Fish Oil Supplementation in Adults With Hematological Malignancies

Inflammatory prognostic scores and cancer outcomes

By Ellen McDonell, ND

Printer Friendly PagePrinter Friendly Page

 

This article is part of the 2018 NMJ Oncology Special Issue. Download the full issue here.  

Reference

Chagas TR, Borges DS, de Oliveira PF, et al. Oral fish oil positively influences nutritional-inflammatory risk in patients with haematological malignancies during chemotherapy with an impact on long-term survival: a randomised clinical trial. J Hum Nutr Diet. 2017;30(6):681-692.

Study Objectives

The primary objective was to evaluate the effect of fish oil supplementation on nutritional parameters and inflammatory status in individuals newly diagnosed with a hematological cancer initiating chemotherapy. A secondary objective was to assess survival at 465 days from the start of supplementation.

Design

Randomized controlled trial, no placebo

Participants

Participants were adults with newly diagnosed leukemia or lymphoma who were about to initiate first-line treatment with chemotherapy. The total population analyzed was 22 individuals (10 women, 12 men). There were no statistically significant differences in characteristics of the participants at baseline, including age, which averaged 53.8 years in the control group and 43.8 years in the fish oil group.

Diagnoses included acute leukemia (n=9), non-Hodgkin lymphoma (n=8), Hodgkin lymphoma (n=4), and chronic leukemia (n=1).

Intervention

Participants were randomized to receive oral fish oil at a dose of 2 g per day (containing 367 mg eicosapentaenoic acid [EPA] and 243 mg docosahexaenoic acid [DHA]) for 9 weeks, starting on the first day of chemotherapy, or no fish oil (control group). The intervention group was instructed to consume the fish oil 20 to 30 minutes before lunch or dinner.

Study Parameters Assessed

Assessment measures included anthropometric data, blood work (complete blood count, albumin, C-reactive protein [CRP], plasma free fatty acids), survival at 465 days, number of hospital readmissions, and number of chemotherapy sessions.

Blood samples and anthropometric measurements were taken at baseline (1 day before initiation of fish oil), and at 9 weeks. Nutritional status was determined by anthropometric data and the Nutritional Risk Index (NRI), which is calculated by the following equation: 1.519 x serum albumin (g/dL) + 41.7 x current weight (kg)/usual weight (kg). A score >100 means no nutrition risk; 99.9-97.5 means borderline nutrition risk; 83.5-97.5 means mild nutrition risk; and <83.5 means severe nutritional risk. Anthropometric measurements included BMI, arm circumference, mid-upper arm circumference (MUAC), triceps skin fold (TS), and mid-upper arm muscle circumference (MUAMC). Inflammatory status was determined by the inflammatory nutrition prognosis index, which is calculated as the CRP/albumin ratio (CAR). The interpretation was defined as no risk <0.4; low risk 0.4-1.2; moderate risk 1.2-2.0; and high risk >2.0.

Although useful as predictive tools, these inflammatory prognostic indices lead a practicing clinician to ask 2 important questions: Are they modifiable, and does modifying the prognostic index change long-term outcomes?

Overall survival at 465 days from study initiation was calculated using the Kaplan-Meier method and compared using log-rank tests. Date of death, hospital admissions, and number of chemotherapy sessions were recorded from medical records.

Primary Outcome Measures

The effects of fish oil on nutritional and inflammatory status was determined by changes in the NRI, CAR, and anthropometric measures from baseline to the end of the 9-week study. Secondary outcomes were determined by overall survival, number of chemotherapy sessions, and change in plasma fatty acids.

Key Findings

Two models were used for statistical analysis. Model 1 included all study participants who finished the 9 weeks of follow up (n=22). Model 2 included only individuals in the control group whose plasma EPA and DHA remained stable at 9 weeks (defined as <50% increase; n=8), and only participants in the fish oil group who had a 100% or greater increase in plasma EPA and DHA (n=6).

Plasma EPA and DHA did not change in the control group in either model of analysis. Plasma EPA and DHA significantly increased in the fish oil group in both models, except for DHA in model 1 where the increase was not statistically significant (P=0.07). There were no statistically significant between group changes for any outcome other than CAR, survival, and number of chemotherapy sessions.

The CAR was significantly reduced (indicating improvement) in both groups in model 1; changes were not statistically significant in model 2. Median scores from baseline to week 9 showed statistically significantly greater improvement in the fish oil compared to control group (5.1 to 1.4 in the control group and 12.6 to 1.1 in the fish oil group, P<0.05).

There were no deaths in the 14-month follow up in the fish oil group. There were 8 deaths in the control group in model 1 and 6 deaths in model 2; these differences were statistically significant compared to the fish oil group (P=0.005 and P=0.008, respectively). The number of chemotherapy sessions was significantly higher in the fish oil group in both models compared to the control group. There was no difference in hospital readmissions. There were no significant changes in weight, MUAC, MUAMC, or TS with either model.

The NRI was higher (which indicates lower risk) in the fish oil than the control group in model 2 at 9 weeks (P<0.05); however, there were no statistically significant changes from baseline between groups. C-reactive protein was significantly reduced in the fish oil group in model 1 (P<0.05), but there was no change in the control group and no statistically significant change between groups.

In summary, fish oil supplementation increased plasma EPA and DHA. Survival was significantly better in the fish oil vs control group at 14 months, and the fish oil group received more chemotherapy sessions than the control group. Improvement in CAR was greater in the fish oil group compared to the control group at 9 weeks.

Practice Implications

The present study is the first to look at changes in CAR associated with fish oil use in hematological malignancies. It confirms previous findings that CAR is elevated in people with hematological cancers pretreatment, demonstrates that cancer treatment improves this ratio, and suggests that the addition of fish oil may result in greater improvement in this index. The present study also found improved survival at 14 months, providing some preliminary evidence that fish oil may improve survival in hematological malignancy, and that this improvement may be at least partially mediated by changes in systemic inflammation.

The ability of fish oil to improve CAR has been previously demonstrated in colorectal cancer. Patients undergoing chemotherapy for colorectal cancer who were supplemented with 2 g fish oil (600 mg combined EPA/DHA) had significantly reduced CAR status after 9 weeks.1

An inflammatory prognostic score, CAR was initially demonstrated to predict mortality in septic patients2,3 but has more recently been associated with overall survival in patients with a variety of solid tumors, including pancreatic,4 colorectal,5,6 gastric,7 small cell lung,8 and hepatocellular9 cancers. Similarly to other inflammatory prognostic scores, this index is utilized as pretreatment in solid tumors as a method to predict posttreatment survival. Higher CAR indicates a greater level of systemic inflammation and greater risk of mortality. The threshold for low or optimal CAR varies depending on the study, but ranges from 0.038 to 0.441.5,6,8,9

The present study defined no risk as <0.4 and low risk as 0.4 to 1.1. Although CAR has relatively few studies compared to some of the other inflammatory prognostic scores, a study in colorectal cancer found CAR to be positively correlated with other known inflammation-based prognostic indices such as neutrophil-to-lymphocyte ratio (NLR) and Glasgow Prognostic Score (GPS).5 Less is known about the prognostic value of CAR in hematological malignancies. Only 1 study has previously looked at CAR in hematological cancers and found it to be elevated prior to chemotherapy initiation. However, the study did not look at future risk associated with these scores.10

Prognostic inflammatory indices, which include the GPS, Prognostic Nutritional Index (PNI), platelet-to-lymphocyte ratio (PLR), and NLR are well-validated prognostic tools for solid cancers.11-13 These indices are markers of the systemic inflammatory response, which plays an important role in cancer physiology, including carcinogenesis, dedifferentiation, and tumor cell proliferation.6 They are usually measured preoperatively, and predict risk of postoperative complications and overall survival in a variety of malignancies.7,8

Although useful as predictive tools, these inflammatory prognostic indices lead a practicing clinician to ask 2 important questions: Are they modifiable, and does modifying the prognostic index change long-term outcomes?

Inflammatory prognostic tools such as CAR, NLR, and GPS are useful for clinicians. They are strong predictors of long-term outcomes and they are usually readily available because their components are often ordered in standard blood work. While research on the ability of natural therapies such as fish oil to modify these indices, including the implications for overall survival, is still limited, this study provides some preliminary indication that systemic inflammation can be modified with natural therapies, and this may confer a survival advantage. Given other known benefits of fish oil, it is certainly warranted to consider its use for patients with hematological cancers initiating treatment.

Very few prior prospective clinical trials have evaluated fish oil supplementation for people with hematological malignancies. One study in children with leukemia found that fish oil supplementation improved appetite, caloric intake, and MUAMC after 8 weeks compared to control.14 Another study in children with acute lymphoblastic leukemia found that the addition of fish oil alongside maintenance treatment with methotrexate reduced hepatotoxicity compared to placebo.15 Fish oil is unlikely to be effective for reducing risk of severe neutropenic enterocolitis in patients with AML.16 There may be benefit to fish oil supplementation around bone marrow transplant (BMT) and hematopoietic stem cell transplant (HSCT). One small study in 16 people found that EPA supplementation before and for 180 days after BMT reduced complications and improved survival, and the authors hypothesize the effect was mediated through EPA lowering the systemic inflammatory response.17,18 Pretreatment with EPA in one study of BMT reduced risk of acute colonic graft-versus-host disease. However, short-term use of omega-3 fats after stem cell transplants may not be sufficient to modify inflammatory markers,19 but it may improve antioxidant status.20

There are several limitations to the present study. The study had a very small sample size, which limits the generalizability of the findings and resulted in large confidence intervals giving an imprecise estimate of effect. The study was not placebo-controlled, potentially inflating results due to the placebo effect. The population may have had slightly different baseline characteristics in terms of disease aggressiveness; the control group had 5 individuals with acute leukemia, 6 with non-Hodgkin lymphoma (NHL), and 1 with Hodgkin disease (HD), while the fish oil group had 4 with acute leukemia, 2 with NHL, and 3 with HD. Recognizing that HD has a high cure rate and acute leukemias are typically more aggressive, with the small sample size it is possible that small differences between cancer type could alter the findings. The heterogeneity in the study population (type of hematological malignancy, staging, and chemotherapy regimens) makes it difficult to interpret outcomes and may play a role in differences seen, especially given the small sample size. Lastly, the dose of EPA/DHA used in this study is quite low—only 610 mg combined. In practice, it is likely that most naturopathic doctors are using a higher dose, and although more is not always better, it would be interesting to look at the impact of a higher and possibly more therapeutic dose of fish oil on the outcomes evaluated in this study. Further research with larger sample sizes is warranted.

Conclusion

Preliminary evidence from this study suggests that fish oil supplementation may improve the CAR inflammatory index and improve survival at 14 months for individuals with lymphoma and leukemia initiating chemotherapy. Therapies that can modify systemic inflammation may be able to improve survival, and more research should investigate anti-inflammatory agents and their impact on inflammatory-based prognostic scores and overall survival. Due to methodological limitations, the results should be interpreted cautiously, and future studies should further evaluate the impact of fish oil supplementation on inflammation and survival for people with hematological cancers.

About the Author

Ellen McDonell, ND, is a clinician scientist at the Ottawa Integrative Cancer Centre. McDonell earned a bachelor of science in biochemistry from the University of Ottawa before completing her doctor of naturopathic medicine degree at the Canadian College of Naturopathic Medicine. After graduation, McDonell completed a research residency in integrative oncology at the Ottawa Integrative Cancer Centre. In addition to maintaining a clinical practice with a focus in adjunctive cancer care, McDonell is involved in several research projects, including the Canadian US Integrative Oncology Study and the Thoracic Peri-Operative Integrative Surgical Care Evaluation (POISE).

References

  1. Mocellin MC, Pastore e Silva J de A, Camargo C de Q, 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.
  2. Ranzani OT, Zampieri FG, Forte DN, Azevedo LCP, Park M. C-reactive protein/albumin ratio predicts 90-day mortality of septic patients. PLoS One. 2013;8(3):e59321.
  3. Kim MH, Ahn JY, Song JE, et al. The C-reactive protein/albumin ratio as an independent predictor of mortality in patients with severe sepsis or septic shock treated with early goal-directed therapy. PLoS One. 2015;10(7):e0132109.
  4. Haruki K, Shiba H, Shirai Y, et al. The C-reactive protein to albumin ratio predicts long-term outcomes in patients with pancreatic cancer after pancreatic resection. World J Surg. 2016;40(9):2254-2260.
  5. Ishizuka M, Nagata H, Takagi K, Iwasaki Y, Shibuya N, Kubota K. Clinical significance of the C-reactive protein to albumin ratio for survival after surgery for colorectal cancer. Ann Surg Oncol. 2016;23(3):900-907.
  6. Shibutani M, Maeda K, Nagahara H, Iseki Y, Hirakawa K, Ohira M. The significance of the C-reactive protein to albumin ratio as a marker for predicting survival and monitoring chemotherapeutic effectiveness in patients with unresectable metastatic colorectal cancer. SpringerPlus. 2016;5(1):1798.
  7. Toiyama Y, Shimura T, Yasuda H, et al. Clinical burden of C-reactive protein/albumin ratio before curative surgery for patients with gastric cancer. Anticancer Res. 2016;36(12):6491-6498.
  8. Zhou T, Zhan J, Hong S, et al. Ratio of C-reactive protein/albumin is an inflammatory prognostic score for predicting overall survival of patients with small-cell lung cancer. Sci Rep. 2015;5(1):10481.
  9. Kinoshita A, Onoda H, Imai N, et al. The C-reactive protein/albumin ratio, a novel inflammation-based prognostic score, predicts outcomes in patients with hepatocellular carcinoma. Ann Surg Oncol. 2015;22(3):803-810.
  10. Camargo C de Q, Borges D da S, Oliveira PF de, et al. Individuals with hematological malignancies before undergoing chemotherapy present oxidative stress parameters and acute phase proteins correlated with nutritional status. Nutr Cancer. 2015;67(3):463-471.
  11. Bugada D, Allegri M, Lavand’homme P, De Kock M, Fanelli G. Inflammation-based scores: a new method for patient-targeted strategies and improved perioperative outcome in cancer patients. Biomed Res Int. 2014;2014:1-11.
  12. Roxburgh CS, McMillan DC. Role of systemic inflammatory response in predicting survival in patients with primary operable cancer. Futur Oncol. 2010;6(1):149-163.
  13. Proctor MJ, Morrison DS, Talwar D, et al. A comparison of inflammation-based prognostic scores in patients with cancer. A Glasgow Inflammation Outcome Study. Eur J Cancer. 2011;47(17):2633-2641.
  14. Abu Zaid Z, Shahar S, Jamal ARA, Mohd Yusof NA. Fish oil supplementation is beneficial on caloric intake, appetite and mid upper arm muscle circumference in children with leukaemia. Asia Pac J Clin Nutr. 2012;21(4):502-510.
  15. Elbarbary NS, Ismail EAR, Farahat RK, El-Hamamsy M. ω-3 fatty acids as an adjuvant therapy ameliorates methotrexate-induced hepatotoxicity in children and adolescents with acute lymphoblastic leukemia: a randomized placebo-controlled study. Nutrition. 2016;32(1):41-47.
  16. Bükki J, Stanga Z, Tellez FB, et al. Omega-3 poly-unsaturated fatty acids for the prevention of severe neutropenic enterocolitis in patients with acute myeloid leukemia. Nutr Cancer. 2013;65(6):834-842.
  17. Takatsuka H, Takemoto Y, Iwata N, et al. Oral eicosapentaenoic acid for complications of bone marrow transplantation. Bone Marrow Transplant. 2001;28(8):769-774.
  18. Takatsuka H, Takemoto Y, Yamada S, et al. Oral eicosapentaenoic acid for acute colonic graft-versus-host disease after bone marrow transplantation. Drugs Exp Clin Res. 2002;28(4):121-125..
  19. Baena-Gómez MA, de la Torre-Aguilar MJ, Aguilera-García CM, Olza J, Pérez-Navero JL, Gil-Campos M. Inflammatory response using different lipid parenteral nutrition formulas in children after hematopoietic stem cell transplantation. Nutr Cancer. 2016;68(5):804-810.
  20. Baena-Gómez M, Aguilar M, Mesa M, Navero J, Gil-Campos M. Changes in antioxidant defense system using different lipid emulsions in parenteral nutrition in children after hematopoietic stem cell transplantation. Nutrients. 2015;7(9):7242-7255.