Evaluating the Effects of Duloxetine on oxaliplatin Induced Peripheral Neuropathy Prophylaxis in Gastrointestinal Cancer Patients, randomized double-blind placebo controlled clinical Trial

oxaliplatin is a key drug in gastrointestinal (GI) cancer treatment. Peripheral Neuropathy is a troublesome and dose-dependent adverse effect of oxaliplatin. It can occur in two distinct forms: acute and chronic. Its incidence is estimated about 65-98 percent, of which 22 percent needed to stop chemotherapy. In some cases peripheral neuropathy has a long lasting impact on patient’s quality of life. The purpose of this study is to evaluate the ecacy of duloxetine on the prevention of oxaliplatin induced peripheral neuropathy in GI cancer patients.


Abstract
Background oxaliplatin is a key drug in gastrointestinal (GI) cancer treatment. Peripheral Neuropathy is a troublesome and dose-dependent adverse effect of oxaliplatin. It can occur in two distinct forms: acute and chronic. Its incidence is estimated about 65-98 percent, of which 22 percent needed to stop chemotherapy. In some cases peripheral neuropathy has a long lasting impact on patient's quality of life. The purpose of this study is to evaluate the e cacy of duloxetine on the prevention of oxaliplatin induced peripheral neuropathy in GI cancer patients.

Methods
In this randomized and double blind study, which was conducted in a tertiary teaching hospital, eligible patients were divided in to two groups. Treatment group was received Duloxetine the day before chemotherapy regimen initiation with the dose of 30 mg/day for one week and then was titrated up to 60 mg/day until 12 weeks. One placebo capsule daily for one week then two capsules daily until 12 weeks was prescribed for placebo group. In every chemotherapy courses peripheral neuropathy was assessed by using NCI-CTCAE v4.03. Also chemotherapy related quality of life (QOL) at the baseline and 12 weeks was assessed by using FACT/GOG-NTX.

Results
Forty patients were randomized to the treatment and placebo group which were similar with chemotherapy regimen, type and stage of cancer. Data analysis of NCI-CTCAE showed duloxetine could prevent worsening of paresthesia more than placebo (P = 0.025) and patients in duloxetine group experience less peripheral sensory neuropathy (P = 0.001) than placebo. FACT/GOG-NTX analysis showed signi cant worsening of tingling and discomfort in hands (respectively P = 0.002, 0.001) and feet (respectively P = 0.017, 0.019), having pain in hands and feet (P = 0.001) and di culty breathing in cold temperature exposure (P = 0.023) in placebo compared with duloxetine group. In the other hand, duloxetine could not improve QOL (P = 0.06) and hadn't signi cant effects on Trouble feeling the shape of small objects in hand (P = 0.420) or Trouble buttoning buttons (P = 0.086).

Conclusion
Duloxetine can consider as a safe and effective medication for the prevention of oxaliplatin induced peripheral neuropathy in GI cancer. Nonetheless, more studies with larger population are needed. oxaliplatin is a third generation platinum compound which is considered as a key drug in gastrointestinal cancer treatment (1). One of the most common adverse effects of oxaliplatin is peripheral neuropathy which is abbreviated as oxaliplatin induced peripheral neuropathy (OIPN). Incidence of peripheral neuropathy due to oxaliplatin is high, according to one study the incidence rate of OIPN, when oxaliplatin was administrated 85-130 mg/m², was 65-98% (2). It can occur in two distinct forms: acute and chronic. The most important trigger of acute peripheral neuropathy is cold temperature exposure. Chronic peripheral neuropathy risk factors are various such as: cumulative dose, time of infusion, history of chemotherapy induced peripheral neuropathy (CIPN) in previous courses and chemotherapy regimen (3)(4)(5). Chronic peripheral neuropathy is so hard to treat and in some cases it is not a reversible side effect (2). Peripheral neuropathy symptoms include paresthesia, tingling and numbness in hands and feet, pain in lower extremities and di cult breath in cold temperature exposure (6,7). This adverse effect is so troublesome and has a negative impact on patient's Quality Of Life (QOL) (8). Duloxetine is a Serotonin, Norepinephrine Reuptake Inhibitor (SNRI drug) can impact on peripheral stimulants transmission because of its mechanism and also inhibits the activation of p38 phosphorylation, as a result, the activation and nuclear translocation of the NF-kB transcription factor is inhibited, reducing the in ammatory response and inhibiting nerve injury by regulating nerve growth factor (9,14). These two neurotransmitters have a key role on suppression of peripheral stimulants transmission which can affect the sensation of pain (10). Duloxetine got FDA (Food and Drug Administration) approve for bromyalgia, chronic muscle or joint pain and diabetic peripheral neuropathy treatment (11,12). In most study Duloxetine showed positive effect on treating CIPN but based on our evaluation there is not any study that focus on duloxetine prophylactic effect on OIPN (1-4).

Methods
This randomized and double blind study was performed in Taleghani teaching hospital, Tehran, Iran.
Patient's enrollment and follow up was started on July 2016 and nished in August 2018. This study was approved by Iranian Registry of Clinical Trials (IRCT20100127003210N15) and was con rmed by Ethics Committee of Shahid Beheshti University of Medical Sciences (IR.SBMU.PHNM.1395.418). Forty patients with Gastrointestinal cancer who are over 18 years old and assumed to receive rst chemotherapy course based on oxaliplatin (new case patients who never expose to chemotherapy agents) were randomized (strati ed by CIPN comorbid risk and chemotherapy regimen) to the treatment and placebo group.
Exclusion criteria include: uncontrolled hypertension (blood pressure more than 140/90 mmHg), ClCr < 30 ml/min, liver impairment (ALT or AST > 3 Upper Normal Limit), liver metastasis, pregnancy,major drug interaction with Duloxetine and history of allergy to Duloxetine. We considered comorbid illness (eg diabetes mellitus) as a potential confounder so we assigned equal number of these patients to each group.
Treatment group received Duloxetine the day before chemotherapy regimen initiation with the dose of 30 mg/day for one week and then was titrated up to 60 mg/day from second week until 12 weeks. One placebo capsule daily for one week then two capsules daily until 12 weeks was prescribed for placebo group.
The primary outcome was the 12 weeks change in paresthesia and neuropathy severity which was assessed under supervision of a neurologist using NCI-CTCAE (every chemotherapy course) and FACT/GOG-NTX (at baseline and the end of the study which means twelfth week). In this questionnaire patients scored their neuropathy parameter (numbness, tingling, discomfort in hand and feet, di culty hearing, joint pain and muscle cramp, buttoning buttons and having pain in extrimities and di culty breathing in cold temperature exposure). Secondary outcome was 12weeeks changes in CIPN related QOL which measured by FACT/GOG-NTX and FACT-C.
Due to the fact that these kind of parameters (paresthesia, numbness, pain and…) are subjective and strongly depend on the patient's pain tolerance threshold, so we decided to use an independent parameter named 12 weeks changes from baseline for determining the difference in patients neuropathy severity and QOL. Data analysis was done by IBM SPSS (version 24). Evaluation of data distribution was performed using the Shapiro-Wilk test. For analyzing categorical data, Chi² test and for quantitative and independent data, Mann-Whitney was chosen. The P-value ≤ 0.05 was considered to be signi cant.
According to table 1, there was no signi cant difference in gender, age, cancer type and stage, chemotherapy regimen and Para clinical parameters between 2 groups. At the baseline there was no signi cant difference in neuropathy condition between groups. The P-values for paresthesia (0.603), peripheral sensory neuropathy (0.637) and peripheral motor neuropathy (0.272) were more than 0.05.  (table 3). These parameters were signi cantly different in NTX1, NTX2, NTX3, NTX4, NTX10, NTX11 between two group with better result in duloxetine group.
According to the results of FACT-C questionnaire, which include physical, emotional, social, functional and some other concerns, duloxetine couldn't improve the QOL.  The current clinical trial had strength and limitation. Strength include focus on prophylaxis of neuropathy, patients were receiving a speci c regimen (taxan) and contains speci c cancer type. Also there was some limitation in our study such as patient's lake of cooperation because long follow up duration.

Conclusion
Regarding to this double blind, placebo-treatment and randomized clinical trial, duloxetine could be effective on oxaliplatin induced peripheral neuropathy prophylaxis. Duloxetine was more effective on sensory neuropathy symptoms and it could decrease severity of hands neuropathy better than feet. It could give relief on cold exposure neuropathy like lower extremities paresthesia or di cult breathing. All of the data analyzed during this study are included in this article.
Competing interest