Pharmacogenetics and Adverse Events in the Use of Fluoropyrimidine in a Cohort of Cancer Patients on Standard of Care Treatment in Zimbabwe.

Fluoropyrimidines are commonly used in the treatment of colorectal cancer. They are, however, associated with adverse events (AEs), of which gastrointestinal, myelosuppression and palmar-plantar erythrodysesthesia are the most common. Clinical guidelines are used for fluoropyrimidine dosing based on dihydropyrimidine dehydrogenase (DPYD) genetic polymorphism and have been shown to reduce these AEs in patients of European ancestry. This study aimed to evaluate, for the first time, the clinical applicability of these guidelines in a cohort of cancer patients on fluoropyrimidine standard of care treatment in Zimbabwe. DNA was extracted from whole blood and used for DPYD genotyping. Adverse events were monitored for six months using the Common Terminology Criteria for AEs (CTCAE) v.5.0. None of the 150 genotyped patients was a carrier of any of the pathogenic variants (DPYD*2A, DPYD*13, rs67376798, or rs75017182). However, severe AEs were high (36%) compared to those reported in the literature from other populations. There was a statistically significant association between BSA (p = 0.0074) and BMI (p = 0.0001) with severe global AEs. This study has shown the absence of the currently known actionable DPYD variants in the Zimbabwean cancer patient cohort. Therefore, the current pathogenic variants in the guidelines might not be feasible for all populations hence the call for modification of the current DPYD guidelines to include minority populations for the benefit of all diverse patients.

Cardiotoxicity and pharmacogenetics of doxorubicin in black Zimbabwean breast cancer patients.

AIMS: Doxorubicin-induced cardiotoxicity (DIC) is a significant cause of mortality in cancer care. This study was conducted to establish the frequency of DIC in Zimbabwean breast cancer patients on doxorubicin and to test the DIC predictive power of genetic biomarkers. METHODS: A cohort of 50 Zimbabwean breast cancer patients treated with doxorubicin were followed up for 12 months with serial echocardiography and genotyped for UGTA1A6*4, SLC28A3 and RARG. Eleven per cent of the patients experienced DIC. RESULTS: The frequencies of SLC28A3 (rs7853758), UGT1A6*4 (rs17863783) and RARG (rs2229774) were 60.7%, 17.9% and 14.3%, respectively. No association between DIC and the three variants was observed. CONCLUSIONS: This is the first study on the prevalence of DIC and associated genetic biomarker predictive evaluation in Zimbabwean breast cancer patients. The genetic frequencies observed in our study were different to those reported in other populations. A larger sample size with a longer follow-up time will be necessary in future studies.

Metabolic and cardiovascular disease risk for Zimbabwean men with prostate cancer receiving long-term androgen deprivation therapy.

Introduction: Prostate cancer is a leading cause of cancer-related mortality in the majority of sub-Saharan Africa region countries. Androgen deprivation therapy (ADT) is effective treatment, however ADT is associated with complications including metabolic syndrome and cardiovascular disease. Although cardiovascular disease is a leading cause of mortality among prostate cancer patients, there is limited information on ADT impact on metabolic syndrome and cardiovascular disease risk among Africans. An observational prospective cohort study was carried out in Harare, Zimbabwe. Prostate cancer patients due to be initiated on ADT (medical or surgical) were assessed for metabolic syndrome and a 10-year Atherosclerotic Cardiovascular Disease (ASCVD) 10-year risk probability score was done before ADT and followed up to 9 months. Results: 17 black Zimbabwean men were enrolled with a median age 72 years. Most participants (59%) had stage IV disease and 75% opted for surgical castration. At enrolment 23.5% had metabolic syndrome and this increased to 33% after 9 months of ADT. Baseline ASCVD risk was in the high risk category for 68.8% of participants and remained above 50% after 9 months of ADT. In this cohort, there is a 10% absolute increase in metabolic syndrome prevalence amongst African men with prostate cancer within 9 months of ADT initiation.

Working title: high dose rate intra-cavitary brachytherapy with cobalt 60 source for locally advanced cervical cancer: the Zimbabwean experience.

BACKGROUND AND PURPOSE: Cervical cancer is the fourth commonest cancer in women in the world with the highest regional incidence and mortality seen in Southern, Eastern and Western Africa. It is the commonest cause of cancer morbidity and mortality among Zimbabwean women. Most patients present with locally advanced disease that is no longer amenable to surgery. Definitive concurrent chemoradiation (CCRT), which is the use of external beam radiotherapy (EBRT) and weekly cisplatin, includes use of intracavitary brachytherapy, as the standard treatment. In the setting of this study, cobalt-60 (Co60)-based high dose rate brachytherapy (HDR-BT) has been in use since 2013. This study sought to review practices pertaining to use of brachytherapy in Zimbabwe, including timing with external beam radiotherapy, adverse effects and patient outcomes. METHODS: A retrospective analysis of data from records of patients with histologically confirmed cervical cancer treated with HDR-BT at the main radiotherapy centre in Zimbabwe from January 2013 to December 2014 was done. Outcome measures were local control, overall survival as well as gastro-intestinal and genito-urinary toxicity. RESULTS: A total of 226 patients were treated with HDR-BT during the study period, with a 97% treatment completion rate. All patients received between 45-50Gy of pelvic EBRT. Seventy-four percent received concurrent platinum-based chemotherapy. In 52% of the patients, HDR-BT was started when they were still receiving EBRT. The commonest fractionation schedule used was the 7Gy × 3 fractions, once a week (87%). Clinical complete tumour response was achieved in 75% at 6 weeks post treatment, 23% had partial response. Follow-up rates at 1 year and 2 years were 40 and 19% respectively. Disease free survival at 1 year and 2 years was 94 and 95% respectively. Vaginal stenosis was the commonest toxicity recorded, high incidence noted with increasing age. Four patients developed vesico-vaginal fistulae and two patients had rectovaginal fistulae. CONCLUSION: One hundred and seventeen patients patients started HDR-BT during EBRT course, with a treatment completion rate of 97%. The overall treatment duration was within 56 days in the majority of patients. Early local tumour control was similar for all the HDR-BT fractionation regimes used in the study, with a high rate (75%) of complete clinical response at 6 weeks post-treatment. Prospective studies to evaluate early and long-term outcomes of HDR-BT in our setting are recommended.