A new prospective-retrospective study published in the November 2023 issue of the Journal of the National Comprehensive Cancer Network provides evidence that vitamin D insufficiency may increase the risk of chemotherapy-induced peripheral neuropathy (CIPN) in breast cancer patients receiving paclitaxel. The study, conducted by researchers at multiple institutions and funded in part by Amgen, Inc. and the National Cancer Institute, analyzed data and samples from the SWOG S0221 clinical trial to validate vitamin D insufficiency as a potential risk factor for CIPN.
The SWOG S0221 trial was a phase III randomized study comparing different dosing schedules of doxorubicin, cyclophosphamide, and paclitaxel as adjuvant chemotherapy for early-stage breast cancer. For this analysis, the researchers examined a subset of 1,191 female patients from the trial who had available pretreatment serum samples. The primary objective was to assess the relationship between pretreatment vitamin D insufficiency (defined as total 25-hydroxyvitamin D ≤20 ng/mL) and the development of grade ≥3 sensory CIPN.
Patients included in the analysis had received paclitaxel within 5% of the target dose for their assigned treatment arm and continued treatment for at least 45 days. The cohort was predominantly White (83.7%) with a mean age of 51.1 years. Vitamin D levels were measured in banked serum samples using a validated liquid chromatography-tandem mass spectrometry assay.
The results showed that 33.3% of patients had vitamin D insufficiency prior to starting chemotherapy. Overall, 16.4% of patients developed grade ≥3 sensory CIPN during treatment. In the primary unadjusted analysis, patients with vitamin D insufficiency had a significantly higher incidence of grade ≥3 CIPN compared to those with sufficient vitamin D levels (20.7% vs 14.2%; odds ratio [OR] 1.57, 95% CI 1.14-2.15, p=0.005).
This association remained significant after adjusting for age and paclitaxel dosing schedule (adjusted OR 1.65, 95% CI 1.18-2.30, p=0.003). However, when additionally adjusting for self-reported race, the relationship was attenuated and no longer statistically significant (adjusted OR 1.39, 95% CI 0.98-1.97, p=0.066). This suggests race may be an important confounding factor in the relationship between vitamin D status and CIPN risk.
Interestingly, the study found that Black patients had both a higher prevalence of vitamin D insufficiency (77.1% vs 28.2% in White patients) and a higher incidence of CIPN (29.4% vs 14.3% in White patients). This raises the possibility that vitamin D insufficiency could partially explain the increased CIPN risk observed in Black patients receiving paclitaxel-based chemotherapy.
To further explore the biological plausibility of this relationship, the researchers conducted a complementary study in mice. They found that mice fed a vitamin D-deficient diet developed mechanical hypersensitivity and showed increased sensitivity to paclitaxel-induced neuropathy compared to mice on a regular diet. This provides additional evidence for a potential causal link between vitamin D deficiency and CIPN risk.
The study has several strengths, including its prospective-retrospective design using data from a large randomized clinical trial, the use of a validated assay for vitamin D measurement, and a pre-specified statistical analysis plan. However, there are also important limitations to consider. The analysis was limited to grade ≥3 CIPN due to the data available from the parent trial, potentially missing more subtle neuropathy. Additionally, information on other known CIPN risk factors like pre-existing neuropathy and diabetes status was not available.
The authors conclude that pretreatment vitamin D insufficiency appears to be the first validated, potentially modifiable predictive biomarker for paclitaxel-induced CIPN. They suggest this finding could have important clinical implications if confirmed in future studies. Specifically, vitamin D testing and supplementation could potentially be used to reduce CIPN risk in patients receiving paclitaxel-based chemotherapy.
However, the researchers emphasize that prospective clinical trials are needed to determine whether vitamin D supplementation can actually prevent or reduce CIPN incidence. One such trial (NCT05259527) is currently ongoing. If proven effective, vitamin D supplementation could represent a low-cost, low-risk intervention to improve tolerability of paclitaxel treatment and potentially allow more patients to complete their planned chemotherapy without dose reductions or early discontinuation.
For oncologists and other clinicians treating breast cancer patients, these findings suggest that assessing vitamin D status prior to initiating paclitaxel-based chemotherapy may provide useful information about CIPN risk. Patients found to be vitamin D insufficient could potentially benefit from supplementation, although this requires further study. The results also highlight the importance of considering racial disparities in both vitamin D status and CIPN risk when treating diverse patient populations.
While these results are promising, it is important to note that they do not definitively establish causation or prove that vitamin D supplementation will prevent CIPN. The attenuated association after adjusting for race indicates that other factors correlated with vitamin D status likely play a role. Additionally, the optimal vitamin D levels for reducing CIPN risk, if any, remain to be determined.
In conclusion, this study provides important new evidence supporting vitamin D insufficiency as a risk factor for paclitaxel-induced peripheral neuropathy in breast cancer patients. It sets the stage for future clinical trials to assess whether vitamin D supplementation could be an effective strategy for CIPN prevention. If confirmed, this could lead to new approaches for reducing this common and often debilitating side effect of cancer treatment, potentially improving quality of life and treatment outcomes for breast cancer patients.
References
Chen CS, Zirpoli G, Barlow WE, et al. Vitamin D Insufficiency as a Risk Factor for Paclitaxel-Induced Peripheral Neuropathy in SWOG S0221. J Natl Compr Canc Netw. 2023;21(11):1172-1180.e3. doi:10.6004/jnccn.2023.7062
