The multivariate ordered logistic regression analysis performed in this study showed that significant predictors for the development of OXAIPN included use of BMI, number of cycles, SOX regimen, concomitant use of PPI and concomitant use of an analgesic adjuvant. Although RAS inhibitor was not extracted as a significant variable in multivariate analysis, the combined use of RAS inhibitors tended to reduce OXAIPN.
In this study, BMI was extracted as a significant predictor for the development of OXAIPN. Obesity has been reported as a risk factor for chemotherapy-induced peripheral neuropathy (CIPN) [7–10]. The results of this study were also consistent with findings from previous studies. When the body fat content is high, anticancer drugs reportedly accumulate in adipose tissue and excretion is thus delayed . This may be one reason why OXAIPN is more likely to occur in obese patients. On the other hand, there are many reports contrary to our result of this study that the effect of anticancer drugs is diminished in obese patients . Further verification is needed in this issue.
The ROC curve analysis revealed a BMI cut-off of 20.5 kg/m2 for the group likely to develop OXAIPN (grade 2 or higher). World Health Organization have defined obesity or overweight patients as individuals with BMI ≥25 kg/m2 . However, in this study, CIPN was more likely to occur with BMI ≥20.5 kg/m2. This may be due to the difference in physique between Japanese and Westerners. In particular, CIPN in the lower limbs may be partly due to the weight load caused by obesity. Clinicians should pay close attention to the onset of OXAIPN among patients with BMI ≥20.5 kg/m2, not necessarily the obese population.
The results also showed that OXAIPN was more likely to develop as the number of administration cycles increased. ROC analysis revealed that OXAIPN (grade 2 or higher) was more likely to occur with ≥8 cycles. Regarding the number of doses, OXAIPN reportedly tends to become chronic depending on the total dose [5, 14–17]. Beijers et al. demonstrated that a higher cumulative dose is associated with the development of long-term OXAIPN . Careful attention should be paid to the cumulative dose of oxaliplatin, particularly administration of ≥8 cycles.
Among the chemotherapy regimens, SOX therapy has resulted in a lower risk of developing OXAIPN. SOX therapy is administered every 3 weeks, while FOLFOX and FOLFIRINOX are administered every 2 weeks. The concept of the stop-and-go strategy (strategy of intermittent oxaliplatin treatment) was proposed in the OPTIMOX trial to avoid aggravation of OXAIPN . Our results suggested the severity of OXAIPN can be prevented by increasing the dosing interval. Our results are consistent with the results of OPTIMOX trial that OXAIPN can be avoided using the stop-and-go strategy.
Previous studies have reported PPI as a risk factor for peripheral neuropathy [19–21]. Makunts et al. found a significant increase in a wide variety of peripheral neurological and neuropathic adverse events due to PPI . They reported that an increased gastric pH level correlated with decreased levels of vitamin B12. In turn, B12 deficiency has been associated with reversible peripheral neuropathy . Clinicians should thus be careful in prescribing PPIs when performing chemotherapy with oxaliplatin.
Although analgesic adjuvants tend to be used in combination therapy, the result was that OXAIPN developed even with analgesic adjuvants.
The analgesic adjuvants used to relieve the symptoms of OXAIPN during chemotherapy did not show adequate therapeutic efficacy. This finding supports earlier observations that effective analgesic adjuvants are currently unavailable for CIPN [16, 22, 23].
Although not significant, concomitant use of RAS inhibitors was suggested to prevent OXAIPN . Previous research has reported RAS inhibitors could prevent OXAIPN. Further research is needed on this point.
Several limitations to the current study need to be considered. First, the retrospective nature of the study may have decreased the validity of the data obtained. Second, since this study was performed at a single institute, prospective multicentre studies are needed to confirm the results.
In conclusion, BMI, number of cycles, SOX regimen, concomitant use of PPI and concomitant use of analgesic adjuvant were identified as significant predictors for the development of OXAIPN. However, our findings need to be confirmed in further studies. Nevertheless, these results may assist in developing strategies to improve the safety, efficacy, and QOL among patients receiving oxaliplatin.