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Comment & Response
September 2015

Let Them Eat Fish—Reply

Author Affiliations
  • 1Department of Medical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands
  • 2Department of Medical Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands
JAMA Oncol. 2015;1(6):841. doi:10.1001/jamaoncol.2015.2056

In Reply Mazurak et al and Baracos provide a welcome discussion on a topic that is subject to debate: fish oil use in anticancer therapy and—in a broader context—the use of supplements by patients with cancer in general. It is becoming increasingly clear that use of certain supplements can impair the effectiveness of chemotherapy and other anticancer therapies. Examples are St John’s wort and betacarotene.

There is no discussion on the necessity of ω-3 fatty acids as essential parts of a healthful diet. These fatty acids are not produced by the body and have to be ingested from dietary sources. However, it is important to realize that fish oil is a complex and unstandardized mixture of fatty acids. Its production requires no Food and Drug Administration review or approval. The identity and function of a large part of ω-3 fatty acids present in fish oil remains unclear, and it might therefore contain unknown biologically active molecules. We have identified 16:4(n-3) as an example, which induces chemoresistance in preclinical tumor models.1,2 This effect is seen when minor quantities of 16:4(n-3) are administered, which is underscored by the calculations performed by Mazurak et al.

In our article we show that 16:4(n-3) is effectively taken up into the blood of humans after fish oil or fatty fish intake, but the plasma peak is limited to the first hours after intake and depends on the amount ingested.3 We have analyzed epidemiological data sets for information on the type, dose, or timing of fish or fish oil consumption in relation to chemotherapy. Unfortunately, it is not possible to extract this type of information, making it impossible to draw conclusions on 16:4(n-3) exposure and to correctly interpret statements on the effectiveness of chemotherapy in countries with high levels of fish consumption.

Mazurak et al cite a small clinical study to support their arguments, including 15 patients with lung cancer treated with chemotherapy and fish oil. No information was provided on 16:4(n-3) content of the supplement that was used. Larger prospective trials with well-defined fish oil products are not available. On the basis of our preclinical findings, we believe that a trial with 16:4(n-3)–containing fish oil supplements would not be ethical.

In the last few years, meta-analyses on fish oil have shown no benefits of the use of these supplements in prevention of cognitive decline,4 or the risk of major cardiovascular events.5 Moreover, the use of fish oil was found to be potentially harmful in patients with acute lung injury.6 Our preclinical studies now show that many bioactive molecules such as 16:4(n-3) may be present in fish oil supplements, which can adversely affect anticancer treatment. These fatty acids may be circulating in the blood of patients after ingestion of fish oil. In the absence of a US Food and Drug Administration–controlled product and of convincing clinical evidence to support fish oil use during chemotherapy, we believe that physicians and patients should be made aware of these findings, and that caution is required when chemotherapy is combined with fish oil consumption.

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Article Information

Corresponding Author: Emile E. Voest, MD, PhD, Department of Molecular Oncology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands (e.voest@nki.nl).

Conflict of Interest Disclosures: None reported.

References
1.
Roodhart  JM, Daenen  LG, Stigter  EC,  et al.  Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids.  Cancer Cell. 2011;20(3):370-383.PubMedGoogle ScholarCrossref
2.
Houthuijzen  JM, Daenen  LG, Roodhart  JM,  et al.  Lysophospholipids secreted by splenic macrophages induce chemotherapy resistance via interference with the DNA damage response.  Nat Commun. 2014;5:5275.PubMedGoogle ScholarCrossref
3.
Daenen  LGM, Cirkel  GA, Houthuijzen  JM,  et al.  Increased plasma levels of chemoresistance-inducing fatty acid 16:4(n-3) after consumption of fish and fish oil.  JAMA Oncol. 2015;1(3):350-358.PubMedGoogle ScholarCrossref
4.
Sydenham  E, Dangour  AD, Lim  WS.  Omega 3 fatty acid for the prevention of cognitive decline and dementia.  Cochrane Database Syst Rev. 2012;6:CD005379.PubMedGoogle Scholar
5.
Rizos  EC, Ntzani  EE, Bika  E, Kostapanos  MS, Elisaf  MS.  Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis.  JAMA. 2012;308(10):1024-1033.PubMedGoogle ScholarCrossref
6.
Rice  TW, Wheeler  AP, Thompson  BT, deBoisblanc  BP, Steingrub  J, Rock  P; NIH NHLBI Acute Respiratory Distress Syndrome Network of Investigators.  Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury.  JAMA. 2011;306(14):1574-1581.PubMedGoogle ScholarCrossref
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