A new randomized, placebo-controlled, double-blind pilot study has found that omega-3 fatty acid supplementation did not reduce or prevent paclitaxel-associated acute pain syndrome (P-APS) or chemotherapy-induced peripheral neuropathy (CIPN) in breast cancer patients receiving weekly paclitaxel chemotherapy. The study was conducted at the University of New Mexico Comprehensive Cancer Center and funded by the National Cancer Institute. It was published in December 2023 in the journal Supportive Care in Cancer.
The purpose of this pilot study was to assess whether omega-3 fatty acid supplementation could decrease P-APS and subsequent CIPN in breast cancer patients receiving weekly paclitaxel chemotherapy. P-APS is a common side effect of paclitaxel, affecting 58-90% of patients, that typically occurs in the first 3-4 days after chemotherapy administration. It has been associated with a higher risk of developing chronic CIPN. Currently, there is no standard of care for preventing or treating P-APS.
The study enrolled 60 breast cancer patients scheduled to receive weekly paclitaxel (70-90 mg/m2) chemotherapy. Patients were randomized 1:1 to receive either 4 g of omega-3 acid ethyl esters (Lovaza, containing 38% DHA and 47% EPA) or matching placebo daily, starting one week prior to initiating paclitaxel and continuing until paclitaxel was discontinued, for a maximum of 12 weeks.
To be eligible, patients had to be diagnosed with stage I-IV breast cancer, be at least 18 years old, have an ECOG performance status of 0-2, not have taken omega-3 supplements in the previous month, and not have taken analgesics in the week prior to enrollment. Patients with pre-existing peripheral neuropathy, fibromyalgia, planned use of granulocyte-stimulating factor, or prior paclitaxel use within 6 months were excluded.
Of the 60 patients enrolled, 49 were evaluable for analysis (24 in the placebo group, 25 in the intervention group). All participants were female, with a median age of 53 years (range 45-61 years). The majority were white (77.6%), with 36.7% identifying as Hispanic or Latino.
The primary outcome was the incidence of pain (any pain vs. no pain) following paclitaxel treatment over the 12-week cycle. Secondary outcomes included maximum pain scores, pain medication use, severity of CIPN, and tolerability of the omega-3 supplementation.
Results showed no significant difference between the omega-3 and placebo groups in the primary outcome. In the first week of treatment, 68.0% of patients receiving omega-3 supplementation experienced P-APS, compared to 62.5% in the placebo group (p = 0.77). Over the full 12-week study period, 84.0% in the omega-3 group experienced P-APS, versus 87.5% in the placebo group (p = 1.0).
Analysis of maximum reported pain scores also showed no significant differences between groups. In the first week, those in the omega-3 group reported maximal pain scores 1.53 times higher than the placebo group (95% CI: 0.81-2.90, p = 0.20). Over the full 12 weeks, pain scores were 1.21 times higher in the omega-3 group (95% CI: 0.72-2.02, p = 0.48).
Secondary outcomes similarly showed no benefit from omega-3 supplementation. When controlling for week-to-week differences, the omega-3 group had non-significantly higher odds of using over-the-counter analgesics (OR: 1.65, 95% CI: 0.72-3.78, p = 0.23) and opioids (OR: 2.06, 95% CI: 0.55-7.75, p = 0.28). They also had higher average CIPN scores (12.8, 95% CI: 7.6-19.4) compared to placebo (8.4, 95% CI: 4.6-13.2), though this difference was not statistically significant (p = 0.21).
The study did find a significant association between paclitaxel-associated pain scores and reported CIPN scores, suggesting that P-APS may be an early marker for future CIPN development. The strength of this relationship tended to increase over time (p = 0.005).
Adverse events were mild and similar between groups. There were no concerning safety signals or significant changes in cholesterol levels associated with omega-3 supplementation.
The authors noted several limitations to the study. The sample size was smaller than anticipated, with only 49 of 60 enrolled patients being evaluable, potentially leading to an underpowered study. As a single-center study with a large minority population, the results may not be generalizable to other centers. The reliance on patient-reported outcomes for pain scores and medication use introduces potential for recall bias and incomplete data. Additionally, the study did not account for dietary intake of arachidonic acid, which can affect omega-3 metabolism and may vary regionally.
The authors concluded that omega-3 fatty acid supplementation at the dose and formulation used in this study does not appear to be effective for preventing P-APS or CIPN in breast cancer patients receiving weekly paclitaxel. They do not recommend further exploration of omega-3 supplements as a prevention strategy in this patient population.
This study adds to the growing body of research on potential interventions for P-APS and CIPN prevention, which remains an area of unmet clinical need. While previous studies had suggested a possible benefit of omega-3 supplementation for chemotherapy-induced neuropathy, this well-designed randomized controlled trial did not support those findings.
The results have potential clinical implications for oncologists and patients considering strategies to prevent paclitaxel-related pain and neuropathy. Based on this data, clinicians should not recommend omega-3 supplements for P-APS or CIPN prevention in breast cancer patients receiving weekly paclitaxel. However, the study does reinforce the connection between early paclitaxel-associated pain and later development of chronic neuropathy, highlighting the importance of monitoring for P-APS as a potential predictor of CIPN risk.
It's worth noting that this study used a specific formulation of omega-3 fatty acids (38% DHA and 47% EPA), which differs from some previous studies that used formulations with higher DHA content. It's possible that different ratios of omega-3 fatty acids could yield different results. Additionally, the dosing and timing of supplementation may impact efficacy - this study began supplementation only one week prior to chemotherapy initiation, which may not have been sufficient time to achieve therapeutic levels.
The study's findings align with current clinical guidelines. The American Society of Clinical Oncology (ASCO) does not currently recommend dietary omega-3 supplementation for CIPN prevention, and this study provides further evidence supporting that recommendation.
While disappointing that omega-3 supplementation did not prove effective in this context, the study does provide valuable data to inform clinical practice and future research directions. It highlights the ongoing need for effective strategies to prevent and manage chemotherapy-induced pain and neuropathy, which remain significant sources of morbidity for cancer patients.
Future research in this area may focus on alternative formulations or dosing schedules of omega-3 fatty acids, or explore other potential neuroprotective agents. The observed correlation between early paclitaxel-associated pain and later neuropathy development also warrants further investigation, as it could potentially inform risk stratification and early intervention strategies for CIPN.
In conclusion, this rigorously designed pilot study provides important evidence that omega-3 fatty acid supplementation, at least in the formulation and dosing schedule used, is not effective for preventing paclitaxel-associated acute pain syndrome or chemotherapy-induced peripheral neuropathy in breast cancer patients. While negative results can be disappointing, they play a crucial role in advancing medical knowledge and guiding clinical practice. This study contributes valuable data to the ongoing effort to improve supportive care for cancer patients undergoing chemotherapy.
References
Tawfik B, Dayao ZR, Brown-Glaberman UA, et al. A pilot randomized, placebo-controlled, double-blind study of omega-3 fatty acids to prevent paclitaxel-associated acute pain syndrome in breast cancer patients: Alliance A22_Pilot2. Support Care Cancer. 2023;31(12):637. Published 2023 Oct 17. doi:10.1007/s00520-023-08082-x
