Clinical Study Evaluating the Anticancer Effect of Pentoxiphylline in Patients With Metastatic Colorectal Cancer

The aim of this work is to assess the antitumor effect of Pentoxiphylline in patients with metastatic colorectal cancer receiving stomatal chemotherapy ± targeted therapy.

Colorectal cancer (CRC) ranks as the third most common cancer globally and second in terms of mortality. Although CRC incidence rates are higher in high-income compared with low-to-middle-income countries (LMICs), mortality is higher in LMICs. And although more than 90% of CRC cases are diagnosed in individuals over age 55, CRC incidence is rising in younger populations. For example, Egypt, Saudi Arabia, the Philippines, and Iran have CRC incidence rates in individuals under age 40 of 38%, 21%, 17%, and 15%-35%, respectively. This is compared with only 2%-8% of new cases in the U.S. and the European Union in individuals in this age bracket. Along with the high incidence rate of CRC in individuals under age 40 in Egypt, CRC is diagnosed at more advanced stages in these younger Egyptians. CRC survival is highly dependent upon the stage of disease at diagnosis and typically ranges from a 90% 5-year survival rate for cancers detected at the localized stage to 14% for individuals diagnosed with distant metastatic cancer.

Apoptosis may occur via two major interconnected pathways: the extrinsic or death receptor-mediated pathway, which is activated by the binding of specific ligands (such as FasL, TNF-α and TRAIL) to the receptors of cell surfaces; and the intrinsic or mitochondrial-mediated pathway, which is regulated through proteins of the Bcl-2 family and triggered either by the loss of growth factor signals or in response to genotoxic stress. Therefore the replication of cells with DNA damage is generally avoided because harmful genomic alterations typically induce the activation of apoptosis. It has been widely accepted that alterations in the physiologic response to DNA damage can facilitate the accumulation of oncogenic mutations; this accumulation may eventually lead to the development of neoplasia.

Angiogenesis is a complex process by which new blood vessels are formed from endothelial precursor. It is a critical step in cancer progression and is considered one of the hallmarks of cancer. This process is mediated through a group of ligands and receptors that work in tight regulation. A group of glycoproteins, including the VEGFs (VEGF-A, VEGF-B, VEGF-C, and VEGF-D) and the placental growth factor (PIGF), act as effectors of angiogenesis. These factors interact with three VEGF receptors (VEGFR- 1, VEGFR-2, and VEGFR-3) and two neuropilin co-receptors (NRP1 and NRP2). The VEGF-A gene consists of eight exons with splice variants forming different isoforms, namely, VEGFA121, VEGFA165, VEGFA189, and VEGFA209; VEGFA165 is the most biologically active of these isoforms \[14\]. The VEGFRs are tyrosine kinase receptors that are primarily located in the vascular endothelial cells. The binding of VEGF-A to VEGFR-2 is believed to be the most important activator of angiogenesis.

Pentoxifylline (PTX) is a methylxanthine derivative that is commercially available in the name of Trental. It is currently used for management of peripheral vascular diseases. Its postulated mechanism of action is thought to be mediated through reducing blood viscosity and enhancing RBCs flexibility. However, it has been shown that PTX also may potentially be used in the anticancer therapy.

The studies demonstrated the potential effects of pentoxifylline on angiogenesis inhibition. It can affect the release and function of some predominantly proangiogenic vascular endothelial growth factors. Specifically, the release of the VEGF family of pro-angiogenesis factors (notably VEGF-A and VEGF-C) \[16\]. Furthermore, the mechanism by which pentoxifylline inhibits angiogenesis may be through the inhibition of activation of STAT3 which contributes to tumor cell survival by regulating the expression of metastatic genes, MMPs, serine protease uPA and potent angiogenic genes.

In addition, PTX has also the ability to induce apoptosis and potentiate the apoptotic effects of chemotherapy in several cancer types, one major mechanism is through activation of the caspase-dependent apoptosis that is accompanied by a decrease in kappa B-alpha- phosphorylation and up-regulation of the pro-apoptotic genes Bax, Bad, Bak, and caspases- 3,

-8, and -9.

Eligibility Criteria:
Inclusion Criteria:

* Patients with histologically and/or radiologically confirmed diagnosis of metastatic colorectal carcinoma.
* Both genders.
* Age ≥ 18 years old, and ≤ 75 years old.
* Performance status 0-1 according to the Eastern Cooperative Oncology Group (ECOG).
* Patients with adequate hematologic parameters (white blood cell count

  ≥3000/mm3, granulocytes ≥1500/mm3, platelets ≥100,000/mm3, hemoglobin ≥ 8 gm/l).
* Patients with adequate renal functions (serum creatinine ≤1.5 mg/dL).
* Patients with adequate hepatic functions (bilirubin ≤1.5 mg/dL or albumin ≥3 g/dL).

Exclusion Criteria:

* Patients with active liver diseases (chronic viral hepatitis, autoimmune hepatitis, alcoholic hepatitis, Wilson's disease, hemochromatosis, or cirrhosis).
* Patients with brain metastasis.
* Patients with active infection.
* Patients on chronic use of corticosteroids.
* Patients receiving blood thinning agents(aspirin, clopidogrel, warfarin)
* Patients with other malignancy (synchronous, or metachronous)
* Prior exposure to neurotoxic drugs (oxaliplatin, cisplatin, vincristine, paclitaxel, or docetaxel, INH) for at least 6 months prior the study treatment.
* Evidence of pre-existing peripheral neuropathy resulting from another reason (diabetes, brain tumor, brain trauma, HCV, thyroid disorder).
* Patients with diabetes and other conditions that predispose to neuropathy as hypothyroidism, autoimmune diseases, hepatitis C.
* History of known allergy to oxaliplatin or other platinum agents.
* Patients with moderate and severe renal impairment (CrCl \<50 ml/min) or serum creatinine \>1.5 mg/dl.
* Pregnant and breastfeeding women.