In this observational study as an ancillary analysis of a previous randomized trial investigating the preventive effect of cryotherapy on weekly paclitaxel-induced CIPN of breast cancer patients, cryotherapy resulted in a numerical decrease in the incidence of persistent CIPN at more than one year after completion of treatment. Age 60 years or older was a significant predictive factor for persistent CIPN in multivariate logistic regression analysis.
With the widespread administration of systemic adjuvant therapy for breast cancer, a substantial proportion of patients has an excellent prognosis[9, 10]. In HER2 positive breast cancer, the introduction of adjuvant trastuzumab with taxane-based chemotherapy resulted in significant improvement of long-term prognosis[11-13]. For example, adjuvant weekly paclitaxel and trastuzumab therapy resulted in a 7-year OS of 95% and 7-year RFI of 97.5% in HER2-positive and node negative breast cancer. Thus, persistent CIPN has become an important issue for the growing number of breast cancer survivors who received adjuvant taxane-based therapy.
In our study, persistent CIPN determined with significant decrease of FACT-NTx score was observed in approximately quarter of all cases (26.3%) with median of 2.3 years after completion of weekly paclitaxel. In addition, more than one-third (36.8%) of cases in control group showed persistent CIPN. Common symptom of persistent CIPN was sensory neuropathy, with the finding more than cases showed hand and foot numbness in control group. Our finding of the incidence of persistent CIPN is compatible with previous reports[3, 15, 16]. In a randomized trial of acetyl-L-carnitine (SWOG S0715), 34.4% on the placebo arm reported a significant decrease of FACT-NTx score from baseline at 104 weeks from randomization. In an observational study of early-stage breast cancer patients who received adjuvant paclitaxel therapy also showed that severe symptoms of numbness or discomfort for the hands and the feet in a quarter of cases . Although our study is cross-sectional analysis with various duration since completion of paclitaxel therapy, the duration seems a small impact on the incidence of CIPN. A multivariate logistic regression analysis in our study showed that interval from end of paclitaxel therapy was not associated with persistent CIPN. In SWOG S0715 also showed persistent low NTX scores at weeks 12, 24, 36, 52, and 104. In the prospective observational study, the mean scores on the FACT NTx score low 12 months after treatment. These findings show that taxane-related CIPN can persist over years and persistent CIPN is an important clinical issue to be resolved in breast cancer patients.
As risk factors of CIPN, age and is reported to be associated with an incidence of CIPN and persistent CIPN. In regard to incidence of CIPN, a cohort study including 333 participants treated with paclitaxel or oxaliplatin showed that an older age was associated with worse CIPN in multivariate analysis. A cohort study of the Southwest Oncology Group database also showed that the incidence of grade2-4 taxane-induced CIPN increases by 4% for each year of age. In regard to persistent CIPN, a retrospective analysis of 219 breast cancer cases showed that age 60 years or younger showed a significant less duration of taxane-related CIPN (HR 0.55, P=0.027). SWOG S0715 trial also showed age 60 years or older had an risk factor for occurrence of CIPN at year 1 (HR 1.74, p=0.02) and year 2 (HR 1.67, p=0.04). In our study, age 60 years or older was shown as a significantly increased risk of persistent CIPN. The incidence of persistent CIPN was 8.7% and 53.3% in the age < 60 and age 60 or older, respectively. These findings indicate that pronounced precaution should be taken to prevention and treatment of CIPN when older patients are treated with weekly paclitaxel.
Although no effective treatment of persistent CIPN has not been reported, preventive approach of CIPN could be associated with decrease of persistent CIPN. At first, occurrence of CIPN is significant risk factor of persistent CIPN. A retrospective study showed that duration of CIPN was significantly longer in cases with Grade2/3 peripheral neuropathy compared with Grade1 peripheral neuropathy (HR 0.55, p=0.015). In our study, no case without CIPN during paclitaxel therapy showed persistent CIPN, whereas half of cases (50%) that experienced CIPN during weekly paclitaxel therapy showed persistent CIPN. These findings suggest that prevention of CIPN during taxane-based therapy leas to a prevention of persistent CIPN. As shown in previous clinical trials, cryotherapy or compression therapy may be associated with decrease in incidence of CIPN in breast cancer patients[4-6, 9-11]. A randomized trial or ancillary analysis of previous randomized trials are warranted to confirm the preventive effect of cryotherapy or compression therapy on persistent CIPN.
Our study has several limitations. First, the nature of unplanned ancillary analysis results in a lack of statistical power to detect the difference between cryotherapy and the control group. Second, evaluation of persistent CIPN in this study was based on a subjective patient questionnaire. Objective evaluation, such as the Semmes-Weinstein monofilament test, should be incorporated to improve the robustness of our finding. Finally, although the degree of persistent CIPN seems to be fixed over time, further serial assessments of CIPN on individual case might strengthen the findings of our study.
In conclusion, we showed that cryotherapy resulted in a numerical decrease in the incidence of persistent CIPN at more than one year after completion of treatment in breast cancer patients treated with weekly paclitaxel. A prospective randomized trial with a long-term period is warranted to confirm the preventive effect of cryotherapy on persistent CIPN.