Smith, Elizabeth

Background/Objectives. Decades of research have failed to uncover effective approaches to prevent chemotherapy-induced peripheral neuropathy (CIPN), a common side effect of neurotoxic chemotherapy. Increased interest in placebo response as a potentially under-recognized confounder in CIPN trials was recently sparked by the results of a multisite NCI-funded phase II-III CIPN prevention study of duloxetine, a promising serotonin–norepinephrine reuptake inhibitor that enhances pain-inhibitory mechanisms within the central nervous system. Study findings revealed high and nearly equivalent response rates in three randomized treatment groups—little to no CIPN was reported by 65.2%, 66.0%, and 68.0% of study participants who received duloxetine 30 mg, 60 mg, or placebo treatment, respectively. Methods. We performed a meta-analysis of placebo response rates from seven randomized, double-blinded, placebo-controlled trials conducted over the past 20 years and comprising 191 placebo participants that were specifically testing interventions for oxaliplatin- and paclitaxel-induced peripheral neuropathy and that serially collected patient responses on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Chemotherapy-Induced Neuropathy questionnaire. Additionally, we sought to identify trial- and patient-specific factors that predicted higher placebo response rates from a participant-level pooled analysis. Results. The placebo response rate was 10.0% [95% CI: 5.8%, 16.6%] when response was defined more conservatively as patients reporting no neuropathy at all. When the placebo response was defined more broadly based on patients reporting no or a little neuropathy, the placebo response rate was higher (39.6% [95% CI: 27.4%, 53.2%]). Male participants, receipt of oxaliplatin, and a 2:1 randomization ratio favoring the intervention arm were individually associated with a higher placebo response. Conclusions. High placebo response rates can threaten scientific progress toward identifying effective treatments for cancer treatment-associated side effects, like CIPN. Careful attention to study design factors, participant eligibility, and patient and research staff expectations may help to minimize placebo response rates in future CIPN intervention studies.

Abstract Background The Patient Cloud ePRO app was adopted by the National Cancer Institute National Clinical Trials Network (NCTN) to facilitate capturing electronic patient-reported (ePRO) outcome data, but use has been low. The study objectives were to test whether a patient-targeted ePRO educational resource (ePRO-E) would increase ePRO intent (number of users) and improve data quality (high quality: ≥80% of the required surveys submitted) within an ongoing NCTN study. Methods The ePRO-E intervention, a patient-targeted educational resource (written material and 6-minute animated YouTube video), was designed to address ePRO barriers. ePRO intent and data quality were compared between 2 groups (N = 69): a historical control group and a prospectively recruited intervention group exposed to ePRO-E. Covariates included technology attitudes, age, sex, education, socioeconomic status, and comorbidity. Results Intervention group ePRO intent (78.8%) was statistically significantly higher than historical control group intent (47.1%) (P = .03). Patients choosing ePRO versus paper surveys had more positive and higher technology attitudes scores (P = .03). The odds of choosing ePRO were 4.7 times higher (95% Confidence Interval [CI] = 1.2 to 17.8) (P = .02) among intervention group patients and 5.2 times higher (95% CI = 1.3 to 21.6) (P = .02) among patients with high technology attitudes scores, after controlling for covariates. However, the 80% submission rate (percentage submitting ≥80% of required surveys) in the ePRO group (30.6%) was statistically significantly lower than in the paper group (57.9%) (P = .05). Conclusions ePRO-E exposure increased ePRO intent. High technology attitudes scores were associated with ePRO selection. Since the ePRO survey submission rate was low, additional strategies are needed to promote high-quality data submission.

While oxaliplatin-induced peripheral neuropathy (OIPN) is more common and severe in patients who receive the previous standard, 6-month oxaliplatin-based treatment, we hypothesized that OIPN was still pervasive in patients who received shorter, 3-month-treatment regimens. Using six EORTC QLQ-CIPN20 questions that quantify numbness (N), tingling (T) and shooting/burning pain (P) in upper/lower distal extremities, our aim is to quantify patient-reported responses over 3 months (6 cycles) of oxaliplatin regarding symptom-specific timing, location and severity. For each question, patients were asked how each of the sensory symptoms had affected them during the preceding week, with 1 = “Not at all”, 2 = “A little”, 3 = “Quite a bit” and 4 = “Very much”. The proportional odds model for the cumulative log odds of response that allowed symptom-specific patient heterogeneity to be obtained was applied to a pooled dataset from the placebo arms of two multisite OIPN prevention trials and fit separately to the upper/lower distal extremities. For each symptom, we report the cycle-specific marginal probabilities for each response. In 141 patients, substantial patient heterogeneity in the likelihood, at a given cycle, of a more severe response for a symptom was present. Distinct patterns in the probabilities for each response over time for N and T were observed between the upper/lower distal extremities, while the probabilities of a response >1 for P was largely negligible in both locations. Despite the decrease in exposure to oxaliplatin from 6 to 3 months, OIPN was still pervasive with patients experiencing considerable N and T in the fingers (or hands) and toes (or feet).