Support Care Cancer (2016) 24:547–553 DOI 10.1007/s00520-015-2807-5

ORIGINAL ARTICLE

Can pregabalin prevent paclitaxel-associated neuropathy?—An ACCRU pilot trial Shivani S. Shinde 1 & Drew Seisler 2 & Gamini Soori 3 & Pamela J. Atherton 2 & Deirdre R. Pachman 1 & Jacqueline Lafky 1 & Kathryn J. Ruddy 1 & Charles L. Loprinzi 1

Received: 5 March 2015 / Accepted: 8 June 2015 / Published online: 9 July 2015 # Springer-Verlag Berlin Heidelberg 2015

Abstract Purpose Paclitaxel can cause an acute pain syndrome (PAPS), considered to be an acute form of neuropathy and chronic chemotherapy-induced peripheral neuropathy (CIPN). Anecdotal reports suggested that gabapentin may be helpful in the prevention of these toxicities. The purpose of this pilot study was to obtain data to support or refute the utility of pregabalin for the prevention of P-APS and CIPN. Methods Patients scheduled to receive weekly paclitaxel (80 mg/m2/dose) were randomized 1:1 to receive pregabalin 75 mg or a placebo, twice daily, during the 12 weeks of chemotherapy. Patients completed the European Organization of Research and Treatment of Cancer Quality of Life (EORTC QLQ) CIPN20 questionnaire at baseline, prior to each dose of paclitaxel and monthly for 6 months post-treatment. Patients completed a post-paclitaxel questionnaire for 6 days after each dose of paclitaxel and an acute pain syndrome symptom questionnaire on day 8. The primary end point was to determine the effect of pregabalin on the maximum of the worst acute pain scores for the week following paclitaxel administration for cycle 1. Results Forty-six patients were randomly assigned to the treatment or placebo arm. There was no suggestion of a Electronic supplementary material The online version of this article (doi:10.1007/s00520-015-2807-5) contains supplementary material, which is available to authorized users. * Charles L. Loprinzi [email protected] 1

Department of Oncology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

2

Department of Biostatistics, Mayo Clinic, Rochester, MN, USA

3

Medical Oncology, Nebraska Cancer Specialists, Omaha, NE, USA

difference between the two study arms with regard to P-APS measures. While there was a suggestion that pregabalin decreased numbness, there was no suggestion that it decreased tingling, pain, or the EORTC QLQ-CIPN20 subscale scores. There were no evident toxicity differences between the two study arms. Conclusions The results of this pilot trial do not support that pregabalin is helpful for preventing P-APS or paclitaxelassociated CIPN. Keywords Paclitaxel-associated acute pain syndrome . Chemotherapy-induced peripheral neuropathy . Pregabalin . Prevention

Introduction Paclitaxel, a commonly used chemotherapeutic drug, can cause peripheral numbness, tingling, and pain, resulting in a syndrome known as chemotherapy-induced peripheral neuropathy (CIPN). It can also cause an acute pain syndrome, described in up to 58 % of patients [1]. Historically, this syndrome, characterized by subacute onset of aches and pain developing within 1 to 3 days of paclitaxel administration, has been commonly referred to as paclitaxel-induced arthralgias/myalgias [1]. Although historically described as myalgia/arthralgia, the paclitaxel-induced acute pain syndrome (P-APS) has been hypothesized to be a type of neurotoxicity, possibly due to preferential sensitization of mechanical nociceptive neurons [2]. Consistent with this hypothesis, patients with severe P-APS appear to be at an increased risk of developing CIPN [3]. Gabapentin and pregabalin are effective in treating many forms of neuropathic pain [4–6]. Their role for the treatment of CIPN, however, is not clearly established. A randomized

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controlled trial failed to show significant benefit of using gabapentin to treat established symptoms caused by CIPN [7]. While these medications have not been tested in a randomized clinical trial to treat P-APS, two case series, consisting of two [8] and ten [9] patients each, suggested that gabapentin could diminish the severity of P-APS. Additionally, there are animal models to support that gabapentin can decrease paclitaxel-induced nerve injury [10]. A review of several clinical trials showed that perioperative administration of gabapentin and pregabalin decreased the incidence of postsurgical chronic pain, i.e., pain persistent for 2 or more months after surgery [11]. These data led to the hypothesis that a gabapentinoid agent would decrease the incidence and/or severity of the P-APS and paclitaxel-associated CIPN. Pregabalin was chosen over gabapentin for the current study as it has some improved analgesic properties and is more convenient in terms of dosing [12, 13]; additionally, Pfizer was willing to provide this agent and a placebo for this clinical trial. The current clinical trial was developed to provide pilot data regarding the potential role of pregabalin for the prevention and management of P-APS, to hopefully provide enough positive data to support the conduct of a subsequent large definitive randomized placebo-controlled trial.

Methods Study design This was a multi-centric, randomized, double-blinded, pilot trial. Institutional Review Board approval was obtained at each of the 11 registering institutions. Eligibility characteristics Inclusion criteria included age≥18 years, an Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 1, and life expectancy greater than 6 months. All of the participants were women scheduled to receive weekly paclitaxel at a dose of 80 mg/m2, in the adjuvant (post-operative) or neo-adjuvant setting for breast cancer, for a planned course of 12 weeks, without any other concurrent cytotoxic chemotherapy (trastuzumab and/or other antibody and/or small molecule treatments being allowed, except for poly-ADP ribose polymerase [PARP] inhibitors). Participants also needed to have the ability to complete questionnaires by themselves or with assistance and have the ability to provide informed written consent. Exclusion criteria included pregnant or nursing women, previous diagnosis of diabetic or other peripheral neuropathy, fibromyalgia, seizure disorder, significant renal insufficiency, prior exposure to neurotoxic chemotherapy, and a history of

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allergic or other adverse reactions to gabapentin or pregabalin. Patients receiving gabapentin, pregabalin, or a PARP inhibitor within the preceding 6 months were also excluded. Protocol treatment Patients were randomized 1:1, using the Pocock-Simon dynamic allocation procedure, to either the pregabalin or placebo arm. After the treatment assignment had been ascertained, the patient’s study medication code number was listed on the confirmation of registration screen. The blinded data manager/ nurse/pharmacist at the patient’s institution contacted the ACCRU Registration Office for a code number when study product was needed for the patient. The treating physicians were also blinded. Patients received pregabalin 75 mg or placebo twice daily, starting on the first night of chemotherapy and continuing through the planned 12 weeks of chemotherapy. During the 13th week, the dose was decreased to once a day at bedtime, after which patients went off-study. Patients were instructed to use acetaminophen 500 mg every 6 h and/or oxycodone 5 mg every 1–2 h as needed for breakthrough pain associated with the P-APS. Treatment evaluation At baseline, patients had a history and physical examination and completed a pre-paclitaxel questionnaire which addressed the presence of symptoms related to baseline pain and symptoms that might be related to potential pregabalin toxicities (to obtain baseline data prior to starting pregabalin). A day after receiving paclitaxel, patients were asked to complete a daily postpaclitaxel questionnaire for 6 days. This questionnaire included questions to assess worst, least, and average pain scores and the need for analgesics over the last 24 h. On day 8 after paclitaxel treatment, just prior to receiving the next dose of paclitaxel, patients were required to complete an acute pain syndrome symptom summary questionnaire, which summarized symptoms and analgesic use over the preceding week and evaluated patients for potential pregabalin toxicities. CIPN was measured using the European Organization for Research and Treatment of Cancer Quality of Life (EORTC-QLQ) CIPN20 questionnaire at baseline, prior to each paclitaxel cycle, and then every 30 days following completion of paclitaxel treatment, for 6 months. The EORTC QLQ-CIPN20 has been shown to be reliable, valid, and responsive to change [14, 15]. The tools used to assess the P-APS were the ones used to define the syndrome [1–3]. Adverse events were monitored per the patient questionnaires noted above, along with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

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Statistical methods The primary goal was to assess the effectiveness of pregabalin on the P-APS. The primary end point was the maximum of the worst pain scores for the week following the first cycle of paclitaxel administration, as measured by a question on the daily post-paclitaxel questionnaire. A non-parametric Kruskal-Wallis test was used to compare primary end points between the two study arms. Secondary end points included the maximum of average pain and area under the curve (AUC) of the worst, least, and average pain following the first cycle of paclitaxel; opioid, and non-prescription drug use; maximum EORTC CIPN20 subscales; and item responses over the course of treatment and toxicities associated with pregabalin. The EORTC QLQ-CIPN20 was scored by a standard scoring algorithm and converted to a 0–100 scale, where higher scores represent better quality of life. Linear growth curve models, accounting for repeated measures from patients over the course of treatment, and AUC analysis were used to assess the difference in CIPN20 subscales and items relating to tingling, numbness, and pain in the extremities by treatment arm. Longitudinal plots were also employed to depict differences in patient-reported data over time.

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respectively) were over age 50 years (mean age 53.7, standard deviation 13.7). Neuropathy data Paclitaxel acute pain syndrome The primary end point of worst pain scores over the first cycle of treatment was not significantly different between arms (p= 0.56). Patient-reported acute pain syndrome data, for 6 days after each chemotherapy dose, are illustrated in Table 1 and Fig. 2. The maximum of average pain, as well as the AUCs of the worst, average, and least pain over the first cycle of treatment, were also not significantly different between arms (p= 0.48, 0.62, 0.22, and 0.07, respectively). There, likewise, was no significant difference between the study arms in the proportion of patients who used opioid or non-prescription medications for control of the paclitaxel acute pain syndrome. The percentages of patients who took non-prescription analgesics in the 7 days after the first dose of paclitaxel, for paclitaxelassociated pain, were 53 and 50 % for the pregabalin and placebo arms, respectively, while 16 and 18 % used opioids. Chronic peripheral neurotoxicity

Results Baseline characteristics This study accrued 46 patients between March 2012 and November 2013, from 11 individual sites. A patient consort diagram is provided (Fig. 1). Five patients (four pregabalin; one placebo) either cancelled or withdrew or did not provide baseline pre-paclitaxel data and were not evaluable for primary end point analyses. Baseline demographics were balanced among the remaining 41 patients. All the patients were females and 23 (56 %; 53 and 59 % of pregabalin and placebo patients,

Growth curve models, as well as AUC analysis, show no significant differences in the EORTC CIPN20 sensory subscale (p = 0.88 and p = 0.46, respectively) between arms (Fig. 3). Similarly, there were no differences in the motor neuropathy or autonomic neuropathy subscales. Data from six individual questions regarding numbness, tingling, and shooting/burning pains, in fingers/hands and in toes/feet, are illustrated in Fig. 4, with a suggestion of a potential small difference for numbness symptom but not for tingling or shooting/burning pain. None of the other 14 individual EORTC CIPN20 instrument questions provided any suggestion of a difference between the study arms. Evaluation of pregabalin toxicity There were no statistically significant or clinically apparent differences between the two study arms with regard to multiple toxicities (including increased swelling, sleepiness, Table 1

Effect of pregabalin on P-APS pain scores

P-APS (pain score over the first 6 days following initiation of paclitaxel; higher scores are worse) Placebo (N=22) Worse pain: mean (SD) 3.2 (3.0) Average pain: mean (SD) 2.2 (2.6) Fig. 1 Consort diagram

Pregabalin (N=19)

p value

2.6 (2.5) 2.6 (2.2)

0.56 0.48

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Fig. 2 Worse pain (a) and average pain (b) scores over 6 days following paclitaxel doses for each cycle. Higher scores represent more pain

nausea, fatigue, trouble sleeping, nervousness, negative mood changes, and dizziness or difficulty walking) which were evaluated using weekly symptom questionnaires. Likewise, there were no apparent differences in adverse events per NCI CTCAE criteria.

Discussion Findings from the current pilot trial were unable to support the pre-study hypothesis that this study would provide data to support the conduct of a placebo-controlled phase III trial, to test the efficacy of pregabalin for the prevention of paclitaxel-

associated neuropathy. The results are in concert with reported findings of another randomized, double-blind, placebocontrolled trial that assessed the efficacy of pregabalin for the prevention/treatment of CIPN [16]. This clinical trial, conducted in patients with advanced colorectal cancer who were receiving oxaliplatin-based chemotherapy, enrolled 64 patients. The primary end point of this trial was the durationadjusted average paresthesia change measured by a numerical rating scale. Patients received flexible pregabalin dosing, from 150 to 600 mg/day versus placebos. The trial was terminated early, as an interim analysis found that there were no sufficiently positive data to continue the trial, based on a Bconditional power to detect a difference in treatment groups.^ To

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Fig. 3 CIPN scores during 12 weeks of treatment and over 6-month follow-up for the EORTC CIPN20 sensory neuropathy scores. Higher scores represent fewer symptoms

our knowledge, there are no other reported trials of pregabalin or gabapentin, to prevent chemotherapy-induced neuropathy. Similarly, there are no positive randomized clinical trials of a gabapentinoid drug for the treatment of established CIPN. The one published randomized placebo-controlled doubleblinded trial that studied this topic did not provide any suggestion of benefit for gabapentin for the treatment of established CIPN [17]. Recently published American Society of Clinical Oncology guidelines acknowledge that gabapentinoids are not established as being beneficial. Nonetheless, these guidelines suggested that it is reasonable to try gabapentinoids as a treatment option for selected patients with CIPN, given (1) the established efficacy of gabapentin and pregabalin for other forms of neuropathic pain [18], (2) that only a single negative randomized, placebo-controlled double-blinded trial for this agent was completed [7], and (3) the limited treatment options for CIPN. While the current trial was established to study the role of pregabalin in prevention of paclitaxel-induced neuropathy, it can be argued that, indirectly, the results point against its utility for treating established CIPN. If the drug was effective for treatment of established neuropathy, then it should have led to an improvement in CIPN scores in patients who developed CIPN. Although this trial had a low statistical power to demonstrate such a difference, the lack of even a trend in favor of pregabalin suggests that it is not effective for treating CIPN. It should be noted that pregabalin patients reported fewer numbness symptoms in both lower and upper extremities, throughout treatment and follow-up, though not significantly so. It is not known whether this is a true benefit that can be attributed to pregabalin or if this occurred by chance, given the large number of items examined in this trial. However, the fact

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that these results are consistent in both lower and upper extremities supports that there may be a real benefit from pregabalin in preventing numbness. Of note, numbness is one of the more common problematic symptoms associated with paclitaxel neurotoxicity [19]. Despite the suggestion that pregabalin might influence numbness, the current data are not strong enough to recommend that pregabalin be used to prevent paclitaxel-associated numbness in clinical practice. Likewise, these data, in and of themselves, are not strong enough to support another clinical trial to evaluate the efficacy of pregabalin for this situation. A potential weakness of the current trial is that pilot trial reports of gabapentin suggested a benefit for this agent, while the current trial evaluated pregabalin, not gabapentin. Although there are no direct comparisons between gabapentin and pregabalin for any situation, to the best of our knowledge, both these drugs are commonly used for treatment of neuropathic pain. In fact, pregabalin has been found to have distinct pharmacokinetic advantages over gabapentin. It has higher bioavailability (90 versus 33–66 % as compared to gabapentin) and is rapidly absorbed, reaching peak concentrations within 1 h. Gabapentin, unlike pregabalin, exhibits a non-linear relationship between drug dose and plasma concentration, making its pharmacokinetics less predictable. Also, based on the population pharmacokinetic-pharmacodynamic model, pregabalin achieves a greater treatment effect in post-herpetic neuralgia and epilepsy [20]. For these reasons, we felt that pregabalin would have had as reasonable a chance at preventing P-APS in this patient population as gabapentin would have. A second potential weakness is related to the dose chosen to be studied in this trial. In a recent Cochrane review for treatment of neuropathic pain, in situations other than CIPN, pregabalin was found to be more beneficial at doses ranging between 300 and 600 mg daily, while 150 mg daily was less effective [21]. Three points can be made in defense of the current trial’s dose: First, this Cochrane review reported somnolence and dizziness as common side effects at higher doses, requiring treatment discontinuation in 18–28 % of patients. Second, the dose chosen for the current trial was one that was hoped that would lead to efficacy, without providing substantial additional toxicity over and above that caused by the paclitaxel. Third, the previous gabapentin CIPN treatment trial did use large drug doses (2700 mg/day) without reported benefit [7]. A third potential weakness might be that it was chosen to study weekly paclitaxel doses at 80 mg/m2/dose, as opposed to every 3-week dose of 175 mg/m2/dose. While each of these schedules result in similar CIPN toxicities, the lower individual doses cause substantially less P-APS symptoms [1, 2]. While it could be argued that studying the higher individual doses would have allowed a bigger opportunity for observing

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Fig. 4 EORTC CIPN20 selected individual item scores during treatment and over 6-month follow-up for tingling fingers/hands (a), tingling toes/ feet (b), numbness of fingers/hands (c), numbness of toes/feet (d)

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shooting/burning pain of fingers/hands (e), and shooting/burning pain of toes/feet (f). Higher scores represent fewer symptoms

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a beneficial result for the P-APS, the weekly dose was chosen for the following reasons: (1) The weekly paclitaxel dose is frequently used for adjuvant breast cancer therapy, given that a randomized trial supported that this schedule was more effective in this setting than an every 3-week dose schedule [22], and (2) it could be argued that the effect of an effective agent, such as was hoped with pregabalin, might be even more pronounced with a paclitaxel dose that caused less P-APS severity. In total, the data from this randomized placebo-controlled pilot study are unable to provide enough support to warrant the conduct of a more formal phase III clinical trial to test the efficacy of pregabalin for reducing or preventing symptoms of P-APS or paclitaxel-induced CIPN. In addition, the data from this trial provide further information that fails to support the value of gabapentinoids as an effective treatment of established CIPN. Such data may lead to subsequent guideline recommendations that do not support the use of gabapentinoids for treating CIPN.

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Acknowledgments This project was funded by Pfizer and conducted by the Academic and Community Research United (ACCRU) group. 15. Conflict of interest Pfizer funded this study but had no input into the writing of this manuscript. We have control of the primary data, which are available to the journal to review, if indicated. 16.

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