Nephroprotective Effect of Pentoxifylline Against Cisplatin in Patients With Head and Neck Cancer

Clinical Study Evaluating the Nephroprotective Effect of Pentoxifylline Against Cisplatin in Patients With Head and Neck Cancer

Head and neck squamous cell carcinoma (HNSCC) encompasses a variety of tumors originating in the lip, oral cavity, hypopharynx, oropharynx, nasopharynx and larynx. It is the sixth most common malignancy worldwide accounting for approximately 6% of all cancer cases (Rettig and D'Souza., 2015). HNSCC represents the third most common cause of cancer death worldwide. Platinum based regimens represent cornerstone in its treatment (Galbiattiet al., 2013).

Cisplatin (cis-diammine dichloroplatinum (II), CDDP) is an inorganic platinum-based chemotherapeutic agent that is widely used in treatment of various solid malignancies as head and neck, lung, testis, ovarian, and bladder cancers (Aparecida et al., 2012). The use of cisplatin is frequently limited by significant side effects including bone marrow suppression, peripheral neuropathy, ototoxicity, anaphylaxis and nephrotoxicity with the latter representing the main dose limiting one (Aparecida et al., 2012).

Acute kidney injury (AKI), distal renal tubular acidosis, renal concentrating defect, transient proteinuria, hyperuricemia, Fanconi-like syndrome, hypomagnesemia, hypocalcemia, renal salt wasting, erythropoietin deficiency, thrombotic microangiopathy, and chronic renal failure are among the renal side effects of cisplatin (Miller et al., 2010).Renal function deterioration is seen in 25% to 35% of patients treated with a single dose of cisplatin (Miller et al., 2010).Cisplatin-induced injury to renal epithelial cells results in the production of various inflammatory factors, including TNF-α. Cisplatin also increases ROS production, which leads to the activation of apoptosis and necrosis pathways (Miller et al., 2010).

Pentoxifylline (PTX), a nonspecific phosphodiesterase inhibitor, was first considered in the treatment of peripheral vascular diseases (Nasiri-Toosi et al., 2013). PTX has anti-inflammatory effects as it down regulates several pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1) and IL-6 (Mostafa-Hedeab et al., 2022). In addition, PTX has gained considerable interest as a reactive oxygen species (ROS) scavenger, and several studies show its potential antioxidant effects (Zhang et al., 2016). Several studies evaluate the renoprotective effects of PTX against drug-induced nephrotoxicity (Ramesh and Reeves, 2002; Kasap et al., 2013;Nasiri-Toosi et al.,2013; Panahi-Shokouh etal., 2020; Alorabi et al., 2022).

Study Overview

• Status: Not yet recruiting
• Conditions: Pentoxifylline, Cisplatin, Nephrotoxixcity
• Intervention / Treatment: Drug: cisplatin with standard hydration with normal saline; Drug: Pentoxifylline 400 mg SR tablets

• Study Type: Interventional
• Enrollment (Anticipated): 90
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Patient aged 18 years or more with head and neck cancer who will receive cisplatin for the first time.
2. Baseline estimated glomerular filtration rate (eGFR) ≥ 59 ml/min/1.73 m2.
3. Eastern Cooperative Oncology Group performance status (ECOG) < 2.

4. Patients with normal organic function as defined for the following criteria:

   • Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5 times the upper normal limit of the local laboratory ;
   • Total serum bilirubin ≤ 2.0 x ULN-LL;
   • Absolute neutrophil count ≥ 1,500 / mm3;
   • Platelet count ≥ 100,000 / mm3;
   • Hemoglobin ≥ 8.0 g / dl;
   • Serum creatinine ≤ 1.5 x ULN-LL

Exclusion criteria:

1. Pregnant or nursing women, or females intending pregnancy were all prohibited
2. Patients with concurrent other malignancy or history of other malignancy treated within the past 3 years.
3. Baseline estimated glomerular filtration rate (eGFR) < 59 ml/min/1.73 m2.
4. Alanine aminotransferase (ALT) > 3× times ULN.
5. Eastern Cooperative Oncology Group performance status (ECOG) ≥2.
6. Patients have Diabetes mellitus.
7. Patients have current participation in other protocols with experimental drugs.
8. Patients with no ability to ingest food orally.
9. Pentoxifylline hypersensitivity.
10. Use of other nephrotoxic drugs as aminoglycosides, non-steroidal anti-inflammatory drugs and contrast media.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group 1 as control group; cisplatin with standard hydration with normal saline	Drug: cisplatin with standard hydration with normal saline; chemotherapy
Active Comparator: Group two as Pentoxifylline; receive cisplatin with standard hydration with normal saline and Pentoxifylline 400 mg SR tablets twice daily for three cycles.	Drug: Pentoxifylline 400 mg SR tablets; a nonspecific phosphodiesterase inhibitor, was first considered in the treatment of peripheral vascular diseases

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
nephrotoxicity improvement as measured by CTACE version 5.0	up to 6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Kidney injury molecule 1 decrease serum level	up to 6 months

Collaborators and Investigators

• Sponsor: Tanta University

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2022
• Primary Completion (Anticipated): May 1, 2023
• Study Completion (Anticipated): June 1, 2023

Study Registration Dates

• First Submitted: November 30, 2022
• First Submitted That Met QC Criteria: November 30, 2022
• First Posted (Estimate): December 7, 2022

Study Record Updates

• Last Update Posted (Estimate): December 7, 2022
• Last Update Submitted That Met QC Criteria: November 30, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Antioxidants; Phosphodiesterase Inhibitors; Free Radical Scavengers; Radiation-Protective Agents; Pentoxifylline
• Other Study ID Numbers: PTX122022

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No