Poor oral health and the risk of esophageal squamous cell carcinoma in Malawi.

Esophageal squamous cell carcinoma (ESCC) is the second most common cancer in Malawi. Risk factors for this cancer in Malawi are poorly understood. Poor oral health has previously been linked to increased ESCC risk in other high-incidence regions, including parts of Eastern and Southern Africa. We assessed the relationship between oral health and ESCC risk in a sex, age and location frequency-matched case-control study based at two hospitals in Lilongwe, Malawi from 2017 to 2020. Trained interviewers used a structured questionnaire and direct observation to collect data on demographics; behaviors; oral hygiene habits; the sum of decayed, missing or filled teeth (DMFT score); oral mucosa status; lip depigmentation and dental fluorosis via a visual scale. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI), adjusted for known and suspected ESCC risk factors. During the study period, 300 cases and 300 controls were enrolled. Subjects in the highest tertile of DMFT score (≥7) had an increased risk of ESCC with an adjusted OR of 1.96 (95% CI: 1.16-3.36) compared to those with a DMFT score of 0. Severe dental fluorosis was associated with a statistically nonsignificant increased risk of ESCC (adjusted OR = 2.24, 95% CI: 0.97-5.49) compared to individuals with no fluorosis. Associations with oral mucosa status, lip depigmentation and toothbrushing method and frequency were mostly null or uncertain. Poor oral health, indicated by a higher DMFT score, was associated with increased ESCC risk in Malawi. Dental fluorosis is another possible risk factor in this population, but further evaluation is necessary to clarify any effects of fluorosis on ESCC risk.

An international report on bacterial communities in esophageal squamous cell carcinoma.

The incidence of esophageal squamous cell carcinoma (ESCC) is disproportionately high in the eastern corridor of Africa and parts of Asia. Emerging research has identified a potential association between poor oral health and ESCC. One possible link between poor oral health and ESCC involves the alteration of the microbiome. We performed an integrated analysis of four independent sequencing efforts of ESCC tumors from patients from high- and low-incidence regions of the world. Using whole genome sequencing (WGS) and RNA sequencing (RNAseq) of ESCC tumors from 61 patients in Tanzania, we identified a community of bacteria, including members of the genera Fusobacterium, Selenomonas, Prevotella, Streptococcus, Porphyromonas, Veillonella and Campylobacter, present at high abundance in ESCC tumors. We then characterized the microbiome of 238 ESCC tumor specimens collected in two additional independent sequencing efforts consisting of patients from other high-ESCC incidence regions (Tanzania, Malawi, Kenya, Iran, China). This analysis revealed similar ESCC-associated bacterial communities in these cancers. Because these genera are traditionally considered members of the oral microbiota, we next explored whether there was a relationship between the synchronous saliva and tumor microbiomes of ESCC patients in Tanzania. Comparative analyses revealed that paired saliva and tumor microbiomes were significantly similar with a specific enrichment of Fusobacterium and Prevotella in the tumor microbiome. Together, these data indicate that cancer-associated oral bacteria are associated with ESCC tumors at the time of diagnosis and support a model in which oral bacteria are present in high abundance in both saliva and tumors of some ESCC patients.

Treatment outcomes of esophageal cancer in Eastern Africa: protocol of a multi-center, prospective, observational, open cohort study.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a major cause of cancer morbidity and mortality in Eastern Africa. The majority of patients with ESCC in Eastern Africa present with advanced disease at the time of diagnosis. Several palliative interventions for ESCC are currently in use within the region, including chemotherapy, radiation therapy with and without chemotherapy, and esophageal stenting with self-expandable metallic stents; however, the comparative effectiveness of these interventions in a low resource setting has yet to be examined. METHODS: This prospective, observational, multi-center, open cohort study aims to describe the therapeutic landscape of ESCC in Eastern Africa and investigate the outcomes of different treatment strategies within the region. The 4.5-year study will recruit at a total of six sites in Kenya, Malawi and Tanzania (Ocean Road Cancer Institute and Muhimbili National Hospital in Dar es Salaam, Tanzania; Kilimanjaro Christian Medical Center in Moshi, Tanzania; Tenwek Hospital in Bomet, Kenya; Moi Teaching and Referral Hospital in Eldoret, Kenya; and Kamuzu Central Hospital in Lilongwe, Malawi). Treatment outcomes that will be evaluated include overall survival, quality of life (QOL) and safety. All patients (≥18 years old) who present to participating sites with a histopathologically-confirmed or presumptive clinical diagnosis of ESCC based on endoscopy or barium swallow will be recruited to participate. Key clinical and treatment-related data including standardized QOL metrics will be collected at study enrollment, 1 month following treatment, 3 months following treatment, and thereafter at 3-month intervals until death. Vital status and QOL data will be collected through mobile phone outreach. DISCUSSION: This study will be the first study to prospectively compare ESCC treatment strategies in Eastern Africa, and the first to investigate QOL benefits associated with different treatments in sub-Saharan Africa. Findings from this study will help define optimal management strategies for ESCC in Eastern Africa and other resource-limited settings and will serve as a benchmark for future research. TRIAL REGISTRATION: This study was retrospectively registered with the ClinicalTrials.gov database on December 15, 2021,  NCT05177393 .

Mature outcomes and prognostic indices in diffuse large B-cell lymphoma in Malawi: a prospective cohort.

Outcomes for diffuse large B-cell lymphoma (DLBCL) in sub-Saharan Africa (SSA) are poorly described. We report mature data from one of the first prospective SSA cohorts. Patients aged ≥18 years with DLBCL were enrolled in Malawi 2013-2017. Participants were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy and concurrent antiretroviral therapy (ART) if positive for human immunodeficiency virus (HIV+). Eighty-six participants (mean age 47 years, standard deviation 13) were enrolled: 54 (63%) were male and 51 (59%) were HIV+, of whom 34 (67%) were on ART at DLBCL diagnosis. Median CD4 count was 0·113 cells × 109 /l (interquartile range [IQR] 0·062-0·227) and 25 (49%) had HIV viral load <400 copies/µl. Participants received median six cycles CHOP (IQR 4-6). No patients were lost to follow-up and the 2-year overall survival was 38% (95% confidence interval 28-49). In multivariable analyses, Eastern Cooperative Oncology Group performance status (PS) ≥2 and lactate dehydrogenase (LDH) >2× upper limit of normal (ULN) were associated with mortality. HIV status was not associated with mortality. A simplified prognostic model of LDH >2× ULN and PS ≥2 performed at least as well as the age-adjusted International Prognostic Index. DLBCL can be successfully treated in SSA and outcomes did not differ by HIV status. A simplified prognostic model prognosticates well and may be easier to use in resource-limited settings but requires validation.

Hodgkin lymphoma, HIV, and Epstein-Barr virus in Malawi: Longitudinal results from the Kamuzu Central Hospital Lymphoma study.

BACKGROUND: Contemporary descriptions of classical Hodgkin lymphoma (cHL) are lacking from sub-Saharan Africa where human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) are prevalent. METHODS: We describe a prospective cHL cohort in Malawi enrolled from 2013 to 2015. Patients received standardized treatment and evaluation, including HIV status and EBV testing of tumors and plasma. RESULTS: Among 31 patients with confirmed cHL, the median age was 19 years (range, 2-51 years) and 22 (71%) were male. Sixteen patients (52%) had stage III/IV, 25 (81%) B symptoms, and 16 (52%) performance status impairment. Twenty-three patients (74%) had symptoms >6 months, and 11 of 29 (38%) had received empiric antituberculosis treatment. Anemia was common with median hemoglobin 8.2 g/dL (range, 3.1-17.1 g/dL), which improved during treatment. No children and 5 of 15 adults (33%) were HIV+. All HIV+ patients were on antiretroviral therapy for a median 15 months (range, 2-137 months), with median CD4 count 138 cells/µL (range, 23-329 cells/µL) and four (80%) having undetectable HIV. EBV was present in 18 of 24 (75%) tumor specimens, including 14 of 20 (70%) HIV- and 4 of 4 (100%) HIV+. Baseline plasma EBV DNA was detected in 25 of 28 (89%) patients, with median viral load 4.7 (range, 2.0-6.7) log10 copies/mL, and subsequently declined in most patients. At 12 months, overall survival was 75% (95% confidence interval [CI], 55%-88%) and progression-free survival 65% (95% CI, 42%-81%). Baseline plasma EBV DNA and persistent viremia during treatment were associated with poorer outcomes. CONCLUSION: cHL in Malawi is characterized by delayed diagnosis and advanced disease. Most cases were EBV associated and one-third of adults were HIV+. Despite resource limitations, 12-month outcomes were good.

Outcomes for paediatric Burkitt lymphoma treated with anthracycline-based therapy in Malawi.

Burkitt lymphoma (BL) is the most common paediatric cancer in sub-Saharan Africa (SSA). Anthracyline-based treatment is standard in resource-rich settings, but has not been described in SSA. Children ≤18 years of age with newly diagnosed BL were prospectively enrolled from June 2013 to May 2015 in Malawi. Staging and supportive care were standardized, as was treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) for six cycles. Among 73 children with BL, median age was 9·2 years (interquartile range 7·7-11·8), 48 (66%) were male and two were positive for human immunodeficiency virus. Twelve (16%) had stage I/II disease, 36 (49%) stage III and 25 (34%) stage IV. Grade 3/4 neutropenia occurred in 17 (25%), and grade 3/4 anaemia in 29 (42%) of 69 evaluable children. Eighteen-month overall survival was 29% (95% confidence interval [CI] 18-41%) overall. Mortality was associated with age >9 years [hazard ratio [HR] 2·13, 95% CI 1·15-3·94], female gender (HR 2·12, 95% CI 1·12-4·03), stage (HR 1·52 per unit, 95% CI 1·07-2·17), lactate dehydrogenase (HR 1·03 per 100 iu/l, 95% CI 1·01-1·05), albumin (HR 0·96 per g/l, 95% CI 0·93-0·99) and performance status (HR 0·78 per 10-point increase, 95% CI 0·69-0·89). CHOP did not improve outcomes in paediatric BL compared to less intensive regimens in Malawi.

Survival After Diagnosis of Esophageal Squamous Cell Carcinoma in Malawi.

PURPOSE: Esophageal cancer (EC) is the second most common cancer in Malawi, with esophageal squamous cell carcinoma (ESCC) representing >90% of all ECs. Despite significant morbidity and mortality, little is known about disease outcomes. In this study, we assess survival after ESCC diagnosis in Malawi. METHODS: We report on ESCC cases enrolled in a case-control study at Kamuzu Central Hospital in Lilongwe from August 2017 to April 2020. Suspected cases completed a questionnaire interview; provided blood, urine, and saliva specimens; and underwent a tumor biopsy for histologic confirmation. Cases were followed up by phone biweekly from enrollment to the study end date (December 31, 2020), date of death, or loss to follow-up. Survival was assessed using Kaplan-Meier analysis with the log-rank test. We also examined associations between treatment and ESCC mortality using Cox regression models. RESULTS: There were 300 patients with ESCC enrolled in this study, of whom 290 (97%) had known vital status at the end of follow-up and 10 (3%) were lost to follow-up. Among the 290 patients, 282 (97%) died during follow-up. The median age at enrollment was 55 years (IQR, 48-66), and the median time to death was 106 days (95% CI, 92 to 127). The 1-year, 2-year, and 3-year survival rates were 11% (95% CI, 8 to 15), 3% (95% CI, 1 to 6), and 0.9% (95% CI, 0.8 to 4), respectively. Palliative chemotherapy significantly improved the overall survival of patients with ESCC (Plog-rank = .038) and was significantly associated with reduced mortality (adjusted hazard ratio, 0.71 [95% CI, 0.51 to 0.99]). No significant association was observed between tobacco use, alcohol consumption, or HIV status and mortality. CONCLUSION: Survival after diagnosis of ESCC was poor in Malawi. Although palliative chemotherapy was associated with improved survival, prevention and earlier detection remain key priorities to improve ESCC mortality at a population level.

A Genomic Analysis of Esophageal Squamous Cell Carcinoma in Eastern Africa.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) comprises 90% of all esophageal cancer cases globally and is the most common histology in low-resource settings. Eastern Africa has a disproportionately high incidence of ESCC. METHODS: We describe the genomic profiles of 61 ESCC cases from Tanzania and compare them to profiles from an existing cohort of ESCC cases from Malawi. We also provide a comparison to ESCC tumors in The Cancer Genome Atlas (TCGA). RESULTS: We observed substantial transcriptional overlap with other squamous histologies via comparison with TCGA PanCan dataset. DNA analysis revealed known mutational patterns, both genome-wide as well as in genes known to be commonly mutated in ESCC. TP53 mutations were the most common somatic mutation in tumors from both Tanzania and Malawi but were detected at lower frequencies than previously reported in ESCC cases from other settings. In a combined analysis, two unique transcriptional clusters were identified: a proliferative/epithelial cluster and an invasive/migrative/mesenchymal cluster. Mutational signature analysis of the Tanzanian cohort revealed common signatures associated with aging and cytidine deaminase activity (APOBEC) and an absence of signature 29, which was previously reported in the Malawi cohort. CONCLUSIONS: This study defines the molecular characteristics of ESCC in Tanzania, and enriches the Eastern African dataset, with findings of overall similarities but also some heterogeneity across two unique sites. IMPACT: Despite a high burden of ESCC in Eastern Africa, investigations into the genomics in this region are nascent. This represents the largest comprehensive genomic analysis ESCC from sub-Saharan Africa to date.

Tobacco and other risk factors for esophageal squamous cell carcinoma in Lilongwe Malawi: Results from the Lilongwe esophageal cancer case: Control study.

OBJECTIVE: Esophageal cancer is the second commonest cancer in Malawi, and 95% of all cases are esophageal squamous cell carcinoma (ESCC). Very little is known about the epidemiology of ESCC in Malawi including risk factors. The main objective of the study was to evaluate and describe risk factors of ESCC in Malawi. METHODS: We conducted a case-control study from 2017 to 2020 at two hospitals in Lilongwe, Malawi and consenting adults were eligible for inclusion. Endoscopy was conducted on all cases and biopsies were obtained for histological confirmation. Controls were selected from patients or their guardians in orthopedic, dental and ophthalmology wards and they were frequency matched by sex, age, and region of origin to cases. An electronic structured questionnaire was delivered by a trained interviewer. Multivariate conditional logistic regression models were used to assess the associations between subject characteristics, habits, and medical history and risk of ESCC. RESULTS: During the study period, 300 cases and 300 controls were enrolled into the study. Median age of cases and controls was 56 years and 62% of the cases were male. Among cases, 30% were ever cigarette smokers as were 22% of controls. Smoking cigarettes had an adjusted odds ratio of 2.4 (95% CI 1.4-4.2 p = 0.003). HIV+ status was present in 11% of cases and 4% controls, which resulted in an adjusted odds ratio was 4.0 (95% CI 1.8-9.0 p = 0.001). Drinking hot tea was associated with an adjusted odd ratio of 2.9 (95% CI 1.3-6.3 p = 0.007). Mold on stored grain has an adjusted odd ratio of 1.6 (95% CI 1.1-2.5 p = 0.021). CONCLUSION: Reducing smoking cigarettes, consumption of scalding hot tea, and consumption of contaminated grain, could potentially help reduce the burden of ESCC in Malawi. Further investigation of the association between HIV status and ESCC are warranted.

Comparison of baseline lymphoma and HIV characteristics in Malawi before and after implementation of universal antiretroviral therapy.

Access to antiretroviral therapy (ART) led to epidemiological changes in human immunodeficiency virus (HIV) associated lymphoma in high-income countries such as reductions in diffuse large B-cell lymphoma (DLBCL) and stable or increased Hodgkin lymphoma (HL) and Burkitt lymphoma (BL). In 2016, Malawi implemented a universal ART (UART) policy, expanding ART eligibility to all persons living with HIV (PLWH). We compare the distribution of lymphoma subtypes and baseline HIV and prognostic characteristics for lymphoma patients in Malawi before and after implementation of UART. We enrolled patients with pathologically confirmed incident lymphoproliferative disorders into a observational clinical cohort. At diagnosis, a comprehensive clinicopathological evaluation was performed. Of 412 participants, 156 (38%) were pre-UART (2013-June 2016) and 256 (62%) post-UART (July 2016-2020). HIV prevalence was 50% in both groups. The most common pre-UART diagnoses were DLBCL [75 (48%)], low-grade non-Hodgkin lymphoma (NHL) [19 (12%)], HL [17 (11%)] and, BL [13 (8%)]. For post-UART they were DLBCL [111 (43%)], NHL [28 (11%)], BL [27 11%)] and, HL [20 (8%)]. Among PLWH, 44 (57%) pre-UART initiated ART prior to lymphoma diagnosis compared to 99 (78%) post-UART (p = 0.02). HIV-ribonucleic acid was suppressed <1000 copies/mL in 56% (33/59) pre-UART and 71% (73/103) post-UART (p = 0.05). CD4 T-cell counts were similar for both groups. We observed similar findings in the subset of participants with DLBCL. Overall, there were no significant changes in incident lymphoma subtypes (p = 0.61) after implementation of UART, but HIV was better controlled. Emerging trends bear monitoring and may have implications for prognosis and health system priority setting. Trial registration: ClinicalTrials.gov identifier: NCT02835911.

Clinical Characteristics and Outcomes of Acute Lymphoblastic Leukemia in Adolescents and Young Adults in Malawi.

PURPOSE: There are limited data on treatment and outcomes for acute lymphoblastic leukemia (ALL) among adolescents and young adults in sub-Saharan Africa. We describe a prospective observational cohort in Malawi. METHODS: Patients age 15-39 years with newly diagnosed ALL at Kamuzu Central Hospital, Malawi, were enrolled from 2013 to 2019; follow-up was censored on December 2020. ALL diagnosis was confirmed on-site using immunohistochemistry and telepathology consultation involving pathologists in Malawi and the United States. All but four patients were treated with a modified pediatric-inspired regimen (Cancer and Leukemia Group B 10403 protocol). Key modifications included omission of asparaginase and no dose escalation for methotrexate. RESULTS: Of 19 participants, the median age was 22 (range 15-36) years. Of the 15 patients who initiated treatment, 11 (73%) achieved remission after induction, one (7%) died during induction, two (13%) had refractory disease, and one (7%) absconded. No patients were lost to follow-up. Eventually, 10 of 11 patients (91%) with confirmed remission relapsed. The median duration of first remission was 10 (range 3-22) months. Twelve of 15 treated patients (80%) had died at the time of censoring. Among treated patients, the 12- and 24-month overall survival was 50% (95% CI, 23 to 72) and 17% (95% CI, 3 to 42), respectively. CNS involvement was associated with worse survival. CONCLUSION: It is possible to treat adolescents and young adults with ALL in low-resource settings using a low-cost, pediatric-inspired regimen; however, outcomes are poor. Both cost and limitations in supportive care infrastructure limit intensive cytotoxic approaches such as asparaginase. Patient-reported outcomes are needed to understand the quality of life and cost-effectiveness. Critically, innovative, leap-frog therapies, such as monoclonal or bispecific antibodies, and feasible economic models for resource-limited settings are urgently needed.

Implementation and Evaluation of Educational Videos to Improve Cancer Knowledge and Patient Empowerment.

PURPOSE: Low health literacy is a leading cause of treatment abandonment among patients receiving cancer care at Kamuzu Central Hospital (KCH) in Malawi. METHODS: We developed cancer educational videos featuring Malawian providers and played them in the KCH oncology clinic. The videos addressed cancer-related topics, including disease biology, common myths, diagnostic procedures, treatment, side effects, and survivorship. After 6 months of implementation, we compared results from 50 pre- and postintervention surveys to assess change in cancer knowledge and care experience. RESULTS: Both pre- and postintervention cancer knowledge were good: a median of nine questions were answered correctly of 11 in both assessments. Despite the intervention, most continued to incorrectly identify cancer as an infection (pre: n = 26, 52%; post: n = 25, 50%; P = 1.0), although improvements were observed in patients' knowledge of correct actions for fever at home (pre: n = 38, 76%; post: n = 43, 86%; P = .31). Care experiences were overall good. Postintervention results indicate that more patients felt always listened to by their providers (pre: n = 18, 36%; post: n = 29, 58%; P < .01). However, we also noted a higher rate of patient dissatisfaction of care as more patients felt that they could not understand chemotherapy counseling (pre: n = 11, 22%; post: n = 22, 44%; P < .01). Assessments of video satisfaction indicate that patients found the videos very helpful in terms of understanding their disease (n = 47, 96%) and side effects (n = 48, 98%) and felt empowered to speak up with their providers (n = 46, 96%). CONCLUSION: Standardized education materials for patients that can be feasibly implemented throughout sub-Saharan Africa are urgently needed. Cancer educational videos are a low-cost way to educate and empower patients with cancer in resource-constrained settings although in-person discussions remain a crucial part of care.

Esophageal Cancer in Tanzania: A Welcome Stimulus in Primary Prevention Research.

In this issue, Mmbaga and colleagues present results of a case-control study to investigate environmental and lifestyle risk factors for esophageal cancer in Tanzania, East Africa. The results contribute to the early stage of a growing evidence base aimed to inform primary prevention of a major poor prognosis cancer in East Africa. In this commentary, we first discuss considerations needed to evaluate causality of associations, a feature needed for primary prevention. There is a need for further studies across the African esophageal cancer corridor, for more refined exposure assessment and a careful consideration of potential epidemiologic biases within study designs for real-life situations in the setting. This study also forms a prime example of the broader research needs for cancer in low- and middle-income countries and in Sub-Saharan Africa, a setting with distinct and underresearched cancers and exposure patterns. While this etiologic research is challenging, it is an essential component of the ground-shot approach to global health research needed to inform primary prevention.See related article by Mmbaga et al., p. 305.

Comparison of best supportive care, CHOP, or R-CHOP for treatment of diffuse large B-cell lymphoma in Malawi: a cost-effectiveness analysis.

BACKGROUND: Cost-effectiveness data for cancer treatment are needed from sub-Saharan Africa, where diffuse large B-cell lymphoma (DLBCL) is a common, curable cancer. In high-income countries, the standard of care for DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemoimmunotherapy. Rituximab is often not available in sub-Saharan Africa due to perceived unaffordability, and treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) is common. We aimed to evaluate the cost-effectiveness of treatment in Malawi, comparing best supportive care, CHOP, or R-CHOP in patients with DLBCL. METHODS: For this cost-effectiveness analysis, we used published Malawi microcosting data, clinical data from a prospective cohort treated with CHOP, and clinical trial data evaluating R-CHOP. We used a decision-tree model to calculate costs per disability-adjusted life-year (DALY) averted from the health system perspective for the treatment of patients with DLBCL with best supportive care, CHOP, or R-CHOP, running the model on a per-patient basis and a Malawi population-level basis. We used the WHO definitions of cost-effective (three times the GDP per capita of the country) and extremely cost-effective (equal to the GDP per capita of the country) as willingness-to-pay thresholds for Malawi. FINDINGS: On a per-patient level, compared with best supportive care, CHOP was estimated to avert a mean 7·4 DALYs at an incremental cost of US$1384, for an incremental cost-effectiveness ratio (ICER) of $189 per DALY averted, which is substantially lower than the willingness-to-pay threshold (extremely cost-effective). Compared with CHOP, R-CHOP was estimated to avert 2·8 DALYs at an incremental cost of $3324, resulting in an ICER of $1204 per DALY averted, which is slightly higher than the cost-effective willingness-to-pay threshold. In probabilistic sensitivity analyses, CHOP remained cost-effective for DLBCL treatment in more than 99% of simulations, whereas R-CHOP was lower than the threshold in 46% of simulations. INTERPRETATION: We estimated CHOP to be cost-effective for DLBCL treatment in Malawi, and that the addition of rituximab might be cost-effective. Despite upfront costs, DLBCL treatment is probably a prudent investment relative to other accepted health interventions in sub-Saharan Africa. FUNDING: National Institutes of Health.

Gastrointestinal endoscopy capacity in Eastern Africa.

Background and study aims Limited evidence suggests that endoscopy capacity in sub-Saharan Africa is insufficient to meet the levels of gastrointestinal disease. We aimed to quantify the human and material resources for endoscopy services in eastern African countries, and to identify barriers to expanding endoscopy capacity. Patients and methods In partnership with national professional societies, digestive healthcare professionals in participating countries were invited to complete an online survey between August 2018 and August 2020. Results Of 344 digestive healthcare professionals in Ethiopia, Kenya, Malawi, and Zambia, 87 (25.3 %) completed the survey, reporting data for 91 healthcare facilities and identifying 20 additional facilities. Most respondents (73.6 %) perform endoscopy and 59.8 % perform at least one therapeutic modality. Facilities have a median of two functioning gastroscopes and one functioning colonoscope each. Overall endoscopy capacity, adjusted for non-response and additional facilities, includes 0.12 endoscopists, 0.12 gastroscopes, and 0.09 colonoscopes per 100,000 population in the participating countries. Adjusted maximum upper gastrointestinal and lower gastrointestinal endoscopic capacity were 106 and 45 procedures per 100,000 persons per year, respectively. These values are 1 % to 10 % of those reported from resource-rich countries. Most respondents identified a lack of endoscopic equipment, lack of trained endoscopists and costs as barriers to provision of endoscopy services. Conclusions Endoscopy capacity is severely limited in eastern sub-Saharan Africa, despite a high burden of gastrointestinal disease. Expanding capacity requires investment in additional human and material resources, and technological innovations that improve the cost and sustainability of endoscopic services.

Feasibility of upfront mobile money transfers for transportation reimbursement to promote retention among patients receiving lymphoma treatment in Malawi.

BACKGROUND: Cancer outcomes in sub-Saharan Africa (SSA) remain suboptimal, in part due to poor patient retention. Many patients travel long distances to receive care, and transportation costs are often prohibitively expensive. These are well-known and established causes of delayed treatment and care abandonment in Malawi and across SSA. METHODS: We sent visit reminder texts and offered upfront money to cover transportation costs through a mobile money transfer (MMT) platform to lymphoma patients enrolled in a prospective cohort in Malawi. The primary aim was to test the feasibility of upfront MMTs. RESULTS: We sent 1034 visit reminder texts to 189 participating patients. Of these texts, 614 (59%) were successfully delivered, with 536 (52%) responses. 320/536 (60%) MMTs were sent to interested patients and 312/320 (98%) came to their appointment on time. Of 189 total patients, 120 (63%) were reached via text and 84 (44%) received MMTs a median of three times (IQR 2-5). Median age of reachable patients was 41 (IQR 30-50), 75 (63%) were male, 62 (52%) were HIV+ and 79 (66%) resided outside of Lilongwe. CONCLUSION: MMTs were a feasible way to cover upfront transportation costs for patients reachable via text, however many of our patients were unreachable. Future studies exploring barriers to care, particularly among unreachable patients, may help improve the efficacy of MMT initiatives and guide retention strategies throughout SSA.

Improving Access to Self-Expanding Metal Stents for Patients With Esophageal Cancer in Eastern Africa: A Stepwise Implementation Strategy.

PURPOSE: The eastern corridor of Africa is affected by a high burden of esophageal cancer (EC), with > 90% of patients presenting with advanced disease. Self-expanding metal stents (SEMS) have been previously reported as safe and effective for palliation of malignant dysphagia in resource-limited settings; however, access is limited throughout Eastern Africa. METHODS: In response to demand for palliative interventions for patients with dysphagia because of EC, the African Esophageal Cancer Consortium (AfrECC) partnered with the Clinton Health Access Initiative to improve access to SEMS in Eastern Africa. We undertook a stepwise implementation approach to (1) identify barriers to SEMS access, (2) conduct a market analysis, (3) select an industry partner, (4) establish regulatory and procurement processes, (5) develop endoscopic training resources, (6) create a medical device registry, and (7) establish principles of accountability. RESULTS: Following an evaluation of market demand and potential SEMS manufacturers, Boston Scientific Corporation announced its commitment to launch an access program to provide esophageal SEMS to patients in Tanzania, Kenya, Malawi, and Zambia at a subsidized price. Parallel regulatory and procurement processes were established in each participating country. Endoscopy training courses were designed and conducted, using the Training-of-Trainers model. A device registry was created to centralize data for quality control and to monitor channels of SEMS distribution. Principles of accountability were developed to guide the sustainability of this endeavor. CONCLUSION: The AfrECC Stent Access Initiative is an example of a multisector partnership formed to provide an innovative solution to align regional needs with a supply chain for a high-priority medical device.

Safety and efficacy of rituximab in patients with diffuse large B-cell lymphoma in Malawi: a prospective, single-arm, non-randomised phase 1/2 clinical trial.

BACKGROUND: There are no clinical trials involving patients with diffuse large B-cell lymphoma (DLBCL) in sub-Saharan Africa since antiretroviral therapy (ART) for HIV became widely available in this region. We aimed to establish the safety and efficacy of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with DLBCL in Malawi. METHODS: This prospective, single-arm, non-randomised phase 1/2 clinical trial was done at Kamuzu Central Hospital Cancer Clinic (Lilongwe, Malawi). Eligible patients were adults (aged 18-60 years) with newly diagnosed DLBCL, an Eastern Cooperative Oncology Group performance status of 0-2, a CD4 count of 100 cells per µL or higher (if HIV-positive), measurable disease by physical examination, an absolute neutrophil count of 1000 × 109 cells per L or higher, a platelet count of 100 × 109 platelets per L or higher, a serum creatinine concentration of 132·60 µmol/L or less, a total bilirubin concentration of 34·21 µmol/L or less, a negative urine pregnancy test in women of childbearing potential, and no previous cytotoxic therapy. Pregnant or breastfeeding women, and individuals with CNS involvement from DLBCL, chronic hepatitis B infection (unless they were receiving tenofovir plus lamivudine), or any other comorbidities that would compromise the protocol objectives were excluded. Eligible patients received intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 (maximum 2 mg/m2), and oral prednisone 100 mg or an equivalent drug every 21 days for up to six cycles. HIV-positive patients received concurrent ART. The primary outcome was the proportion of patients with National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 or 4 non-haematological toxic effects or treatment-related deaths after six cycles of treatment. Secondary efficacy outcomes included the proportion of patients with a complete response after six cycles of treatment, and progression-free survival and overall survival at 12 months and 24 months. This trial is registered with ClinicalTrials.gov, NCT02660710. FINDINGS: Between Aug 1, 2016, and July 31, 2019, 76 patients were screened, of whom 37 were eligible for the study and received R-CHOP. The median age of patients was 44 years (IQR 39-49) and 16 (43%) were women. Of all 37 patients, 20 (54%) had stage III or IV DLBCL, and the age-adjusted international prognostic index was 2 or higher in 25 (68%) patients. 27 (73%) patients were HIV-positive, with a median CD4 count of 208 cells per µL (IQR 144-422), and 21 (78%) patients were receiving ART at enrolment. Patients completed a median of six cycles (IQR 4-6). Grade 3 or 4 non-haematological toxic effects were reported in 12 (32% [95% CI 19-49]) patients, the most common of which was infection (nine [24%] patients). Of 16 (43%) deaths, ten were due to progression of DLBCL, four were due to treatment-related complications, and two were due to other causes, yielding a treatment-related mortality of 11% (95% CI 4-26%). Grade 3 or 4 neutropenia was observed in 26 (70%) patients, and grade 3 or 4 anaemia was observed in 11 (29%) patients. A total of 22 (59%) patients had a complete response. Overall survival was 68% (95% CI 50-80) at 12 months and 55% (37-70) at 24 months, and progression-free survival was 59% (42-73) at 12 months and 53% (35-68) at 24 months. INTERPRETATION: R-CHOP could be feasible, safe, and efficacious in patients with DLBCL in Malawi. This is the first completed clinical trial on DLBCL focused on sub-Saharan African populations. Given the paucity of data on treatment of DLBCL from this region, these results could inform emerging cancer treatment programmes in sub-Saharan Africa. FUNDING: The University of North Carolina Lineberger Comprehensive Cancer Center.

Challenges of HIV Lymphoma Clinical Trials in Africa: Lessons From the AIDS Malignancy Consortium 068 Study.

The purpose of this article is to describe lessons from the first lymphoma clinical trial conducted by the AIDS Malignancy Consortium (AMC) in sub-Saharan Africa (SSA). AMC-068 was a randomized phase II comparison of intravenous versus oral chemotherapy for HIV-positive diffuse large B-cell lymphoma. Opening in 2016, AMC-068 planned to enroll 90 patients (45 per arm) in Kenya, Malawi, Uganda, and Zimbabwe over 24 months and follow patients for 24 months to assess overall survival. In 2018, the study closed after screening 42 patients but enrolling only 7. Challenges occurred during protocol development, pre-activation, and postactivation. During protocol development (2011-2012), major obstacles were limited baseline data to inform study design; lack of consensus among investigators and approving bodies regarding appropriateness of the oral regimen and need for randomized comparison with cyclophosphamide, doxorubicin, vincristine, and prednisone; and heterogeneity across sites in local standards for diagnosis, staging, and treatment. During pre-activation (2012-2016), challenges included unexpected length and layers of regulatory approval across multiple countries, need to upgrade pathology capacity at sites, need to augment existing chemotherapy infusion capacity at sites, and procurement issues for drugs and supplies. Finally, during postactivation (2016-2018), challenges included long delays between symptom onset and screening entry for many patients, leading to compromised performance status and organ function; other patient characteristics that frequently led to exclusion, including high tumor proliferative index or other pathologic features that were disallowed; and costs of routine diagnostic procedures often being borne by patients, which also contributed to pre-enrollment delays. Lessons from AMC-068 are being applied to the design and conduct of new AMC lymphoma trials in SSA, and the study has contributed to a strong operational foundation that will support innovative clinical trials in the future.