1. n-3 PUFA and Cancer Cachexia
Apart from cardiovascular diseases, cancer is currently the second leading cause of death in China. According to statistics, 31-87% of patients with malignant tumors suffer from malnutrition. Furthermore, 15% of patients with malignant tumors experience weight loss at the time of diagnosis. Research reports indicate that approximately 20% of cancer patients die directly from malnutrition, rather than the disease itself. Some patients exhibit signs of cachexia, characterized by anorexia, progressive weight loss, anemia, or hypoproteinemia. In the late stages, they may also experience pain, dyspnea, or organ failure. Cachexia is a common fatal factor in malignant tumors, directly affecting treatment outcomes, increasing the incidence of complications, and reducing quality of life, survival time, while prolonging treatment duration and increasing medical expenses. The development of cachexia progresses through three stages: pre-cachexia, cachexia, and refractory cachexia. Inflammatory factors play a crucial role in the pathogenesis of cancer cachexia, while n-3 PUFA can negatively regulate the inflammatory cascade response. Additionally, it can reduce the occurrence of skeletal muscle wasting. Therefore, n-3 PUFA plays a significant role in the prevention and treatment of cancer cachexia.
Numerous clinical trials have demonstrated that nutritional supplements containing n-3 PUFAs can help alleviate cachexia symptoms, reduce weight loss, and even increase weight in patients with advanced malignancies. However, some clinical studies have reported varying effects of n-3 PUFA supplementation in patients with advanced cancer. This discrepancy may be attributed to individual differences in patients' tolerance to dietary n-3 PUFA supplementation. Dewey reported in a retrospective study that there was insufficient evidence to support the argument that oral EPA can treat cancer cachexia. Nevertheless, evidence suggests that when cancer patients consume large amounts of EPA, they can maintain stable weight or even gain weight. This indicates that n-3 PUFAs may play a role in nutritional support in cancer patients, but a higher intake may be required. Existing clinical studies have confirmed that supplementation with n-3 PUFAs can improve the nutritional status of patients with colorectal cancer, head and neck tumors, among others. Synthetic COX-2 inhibitors such as celecoxib, used alone or in combination with n-3 PUFAs, can also improve cachexia in cancer patients. Another mechanism by which n-3 PUFAs improve the condition of cancer patients is their immunomodulatory effect. Supplementation with n-3 PUFAs before and after abdominal surgery in cancer patients can reduce inflammatory cytokines and improve liver and pancreatic function. Patients receiving intravenous immunonutritional support containing glutamine or n-3 PUFAs have significantly lower infection rates and improved immune function. Bougnoux found that supplementing DHA during anthracycline chemotherapy for breast cancer patients can significantly slow cancer progression, improve tolerance to chemotherapy side effects, and increase survival rates. Supplementation with n-3 PUFAs in patients with colorectal, gastric, and pancreatic cancer can effectively reduce postoperative complications and alleviate inflammatory responses.
2. Related Clinical Research
Vander Meij BS et al randomly divided 40 patients with stage III non-small cell lung cancer (NSCLC) receiving comprehensive treatment into two groups. The experimental group was given an oral diet supplemented with n-3 PUFA (n=20, EPA 2.02g/d + DHA 0.92g/d), while the control group received an oral control diet with the same caloric content. The study found that compared with the control group, the n-3 PUFA diet group had advantages in maintaining body weight, upper arm circumference, and energy expenditure at rest. Although both groups experienced weight loss, the ω-3 PUFA group had a lesser degree of weight loss.
Murphy RA et al administered EPA (2.2g EPA/d) as a dietary supplement to 16 out of 40 NSCLC patients undergoing initial chemotherapy. After 10 weeks, patients who had the highest increase in serum EPA concentration from the EPA-containing diet also had the greatest increase in muscle mass. Approximately 69% of patients in the experimental group had increased or maintained their muscle mass at baseline levels, while only 29% of the control group maintained their muscle mass at baseline. The average muscle mass of the entire control group decreased by approximately 1 kg.
Ryan AM et al randomly divided 53 esophageal cancer patients into an experimental group (n=28, EPA 2.2g/d) and a control group (n=25, standard enteral nutrition with the same caloric content). The patients in both groups began oral administration 5 days before surgery and continued via jejunostomy pumps after surgery. After 21 days, no differences in complications were observed between the two groups, but patients in the EPA diet group maintained better lean body mass, while the control group had an average weight loss of approximately 1.9 kg (P=0.03). The reduction in skeletal muscle mass not only increases the risk of cachexia but also elevates the risk of infection.
Lieffers JR et al found that 38.9% (91/234) of patients undergoing rectal surgery experienced a decrease in skeletal muscle mass postoperatively, which was accompanied by an increased risk of infection (23.7% vs 12.5%, P=0.025) and a longer hospital stay (15.9 vs 12.3 days, P=0.038).
3. Related Guidelines
I. Oncology Evidence-Based Nutrition Practice Guideline for Adults (2016), Academy of Nutrition and Dietetics, USA:
If suboptimal symptom control or inadequate dietary intake has been addressed, and the adult oncology patient continues to experience weight loss and lean body mass (LBM) reduction, a Registered Dietitian Nutritionist (RDN) may consider incorporating dietary supplements containing EPA as a component of the nutrition intervention strategy. (Rating: Strong; Imperative)
II. ESPEN Guideline on Nutrition in Cancer Patients 2016, European Society for Clinical Nutrition and Metabolism
For patients with advanced cancer undergoing chemotherapy who are at risk of weight loss or malnourished, we suggest supplementation with long-chain omega-3 fatty acids or fish oil to stabilize or improve appetite, food intake, lean body mass, and body weight. (Strength of recommendation: weak; Level of evidence: low) Considering clinical efficacy and safety, an optimal intake of n-3 fatty acids (EPA and/or DHA) is 2g/d.
III. Expert Consensus on Enteral Nutrition for Patients Undergoing Radiotherapy for Malignant Tumors (2017), Chinese Anti-Cancer Association Tumor Nutrition and Support Therapy Professional Committee, Chinese Medical Doctor Association Radiation Oncology Therapy Physicians Branch Nutrition Therapy Committee:
Omega-3 PUFA is beneficial in enhancing immune function and modulating inflammatory responses in radiotherapy patients, and its inclusion in enteral nutrition formulations is recommended.
IV. A.S.P.E.N. Clinical Guidelines: Nutrition Support Therapy During Adult Anticancer Treatment and in Hematopoietic Cell Transplantation (American Society for Parenteral and Enteral Nutrition, A.S.P.E.N.):
Omega-3 fatty acid supplementation may assist in stabilizing weight in cancer patients on oral diets experiencing progressive, unintentional weight loss. (Grade: B) An EPA target dose of 2g/d is considered appropriate.
V. Guidelines for Nutritional Support in Cancer Patients, Chinese Society for Parenteral and Enteral Nutrition (CSPEN):
For patients with advanced cancer accompanied by malnutrition or nutritional risk, supplementation with omega-3 PUFA during radiotherapy and chemotherapy can reduce weight loss, maintain lean body mass, and improve overall nutritional status (Level of Evidence: Low; Conditional Recommendation).
VI. Expert Consensus on Enteral Nutrition for Patients Undergoing Radiotherapy for Malignant Tumors (2017):
Omega-3 PUFA enhances immune function and modulates inflammatory responses in radiotherapy patients, and its inclusion in enteral nutrition formulations is advised. (Class 2B) Supplementation with omega-3 PUFA during radiotherapy aids in maintaining or increasing weight, boosting immunity, reducing inflammatory responses, and improving patients' quality of life.
VII. Expert Consensus on Nutrition Management During Cancer Rehabilitation (2017):
Limit saturated fat intake and increase consumption of n-3 polyunsaturated fatty acids and monounsaturated fatty acids. (B, 2b)
VIII. Guidelines for Nutritional Therapy in Chemotherapy Patients (2016):
Omega-3 PUFA-fortified oral nutritional supplements (ONS) can help stabilize weight in cancer patients experiencing non-intentional weight loss. (B)
IX. Guidelines for Nutritional Therapy in Cancer Cachexia (2015):
Dietary, enteral, or parenteral nutrition formulations rich in omega-3 PUFA may be beneficial, potentially more effective when ensuring adequate total energy intake. (B)
X. Expert Consensus on the Application of Special Medical Purpose Foods for Cancer Patients (2016):
Omega-3 fatty acids may influence many regulatory mediators of cachexia, inhibiting the growth of certain tumors, halting the progression of cachexia in cancer patients, slowing weight loss, increasing lean body mass, and improving quality of life.
4. n-3 PUFA and Cancer Risk
Research on the relationship between n-3 PUFA and cancer prevention began three decades ago, yet it remains controversial. Brasky TM et al. suggested that dietary supplementation with n-3 PUFA could reduce the risk of breast cancer (HR=0.68, 95% CI=0.50-0.92). In 2013, a meta-analysis4 on breast cancer risk and Omega-3 intake, jointly published by the Nutrition and Food Safety Center of the Asia-Pacific Clinical Nutrition Society (ASIA-PACIFIC Clinical Nutrition Society) and Zhejiang University, encompassed 20,905 breast cancer cases and 883,585 participants from 21 independent prospective cohort studies. The findings revealed that a higher daily intake of marine-derived Omega-3 supplements was associated with a decreased incidence of breast cancer (RR~0.86 (95% CI 0.78 to 0.94), I²=54%). A dose-response analysis further indicated that every additional 100 mg of Omega-3 intake per day could reduce the risk of breast cancer by 5%.
In 1982, Chavarro JE et al. conducted a 13-year follow-up study on blood n-3 PUFA levels in 14,916 healthy men, of whom 476 were later diagnosed with prostate cancer. When matched with controls, a lower blood n-3 PUFA level was found to increase the risk of prostate cancer (RR=0.59, 95% CI=0.38-0.93). Hall MN et al. tracked blood n-3 PUFA concentrations in 21,406 healthy individuals over 22 years, with 500 eventually diagnosed with colorectal cancer (388 colon, 112 rectal). They concluded that an increased intake of n-3 PUFA reduced the risk of colorectal cancer (RR=0.74, 95% CI=0.57-0.95). However, a prospective study by Butler LM et al. provided contradictory evidence. Among 61,321 participants recruited from 1993 to 1998, 961 cases of colorectal cancer were diagnosed by December 31, 2005. It was found that a diet rich in n-3 PUFA increased the risk of Dukes' C or D stage colorectal cancer (HR=1.33, 95% CI=1.05-1.70). Possible explanations for these conflicting conclusions include the multifactorial nature of cancer development, involving genetic background, lifestyle, and other factors. Notably, a recent study published in the prestigious journal GUT5 demonstrated that high-dose intake of marine-derived Omega-3 polyunsaturated fatty acids could reduce mortality from colorectal cancer, highlighting the significance of increased Omega-3 intake for patients with confirmed colorectal cancer.
Researchers reviewed mortality from colorectal cancer and Omega-3 intake in the Nurses Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), analyzing a total of 1,659 cases. Participants were divided into four groups based on their Omega-3 intake: 0.15 g after diagnosis reduced the risk of colon cancer death by 70%, while decreased daily intake was associated with a 10% increase in this risk.
Another cohort study from Japan on pancreatic cancer risk and Omega-3/fish supplementation6 found that a high intake of Omega-3, particularly from marine sources, was associated with a lower risk of pancreatic cancer. Analyzing 82,024 eligible participants aged 45-74 in the JPHC study, the group with higher Omega-3 intake showed a relative risk of ~0.70 compared to the lower intake group ((95% CI: 0.51, 0.95; P-trend = 0.07).
5. n-3 PUFA and antitumor-related toxicity
The treatment of tumors inevitably leads to numerous toxic reactions, yet the clinical community often overlooks these treatment-related toxicities in reality. These toxicities often cause various discomforts for patients, accompanied by concerns and confusion among their families. Additionally, they can reduce patients' tolerance to treatment, ultimately leading to treatment discontinuation. Despite this, research on preventing and reducing treatment-related toxicities in oncology remains scarce. Recent studies have indicated that dose-limiting toxicities during cancer treatment are associated with sarcopenia. Given the importance of n-3 PUFA in maintaining body weight among cancer patients, researchers have conducted exploratory studies to investigate whether n-3 PUFA intake can reduce the toxic effects of cancer treatment. Ghoreishi Z et al. randomly divided 57 breast cancer patients undergoing paclitaxel chemotherapy into an n-3 PUFA supplementation group (640 mg/d) and a control group. The results showed that only 30% of patients in the experimental group experienced neurotoxicity, compared to 59.3% in the control group (OR=0.3, 95%CI=0.10-0.88, P=0.029). Furthermore, the quality of life in the experimental group was significantly improved compared to the control group. Neutropenia and impaired neutrophil function are common toxic reactions to chemotherapy. Bonatto SJ et al. divided 38 patients receiving postoperative leucovorin and 5-FU adjuvant chemotherapy into an experimental group (EPA 0.3 g/d + DHA 0.4 g/d, n=19) and a control group (no n-3 PUFA supplementation, n=19). The results revealed that patients in the control group lost an average of approximately 2.5 kg after chemotherapy, with significant reductions in the number and function (phagocytosis and peroxidase production) of polymorphonuclear cells (primarily white blood cells) in their blood. In contrast, patients in the experimental group fared better in terms of weight loss, polymorphonuclear cell count reduction, and functional decline after chemotherapy.
6. n-3 PUFA and Tumor Treatment Response
For a long time, it has been believed that n-3 PUFA can enhance the tumor's response to treatment. The combined effect of DHA and antitumor drugs can intensify the cytotoxic effects of the latter, maintaining a higher level of reactive oxygen species (ROS) in tumor cells (preventing the onset of drug resistance), reducing the endogenous antioxidant stress defense mechanisms within tumor cells, and enhancing the absorption of antitumor drugs. Existing animal experiments have shown that adding n-3 PUFA to the diet of tumor-bearing mice can slow the growth of various tumors, such as lung, colon, breast, and prostate cancers, while also improving the efficacy of multiple chemotherapeutic drugs (e.g., doxorubicin, epirubicin, 5-fluorouracil, irinotecan, and tamoxifen) and radiotherapy. Possible mechanisms include modulating arachidonic acid production and inflammatory responses, inhibiting angiogenesis, accelerating apoptosis, and regulating estrogen signaling transduction. Based on findings from animal experiments, an increasing number of clinical trials have also confirmed that n-3 PUFA can enhance the tumor's response to treatment.
A Phase II clinical trial conducted by Bougnoux P et al. involved administering DHA (1.8 g/d for 7-10 days) to 25 patients with advanced breast cancer and visceral metastases prior to chemotherapy. Patients were divided into high-DHA (n=12) and low-DHA (n=13) groups based on their pre-chemotherapy blood DHA levels. The results showed an overall response rate of 44% (95% CI = 24.5-63.5), with median progression-free survival and median overall survival significantly longer in the high-DHA group (8.7 months vs. 3.5 months, P=0.02; and 34 months vs. 18 months, P=0.007, respectively). Additionally, the incidence of vomiting and thrombocytopenia was significantly lower in the high-DHA group (P=0.01). Murphy RA et al. randomly assigned 46 patients with newly diagnosed stage IIIB or IV non-small cell lung cancer to receive DHA and EPA supplements (n=15, 2.5 g/d) or to a control group (n=31). The results revealed that the response rate (complete response + partial response) and clinical benefit rate (complete response + partial response + stable disease) were significantly higher in the experimental group (60.0% vs. 25.8%, P=0.008; and 80.0% vs. 41.9%, P=0.02, respectively). The 1-year survival rate was also higher in the experimental group (60.0% vs. 38.7%, P=0.15), although there was no significant difference in the incidence of chemotherapy-related toxicities between the two groups.
n-3 PUFA appears to play a role in the occurrence, development, prognosis, and treatment of tumors, suggesting its potential as a nutritional supplement requiring additional intake. Oral nutritional supplements are the primary mode of n-3 PUFA administration, with a daily dosage of approximately 2.5 g. However, large-scale randomized controlled clinical trials are needed to provide evidence-based support for specific supplementation protocols.
7. Mechanisms of Omega-3's Involvement in Tumor-Related Processes
The potential mechanisms underlying the effect of n-3 PUFA on tumorigenesis are related to its function in modulating inflammatory responses. Inflammation plays a crucial role in the initiation and progression of tumors, suggesting that diets rich in n-3 PUFA may have a preventive effect against tumor development. n-6 PUFA, another type of polyunsaturated fatty acid found in the human body, has its first unsaturated bond located at the sixth position from the methyl end of the carbon chain, encompassing linoleic acid and arachidonic acid (AA). Both n-3 PUFA and n-6 PUFA share the same metabolic enzymes, namely cyclooxygenases and lipoxygenases. EPA and AA, when acted upon by these enzymes, can both produce inflammatory mediators, albeit the pro-inflammatory and pro-proliferative activities induced by the mediators generated from EPA are weaker. n-3 PUFA exhibit a stronger affinity for these enzymes, competitively inhibiting the conversion of n-6 PUFA and reducing AA synthesis, thereby alleviating inflammatory responses. As a result, diets rich in n-3 PUFA can negatively regulate the inflammatory cascade, decreasing the risk of tumor development. The recommended dietary ratio of n-6 PUFA to n-3 PUFA is 1:1 to 2:1. Studies have found that an increase in this ratio may elevate the risk of prostate cancer. Furthermore, Giros A et al. discovered that DHA and EPA can enhance the activity of caspase enzymes, leading to the induction of tumor cell apoptosis and exerting a preventive effect against tumorigenesis.
7.1 Role of n-3 Polyunsaturated Fatty Acids in Inhibiting Tumor Neovascularization
Neovascularization, or the formation of new blood vessels, is a crucial prerequisite for tumor growth, invasion, and metastasis. Consequently, inhibiting tumor neovascularization represents a vital strategy in controlling cancer progression. Vascular endothelial cell proliferation, migration, and lumen formation all rely on the involvement of vascular growth factors, with Vascular Endothelial Growth Factor (VEGF) being the most significant one identified so far. Studies abroad have demonstrated that EPA can suppress the expression of VEGF-α and VEGF receptor Kdr, thereby inhibiting the formation of tumor neovessels. Additionally, Prostaglandin E2 (PGE-2) promotes cell proliferation and inhibits apoptosis, leading to an imbalance between proliferation and apoptosis, which facilitates tumorigenesis. PGE-2 also induces the production of various pro-angiogenic factors and accelerates the degradation of extracellular matrix, generating substances like thromboxane that promote platelet aggregation, thereby facilitating cancer cell invasion and metastasis. Consequently, n-3 PUFAs can inhibit tumor growth, neovascularization, invasion, and metastasis by suppressing PGE-2 production.
7.2. n-3 Polyunsaturated Fatty Acids Enhance Anticancer Function of the Immune System
n-3 PUFAs can alter the composition of tumor cells, thereby modifying their responsiveness to the immune system. Furthermore, n-3 PUFAs possess potent immunomodulatory properties, actively participating in immune regulation within the body. Research by Ma Dongzhu et al. indicates that DHA reduces the activity of the death receptor Fas on the surface of T lymphocytes, decreasing the number of apoptotic T lymphocytes during tumor cell killing, thus prolonging their antitumor effects. DHA also promotes T lymphocyte proliferation and enhances the transcriptional activity of cytokines such as TNF-α, IL-1B, and IL-6, thereby strengthening the function of immune cells and improving their ability to kill tumor cells. In summary, n-3 PUFAs bolster the immune system's function, ultimately contributing to their antitumor effects.
7.3. Synergistic Effects of n-3 Polyunsaturated Fatty Acids with Anticancer Drugs
Numerous studies have revealed that n-3 PUFAs contribute to enhancing the efficacy of commonly used anticancer drugs. Arsenic trioxide (As2S3), despite its ability to induce tumor cell apoptosis through accumulating reactive oxygen species (ROS) within cells, has limited applications due to its significant toxicity and side effects at effective plasma concentrations. The presence of multiple double bonds in DHA enables a reduction in the effective therapeutic concentration of As2S3, enhancing its efficacy in treating leukemia. Research by Bradley et al. suggests that the combined use of DHA and paclitaxel not only increases the concentration of the drug within tumor cells and maintains it for an extended period but also decreases its concentration in normal cells, thereby mitigating adverse reactions such as nausea, vomiting, alopecia, and peripheral neuropathy. Furthermore, n-3 PUFAs enhance the efficacy of the antitumor drug 5-FU and potently inhibit the activity of Epstein-Barr virus early antigen (EBV-EA). In summary, the combined application of DHA with anticancer drugs enhances drug efficacy, reduces their effective plasma concentrations, and mitigates toxicity and side effects.
7.4. n-3 Polyunsaturated Fatty Acids Increase the Expression of Tumor Suppressor Genes in Cancer Cells
n-3 PUFAs may be associated with increasing the expression of tumor suppressor genes in cancer cells. DHA influences the expression of nuclear transcription factors, inhibiting the expression of anti-apoptotic genes from the bcl-2 family and upregulating the expression of pro-apoptotic genes such as Caspase-5, Caspase-8, Caspase-9, Caspase-10, and Caspase-13. Additionally, n-3 PUFAs inhibit the localization, activation, and signal transduction of Ras protein (encoded by Ras genes) on the endoplasmic reticulum of cells, thereby suppressing tumor cell proliferation.
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