The aims of our study were 1) to investigate the impact of the nutritional state on the immune response and survival of patients with generalized malignancy and 2) to evaluate the significance of dietary omega-3 PUFA supplementation for immunomodulation and survival, especially in the subgroup of the mostly immunocompromised, severely malnourished cancer patients.
We measured serum IL-1, IL-6, and TNF levels, as well as IL-1, IL-6 and TNF production, by peripheral blood mononuclear cells (PBMC). TNF and IL-1 detection in the circulation was only sporadic, whereas low levels of IL-6 (<100 pg/mL) were detected in almost all our patients. It was not possible to demonstrate any significant differences in serum cytokines in any patient group.
TNF synthesis by PBMC stimulated in vitro by endotoxin was significantly (P < 0.001) lower in malnourished cancer patients than in those with a good nutritional status, whereas no significant differences were detected in IL-1 and IL-6 production. Omega-3 supplementation resulted in a significant (P < 0.05) increase in TNF production by PBMC of malnourished patients, and the values afterwards were not different from those for the well-nourished patients. No significant effects were shown on the production of either IL-1 or IL-6. The effects of omega-3 PUFA on cytokine synthesis in the various study groups are shown in Table 4.
Table 4. Cytokine Production (pg/mL) by Endotoxin-Stimulated Peripheral Blood Mononuclear Cells (± Standard Deviation)
| ||WNA group||MNA group||WNB group||MNB group||C group|
| Before||1810 ± 180||2160 ± 510||1685 ± 236||1894 ± 332||2087 ± 164|
| Day 40||1720 ± 50||3540 ± 730||2150 ± 144||2730 ± 98|
| Before||2089 ± 178||2056 ± 264||2340 ± 328||1943 ± 165||2376 ± 163|
| Day 40||1818 ± 197||1998 ± 87||1976 ± 181||2117 ± 133|
| Before||778a ± 88||369b ± 32||813a ± 135a||578b ± 54||823 ± 71|
| Day 40||1139c ± 186||784d ± 207||756 ± 206||492 ± 154|
Finally, no statistically significant differences were observed in either T-cell subsets or cytokine production in the group of patients under placebo diet before and on Day 40 (Tables 2-4).
We observed significantly (P < 0.001) prolonged survival among well-nourished compared with malnourished patients (Fig. 2 (4K)). In the survival curves of Figure 3 (4K), it is demonstrated that the best survival was noted for the group of well-nourished patients treated with omega-3 PUFA plus vit E and the worst survival in malnourished patients on the placebo diet. The most noteworthy finding, however, was that omega-3 PUFA plus vit E dietary supplementation resulted in a significant (P < 0.025) increase in survival for all patients compared with the placebo group (Fig. 4 (4K)). No differences were noted regarding days of hospitalization or infectious complications among the study groups.
Figure 2. Cumulative survival is shown for well-nourished (Groups WNA + WNB) versus malnourished (Groups MNA + MNB) patients. The survival was significantly prolonged (P < 0.001) for well-nourished patients.
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Figure 3. Survival curves are shown for all patient groups (WNA: well-nourished patients receiving omega-3 polyunsaturated fatty acids (PUFA) plus vitamin E; WNB: well-nourished patients receiving a placebo diet; MNA: malnourished patients receiving omega-3 PUFA plus vitamin E; MNB: malnourished patients receiving a placebo diet. There was a significant difference (P < 0.05) among all groups.
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Figure 4. Survival curves are shown from a curve analysis of pooled patients receiving omega-3 polyunsaturated fatty acids (PUFA) plus vitamin E (groups WNA + MNA) or a placebo diet (WNB + MNB). The survival was significantly longer for patients receiving omega-3 PUFA (P < 0.025).
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Finally, no serious toxicity was observed in our patients, except for mild abdominal discomfort and transient diarrhea.
Generalized malignancy due to solid tumors is a perplexing clinical problem with various medical, social, and even economic aspects. Although modern chemotherapeutic regimens have appeared, there was no progress to improve the quality of life and survival of patients with end stage cancer. Therefore, it would be interesting to consider alternative, less toxic treatment approaches based on our better understanding of cancer immunobiology and the immunologic interactions between tumor and host.
Tumor cell proliferation, metastatic disease, and tumor-host interaction seem to be mediated by a complexity of interactions among the immune system (mainly cytokines, T cells, and natural killer cells), growth factors, and classic hormones.23, 24 Prostaglandins, mainly PGE2, which have an active role in cell proliferative processes in a variety of tissues, may also play a role in tumor growth. They seem to be important factors in the cascades that determine the balance between growth arrest and tumor progression in experimental and clinical studies of cancer.25 Cancer cachexia (e.g., inanition, anorexia, weakness, tissue wasting, and organ dysfunction in patients with cancer) seems to be a major factor contributing to the weakening of the already compromised immune system of the cancer patient. Cancer cachexia affects nearly 50% of cancer patients at the time of diagnosis and appears to influence outcome adversely. A current belief is that the mechanism of cancer cachexia involves the host's production of certain cytokines, such as IL-1, IL-6, TNF, and interferon gamma (IFN-γ), and perhaps additional factors, such as D-factor or a recently characterized wasting factor, 24K proteoglycan.26
Thus, a major clinical question is whether new treatment strategies based on immunologic approaches, prostaglandin interventions, or anticachexia treatment might improve life expectancy and quality of life for cachectic patients with advanced cancer.
In the current study, we tried to evaluate the effect of dietary supplementation with omega-3 PUFA on the immune status and survival of patients with generalized malignancy. We detected that malnutrition is a major factor contributing to morbidity in cancer patients, as the mean survival of malnourished patients was 213 ± 19 days compared with 481 ± 35 days for well-nourished patients. The relatively long survival of the WNB group seems to be the result of both the absence of cachexia (body weight, serum albumin, and Karnofsky performance status near normal) and the presence of a proper immune response. We observed an inverse relationship between the nutritional state of patients with advanced cancer and the T-helper/T-suppressor cell ratio and the capacity of peripheral blood mononuclear cells (PBMC) to synthesize TNF-α in vitro. Our findings were similar to those of Aderka et al., who showed that patients with advanced cancer disease and extensive metastases had lower in vitro lipopolysaccharide (LPS)-induced TNF-α production than individuals with more limited disease.27 Dietary supplementation with omega-3 PUFA (18 g/day) restored both the Th/Ts cell ratio and TNF production by endotoxin-stimulated PBMC. Our finding is not in accordance with former reports that long term consumption of omega-3 PUFA decreases T cell mitogenic response, DTH, and the percentage of T-helper cells,28 and this may be the result of the parallel antioxidant effect of vit E. Most significantly, omega-3 PUFA increased the survival of all our patients, whereas the good nutritional state seems to influence the very long median survival for the WNA group. However, both omega-3 PUFA and nutritional state seem to be independent prognostic factors for survival, as we detected a statistically significant difference (P < 0.05) between the survival curves of Groups WNA and WNB (Fig. 3 (4K)).
A link between dietary fat and cancer has long been established, mainly through epidemiologic data, whereas more recent work with laboratory animals has further strengthened the association of dietary fat with tumor growth and metastasis.29, 30 A beneficial effect of dietary omega-3 PUFA on tumor growth has been well documented by several animal studies,31 and reversal of cachexia by EPA in a mouse model was recently described.32 Our results demonstrate for the first time that high doses of dietary omega-3 PUFA (18 g/day), given in parallel with antioxidant supplementation, may prolong the survival of patients with generalized malignancy. We also noted an immunorestorative effect of fish oil through a significant increase of Th/Ts cell ratio and TNF-α production by PBMC in malnourished patients with advanced cancer.
The effects of omega-3 PUFA on the phospholipid fraction of the immune cell population, alteration in membrane structure, and changes in cellular signal transduction that influence growth and proliferation may be possible mechanisms of tumor growth inhibition by fish oil.33 However, the main antitumor effect of fish oil seems to be the result of a direct reduction of tumor cell proliferation through reduction of the tissue levels of prostaglandin E2 and its metabolites. It is well documented that dietary supplementation with omega-3 PUFA decreases prostaglandin E2 release by in vitro stimulated PBMC,21 and eicosanoids seem to play a significant role in carcinogenesis.15 In 1994, Lundholm et al. demonstrated that prostaglandin synthesis inhibition via anti-inflammatory treatment may prolong the survival of patients with solid advanced cancer.34 Similarly, a recent study by Wigmore et al. suggested that fish oil may temporarily stop the wasting process in cachectic patients with pancreatic carcinoma.35
We believe that dietary omega-3 PUFA, supplemented with an antioxidant such as vit E, may offer palliative support, mainly to undernourished patients with end stage metastatic disease, especially when it appears possible that no other chemotherapeutic approach will affect quality of life and survival. This may be the result of both their anticachectic and antitumor effects, through their action on eicosanoid synthesis and their unique immunomodulating effects. The observed suppressive effect of fish oil on cell-mediated immunity seems to be minimized by a parallel intake of an appropriate level of an antioxidant, such as vit E, without compromising its beneficial effects.