Chemoresistance and Fish Oil

or

Does Fish oil prevent chemotherapy from working?

Jacob Schor, ND, FABNO

February 18, 2016

 

There are occasional studies that contradict our accepted view of things, studies that deliver data that rock the boat.  These studies fascinate me because they provide the opportunity to step back and watch how we as physicians and deal with change, in particular knowledge that influences patient care and that changes what we do.

 

Several important papers have been published, that beg us to question our routine use of fish oil in patients undergoing chemotherapy to treat cancer.  These papers suggest that specific components in fish oil may increase chemoresistance in tumor cells, thus potentially weakening the effect of chemotherapy.

 

Back in September 2011, the first of these papers by Jeanine Roodhart and Laura Daenen was published in the journal Cancer Cell and reported that platinum based chemotherapies activate mesenchymal stem cells (MSCs) to secrete two unique fatty acids identified as platinum-induced polyunsaturated fatty acids (PIFAs) that, in minute quantities, confer resistance to multiple types of chemotherapy in mice .  [By the way, blocking cyclooxygenase-1 and thromboxane synthase blocks the release of these fatty acids and prevents the chemoresistance.]

 

Then a second paper on these PIFAs was published online on April 2, 2015 in JAMA Oncology.  This paper is the one that really got our attention.  Starting with their earlier finding that these PIFAs conferred chemotherapy resistance in mice, they questioned whether these findings were relevant in humans.   They found that approximately 11% of their cancer patients (at the University Medical Center Utrecht) were taking fish oil. (In the US, it is estimated that 20% of cancer patients take fish oil .)  An analysis of the fish oil showed that it contained enough of  the 16:4(n-3) PIFAs (from 0.2 to 5.7 µM ) to be concerned.  In mice the addition of 1 µL of fish oil to cisplatin was sufficient to induce chemoresistance, to the degree that treatment no longer inhibited tumor growth.

 

When 10 mL doses of fish oil were given to healthy human volunteers plasma levels of 16:4(n-3) levels increased to over 20 times baseline.  Consumption of herring or mackerel, which also contain high levels of 16:4(n-3), was also associated with elevated plasma levels of these PIFAs.  Thus consuming fish oil capsules or eating certain oily fish could conceivably induce chemoresistance to cisplatin.   This led the authors to “….. raise concern about the simultaneous use of chemotherapy and fish oil.” And write,  “Based on our findings, and until further data become available, we advise patients to temporarily avoid fish oil from the day before chemotherapy until the day thereafter… Although further evidence on the relation between fish consumption and chemotherapy activity is desired, we would currently also recommend to avoid herring and mackerel in the 48 hours surrounding chemotherapy exposure.”

 

Obviously these findings strongly contrast the common assumption that fish oil enhances chemotherapy action against cancer, and helps cancer patients retain quality of life.  Many naturopathic physicians have been prescribing fish oil to patients for years and the suggestion that this could have been in error was not welcome.

 

This idea stands in such contrast to the generally accepted view of fish oil, that one of my esteemed colleagues described the very notion as being ridiculous.  

 

Another colleague responded with what sounded like anger when I brought up this idea, pointing out that past research with fish oil had not hinted to any development of chemoresistance but rather the opposite:  “Across the board omega-3 fatty acids have been shown to enhance the effectiveness and reduce the toxicity of every cytotoxic chemotherapy out there. In the case of cisplatin, below are 12 studies the majority demonstrating that omega-3 fatty acids enhance the effectiveness of cisplain or no reduction in efficacy” .

 

These responses were all reasonable.  Demonstrating chemoresistance in mice due to fish oil does not prove that the same thing will occur in humans.  Unfortunately, researchers cannot now take the logical next step in putting this problem to rest: it would now be unethical to set up a study to answer this question 

 

The most rationale discussion regarding fish oil and chemo was a presentation at the Society for Integrative Oncology (SIO) last fall in Boston by Dr. Christina Shannon, who is Clinical Director of Naturopathic Medicine at Cancer Treatment Centers of America (CTCA) at their Midwestern Regional Medical Center (MRMC) in Zion, Illinois.  Let me try and summarize the main points of her presentation briefly.

 

Fish oil supplements, in particular high EPA and DHA oil concentrates have been long used to manage a range of conditions in particular a number of issues related to cancer treatment.  These conditions include, Inflammation , chemotherapy induced neuropathy , chemotherapy induced nephrotoxicity , muscle wasting in advanced cancer , cardiovascular conditions , immune support , and for general anticancer effects .

 

Dr. Shannon and her colleagues at CTCA performed a literature review seeking studies that might provide data that would demonstrate chemoresistance caused by fish oil. They searched the medical literature and identified 23 studies that provided data on the combination of fish oil and chemotherapy and that provided information on efficacy of treatment.  They excluded studies that did not include a platinum chemotherapy drug.  Also excluded were studies that used only fish extracts such as only EPA or only DHA.  They were left with 5 studies: four suggested a benefit  [Murphy (2011), Ma (2009), Yam (2001), and Hassan (2014 and 2015)] and this one that suggested a possible negative effect [Roodhart (2011)].

 

 

 

 

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RA Murphy’s 2011 study was a human clinical trial of patients with advanced non-small cell lung cancer.  Of the forty-six patients who completed the study, only fifteen received fish oil, 2.5 grams per day.  The other 31 only received standard of care treatment and did not receive fish oil.

 

Those receiving fish oil were reported to have an increased response compared to the standard of care group (60.0% versus 25.8%, P = 0.008, respectively).  There was also an increased 1-year survival in the fish oil group versus the standard of care group; however, this outcome did not reach statistical significance (60.0% versus 38.7%, P = 0.15, respectively). Patients in the fish oil group were able to complete all cycles of planned chemotherapy compared to the standard of care group (86.7% versus 54.8%, P = 0.03, respectively) .

 

Shannon cited three other positive studies that used mice as participants.  In these the fish oil was used in combination with other nutritional supplements.  Ma et al. found that fish oil combined with vitamins A, E, selenium plus cisplatin was more effective at reducing tumor growth than the combination of vitamins and selenium plus cisplatin alone .

 

Yam also combined fish oil with varying amounts of vitamins E and C, plus cisplatin.  Here as well the addition of fish oil to a combination of antioxidant vitamins appears to have enhanced benefit of cisplatin and also decreased cachexia and anorexia in the treated mice .

 

Hassan has published several papers on fish oil.  A 2014 study used fish oil alone or with cisplatin and compared the outcomes against a grape seed extract alone or with cisplatin.  Both grape seed extract or fish oil reduced nephrotoxity, oxidative stress and DNA damage .  A 2015 paper either reported on similar comparisons though from the extract it is unclear whether this is the same data or a followup study .

 

Several other papers not included in the Shannon review are worth mention.  In 2012 Naqshbandi et al reported that fish oil administered with cisplatin protected the kidneys of rats who had been fed fish oil for 10 days prior to receiving a single dose of cisplatin.  Here too, fish oil provided protection against kidney damage .

In a 2014 rat study, Kamisli et al tell us that fish oil also protects against cisplatin caused nerve damage .

 

There are a few additional human trials worth looking at that did not meet Shannon et al’s strict criteria for inclusion.  A 2014 human randomized trial by Sánchez-Lara et al provided non-small cell lung cancer patients with a nutritional supplement containing eicosapentaenoic acid (EPA). Data from ninety-two patients were analyzed, half having received the nutritional supplement. Fatigue, loss of appetite and neuropathy decreased in the patients receiving the supplement.   There was no difference in response rate or overall survival between groups.  While it is difficult to differentiate the effect of fish oil from that of the supplement, there was no increase in chemoresistance noticed in these patients .

 

In 2012 Finocchiaro et al described the results of a double-blind placebo controlled study giving fish oil supplements or placebo to thirty-three patients with advanced inoperable NSCLC.  The patients who received fish oil had increased body weight and decreased markers of inflammation.  While these data support the assumption that fish oil may prevent or reduce cachexia, they do not inform us whether the fish oil lessened the impact of chemotherapy on survival.

 

The review by Shannon et al, even if we include data from a wider range of papers, provides scant evidence for us to make a decision.  The Murphy trial provides the best human evidence for greater efficacy of fish oil in combination with cisplatin.  But this was a small study, only 15 patients completed the fish oil arm of the study.  The mice studies suggest benefit, especially when used in combination with antioxidants but have not addressed the question of chemotherapy resistance 

 

There are good reasons that we dislike in vitro studies and ex vivo mice studies.  It is difficult to know whether the results will apply to human patients.  So obviously results from human trials far outweigh data from mice or rats.

 

When evaluating research evidence the standard rule is that a clinical trial in a human population is superior to evidence from mouse models and thus the Murphy lung cancer study continues to outweigh the recent Daenon and Roodhart papers.

 

Still it makes one wonder.  Can we or should we incorporate this information into our protocols?

 

Another way to look at these Roothart and Daenon papers is that they provide an additional reason to emphasize COX-1 inhibition in cancer patients because lowering COX-1 limits PIFA secretion by MSCs.

 

Recall that in the earlier Daenon study mesenchymal stem cells were stimulated by platinum based chemotherapy to secrete PIFAs that caused chemo resistance.   Only platinum based chemo drugs caused this reaction.  This action was also inhibited by PLA2, TXAS and COX-1.  In humans the EPA in fish oil inhibits COX-1 production .  One has to wonder if this effect would be adequate to prevent release of PIFAs by the MSCs. MSCs produce chemoresistance by secreting PIFAs regardless of fatty acid intake, that is the same process occurs with or without fish oil.

 

While the evidence currently tips the scale in favor of continuing to use fish oil with platinum chemotherapy, it also suggests caution.  The human studies to date were conducted under the assumption that fish oil would be beneficial.  They were not seeking evidence of chemoresistance.  Nor were they thinking that there would be a short period of time close to chemo administration in which the effects might be negative.  The overall impact of using fish oil might be positive but could be even more so.  We don’t know whether abstaining from use for 48 hours as Daenon suggests might increase the benefit by reducing PIFA production.  At this point, it is difficult to conduct further human trials because of ethical concerns.

 

Sometimes we need to look beyond the existing published evidence.  The problem with this situation is that up to know we haven’t known that this might be a problem.  As a result no one has expected to find evidence of a problem and so may not have looked.  We hardly if ever see things in the world that we don’t expect to find.  We can be blind to elephants until they are pointed out to us.  That’s just human nature.

 

 

 

 

 

 REFERENCES:

 

Roodhart JM, Daenen LG, Stigter EC, Prins HJ, Gerrits J, Houthuijzen JM, Gerritsen 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. doi: 10.1016/j.ccr.2011.08.010.

 

Gupta D, Lis CG, Birdsall TC, Grutsch JF. The use of dietary supplements in a community hospital comprehensive cancer center: implications for conventional cancer care. Support Care Cancer. 2005;13(11):912-919.

 

Daenen LG, Cirkel GA, Houthuijzen JM, Gerrits J, Oosterom I, Roodhart JM, van Tinteren H, et al. Increased Plasma Levels of Chemoresistance-Inducing Fatty Acid 16:4(n-3) After Consumption of Fish and Fish Oil. JAMA Oncol. 2015 Jun;1(3):350-8.

 

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Mocellin MC, Pastore E Silva JDA, Camargo CDQ, et al. Fish oil decreases C-reactive protein/albumin ratio improving nutritional prognosis and plasma fatty acid profile in colorectal cancer patients. Lipids. 2013;48(9):879-888. doi:10.1007/s11745-013-3816-0.

 

 Finocchiaro C, Segre O, Fadda M, et al. Effect of n-3 fatty acids on patients with advanced lung cancer: a double-blind, placebo-controlled study. Br J Nutr. 2012;108(02):327-333. doi:10.1017/S0007114511005551

 

Silva JDAP, Trindade EBSDM, Fabre MEDS, et al. Fish Oil Supplement Alters Markers of Inflammatory and Nutritional Status in Colorectal Cancer Patients. Nutr Cancer. 2012;64(2):267-273. doi:10.1080/01635581.2012.643133.

 

Kamisli S, Ciftci O, Cetin A, Kaya K, Kamisli O, Celik H. Fish oil protects the peripheral and central nervous systems against cisplatin-induced neurotoxicity. Nutr Neurosci. 2014;17(3):116-126. doi:10.1179/1476830513Y.0000000074. 

 

Ghoreishi Z, Esfahani A, Djazayeri A, et al. Omega-3 fatty acids are protective against paclitaxel-induced peripheral neuropathy: A randomized double-blind placebo controlled trial. BMC Cancer. 2012;12(1):355. doi:10.1186/1471-2407-12-355.

 

Hassan H a., Edrees GM, El-Gamel EM, El-sayed E a. Amelioration of cisplatin-induced nephrotoxicity by grape seed extract and fish oil is mediated by lowering oxidative stress and DNA damage. Cytotechnology. 2013:1-11. doi:10.1007/s10616-013-9589-8.

 

Pardini RS. Nutritional intervention with omega-3 fatty acids enhances tumor response to anti-neoplastic agents. Chem Biol Interact. 2006;162(2):89-105. doi:10.1016/j.cbi.2006.05.012.

 

Huang T, Li K, Sailumuhan A, Chen Q, Li D. Effect of vitamin b12 and N-3 polyunsaturated fatty acids on plasma homocysteine, and other cardiovascular risk factors: Randomized controlled trial. Ann Nutr Metab. 2013;63(November 2013):57. doi:10.6133/apjcn.2015.24.3.19.

 

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 Bonatto SJR, Oliveira HHP, Nunes E a., et al. Fish oil supplementation improves neutrophil function during Cancer chemotherapy. Lipids. 2012;47(4):383-389. doi:10.1007/s11745-011-3643-0

 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 Aug 15;117(16):3774-80. doi: 10.1002/cncr.25933. Epub 2011 Feb 15.

 

Ma H, Das T, Pereira S, et al. Efficacy of dietary antioxidants combined with a chemotherapeutic agent on human colon cancer progression in a fluorescent orthotopic mouse model. Anticancer Res. 2009;29(1791-7530 (Electronic)):2421-2426.

 

 

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Hassan HA, Edrees GM, El-Gamel EM, El-Sayed EA. Amelioration of cisplatin-induced nephrotoxicity by grape seed extract and fish oil is mediated by lowering oxidative stress and DNA damage. Cytotechnology. 2014 May;66(3):419-29. doi: 10.1007/s10616-013-9589-8. Epub 2013 Jun 13.

Hassan HA, Edrees GM, El-Gamel EM, El-Sayed EA. Proanthocyanidin and fish oil potent activity against cisplatin-induced renal cell cycle arrest and apoptosis in rats.

Ren Fail. 2015;37(8):1356-62. doi: 10.3109/0886022X.2015.1073528. Epub 2015 Sep 3.

 

Naqshbandi A, Khan MW, Rizwan S, Rehman SU, Khan F. Studies on the protective effect of dietary fish oil on cisplatin induced nephrotoxicity in rats. Food Chem Toxicol. 2012 Feb;50(2):265-73. doi: 10.1016/j.fct.2011.10.039. Epub 2011 Oct 14.

 

Kamisli S, Ciftci O, Cetin A, Kaya K, Kamisli O, Celik H. Fish oil protects the peripheral and central nervous systems against cisplatin-induced neurotoxicity.Nutr Neurosci. 2014 Apr;17(3):116-26. doi: 10.1179/1476830513Y.0000000074. Epub 2013 Nov 26.

 

Sánchez-Lara K1, Turcott JG1, Juárez-Hernández E1, Nuñez-Valencia C1, Villanueva G1, Guevara P2, De la Torre-Vallejo M1, et al. Effects of an oral nutritional supplement containing eicosapentaenoic acid on nutritional and clinical outcomes in patients with advanced non-small cell lung cancer: randomised trial.Clin Nutr. 2014 Dec;33(6):1017-23. doi: 10.1016/j.clnu.2014.03.006. Epub 2014 Apr 4.

 

Finocchiaro C, Segre O, Fadda M, Monge T, Scigliano M, Schena M, Tinivella M, et al. Effect of n-3 fatty acids on patients with advanced lung cancer: a double-blind, placebo-controlled study. Br J Nutr. 2012 Jul;108(2):327-33. doi: 10.1017/S0007114511005551. Epub 2011 Nov 25.

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