In this manuscript, we present QST assessment at baseline, after eight weeks of acupuncture treatment, and at a four-week post-treatment follow-up in a randomized, sham- and usual care-controlled acupuncture for CIPN clinical trial. Our results demonstrate different QST patterns in RA, SA, and UC. After eight weeks of RA, we observed significant improvements in the vibrational detection threshold in feet and cool thermal detection threshold in hands compared to UC. However, there are no statistically significant differences between real and sham acupuncture in QST outcomes.
QST has been used to assess pain sensitivity and mechanistic differences in several clinical pain populations, including peripheral neuropathy pain [7, 28-40]. Hershman et al. demonstrated that increases in CIPN symptoms were significantly associated with a worsening vibration detection threshold, suggesting correlation between CIPN and sensory loss to vibration [9]. Our previous retrospective study suggested that patients with persistent CIPN had more severely impaired sensory perception when compared to patients without CIPN, and those QST outcomes correlated with PROs, suggesting QST’s potential to evaluate CIPN [11, 12].
To the best of our knowledge, this is the first study using QST to characterize CIPN phenotype during an acupuncture intervention. The baseline QST values in all three arms are consistently within the ranges of our prior QST measurements, suggesting QST reproducibility in cancer survivors with persistent CIPN. Our results did not detect significant changes in tactile detection, either in hands or feet, in any of the three arms at any time point. Tactile detection is controlled by the mixed function of nociceptive afferent Aβ, Aδ, and C fibers. Preclinical animal studies suggest that acupuncture works by stimulating Aβ, Aδ, and C fibers via needle insertion, but the QST tactile detection threshold measurement is not very sensitive to the smaller C fiber function changes [41].
Vibration thresholds were no different in the hand but were significantly lower in the feet in both RA and SA when compared to UC (p=0.019 and p=0.046, respectively) at week 8; significant differences were not observed between RA and SA (p=0.637). There were no significant differences between the three arms at week 12 in the feet. It is important to note that the significant difference at week 8 between UC and the other arms is due as much to the UC increase (3.15 points) as it is to the decrease in the RA (3.7 points) and SA (2.5 points) arms. At week 12, the UC and SA arms returned to baseline, but the decrease in RA was maintained.
This finding is consistent with our prior observation and literature indicating that the lower extremities are more sensitive to vibration loss, which might be due to length-dependent Aβ fiber damage in CIPN [42]. This would explain why VDT differences were seen in the feet, but not in the hands. Furthermore, results in the UC arm suggest that without intervention, sensory thresholds might continue to worsen over time, but that an acupuncture intervention could potentially slow the decline, if not improve the thresholds.
Most importantly, this is the first time that we have reported QST assessment in both real and sham acupuncture in cancer survivors with persistent CIPN with the aim to differentiate true effects from real acupuncture to sham acupuncture. Despite finding no significant differences between RA and SA at week 8, we did observe slightly better VDT in RA alone that was maintained at four weeks post-acupuncture follow-up (Figure 1). The placebo effect phenomenon has been well described as a key limitation in acupuncture research, and objective measurement such as QST might be useful to assess RA treatment response. These changes observed in the UC arm may represent hyperalgesia and dysregulation to thermal stimuli due to continued nerve damage. Certainly, the statistical changes in the UC arm are also possibly due to our small sample size, and the absolute changes in these thermal measures were quite small. These results are inconclusive and further studies are needed to further elucidate the QST pattern in patients with CIPN, as well as QST changes corresponding to RA or SA interventions.
Our study has several limitations. First, the sample size is small, and it is a single center study. One third of participants opted out of QST, which might lead to selection bias in our analysis. Moreover, in all 63 participants who completed QST assessments at any timepoint, 52 (82.5%) completed the assessments at two timepoints, and 42 (67%) completed all three assessments, which may also lead to selection bias in our analysis. The parent trial primary outcome is CIPN-related symptom changes at week 8, but not other CIPN symptoms such as numbness and tingling, which might be better characterized by QST. Lastly, QST assessments were exploratory endpoints of the primary study, and the statistical analyses are inadequately powered to evaluate them.
Despite these limitations, this is the first placebo-controlled randomized trial assessing the efficacy of acupuncture in alleviating persistent CIPN symptoms with the incorporation of QST. These preliminary differences in QST measurements reveal the perceived value and benefits of acupuncture from an objective perspective of sensorimotor perception loss. Our study is strengthened by well-balanced baseline characteristics between groups and consistency in assessment fidelity, as the same RSA administered all QST sessions. Here, we found that QST is a feasible and reliable tool to assess CIPN severity and may provide valuable information on treatment response to acupuncture. These preliminary findings can inform future clinical trials of adequate power to delineate QST’s role as a correlative biomarker in CIPN research.