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Withhold Fish Oil During Chemotherapy?

4/8/2015 9:52:04 AM
A recent article published in JAMA Oncology (published online April 2, 2015) titled, “Increased Plasma Levels of Chemoresistance-Inducing Fatty Acid 16:4(n-3) After Consumption of Fish and Fish Oil” by Daenen L. et al. has generated concerns regarding the use of fish oil in people receiving chemotherapy.

Commentary by Lise Alschuler, ND, FABNO
 
Bottom-line: Overall, the investigators have identified one mechanism of chemoresistance to carboplatin, oxaliplatin and irinotecan chemotherapy caused by omega-3 fatty acids in mice. They have not demonstrated this effect in humans. The admonition by these investigators to withhold fish oil during the day of chemotherapy, while deserving of additional research, is premature and not an evidence-based recommendation. Additionally, there is a large body of evidence that supports the use of fish oil as a component of cancer risk reduction, an issue which is not addressed by this study.

This study was based on prior work by these same investigators, which demonstrated that in mice, certain fatty acids activated spleen macrophages which, in turn, led to resistance to chemotherapy.  In this prior work, co-administration of fish oil with cisplatin, oxaliplatin or irinotecan resulted in increased tumor volumes compared to chemotherapy alone or fish oil alone. The underlying mechanism of this chemoresistance observed in rodents was tied to two fatty acids, namely 12S-HHT (12-S-hydroxy-5,8,10- heptadecatrienoic acid) and PIFA 16:4(n-3) (hexadeca-4,7,10,13-tetraenoic acid). One of these, 12S-HHT, can stimulate splenic macrophages to produce lysophospholipids which have chemoresistant properties. Despite the fact that relevant levels of PIFA 16:4(n-3), but not 12S-HHT, are detected in fish oil, fish oil, nonetheless, has been observed to neutralize chemotherapy in various mouse models. The dose that causes this effect is comparable to a dose of 3 mL fish oil for an average-sized human patient.


In the present study, conducted in Finland, the investigators set out to determine if these same fatty acids could be measured in the blood of patients with cancer who were eating fish or taking fish oil. If found in the serum, the investigators surmised that this would suggest the potential for chemoresistance by fish oil, even though the mechanism for PIFA-induced chemoresistance has not been yet clarified.
 
The investigators surveyed 400 patients with cancer who were undergoing treatment on their use of fish oil supplements.  The investigators then randomized 30 healthy volunteers to receive one of 3 different brands of fish oil or 4 different fish species and their blood levels of fatty acid 16:4(n-3) were determined. Volunteers ingested a single dose of 10 or 50 mL of 3 commercially available fish oils (n = 6 per group; total n = 30), and then blood samples were taken. Three fish oils were selected containing variable levels of 16:4(n-3), but all were produced from anchovies and sardines so that fatty acid intake was standardized as much as possible. For the fish study, volunteers received 100 g of raw salmon or tuna, smoked mackerel, or cured herring (n =  5 per group, total n = 20; 11 volunteers in the fish study also took part in the fish oil study). Blood was collected and analyzed for essential fatty acid content at 1, 2, 4, 6, and 8 hours after ingestion, with an additional analysis at 24 hours after consumption of fish.
 
The investigators then set out to determine if PIFA, present in fish and fish oil supplements (but not the fatty acid associated with the chemoresistance in rodents), could be found in human serum after consumption. When the recommended daily amount of 10 mL of fish oil was administered to healthy volunteers, rises in plasma 16:4(n-3) levels were observed, reaching up to 20 times the baseline levels. Herring and mackerel contained high levels of 16:4(n-3) in contrast to salmon and tuna. Consumption of fish with high levels of 16:4(n-3) also resulted in elevated plasma levels of 16:4(n-3).
 
The most robust conclusion that can be drawn from this study is that fish oil contains substantial levels of PIFA 16:4(n-3), a fatty acid with potent chemotherapy-negating effects in preclinical models.  The authors state, “The major limitation of the current study is the difficulty to directly translate our preclinical data to the clinic. This would require a controlled clinical trial to show that 16:4(n-3)-containing fish oil inactivates chemotherapy. We consider this unethical, thereby limiting the information on the relationship of chemotherapy and fish oil to reports in the existing literature.” They go on to state that only one trial has addressed fish oil supplementation and chemotherapy outcome and it showed a beneficial effect. This study was conducted by Murphy et al[1] on patients with stage IIIB/IV non–small-cell lung cancer receiving platinum-based chemotherapy with or without fish oil supplementation. The product used contained 2.2 g of EPA and 500 mg of DHA per day. This study actually showed a higher response rate and a trend toward a higher 1-year survival when fish oil was added as an adjuvant to chemotherapy. In fact, that is not the only clinical study of the fatty acids found in fish oil and chemotherapy. A phase II study was conducted by Bougnoux, et al[2] on patients with rapidly progressive metastatic breast cancer receiving an anthracycline-based chemotherapy (FEC) regimen with 1.8g of DHA, a component of fish oil (in this case, algae-derived). This study found that those patients with the highest plasma DHA incorporation had significantly extended median time to progression and extended overall survival, suggesting a chemosensitizing effect. Additionally, the augmentation of enteral nutrition with EPA and DHA during chemotherapy is an established practice and has been found not to affect response to chemotherapy, and, in fact is associated with improved clinical response and quality of life.[3]

Overall, the investigators have identified one mechanism of chemoresistance caused by omega-3 fatty acids in mice. They have not demonstrated this effect in humans. There are actually a multitude of cellular effects of omega-3 fatty acids, some of which cause chemoresistance and some of which are chemosensitizing. Furthermore, each chemotherapy agent will be more or less susceptible to either chemoresistance or chemosensitizing effects of omega-3 fatty acids. The admonition by these investigators to withhold fish oil during the day of chemotherapy, while deserving of additional research, is premature and not an evidence-based recommendation. The authors suggest that a retrospective review would shed further light on this relationship. Indeed, that seems necessary before clinical conclusions can be drawn.

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[1] Murphy RA, Mourtzakis M, Chu QS, Baracos VE, Reiman T, Mazurak VC. Supplementation with fish oil increases first-line chemotherapy efficacy in patients with advanced nonsmall cell lung cancer. Cancer. 2011;117(16):3774-3780.

[2] Bougnoux P, Hajjaji N, Ferasson M, Giraudeau B, Couet C, and Le Floch O. Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic acid: a phase II trail. Br J Cancer. 2009;101:1978-1985.
[3] Colomer R, Moreno-Nogueira J, García-Luna P, García-Peris P, García-de-Lorenzo A, Zarazaga A, Quecedo L, del Llano J, Usán L, Casimiro C. N-3 fatty acids, cancer and cachexia: a systematic review of the literature. Br J Nutr. 2007 May;97(5):823-31.