Duloxetine for the Prevention of Oxaliplatin Induced Peripheral Neuropathy: A Randomized, Placebo-Controlled, Double-blind Clinical Trial

Peripheral neuropathy is a dose-limiting adverse effect of oxaliplatin. The aim of this study was to evaluate the efficacy and safety of duloxetine in the prevention of oxaliplatin-induced peripheral neuropathy (OIPN). Cancer patients receiving oxaliplatin based chemotherapy were randomized into two arms. Duloxetine 60 mg capsule was given in the first 14 days of each chemotherapy cycle to one arm and placebo was similarly given to another. We compared the two arms based on the incidence of neuropathy and the results of the nerve conduction study (NCS). Grade of complained neuropathy was recorded according to Common Terminology Criteria for Adverse Events (CTCAE). Thirty-two patients mostly rectal cancer (90.6%) were randomized to duloxetine and placebo arms. Highest grade of neuropathy in each cycle was not significantly different between the two groups. Six weeks after treatment incidence of neuropathy of any grade was 52.9 in duloxetine arm compared to 76.9% in placebo arm (P: 0.26). Patients in the duloxetine arm had a lower percentage of chemotherapy cycles (mean) in which they reported distal paresthesia (51% vs. 84%, P = 0.01) and throat discomfort (37% vs. 69%, P = 0.01). Results of NCS were mostly comparable between the two arms except for the velocity in two of the examined nerve which was significantly higher in duloxetine group. Duloxetine was safe and well-tolerated. Although a definite conclusion might be difficult to draw but administering duloxetine for 14 days in each chemotherapy cycle could not decrease the incidence of acute OIPN based on CTCAE grading system.


Introduction
Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a well-known side effect of chemotherapy affecting up to 48% of cancer patients who receive multiple chemotherapeutic agents [1]. By increasing the number of cancer survivors receiving chemotherapy, this complication represents a significant problem affecting physical, emotional, and cognitive functions in cancer survivors [2]. Chemotherapy agents with higher incidence of CIPN are platinum, taxanes, vinca alkaloids, and bortezomib [3].
Oxaliplatin is a third-generation platinum. OIPN remains a treatment-limiting factor and can be divided into two types of neuropathy, acute and chronic [4]. Acute OIPN is transient and occurs in the majority of patients (85-95%), but chronic OIPN can persist for months or years and occurs in 10-20% of patients. Chronic OIPN has been reported to be dose-dependent with severe symptoms occurring at the cumulative dose above 750-850 mg/m 2 [2,5]. Approximately two-thirds of patients will have symptoms 1-year post-treatment or beyond [1,6]. Typical presentations of OIPN are paresthesia (tingling) in hands and feet, coldinduced neuropathy, throat discomfort, and muscle cramps [7].
Several pharmacological agents such as amitriptyline, nortriptyline, and venlafaxine have been studied for treatment and prevention of CIPN with limited success. Duloxetine, a serotonin and norepinephrine (NE) reuptake inhibitor, is an antidepressant drug that has shown some efficacy in treating painful CIPN induced by oxaliplatin and paclitaxel [8,9]. The American Society of Clinical Oncology (ASCO) suggested duloxetine as the only treatment for CIPN (moderate recommendation) in 2020, while no agents was recommended for the prevention of CIPN [10,11].
Considering the efficacy of duloxetine in the treatment of CIPN, we aimed to evaluate prophylactic effect of duloxetine in CIPN in cancer patients receiving oxaliplatin based chemotherapy as well.

Study Design
This randomized double-blinded, placebo-controlled phase П clinical trial was performed in radiation oncology ward at the Iran cancer institute (Tehran University of medical sciences, Tehran, Iran) from December 2016 to March 2019. The study was registered in the Iranian registry of clinical trials (Trial registration code: IRCT20170211032494N2). This study was performed in line with the principles of the Declaration of Helsinki and approved by institutional review board and ethical committee.

Patients
Eligible patients were those with pathologically confirmed colorectal and esophageal cancer patients, aged 18-75, candidate for receiving CAPOX (capecitabine-oxaliplatin) regimen, and good performance status based on Eastern Cooperative Oncology Group (ECOG 0-1) performance scale. Exclusion criteria were history of prior therapy with oxaliplatin, previous cancer except non-metastatic nonmelanoma skin cancer, diabetes mellitus, any kind of neuropathy, chronic renal or liver disease, and concomitant medications that may cause (e.g., certain HIV drugs) or prevent neuropathy (e.g., venlafaxine). Informed consent in written format was obtained from all of the patients participating in the trial.

Chemotherapy Protocol
CAPOX regimen was given with standard dosage (capecitabine 1000 mg/m 2 BD and oxaliplatin 130 mg/m 2 ) every 21 days. Oxaliplatin was diluted in 500 ml of glucose 5% and was infused over 2 h.

Randomization and Intervention
We randomized the eligible patients into two arms using randomly assigned permuted blocks method. The intervention arm received duloxetine on the first 14 days of each chemotherapy cycle (first dose was given 1 h before chemotherapy administration). The Control arm received similarly appearing placebo capsules in the same manner. Duloxetine and placebo capsules were manufactured by the same pharmaceutical company. Neither the physicians nor the patients were aware of the type of drug.

Outcome Assessment
The primary objective of this study was to assess the incidence of acute oxaliplatin-induced neuropathy based on presence of symptoms and graded according to CTCAE4 (Common Terminology Criteria for Adverse Events version 4). The secondary objective was the incidence of objective neuropathy based on nerve conduction studies and the safety of duloxetine. For subjective evaluation of acute OIPN, patients were visited 1 day before and within 1 week after each oxaliplatin administration, and they were questioned by a physician about the presence of paresthesia of the hands and feet (distal paresthesia), cold dysesthesia or cold-induced neuropathy (touching cold or drinking cold liquid), and throat discomfort. Patients were also visited 6 weeks after the last course of chemotherapy for assessment of chronic OIPN. For objective evaluation, before initiating oxaliplatin (baseline), nerve conduction studies (NCS) was done for sensory (sural) and motor nerves (deep peroneal and tibial). This assessment was repeated 6 weeks after the completion of chemotherapy. All the NCS were carried out by one expert specialist to avoid inter-observer bias. To monitor the side effects of duloxetine, patients were also asked about the presence of fatigue, dizziness, somnolence, and other events.

Statistical Analysis
According to a previous pilot study [12] 63.3% improvement in subjective OIPN and 47.4% improvement in objective grade of OIPN were seen in patients who received duloxetine. Thus, considering the incidence of acute OIPN (about 90%) [5,10,13] with 80% power and 10% dropout rate, we needed a maximum 22 subjects in each arm. Analyses were conducted to compare the two arms in each cycle and also entirely. Relative frequency of neuropathy in each cycle was compared between the two arms using the chi-squared test. Independent sample t-test was conducted to compare proportion of chemotherapy cycles (mean) in which patients reported neuropathy. We opted the ANOVA for repeated measures to compare the NCS parameter, such as velocity before and after the intervention between arms. A P-value < 0.05 was considered statistically significant. Data were analyzed with SPSS for Windows version 21.0 (SPSS Inc., Chicago, IL).

Clinical Characteristics of Patient
Forty patients were assessed for eligibility. After the exclusion of 8 patients, 32 were considered for the intervention, 17 in the duloxetine arm and 15 in the placebo arm (Fig. 1).
The general characteristics of the patients were comparable in the two arms (Table 1). Median number of chemotherapy cycles was four. At baseline assessment, none of the patients complained of the paresthesia, throat discomfort, and cold-induced neuropathy. Diagnostic test results of amplitude and velocity in sural, deep peroneal and tibial nerves were comparable in the two arms as well (Supplementary data, Table 5).

Duloxetine Efficacy
Ninety percent of the patients (29 out of 32) suffered from at least one kind of acute OIPN symptoms such as distal paresthesia, throat discomfort, or cold dysesthesia in at least one chemotherapy cycle; only three patients did not complain of any symptoms of OIPN, all in duloxetine arm. In contrast, patient experiencing the most severe neurotoxicity (grade 2 in two out of three courses of chemotherapy) was in the placebo arm. The incidence of neuropathy was compared in each cycle and also entirely between the two arms. Frequency of patient-reported symptoms in almost all cycles was lower in the duloxetine arm compared to placebo arm, although the difference was not significant except for throat discomfort in cycle 4 ( Table 2). Grade of neuropathy based on CTCAE in each cycle and also 6 weeks after last cycle was not significantly different between the two arms ( Table 3). Percentage of chemotherapy cycles (mean) in which patients reported distal paresthesia (51 ± 25% vs. 84 ± 40%, P = 0.01) and throat discomfort was significantly lower in duloxetine arm compared to placebo arm (37 ± 32% Fig. 1 CONSORT diagram of the study vs. 69 ± 37%, P = 0.01) but there was no difference in the percentage of cycles in which patients reported cold-induced dysesthesia (64 ± 36% vs 79 ± 30%, P = 0.13) (Fig. 2).
Six weeks after last cycle of chemotherapy, sensory nerve action potentials (SNAPs) was higher in almost all the examined nerve in duloxetine arm compared to placebo but the difference was not statistically significant. NCV in the examined nerve was comparable between the two groups in the second NCS except in deep peroneal and tibial nerves which were significantly higher in duloxetine arm compared to placebo (Table 4).

Duloxetine Side Effects
Duloxetine was safe and it was tolerated well. None of the patients required a temporary or permanent discontinuation of duloxetine due to adverse effects. The most frequent side effects were nausea, somnolence, dry mouth, and dizziness which were not significantly different between the two arms ( Fig. 3). There were no events of grade 3 or 4 adverse effect.

Other Findings
After a median follow up of 30 months, 22 patients out of 32 were alive; 14 in duloxetine arm and 8 in placebo arm. Rate of neuropathy was 40.9% totally (all grade 1). Five patients in duloxetine arm (35.7%) and four patients in placebo arm (50%) suffered from long term OIPN. Most of long term neuropathy was in form of paresthesia in foot.
To the best of our knowledge this is the first randomized clinical trial to evaluate efficacy of duloxetine in the prevention of CIPN. In this study, duloxetine was ineffective for preventing acute OIPN based on CTCAE4 grading.
We found three clinical trials in which duloxetine were used for treating CIPN. The first one was a pilot study in 39 colorectal cancer patients suffering from CIPN. Duloxetine was effective and tolerable and the authors suggested that "In the future, it may play a role in effectively treating chronic OIPN" [12]. The second one was a high quality randomized clinical trial that led to 2014 American Society of Clinical Oncology's (ASCO) moderate recommendation  on duloxetine as the only drug for the treatment of CIPN. They evaluated 231 patients with CIPN (due to taxane or platinum) randomized to two groups of duloxetine (30 mg/ day in the first week and then continued by 60 mg/day) and placebo. They concluded that among patients with painful CIPN, duloxetine for 5 weeks resulted in a greater reduction in pain intensity compared to placebo [9]. The third study was held in Japan on 34 patients who had received oxaliplatin, paclitaxel, vincristine, or bortezomib. Duloxetine for 4 weeks, at the standard dose in Japan (20 mg/day for 1 week and then increased to 40 mg/day), was associated with improved neuropathy [25]. We planned to start duloxetine at the same dosage as the previous studies but since at the time of study, duloxetine capsule 30 mg was not easily available, we started with 60 mg/day of duloxetine. Acute OIPN occurred in 90 percent of the patients which is consistent with previous studies [5,10,13]. In this study, some objectives were improved and some were not. Interpretation of these results should be done cautiously. Relative frequency of distal paresthesia, throat discomfort, and cold induced neuropathy in each cycle was non-significantly reduced in duloxetine arm compared to placebo arm. Proportion of chemotherapy cycles (mean) in which patients reported symptoms of neuropathy was significantly lower in two out of three measured symptoms (distal paresthesia and throat discomfort) in duloxetine arm. The study did not detect an improvement in the clinician assessment of grade of neuropathy via CTCAE. Most of the patients in this study did not receive high cumulative doses of oxaliplatin (i.e., > 750-850 mg/ m 2 ), so the severity of OIPN in both groups was low (no grade 3 of neuropathy).
In terms of objective assessment, results of the nerve conduction velocity in the tibial and deep peroneal nerves were in favor of duloxetine efficacy. Reduction in sensory nerve action potential (SNAP) amplitudes is also an expected finding of chronic CIPN due to axonal injury, but we did not find significant difference in terms of SNAP amplitude between the two arms. In an interesting study, it was shown that the SNAP amplitude did not significantly change until after 21-24 weeks of oxaliplatin-based chemotherapy initiation (8/9 cycles of chemotherapy) while in our study, most of the patients were examined in < 21 weeks of chemotherapy initiation (4/5 cycles of chemotherapy), so inappropriate time interval or low oxaliplatin cumulative dose might have affected the results [26].
Adverse effects of duloxetine were tolerable. In contrast to previous studies which prescribed duloxetine continuously, we prescribed duloxetine intermittently (2 weeks on and 1 week off) which might explain lower rate of duloxetine discontinuation in this study. None of the patients experienced serotonin syndrome, which has been mentioned as a concern due to the potential interaction of duloxetine and other drugs that inhibit serotonin reuptake (i.e., Granisetron that was used as a premedication drug before chemotherapy) [27].
The most common cited mechanism of acute OIPN is related to the chelation of calcium by oxalate [28], but this is not relevant to the known mechanism of duloxetine effects. In a recent study, duloxetine was shown to be neuroprotective in OIPN, both in vitro and in vivo. Inhibiting the MAPK signaling and consequently preventing the NF-kB activation was considered as the duloxetine mechanism of action in one study [29]. In an animal research, anti-allodynia effect of duloxetine in OIPN was shown to be mediated by the spinal alpha1-adrenergic receptors [30]. Norepinephrine (NE) and serotonin inhibit the transmission of pain signals into Dorsal Root Ganglia (DRG) Placebo (n=15) [31]. Considering duloxetine effect on inhibition of NE and serotonin reuptake, it was thought to be useful for chronic neuropathy like diabetic peripheral neuropathy which may explains the potential efficacy of duloxetine in treating chronic CIPN as well.

Limitation
The findings of this study have to be seen in light of some limitations. The first one is not using validated questionnaire for OIPN assessment which decreases the scientific relevance of the measurement. The second one is not reaching the anticipated sample size and the small number of the patients which decreases the power of the study analysis. The third one is relatively short duration of chemotherapy administration in this trial, so that most of the patients did not receive a high cumulative dose of oxaliplatin. Finally, the study was monocentric.

Conclusion
It is challenging to determine whether this study did or did not indicate efficacy of duloxetine. Duloxetine could not decrease the incidence of acute OIPN based on CTCAE grading system, and on the other hand, some improvement was seen in the study's objectives in duloxetine arm.