The Possible Protective Effect of Pentoxifylline Against Chemotherapy Induced Toxicities in Patients With Colorectal Cancer
Phase: EARLY_PHASE1
Conditions: Colo-rectal Cancer, Neuropathy;Peripheral, Mucositis
Sponsor: Tanta University

                                                                                               
 
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A Research Proposal for Partial Fulfillment of Master Degree of 
Pharmacy (Clinical Pharmacy)  
 
Proposal Title  
The Possible Protective Effect of Pentoxifylline against 
Chemotherapy Induced Toxicities in Patients with Colorectal 
Cancer  
  
Candidate  
Mostafa Tarek Ibrahim Aboelnoor  
B.Sc. Degree of Clinical Pharmacy (2017)  
Pharm D (2021) 
Faculty of Pharmacy - Tanta University  
  
Supervisors 
Prof. Sahar Mohammed El-Ghobashy El-Haggar 
Professor of Clinical Pharmacy 
Faculty of Pharmacy -Tanta University 
 
Prof. Tarek Mohammed Mohammed Mostafa 
Professor of Clinical Pharmacy 
Faculty of Pharmacy - Tanta University 
 
Dr. Fatma Gharib Mohammed Khair Allah 
Assistant Professor of Clinical Oncology 
Faculty of Medicine - Tanta University 
 
Document Date: October 12, 2022 
 

                                                                                               
 
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Introduction 
 
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in 
recent years, and the second leading cause of cancer death globally. In 2020, 
CRC accounts for 10% of global cancer incidence and 9.4% of cancer deaths, 
just lower than lung cancer. The global number of new CRC cases is predicted 
to reach 3.2 million in 2040 (1, 2). 
Oxaliplatin is a third-generation platinum-based chemotherapy drug that 
is considered a key drug in treatment of colorectal cancer (3).The most reported 
adverse effect of oxaliplatin is neurotoxicity. Oxaliplatin induces two forms of 
peripheral sensory neuropathy. The first is transient, acute neuropathy usually 
resolves spontaneously within days. The second form is chronic cumulative 
poorly reversible peripheral neuropathy that worsens with the repetition of 
chemotherapy cycles (4). 
Although a number of interventions have been implicated, none of them 
can be recommended for clinical use (5). This therapeutic failure reflects poor 
understanding of the real mechanism of oxaliplatin-induced neuropathy (6). 
However, oxidative stress is identified to be one of the main bio-molecular 
dysfunctions in this neuropathy (7). 
This oxidative stress can trigger inflammatory reaction which in turn  up-
regulates the expression of pro-inflammatory cytokines like tumor necrosis 
factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), which has 
been well demonstrated to play an important role in the establishment and 
maintenance of the spinal cord sensitization, resulting in hyperalgesia, and 
finally inducing neuropathic pain (8). Neurotensin (NT) is an endogenous 
neuropeptide involved in modulation of pain signal transmission and 
perception (9, 10). There is a significant increase in NT level in rats treated with 
oxaliplatin (11). 
Intestinal mucositis, or damage to the intestinal mucosa, is a major 
contributor to the reduced quality of life, decreased survival rates, and early 
onset of death observed in patients with certain chemotherapeutic agents (12). 
Citrulline is an amino acid mainly produced by enterocytes of the small bowel. 
Decreased levels of plasma citrulline are correlated with significant epithelial 
small bowel loss (13). 
 
 

                                                                                               
 
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Pentoxifylline (PTX), a xanthine derivative, has been shown to have a 
marked effect on cellular mediators of inflammation and tissue injury. It has 
been shown to inhibit TNF-α production, possibly via inhibition of TNFα and 
IL-1 mRNA transcription with relative preservation or even an increase of IL-
10, an anti-inflammatory cytokine (14, 15). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

                                                                                               
 
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Aim of the work 
 
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. 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

                                                                                               
 
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Patients and Methods 
 
- Study design and treatment protocol:  
This study will be a randomized placebo controlled parallel study. Forty-
eight eligible patients with stage II and stage III colorectal cancer will be 
scheduled to receive 12 cycles of folinic acid, flurouracil and oxaliplatin 
(FOLFOX6 regimen). Patients will be recruited from the Oncology Department, 
Tanta University Hospital, Tanta, Egypt. Staging will be done according to the 
American Joint Committee on Cancer 7th edition staging. The patients will be 
randomized using according to the days of hospital admission into two groups: 
Group I (control group; n=24) which will receive 12 cycles of FOLFOX-6 
regimen plus placebo tablets twice daily.   
 
The chemotherapy cycles will be received every 2 weeks and will be as 
follows:  
Day 1: Oxaliplatin 85 mg/m2 intravenous infusion in 250-500 mL 5% dextrose 
solution and leucovorin 400 mg/m2 intravenous infusion in 5% dextrose solution 
both were given over 120 minutes at the same time in separate bags using a Y-
line access, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 
2-4 minutes, followed by 5-fluorouracil 2400 mg/m2 intravenous infusion in 
1000 mL 0.9% SodiumChloride  solution as a 46-hour infusion.  
Additionally, Intravenous 5-HT3 antagonist plus pantoprazole will be 
administered to all participants before each cycle as prophylactic therapy against 
chemotherapy induced nausea, vomiting and mucositis. Furthermore, all 
participants will be submitted to complete blood count analysis before each 
chemotherapy cycle.    
 
Group II (Pentoxiphylline group; n=24) which will receive FOLFOX-6 
regimen in addition to pentoxifylline 400 mg twice daily. 
 
 
 
 
 
 
 

                                                                                               
 
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- 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.   
 
- 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.  
 

                                                                                               
 
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- 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 
 
- Measurements  
A. Demography, physical examination and anthropometric data  
Demographic data collection (age), medication history taking, physical 
examination and measurement of weight and height with subsequent calculation 
of body mass index according the following formula: BMI= [Weight (kg) 
÷Height2 (m)] will be done. Body surface area [Square root (weight "kg" X 
height "cm")/3600] and cumulative doses of chemotherapy will be also 
determined.    
 
B. Blood sample collection and biochemical assessment  
Before starting the first chemotherapy cycle (baseline) and after the last  
chemotherapy cycle, 5 ml of venous blood will be withdrawn by antecubital 
venipuncture from each participant between 8:30 and 10:30 am into plain test 
tube and centrifuged at 3000 rpm for 10 min. The separated sera will be frozen at 
-80°C until analysis of the biological parameters which include:   
- Malondialdehyde (MDA) as oxidative stress marker (colorimetery).  
- 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). 
  
 
 
 
 
 
 

                                                                                               
 
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C. Assessment of Chemotherapy induced toxicities  
I. Clinical assessment of oxaliplatin induced peripheral neuropathy  
Clinical assessment of oxaliplatin induced neuropathy will be done through:   
- The assessment of the severity of neuropathic pain through brief pain 
inventory short form "BPI-SF" worst item (16). Severity of neuropathic 
pain will be assessed 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 (17) at baseline and by the end of every two chemotherapy 
cycles.       
- The use of Neurotoxicity- 12 item questionnaire score (Ntx-12) from the 
validated Functional Assessment of Cancer Therapy/Gynecologic 
Oncology Group "FACT/GOG-Ntx-12" (18) at baseline and by the end of 
every two chemotherapy cycles).  
 
II. Clinical assessment of chemotherapy induced mucositis  
- 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" (17).  
 
D. 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" (17). 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.  
 
 
 
 
 
 

                                                                                               
 
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- 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 % (19, 20).  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. 
 
- Statistical analysis:  
- The collected data will be tabulated using Microsoft® Office Excel, 2019 
(Microsoft Corporation). 
- The statistical analysis will be carried out using SPSS statistical package 
version 26.0 (IBM corporation software group, USA). 
- Data will be tested for normality using Shapiro-Wilk test or Kolmogorov–
Smirnov test.  
- Parametric data will be analyzed using Paired and un-Paired t-test to 
compare the means within the same group and to compare the means of 
the two groups respectively.  
- Non- Parametric data will be analyzed using Mann Whitney U test to 
compare the means within the same group and to compare the means 
between groups. 
- Categorical data will be analyzed using Chi-Square test.  
- Fisher’s exact test will be used to analyses the reported adverse effects.  
- Correlation between variables will be assessed using Pearson or Spearman 
correlation coefficient which appropriate.  
- Data will be expressed as the mean ± SD, medians, range, number and 
percent as appropriate.  
- The significance level will be set at p ≤ 0.05.   

                                                                                               
 
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