogenes and endogenous retroviruses. Meanwhile, vitamin B5 (pantothenate) is crucial for fatty acid production and the Krebs cycle [61].

Several studies have investigated the link between vitamin B and different types of cancers. Based on their findings, it can be deduced that high folate levels can decrease the risk of lung cancer. On the other hand, low folate levels can increase the risk of cervical cancer. In contrast, high levels of vitamin B12 can lead to a higher risk of myeloid leukaemia and malignant lymphoid tumours. These results demonstrate the complex relationship between B vitamins and various types of cancer [66, 67, 68, 69].

Vitamin C uniquely impacts cancer cells by inducing oxidative stress and promoting cell death. Its therapeutic potential affects RNA expression profiles and influences the production of reactive oxygen species and DNA demethylation, affecting cancer cell proliferation and apoptosis. Combining it with vitamin K3 leads to autoschizis, an unconventional form of cell death. Vitamin C’s delicate balance between oxidative stress and antioxidant effects makes it a compelling focus in cancer research [61].

Blood vitamin C concentrations were significantly lower in prostate cancer patients and gastric cancer patients compared to healthy controls, suggesting a potential link between cancer and reduced vitamin C levels; for gastric cancer patients, the depletion was attributed to concomitant Helicobacter pylori infection, which disrupted vitamin C transport, and vitamin levels recovered after infection resolution [70, 71, 72].

Venturelli and colleagues report in an extensive meta-analysis that studies on the relationship between vitamin D, E and K, and various cancers have shown varying results, with some cancers being associated with high vitamin levels, others with low levels, and some showing no significant association, highlighting the complex and context-dependent nature of ‘vitamin’s impact on cancer risk and prognosis [61].

It is important to highlight that inconsistent results of the studies could suggest that vitamins may not directly cause cancer but may play an indirect role as cofactors. Multivitamin/mineral supplements can temporarily fill gaps in micronutrient intake but may not fully address hidden nutritional deficiencies. The meta-analysis conclusion around the vitamin levels in the bloodstream opens the possibility of a non-invasive and widely applicable analytical approach with a significant potential for improving diagnostic and prognostic evaluations [61].

4.2.2 Polyphenols

Polyphenols are natural compounds that can be found in fruits and vegetables. They are essential to a healthy diet and have many potential health benefits [73, 74, 75]. However, the evidence supporting these claims varies between in vitro and animal studies, which generally show positive effects, and in vivo and human epidemiological research, where the evidence is less conclusive [73, 76, 77]. Biomarkers of polyphenol exposure, such as the direct bioavailable forms of these compounds or their metabolites, are likely to be the most accurate indicators of their benefits [77].

Polyphenols include various compounds, such as anthocyanins, flavonols, flavanones, and catechins [78]. The daily intake of these compounds varies, and it is essential to note that they have different absorption patterns and recovery rates [77, 79]. Consuming an adequate amount of these compounds daily is crucial to reap their benefits [80, 81, 82].

Wang et al. conducted research on epidemiological studies and clinical trials that used polyphenol exposure biomarkers to assess their potential anticarcinogenic effects. The studies primarily focused on breast and prostate cancer and were predominantly conducted in Asian and European populations, with validation for green tea polyphenol intake biomarkers [77].

Their research indicates that isoflavones affect breast cancer risk differently, depending on the study. Australian women with increased equol urinary excretion exhibited a significantly reduced breast cancer risk. However, two European studies showed non-significant risk reductions, and another study reported that higher plasma genistein levels were associated with a significant reduction in risk. Moreover, consistent findings among Asian populations included significant reductions in breast cancer risk associated with higher urinary daidzein levels in a study involving a large sample size and a more sensitive analysis technique. A Japanese study also found a significant association between breast cancer risk and plasma genistein concentrations [77].

The group summarised studies that related prostate cancer risk to polyphenol intake. The search revealed that high equol exposure was significantly associated with a reduced risk of total disease development and localised cases in the Japan Public Health Center cohort. There was also a tendency for an inverse association between plasma genistein levels and total prostate cancer. However, similar associations were not evident in European studies, and a study involving a multiethnic population in Hawaii and California showed that urinary daidzein excretion was linked to a reduced risk of prostate cancer, especially high-grade disease. In contrast, no such associations were observed for daidzein and genistein urinary excretion [77].

The group also reported studies that examine the impact of polyphenol exposure on other cancer risks, such as colorectal and gastric cancer, through biomarkers. They concluded that the study’s results varied across different types of cancer and regions, with some indicating a reduced risk in association with specific polyphenols. In contrast, others found no significant effects [77].

In summary, nutritional biomarkers have been utilised to investigate the correlation between polyphenol consumption and cancer risk. The potential for cancer risk reduction associated with polyphenol intake depends on several factors, including the type of cancer, the specific polyphenols studied, and the accuracy of dietary exposure assessment. Additional research is required to gain a deeper understanding of the effects of various subclasses of flavonoids, as well as to explore the role of phenolic acids and other minor groups of polyphenols in mitigating cancer risk.

4.2.3 Omega-3 fatty acids

Omega-3 polyunsaturated fatty acids (PUFAs) are recognised as immunonutrients with diverse biological effects, including roles in cell signalling, cell membrane structure, inflammation resolution, and acting on G protein-coupled receptors [83]. While commonly used in the nutritional therapy of cancer patients, the 2017 European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines primarily focus on omega-3 PUFAs for treating cancer-related cachexia, overlooking their potential benefits for managing other cancer-related complications such as anorexia, pain, depression, paraneoplastic syndromes, and mucositis [83, 84].

The importance of omega-3 intake compared with other free fatty acids was highlighted in a summary of cohort breast cancer risk studies. The total monounsaturated fatty acids, oleic acid, and palmitic acid were associated with an increased risk of breast cancer in postmenopausal women. While studies on cases and controls showed a significant inverse association with alpha-linolenic acid [85].

The investigation revealed an association between cytologic atypia, a short-term breast cancer risk biomarker, and intake of omega-3 and omega-6 fatty acids. The lower levels of total omega-3 fatty acids in red blood cells and plasma phospholipids and lower omega-3:6 ratios in plasma and breast triacylglycerides (TAGs) could be associated with women with cytologic atypia. These findings suggest a potential role for omega-3 fatty acids in reducing breast cancer risk, and cytologic atypia could serve as a surrogate endpoint in breast cancer prevention trials involving omega-3 supplementation [86]. To better understand how dietary fatty acids influence breast cancer development, further research is necessary to integrate dietary fatty acid intake biomarkers.

Hooper and colleagues published a meta-analysis that assessed the impact of plant-based omega-3 fats on health in individuals without pre-existing cardiovascular disease. It found that both long-chain and short-chain omega-3 fats did not clearly affect total mortality, cardiovascular events, or cancer [87].

Another study found that a higher combined intake of fish omega-3 fatty acids in the diet from both diet and supplements is linked to reduced overall mortality and decreased cancer-related mortality, with a modest decrease in cardiovascular disease-related mortality, suggesting that long-chain omega-3 fatty acids may help lower the risk of total and cancer-specific mortality [88].

In a randomised trial involving 60 patients with lung cancer at nutritional risk, those who received omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) for 12 weeks showed improvements in weight, albumin levels, triglycerides, and reductions in inflammatory markers (C-reactive protein and tumour necrosis factor-alpha) compared to the placebo group, suggesting that omega-3 supplementation can enhance the nutritional status and suppress inflammation in lung cancer patients [89].

Some cohort studies need to present an adequate adjustment in the lifestyle factors. Policy and lifestyle decisions should rely on data from randomised clinic trials [74]. To gain a comprehensive understanding of the long-term effects of omega-3 fats, it is crucial to conduct additional high-quality, long-term studies. The available literature on this subject is limited, and the existing studies often present conflicting results. The use of biomarkers for dietary fatty acid intake could be for efficient and personalised strategies, offering new avenues for cancer prevention and management.

5. Prospects for the future

Cancer treatment is a complex process that requires a multi-faceted approach to ensure the best patient outcomes. Integrative medicine emphasises a holistic approach to healthcare, considering the mind, body, and spirit. This approach views individuals as complex systems, recognising that diseases can affect not only physical health but also mental and physiological well-being. Complementary and alternative medicine (CAM) interventions commonly used in cancer care align with this approach, as they have demonstrated their ability to alleviate symptoms caused by circulating cytokines, such as fatigue and cachexia.

Natural products have gained popularity in recent years as potential therapeutic agents due to their accessibility, minimal side effects, and diverse health benefits, including anti-inflammatory, antimicrobial, antiulcerative, and wound-healing properties. These products have shown promise in reducing the side effects of cancer care, although research results vary in strength and consistency. Further research into nutraceuticals is essential because they may target various biological and molecular factors in cancer development and treatment.

In this context, dietary biomarkers play a crucial role in monitoring cancer prevention and evolution, especially when combined with the principles of integrative medicine. They provide valuable insights into an individual’s dietary habits and their potential impact on cancer risk and progression. Integrative medicine can use these biomarkers to create personalised, evidence-based cancer prevention and treatment strategies, highlighting nutritious significance in holistic healthcare.

The present approach recognises the complex interplay between individuals and disease development. Complementary and alternative medicine (CAM) interventions align with the goal of enhancing overall well-being in cancer care. They aim to provide care targeting cancer and addressing patients’ challenges. This includes providing emotional support, effective pain management, and symptom control. Consequently, patients have a better chance of achieving a successful outcome.