الصحة العامة

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Browsing الصحة العامة by Author "Mohammad Khalaf Ali Dweib"

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    Pharmacogenomic and Clinical Factors Associated with the Side Effects of Fluoropyrimidines in Palestinian Cancer Patients PHD
    (Al-Quds Univeersity, 2026-01-10) Mohammad Khalaf Ali Dweib; محمد خلف علي اذويب
    Introduction: Fluoropyrimidines (FPs), a cornerstone of modern chemotherapy, remain among the most prescribed and cost-effective anticancer drugs used around the world. Between 10% and 40% of patients have severe and probably fatal toxicity in the first cycles of FP treatment. Deficiency in dihydropyrimidine dehydrogenase (DPD), caused primarily by pathogenic mutations in the DPYD gene, leads to impaired clearance of FPs and results in excessive accumulation of their toxic metabolites. Testing for DPYD mutations before the beginning of treatment has become an internationally recommended strategy. Other factors such as age, gender and using other drugs were found to affect the prevalence of FP toxicity. Despite the well-proven benefit of pharmacogenomic testing, many countries are still under-utilizing this testing due to many factors such as insufficient resources. Palestine represents the challenges faced by Low- and Middle-Income Countries (LMICs) in adopting pharmacogenomics in general. Aim: This study, through its comprehensive design, aimed to evaluate the importance of pharmacogenomic testing in improving the clinical outcomes of cancer patients in Palestine by exploring the knowledge of oncology specialists and cancer patients regarding pharmacogenomic testing and determining the relationship between DPYD mutations and other clinical factors and the occurrence of side effects of FP anticancer drugs. Methods: Study I was a cross-sectional study which utilized a survey distributed to oncologists, oncology residents, and clinical pharmacists across various hospitals in Palestine between February and May 2024. The questionnaire was adopted from a previous study conducted in Saudi Arabia and was slightly modified to suit the Palestinian context. Study II was also a cross-sectional study which utilized a survey distributed to cancer patients that were treated with chemotherapy at three outpatient oncology clinics in the West Bank, Palestine. The questionnaire was developed based on an extensive literature review of similar studies. In study III, DNA was extracted from blood samples of cancer patients that were using fluoropyrimidines using the salting-out method after using previously prepared standard buffers. Allele-specific Polymerase Chain Reaction (PCR) was performed in 25 µL reactions with appropriate master mix, primers, DNA template, and nuclease-free water. The DPYD activity score (AS) was calculated by assigning values to each allele (normal = 1, decreased function = 0.5, no function = 0) and summing both alleles. Clinical data and toxicity information were acquired through a standardized analysis of the patients' electronic health records (EHRs) by trained study team who were blinded to the group in which the patient was allocated. Severe adverse events comprised toxicities with a grade no less than 3 based on the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results: Study I – Healthcare Providers The questionnaire was completed by a total of 106 healthcare providers (HCPs), consisting of 57.5% specialist physicians, 27.4% clinical pharmacists, and 15.1% resident physicians. More than 70% of participants stated that they had never undergone formal training in pharmacogenomics during their career. Around 80% of participants indicated knowledge of the mutation linked to DPD deficiency and its consequences for FP toxicity. Fewer than 50% of participants indicated that they consistently or occasionally screen for DPD deficiency prior to prescribing FPs. Only 5.7% and 6.6% of participants, respectively, reported the existence of standardized DPD testing and the Palestinian Ministry of Health's promotion of DPD testing before prescribing FPs. About 60% of individuals experienced significant toxicity associated with FPs, a rate considerably higher than the global average of 10–30%. A statistically significant difference was found between HCPs working in private hospitals and those working in governmental institutions in terms of their perception of the influence of DPD testing in clinical practice (p<0.05). No significant differences were seen in awareness of the most important DPYD mutations between groups of different years of experience, designation, nor hospital type (p>0.05). Study II – Patients The study included 368 participants with an almost equal gender distribution (52.4% female, 47.6% male). Only 19.8% of participants had heard of pharmacogenomic testing, and less than 5% had undergone any pharmacogenomic test. One-third reported no understanding of the nature of this test. About 40% of participants believed that pharmacogenomic testing can help doctors choose the best treatment, while 44% trusted its accuracy. Less than half (42%) of participants indicated that they would undergo testing if it was recommended by their physician. More than half of the participants (53%) were willing to pay for the test but 5.4% indicated that patients themselves should be responsible for paying for the test, with a mean WTP of around 230 NIS and a perceived reasonable cost of about 1307 NIS. Most of participants (74%) were willing to provide a blood sample for the test. Study III – Genetic and Clinical Data The study included 134 participants. A high number (85.1%) of participants were found to be normal metabolizers (AS: 2), while 13.4% were intermediate metabolizers (AS: 1–1.5), and 1.5% were poor metabolizers (AS: 0-0.5). The incidence of grade ≥3 side effects in the sample was 17.2%. Hand-foot syndrome and severe fatigue were the most common side effects. All patients who were poor metabolizers experienced side effects, compared to one third (33.3%) of the intermediate metabolizers and 13.2% of the normal metabolizers (p<0.05). Among mutation carriers treated without dose adjustment, 63.6% experienced side effects, while only 11.1% of mutation carriers with adjusted doses experienced side effects (p<0.05). Treatment was interrupted in 6.7% of the participants and completely discontinued in 7.5% of them. Hospitalization due to side effects and complications was reported in 9.7% of the cases. A statistically significant difference (p<0.05) was noted between patients who had a side effect and those who did not have a side effect among these clinical outcomes. Conclusion: These findings support the main hypothesis that DPYD mutations are connected to FP side effects and that genotype-based dosing can improve treatment safety. Palestinian patients demonstrated limited awareness, but moderate acceptance of the pharmacogenomic testing once given some information. Healthcare practitioners are generally well-informed about this important genetic component, nevertheless it is worrisome that fewer than 50% screen for DPD deficiency prior to prescribing. Routine DPYD testing and genotype-guided dosing could improve patient safety, reduce treatment interruption and hospitalization, and support precision oncology in Palestine.