Protective Effect of Pentoxifylline Against Chemotherapy Induced Toxicities in Patients With Colorectal Cancer

Study Overview
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Brief Summary
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This study aims to: - Evaluate the possible protective effect of pentoxifylline against oxaliplatin induced peripheral neuropathy and chemotherapy induced mucositis in patients with stage II and stage III colorectal cancer. This study will be a randomized placebo controlled parallel study.48 patients with colorectal cancer will be randomized to 2 groups: Group I (control group; n=24) which will receive 12 cycles of FOLFOX-6 regimen plus placebo tablets twice daily. Group II (Pentoxiphylline group; n=24) which will receive FOLFOX-6 regimen in addition to pentoxifylline 400 mg twice daily. Blood sample collection and biochemical assessment: Malondialdehyde (MDA) as oxidative stress marker (colorimetry). Tumor necrosis factor alfa (TNF-α) as pro inflammatory marker (ELISA). Neurotensin (NT) as a potential marker for neuropathic pain (ELISA). Citrulline as a biomarker for mucositis (ELISA). Clinical assessment of oxaliplatin induced neuropathy will be done through: The assessment of the severity of neuropathic pain through Brief Pain Inventory-Short Form at baseline and by the end of every two chemotherapy cycles. The implication of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 5, 2017) for grading of neuropathy every 2 cycles. The use of Neurotoxicity- 12 item questionnaire score (Ntx-12) from the validated Functional Assessment of Cancer Therapy/Gynecologic Oncology Group at baseline and by the end of every two chemotherapy cycles). Mucositis will be assessed at baseline and by the end of every two chemotherapy cycles through the use of common terminology criteria for adverse events CTCAE, version 5.00, 2017

Detailed Description
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This study aims to: - Evaluate the possible protective effect of pentoxifylline against oxaliplatin induced peripheral neuropathy and chemotherapy induced mucositis in patients with stage II and stage III colorectal cancer. This study will be a randomized placebo controlled parallel study.48 patients with colorectal cancer will be randomized to 2 groups: Group I (control group; n=24) which will receive 12 cycles of FOLFOX-6 regimen plus placebo tablets twice daily. Group II (Pentoxiphylline group; n=24) which will receive FOLFOX-6 regimen in addition to pentoxifylline 400 mg twice daily. Blood sample collection and biochemical assessment: Malondialdehyde (MDA) as oxidative stress marker (colorimetry). Tumor necrosis factor alfa (TNF-α) as pro inflammatory marker (ELISA). Neurotensin (NT) as a potential marker for neuropathic pain (ELISA). Citrulline as a biomarker for mucositis (ELISA). Clinical assessment of oxaliplatin induced neuropathy will be done through: The assessment of the severity of neuropathic pain through Brief Pain Inventory-Short Form at baseline and by the end of every two chemotherapy cycles. The implication of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 5, 2017) for grading of neuropathy every 2 cycles. The use of Neurotoxicity- 12 item questionnaire score (Ntx-12) from the validated Functional Assessment of Cancer Therapy/Gynecologic Oncology Group at baseline and by the end of every two chemotherapy cycles). Mucositis will be assessed at baseline and by the end of every two chemotherapy cycles through the use of common terminology criteria for adverse events CTCAE, version 5.00, 2017. Assessment of participants' adherence, side effects and tolerability Pentoxiphylline will be provided on biweekly basis and the participants' adherence will be assessed through counting the returned tablets. Participants will be followed-up by weekly telephone calls and direct meetings during chemotherapy cycles to assess their adherence and to report any drug related adverse effects. The adverse effects will be collected and graded according to the National Cancer Institute Common Terminology Criteria for Adverse events NCI-CTCAE; version 5, 2017. Participants will be considered non- adherent and excluded from the study if not consumed the provided tablets or lost the follow-up meeting at any time of intervention or changed regimen. The primary and secondary endpoints: The primary endpoint is the percentage of patients with peripheral sensory neuropathy grade ≥ 2, the variation of 12-item neurotoxicity questionnaire (Ntx- 12) total score and the variation in grades of mucositis. The secondary endpoint is the change in the serum concentrations of the measured biological markers. Sample size calculation: According to the results of previous studies, the total number of subjects required to detect the effect of neuro-protective drugs in patients received neuro- toxic chemotherapy was 41 patients with 5% significance, 80% statistical power and an attrition of 15 %. In this context, during the current study, a total sample size of 41 patients in both arms will be sufficient to detect the effect. Assuming that the attrition rate will be 15 %, the initial sample size will be 48 patients in both arms with 24 patients in each arm. Ethical approval: The study will be performed in accordance with the ethical standards of Helsinki declaration in 1964 and its later amendments. The study will be approved by the Research Ethics Committee of Tanta University. The study will be registered as a clinical trial at ClinicalTrials.gov. All participants will be informed about the benefits and risks of the study. Any unexpected risks that will appear during the course of the research will be clarified to the participants and to the ethical committee on time. The data of the enrolled patients will be confidential. All enrolled patients will give their written informed consents. The study will be conducted between October 2022 and October 2024.

Official Title
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The Possible Protective Effect of Pentoxifylline Against Chemotherapy Induced Toxicities in Patients With Colorectal Cancer

Conditions
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Colo-rectal Cancer, Neuropathy;Peripheral, Mucositis

Intervention / Treatment
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* Drug: Pentoxifylline
* Drug: Placebo
* Drug: FOLFOX-6 regimen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Patients with histologically confirmed diagnosis of stage II and stage III colorectal cancer. Patients who will be scheduled to receive FOLFOX-6 regimen. Patients with no contraindication to chemotherapy. Males and females aged ≥ 18 years old. Adequate baseline hematologic values (absolute neutrophilic count ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L and hemoglobin level ≥ 10 g/dl). Patients with adequate renal function (serum creatinine < 1.5 mg/dL and Creatinine clearance (ClCr) ˃ 45 mL/min). Patients with adequate liver function (serum bilirubin < 1.5 mg/dl). Patients with performance status < 2 according to Eastern Cooperative Oncology Group (ECOG) score. Exclusion Criteria: - Children < 18 years old. Prior exposure to neurotoxic chemotherapy (oxaliplatin, cisplatin, vincristine, paclitaxel, docetaxel or Isoniazid) for at least 6 months prior the study treatment. Evidence of pre-existing peripheral neuropathy resulting from another reason (diabetes, brain tumor or brain trauma). Patients with diabetes and other conditions that predispose to neuropathy as hypothyroidism, autoimmune diseases or hepatitis C. History of known allergy to oxaliplatin or other platinum agents. Patients with other inflammatory diseases (rheumatoid arthritis and ulcerative colitis) or stressful conditions (obesity class 2 and 3, smoking). Concomitant use of multivitamins (vitamins E, C and A), tricyclic antidepressants or other neuro-protective medications (gabapentin, lamotrigine, carbamazepine and phenytoin, etc...). Concurrent active cancer originating from a primary site other than colon or rectum. Patients on blood thinning agents Pregnant and breastfeeding women

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Group 1 placebo<br>n=24 which will receive 12 cycles of FOLFOX-6 regimen plus placebo tablets twice daily. | Drug: Placebo<br>* placebo tablets<br>Drug: FOLFOX-6 regimen<br>* 12 cycles of FOLFOX-6 regimen<br>* Other names: Oxaliplatin, Fluorouracil, calcium leucovorin;|
| Active Comparator: Group 2 pentoxifylline<br>n=24 which will receive FOLFOX-6 regimen in addition to pentoxifylline 400 mg twice daily. | Drug: Pentoxifylline<br>* Pentoxifylline is a potent anti inflammatory may prevent chemotherapy induced neuropathy and mucositis and will be administered 400mg twice daily<br>* Other names: Trental;Drug: FOLFOX-6 regimen<br>* 12 cycles of FOLFOX-6 regimen<br>* Other names: Oxaliplatin, Fluorouracil, calcium leucovorin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| percentage of patients with peripheral sensory neuropathy grade ≥ 2 | Grading according to National Cancer Institute Common Terminology. there are 5 grades; Grade (1) is asymptomatic may be accompanied by loss of tendon reflex or paresthesia. Grade (2) is moderate symptoms which limit instrumental activities of daily life Grade (3) is severe symptoms which limit self-care activates of daily life. Grade (4) is life threatening consequences or urgent intervention indicated. Grade (5) is death. Criteria for Adverse Events (NCI-CTCAE, Version 5, 2017) | 6 months | 
| variation of 12-item neurotoxicity questionnaire (Ntx- 12) total score | the Ntx-12 questionnaire is comprised of 12 statements intended to measure the severity and impact of peripheral sensory neuropathy on patients' lives. Patients will be instructed to complete the Arabic version of the Ntx-12 and choose the number corresponding to how true each statement was for them using a likert-type scale, with 0 indicating not at all; 1, a little bit; 2, somewhat; 3, quite a bit; and 4, very much | 6 months | 
| variation in grades of mucositis | Mucositis will be assessed through the use of common terminology criteria for adverse events CTCAE, version 5.00, 2017. Grade (1) is Asymptomatic or mild symptoms; intervention not indicated. Grade (2) is Moderate pain or ulcer that does not interfere with oral intake; modified diet indicated. Grade (3) is Severe pain, interfering with oral intake. Grade (4) is Life-threatening consequences; urgent intervention indicated. Grade (5) is Death. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the biological marker Malondialdehyde | Malondialdehyde (MDA) as oxidative stress marker will be measured using colorimetry | 6 months | 
| Change in the biological marker Tumor necrosis factor alfa | Tumor necrosis factor alfa (TNF-α) as pro inflammatory marker will be measured using ELISA will be measured using (ELISA). | 6 months | 
| Change in the biological marker Neurotensin | Neurotensin (NT) as a potential marker for neuropathic pain will be measured using ELISA | 6 months | 
| Change in the biological marker Citrulline | Citrulline as a biomarker for mucositis will be measured using ELISA | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal cancer, Neuropathy, Mucositis, Pentoxifylline, Chemotherapy, Toxicity