Abstract
Background:
Paclitaxel-treated patients can suffer from years of peripheral neuropathy with pain, numbness, and tingling. Promising preclinical data with poly (ADP-ribose) polymerase (PARP) inhibitors led us to explore this class of agents to palliate this neuropathy.
Methods:
We relied on a completed trial that tested the antineoplastic effects of veliparib (NCT01012817). Data from patients who had been enrolled on NCT01012817, who previously received paclitaxel, and who had completed a validated pain assessment instrument were evaluated for improvement in their pain scores.
Results:
All 34 eligible patients were women, and all had a metastatic gynecological malignancy. On a 10-point scale (higher numbers indicative of worse pain), the average baseline score was 3.6 (range: 0-7). Seven patients (21%; 95% confidence interval: 9%-38%) manifested a drop in pain score (1 score lower than baseline followed by at least one consecutive value also below baseline). Of note, no patients initiated other therapy for neuropathy while on NCT01012817.
Conclusion:
The PARP inhibitors merit further study for chemotherapy-induced peripheral neuropathy. For patients suffering from peripheral neuropathy, these putative palliative effects might prompt earlier consideration of a PARP inhibitor as part of cancer treatment.
Introduction
Pain, numbness, and tingling characterize paclitaxel-induced peripheral neuropathy. 1 This symptomatology occurs in 20% to 60% of patients with cancer and can last for years. 1 In addition to the distress and discomfort of this chronic pain, patients can suffer from a loss of functionality and, as a result, are at risk for injurious, sometimes life-threatening falls. 2
Despite the prevalence and untoward consequences of paclitaxel-induced neuropathy, few interventions provide effective palliation. In perhaps the only definitively successful clinical trial to demonstrate the efficacy of an intervention for chemotherapy-induced peripheral neuropathy, Smith and others tested duloxetine in a 231-patient, placebo-controlled trial. 3 Although duloxetine reduced pain, the mean improvement in patients’ pain scores amounted to only a 1-point change within a 10-point scale. Although duloxetine remains a palliative option, its modest benefit underscores the importance of continuing to seek ways to better control chemotherapy-induced neuropathic pain.
In a nonclinical setting, Ta and others studied poly (ADP-ribose) polymerase (PARP) inhibition for chemotherapy-induced neuropathic pain. 4 Using an animal model, these investigators observed that the PARP inhibitor veliparib increased nerve-related pain thresholds by 30% to 60% in animals exposed to cytotoxic, neuropathy-inducing chemotherapy. 4 Others have reported similar observations and have invoked attenuation of neuroinflammation and a reduction in oxidative stress as mechanisms to explain these salutatory preclinical findings relevant to neuropathy. 5 -22 Interestingly, although several, large-scale, placebo-controlled antineoplastic trials in ovarian cancer have tested PARP inhibitors, with few exceptions, an absence of data on neuropathy outcomes from patients suffering from neuropathy is evident within these trials, particularly among patients who had been previously prescribed taxanes. 23,24 The question of whether PARP inhibitors can palliate chemotherapy-induced peripheral neuropathy remains unanswered in a cancer clinical setting.
In the study reported here, we built upon the preclinical data described above as well as on a previously conducted clinical trial that tested veliparib as an antineoplastic agent. We used this previously conducted clinical trial as a platform to explore whether PARP inhibition might attenuate pain in patients previously treated with paclitaxel.
Methods
Overview
The current study relied on a completed trial that tested veliparib and topotecan from 2009 through 2015 (NCT01012817) for their antineoplastic effects. 25 Referred to herein as the parent trial, this clinical trial served as a platform for the study reported here. The parent trial tested a range of veliparib doses from 10 mg/d in 3-day treatment intervals on a weekly basis to 300 mg twice a day at the same intervals. The Mayo Clinic institutional review board had separately approved the parent trial as well as the current study.
Eligibility
This study had well-defined patient eligibility criteria. Patients had to have (1) been enrolled in the parent trial, for which the eligibility criteria are reported elsewhere 25 ; (2) previously received paclitaxel; and (3) completed a previously validated patient-reported pain assessment instrument. With respect to the latter, patients were provided with a paper questionnaire that asked them to rate their pain on a 10-point scale, with 10 being the “worst pain you can imagine” and 0 being no pain. 26,27 This instrument was administered to all patients within the Division of Medical Oncology at the Mayo Clinic at each outpatient visit from late 2010 until the time of this report with results integrated into the medical record.
Data Acquisition and Reporting
After obtaining a list of all patients enrolled on the parent trial, the study team reviewed each patient’s medical record to assess eligibility. One investigator (R.A.B.) served as the primary reviewer of the medical records; another investigator (A.J.) undertook a confirmatory review of select items in over half the medical records.
The primary aim and the thresholds for attainment of end points related to that aim were formulated prior to data analyses. The primary aim was to report the percentage of eligible patients who manifested at least a 1-point improvement in pain score from baseline with a sustained improvement, as observed during at least one other consecutive pain assessment. This degree of improvement was chosen based on precedent from the study from Smith and others. 3 Veliparib was to be deemed worthy of further study if 15% or more patients were to have reported this degree of pain improvement. This percentage was chosen based on the rate of pain relief with placebo in the study from Smith and others. 3 All data are reported descriptively; calculations and graphics were completed with JMP Pro (SAS Institute, Cary, North Carolina).
Results
Demographics
From the original cohort of 62 patients, 34 met this study’s eligibility criteria (Figure 1). Baseline characteristics of these eligible patients appear in Table 1. Of note, all were women; 29 had ovarian cancer (with fallopian tube and primary peritoneal cancer included in this category), 4 endometrial cancer, and one cervical cancer.
Consort diagram. This consort diagram shows the derivation of the final sample size for the current study.
Baseline Demographics (n = 34).a
a Numbers in parentheses denote percentages unless otherwise specified.
b At entry into the original poly (ADP-ribose) polymerase (PARP) trial.
Pain Scores
On a 10-point scale, with higher numbers indicative of worse pain, the average baseline pain score was 3.6 (range: 0-7). Seven patients (21% with a 95% confidence interval of 9%-38%) manifested a sustained drop in pain scores (1 drop in pain score followed by at least one consecutive value that was lower than baseline). Change in pain scores from baseline appears in Figure 2.
Pain scores over time. Seven patients (21%: 95% confidence interval: 9%-38%) manifested a sustained drop in pain scores. Each line represents serial pain scores for a specific patient.
Pain Data
Patients did not take medications to try to palliate neuropathy during the original trial, but 2 had initiated such treatment prior to trial enrollment. One had taken gabapentin; the other patient had used various interventions, which included gabapentin, amitriptyline, and scrambler therapy. In the patients who manifested pain relief over time, no other type of pain medication, neither opioids nor nonsteroidal anti-inflammatory agents, was initiated.
Four of 34 patients sustained a fall. Two fell while enrolled on the trial: one before starting the PARP inhibitor and one after discontinuing veliparib. No apparent association was observed between pain scores and falls.
Discussion
To our knowledge, this study is the first to report that a PARP inhibitor might provide clinical palliation of chemotherapy-induced peripheral neuropathy. Our results suggest veliparib might provide very modest palliation, as suggested by the finding that 21% of patients in the current study reported improvement in pain while on this agent. Although the current study did not probe into mechanism of action, purportedly, these effects may be the result of anti-inflammatory effects of this class of drug, as suggested by others. 28 These novel clinical findings suggest that veliparib merits further study for chemotherapy-induced peripheral neuropathy.
Of note, PARP inhibitors give rise to a nontrivial adverse event profile that includes myelosuppression, fatigue, and, on rare occasion, even myeloid malignancies. 23,24 Realistically, in view of such toxicity, it is difficult to conceive of these agents serving a palliative role for chemotherapy-induced neuropathy. However, PARP inhibitors do have an established role in maintenance therapy in ovarian cancer; those patients who developed recurrent cancer, manifested a favorable tumor response to cytotoxic therapy, and then desire a longer cancer progression-free interval can consider taking a PARP inhibitor. 23,24 It seems entirely plausible that the putative, palliative role of PARP inhibitors for peripheral neuropathy might enter into health-care provider/patient conversations as decisions are made on whether or not to use PARP inhibitors as maintenance cancer therapy. If a patient with ovarian cancer is ambivalent about cancer maintenance therapy, a modest promise of relief from peripheral neuropathy might lead to a greater willingness to take a PARP inhibitor for a cancer indication.
This study has shortcomings and strengths. First, although we used a validated instrument to measure pain, this instrument is not specific to neuropathic pain. In short, we did not distinguish between somatic and neuropathic pain. However, future studies should specifically measure peripheral neuropathy. Importantly, this weakness might also be viewed as a strength; the fact that we did not suggest to patients our interests in their neuropathic pain served to banish any so-called placebo effect which can translate into improved symptoms in as many as 30% to 40% of patients with cancer. 29 Indeed, the descriptive findings reported here may speak to very real palliation from veliparib. Second, our definition of success might be viewed as modest, although it was in keeping with what was used in the high-profile study from Smith and others. 3 Nonetheless, future studies might choose to rethink their threshold for palliative benefit.
Finally, a strength of the current study is its design. We used a previously completed clinical trial as a platform to assess the putative off-target effect of veliparib. The time and money entailed in mounting a clinical trial are sizable; hence, the approach of building on a previously completed trial is efficient and cost-effective. As mentioned, the findings reported here are in need of clinical confirmation perhaps in the context of a larger prospective trial, particularly prior to counseling patients about the combined antineoplastic and putative palliative effects of this class of agents.
Footnotes
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
