Omega-3 Safety with Chemotherapy
The Pharmacokinetic Safety of Co-administered Omega-3 Fatty Acids and Chemotherapy
Widespread - and premature - media discussions of a recent JAMA-published study are suggesting that the study data is sufficient to warrant a contraindication of consuming substantial levels of omega-3 fatty acids while on active chemotherapy, especially platinum-based regimens. However, significant methodological limitations of the study, coupled with preexisting divergent evidence from human clinical and epidemiological data, strongly suggest that the study remains insufficiently powered or robust to warrant such a contraindication, and geiven the significant potential benefits of such consumption, it is precipitate and unwarranted based on this study to draw any actionable clinical recommendations. We present the details of the technical discussion supporting our position below.
The Medical Evidence
As to the recent conclusions concerning potentially adverse pharmacokinetics between omega-3 fatty acid consumption and efficacy of certain chemotherapies derived from preclinical data by the Dutch team of Emile Voest and colleagues in the June 2015 issue of JAMA , there are several critical reservations that suggest that extrapolating recommendations into the human clinical context would be both premature, and beyond the evidence. These recent, and comparable earlier claims by the same team , have been disputed .
First, the conclusions are based on preclinical in vivo data from mice implanted with cancer cells, then orally gavaged with fish oils, and with chemotherapy coadministered, particularly platinum based chemotherapy. Such preclinical data - when absent, as it is here, of any accompanying confirming data from human clinical trials - are not directly applicable to humans. Nor was the quantity of exposure to omega-3 fatty acids consistent with human intake (the authors claim the intakes levels in rats are to be considered of relevance to humans, but provide no demonstration of that claim nor any plausible verification.
Indeed, the authors themselves admit in their discussion of the study's limitations that without a controlled clinical trial to show that 16:4(n-3)-containing fish oil actually - and at clinically relevant levels - inactivates chemotherapy, direct translation of the preclinical data to any clinical consequences is unsafe and reasons beyond the data. We should therefore exercise extreme caution in deriving deductions beyond the limited warrant of the preclinical in vivo data. We note that the authors also argue that somehow a human clinical randomized trial would be, going forward, unethical to conduct, given, they claim, the putative strength of the data presented, but this is unconvincing: experimental data alone from mice lacks the power to support legitimate and direct translation into the human clinical context, and it is precisely a human clinical trial that is needed to support and "found" robustly such translational relevance.
Second, epidemiological data does not support the contention of clinically relevant adverse interaction between platinum-based therapies and omega-3 fatty acids consumption, which the authors claim - based only on animal data - would render such therapies essentially ineffective: given that platinum-based therapies are typically the standard of care for lung cancer across large swatches of the globe, yet there is a wholesale absence of evidence that in high-omega-3 fatty acid consumption regions like The Netherlands and Japan, among others, such therapies are less effective comparatively to parallel use in regions where such consumption is minimal [4-7], nor have trials consistently reported significantly reduced objective response rates nor compromised clinical outcomes compared to low usage regions.
Third, we in addition have strongly divergent human trial data of positive benefits of omega-3 fatty acids supplementation in a variety of human cancers patients of supplementation [8-11] which collectively suggest that the therapeutic index of various chemotherapies may in fact be improved - not compromised - as to both enhanced efficacy and reduced toxicity.
Finally, the human nutritional relevance of 16:4(n-3) [hexadecatetraenoic acid] relative to other dietary fatty acids is arguable, and remains opaque given that quantities of hexadecatetraenoic acid are typically found only at trace levels [12,13].
Collectively these reservations dispute the clinical translational relevance of the narrow in vivo data presented, which are insufficiently powered to warrant the recommendations drawn from them by the authors and the medical reporting media, and even at the preclinical level, we would require a far more methodological robust study to warrant actionable caution in the human clinical context. To be dispositive, it is precisely a randomized controlled human clinical trial that is required to support any claims of contraindication in the chemotherapy setting, and the aggregate clinical data to date fail to support the existence of clinically significant reductions in chemotherapeutic efficacies secondary to omega-3 fatty acids co-administration.
Research Director, No Surrender Breast Cancer Foundation (NSBCF)
1. Daenen LG, 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):350-8.
2. 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 Sep 13; 20(3):370-83.
3. Murphy RA, Clandinin MT, Chu QS, Arends J, Mazurak VC. A fishy conclusion regarding n-3 fatty acid supplementation in cancer patients. Clin Nutr 2013; 32(3):466-7.
4. Uramoto H, Nakanishi R, Nagashima A, Uchiyama A, Inoue M, Osaki T, et al. A randomized phase II trial of adjuvant chemotherapy with bi-weekly carboplatin plus paclitaxel versus carboplatin plus gemcitabine in patients with completely resected non-small cell lung cancer. Anticancer Res 2010;30:4695e9.
5. Azzoli CG, Baker S, Temin S, … American Society of Clinical Oncology. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 2009 Dec 20; 27(36):6251-66.
6. Azzoli CG, Temin S, Aliff T, … American Society of Clinical Oncology. 2011 Focused Update of 2009 American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer. J Clin Oncol 2011 Oct 1; 29(28):3825-31.
7. Masters GA, Temin S, Azzoli CG, et al. Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2015 Aug 31.
8. Murphy RA, Mourtzakis M, Reiman T, Chu Q, Baracos VE, Mazurak VC. Supplementation with fish oil increases first-line chemotherapy efficacy in patients with advanced non-small cell lung cancer. Cancer 2011;117:3774e80.
9. Bougnoux P, Hajjaji N, Ferrasson MN, Giraudeau B, Couet C, Le Floch O. Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic acid: a phase II trial. Br J Cancer 2009;101:1978e85.
10. Dupertuis Yves M, Meguid MM, Pichard C. Colon cancer therapy, new perspectives on of nutritional manipulations using polyunsaturated fatty acids. Curr Opin Clin Nutr Metab Care 2007; 10:427e32.
11. Vaughan VC, Hassing MR, Lewandowski PA. Marine polyunsaturated fatty acids and cancer therapy. Br J Cancer 2013 Feb 19; 108(3):486-92.
12. Lovern JA. The nutritional significance of fish lipids. Proc Nutr Soc. 1958;17(2):161-6.
13. Imen Hamed, Fatih Özogul, Yesim Özogul, Joe M. Regenstein. Marine Bioactive Compounds and Their Health Benefits: A Review. Compr Rev Food Sci Food Safety 2015; 14(4):446–465.