Cancer in sub-Saharan Africa: a Lancet Oncology Commission.

In sub-Saharan Africa (SSA), urgent action is needed to curb a growing crisis in cancer incidence and mortality. Without rapid interventions, data estimates show a major increase in cancer mortality from 520 348 in 2020 to about 1 million deaths per year by 2030. Here, we detail the state of cancer in SSA, recommend key actions on the basis of analysis, and highlight case studies and successful models that can be emulated, adapted, or improved across the region to reduce the growing cancer crises. Recommended actions begin with the need to develop or update national cancer control plans in each country. Plans must include childhood cancer plans, managing comorbidities such as HIV and malnutrition, a reliable and predictable supply of medication, and the provision of psychosocial, supportive, and palliative care. Plans should also engage traditional, complementary, and alternative medical practices employed by more than 80% of SSA populations and pathways to reduce missed diagnoses and late referrals. More substantial investment is needed in developing cancer registries and cancer diagnostics for core cancer tests. We show that investments in, and increased adoption of, some approaches used during the COVID-19 pandemic, such as hypofractionated radiotherapy and telehealth, can substantially increase access to cancer care in Africa, accelerate cancer prevention and control efforts, increase survival, and save billions of US dollars over the next decade. The involvement of African First Ladies in cancer prevention efforts represents one practical approach that should be amplified across SSA. Moreover, investments in workforce training are crucial to prevent millions of avoidable deaths by 2030. We present a framework that can be used to strategically plan cancer research enhancement in SSA, with investments in research that can produce a return on investment and help drive policy and effective collaborations. Expansion of universal health coverage to incorporate cancer into essential benefits packages is also vital. Implementation of the recommended actions in this Commission will be crucial for reducing the growing cancer crises in SSA and achieving political commitments to the UN Sustainable Development Goals to reduce premature mortality from non-communicable diseases by a third by 2030.

Implementation research to accelerate scale-up of national screen and treat strategies towards the elimination of cervical cancer.

BACKGROUND: Cervical cancer is a significant public health problem, with 570,000 new cases and 300,000 deaths of women per year globally, mostly in low- and middle-income countries. In 2018 the WHO Director General made a call to action for the elimination of cervical cancer as a public health problem. MAIN BODY: New thinking on programmatic approaches to introduce emerging technologies and screening and treatment interventions of cervical precancer at scale is needed to achieve elimination goals. Implementation research (IR) is an important yet underused tool for facilitating scale-up of evidence-based screening and treatment interventions, as most research has focused on developing and evaluating new interventions. It is time for countries to define their specific IR needs to understand acceptability, feasibility, and cost-effectiveness of interventions as to design and ensure effective implementation, scale-up, and sustainability of evidence-based screening and treatment interventions. WHO convened an expert advisory group to identify priority IR questions for HPV-based screening and treatment interventions in population-based programmes. Several international organizations are supporting large scale introduction of screen-and-treat approaches in many countries, providing ideal platforms to evaluate different approaches and strategies in diverse national contexts. CONCLUSION: For reducing cervical cancer incidence and mortality, the readiness of health systems, the reach and effectiveness of new technologies and algorithms for increasing screening and treatment coverage, and the factors that support sustainability of these programmes need to be better understood. Answering these key IR questions could provide actionable guidance for countries seeking to implement the WHO Global Strategy towards cervical cancer elimination.

Performance of Xpert HPV on Self-collected Vaginal Samples for Cervical Cancer Screening Among Women in South Africa.

OBJECTIVES: Self-sampling may increase access to cervical cancer screening in low-resource settings. Using Xpert HPV, we compared test performance of self- and clinician-collected samples in HIV-positive and HIV-negative women in South Africa. MATERIALS AND METHODS: Three hundred thirty HIV-positive and 375 HIV-negative women in the screening group and 202 HIV-negative and 200 HIV-positive women in the referral group, aged 30-65 years, participated in the study. All women self-collected a vaginal sample, and then, a cervical sample was collected by a clinician (both tested using Xpert HPV), followed by colposcopic examination and collection of histologic specimens. RESULTS: There was good agreement between self- and clinician-collected samples for detection of any high-risk human papillomavirus (HPV, κ = 0.72 [95% CI = 0.669-0.771]). Prevalence of HPV and sensitivity of the test to detect cervical intraepithelial neoplasia 2+ was similar in self- and clinician-collected samples. Specificity was lower in self-collected than in clinician-collected samples in both HIV-negative (self: 77.5% [95% CI = 72.8-81.8] vs clinician: 86.9% [95% CI = 82.9-90.2]) and HIV-positive (self: 44.0% [95% CI = 38.0-50.1] vs clinician: 59.7% [95% CI = 53.6-65.6]) women. Restricting the definition of screen-positive to 3 of 5 channels on HPV Xpert improved specificity in both HIV-negative (self: 83.2% [95% CI = 78.8-87.0] vs clinician: 89.7% [95% CI = 86.1-92.7]) and HIV-positive (self: 54.2% [95% CI = 48.1-60.2] vs clinician: 67.4% [95% CI = 61.5-72.9]) women. CONCLUSIONS: The self-collected sample had good agreement with the clinician-collected sample for the detection of HPV, and restricting the HPV types may improve the specificity in HIV-positive women.

Cervical cancer.

Each year, more than half a million women are diagnosed with cervical cancer and the disease results in over 300 000 deaths worldwide. High-risk subtypes of the human papilloma virus (HPV) are the cause of the disease in most cases. The disease is largely preventable. Approximately 90% of cervical cancers occur in low-income and middle-income countries that lack organised screening and HPV vaccination programmes. In high-income countries, cervical cancer incidence and mortality have more than halved over the past 30 years since the introduction of formal screening programmes. Treatment depends on disease extent at diagnosis and locally available resources, and might involve radical hysterectomy or chemoradiation, or a combination of both. Conservative, fertility-preserving surgical procedures have become standard of care for women with low-risk, early-stage disease. Advances in radiotherapy technology, such as intensity-modulated radiotherapy, have resulted in less treatment-related toxicity for women with locally-advanced disease. For women with metastatic or recurrent disease, the overall prognosis remains poor; nevertheless, the incorporation of the anti-VEGF agent bevacizumab has been able to extend overall survival beyond 12 months. Preliminary results of novel immunotherapeutic approaches, similarly to other solid tumours, have shown promising results so far.

Interventions to close the divide for women with breast and cervical cancer between low-income and middle-income countries and high-income countries.

Breast and cervical cancers are the commonest cancers diagnosed in women living in low-income and middle-income countries (LMICs), where opportunities for prevention, early detection, or both, are few. Yet several cost-effective interventions could be used to reduce the burden of these two cancers in resource-limited environments. Population- wide vaccination against human papillomavirus (HPV) linked to cervical screening, at least once, for adult women has the potential to reduce the incidence of cervical cancer substantially. Strategies such as visual inspection with acetic acid and testing for oncogenic HPV types could make prevention of cervical cancer programmatically feasible. These two cancers need not be viewed as inevitably fatal, and can be cured, particularly if detected and treated at an early stage. Investing in the health of girls and women is an investment in the development of nations and their futures. Here we explore ways to lessen the divide between LMICs and high-income countries for breast and cervical cancers.

Costs, affordability, and feasibility of an essential package of cancer control interventions in low-income and middle-income countries: key messages from Disease Control Priorities, 3rd edition.

Investments in cancer control--prevention, detection, diagnosis, surgery, other treatment, and palliative care--are increasingly needed in low-income and particularly in middle-income countries, where most of the world's cancer deaths occur without treatment or palliation. To help countries expand locally appropriate services, Cancer (the third volume of nine in Disease Control Priorities, 3rd edition) developed an essential package of potentially cost-effective measures for countries to consider and adapt. Interventions included in the package are: prevention of tobacco-related cancer and virus-related liver and cervical cancers; diagnosis and treatment of early breast cancer, cervical cancer, and selected childhood cancers; and widespread availability of palliative care, including opioids. These interventions would cost an additional US$20 billion per year worldwide, constituting 3% of total public spending on health in low-income and middle-income countries. With implementation of an appropriately tailored package, most countries could substantially reduce suffering and premature death from cancer before 2030, with even greater improvements in later decades.

The time is now to implement HPV testing for primary screening in low resource settings.

Unacceptable disparities in cervical cancer between richer and poorer countries persist and serve as reminders of gross disparities in access to and quality of screening services. HPV testing is well-suited to address some of the barriers to implementing adequate screening programs in low resource settings. HPV testing has considerably better sensitivity than cytology providing the same extent of safety with fewer rounds of screening. New robust HPV testing platforms require little to no skill by laboratory workers and some can be used at the point-of-care. This allows for a round of screening to be accomplished in one or two visits, reducing costs and the inevitable attrition that occurs when women need to be recalled to obtain their results. HPV testing is ideal for incorporating into the new "screen-and-treat" approaches designed to overcome limitations of conventional, multi-visit, colposcopy-based approaches to screening. Visual inspection with acetic acid (VIA) is the screening test that has been used most widely in screen-and-treat programs to date but the performance characteristics of this test are poor. HPV-based screen-and-treat is more effective in reducing disease in the population and reduces over-treatment intrinsic to this approach. HPV testing can be adapted or combined with other molecular tests to improve treatment algorithms. Infrastructure established to support VIA-based screen-and-treat can effectively incorporate HPV testing. We are poised at a critical juncture in public health history to implement HPV testing as part of primary screening and thereby improve women's health in low resource settings.

Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial.

BACKGROUND: Despite preventive vaccines for oncogenic human papillomaviruses (HPVs), cervical intraepithelial neoplasia (CIN) is common, and current treatments are ablative and can lead to long-term reproductive morbidity. We assessed whether VGX-3100, synthetic plasmids targeting HPV-16 and HPV-18 E6 and E7 proteins, delivered by electroporation, would cause histopathological regression in women with CIN2/3. METHODS: Efficacy, safety, and immunogenicity of VGX-3100 were assessed in CIN2/3 associated with HPV-16 and HPV-18, in a randomised, double-blind, placebo-controlled phase 2b study. Patients from 36 academic and private gynaecology practices in seven countries were randomised (3:1) to receive 6 mg VGX-3100 or placebo (1 mL), given intramuscularly at 0, 4, and 12 weeks. Randomisation was stratified by age (<25 vs ≥25 years) and CIN2 versus CIN3 by computer-generated allocation sequence (block size 4). Funder and site personnel, participants, and pathologists were masked to treatment. The primary efficacy endpoint was regression to CIN1 or normal pathology 36 weeks after the first dose. Per-protocol and modified intention-to-treat analyses were based on patients receiving three doses without protocol violations, and on patients receiving at least one dose, respectively. The safety population included all patients who received at least one dose. The trial is registered at ClinicalTrials.gov (number NCT01304524) and EudraCT (number 2012-001334-33). FINDINGS: Between Oct 19, 2011, and July 30, 2013, 167 patients received either VGX-3100 (n=125) or placebo (n=42). In the per-protocol analysis 53 (49·5%) of 107 VGX-3100 recipients and 11 (30·6%) of 36 placebo recipients had histopathological regression (percentage point difference 19·0 [95% CI 1·4-36·6]; p=0·034). In the modified intention-to-treat analysis 55 (48·2%) of 114 VGX-3100 recipients and 12 (30·0%) of 40 placebo recipients had histopathological regression (percentage point difference 18·2 [95% CI 1·3-34·4]; p=0·034). Injection-site reactions occurred in most patients, but only erythema was significantly more common in the VGX-3100 group (98/125, 78·4%) than in the placebo group (24/42, 57·1%; percentage point difference 21·3 [95% CI 5·3-37·8]; p=0·007). INTERPRETATION: VGX-3100 is the first therapeutic vaccine to show efficacy against CIN2/3 associated with HPV-16 and HPV-18. VGX-3100 could present a non-surgical therapeutic option for CIN2/3, changing the treatment outlook for this common disease. FUNDING: Inovio Pharmaceuticals.

Sister Society Meeting on Global Education Development and Collaboration: Meeting Report.

OBJECTIVES: To identify common barriers to teaching and training and to identify strategies that would be useful in developing future training programs in gynecologic oncology in low- and middle- income countries. METHODS: There is a lack of overall strategy to meet the needs of education and training in gynecologic oncology in low- and middle- income countries, the leaderships of sister societies and global health volunteers met at the European Society of Gynecologic Oncology in October 23, 2015. The challenges of the training programs supported by gynecologic oncology societies, major universities and individual efforts were presented and discussed. Strategies to improve education and training were identified. RESULTS: Major challenges include language barriers, limited surgical equipment, inadequate internet access, lack of local support for sustainability in training programs, inadequate pathology and radiation oncology, finance and a global deficiency in identifying sites and personnel in partnering or developing training programs. The leaderships identified various key components including consultation with the local Ministry of Health, local educational institutions; inclusion of the program into existing local programs, a needs assessment, and the development of curriculum and regional centers of excellence. CONCLUSIONS: Proper preparation of training sites and trainers, the development of global curriculum, the establishment of centers of excellence, and the ability to measure outcomes are important to improve education and training in gynecologic oncology in low- and middle- income countries.

Performance of an Human Papillomavirus Test in Samples From Women With Histolopathologically Confirmed Invasive Cervical Cancer.

BACKGROUND: High-risk human papillomavirus (hrHPV) is now recognized as a single, necessary cause of cancer of the cervix. Although Pap tests have been central to cervical cancer screening programs for more than 50 years, tests that detect infection with these hrHPV genotypes are now being used increasingly in cervical cancer screening programs. OBJECTIVE: The aim of the study was to determine the sensitivity of an HPV test to detect cervical cancer. MATERIALS AND METHODS: Fifty successive cervical samples from women diagnosed with invasive cervical cancer were tested using a molecular HPV DNA test. Thereafter, the residual sample was further tested with a different HPV genotyping test (capable of detecting 27 low- and high-risk types of HPV) and a nucleic acid hybridization test (capable of detecting 13 high-risk types of HPV). RESULTS: Of the 50 women tested, the first HPV test was positive in 47 cases. Of the 3 negative cases, all were negative by second polymerase chain reaction-based test and 2 were negative by the nucleic acid hybridization test. Human immunodeficiency virus status was positive in 14 women, the majority of whom were positive for HPV 16 (n = 8) and 1 was HPV negative. Most women were diagnosed with having stage II cervical cancer or higher. CONCLUSIONS: With a sensitivity of 94% of the first HPV test, 6 of 100 cervical cancers will be missed if this was the only test used in a population screening program. The missed cancers were however all clinically detectable.

Relationship between female genital tract infections, mucosal interleukin-17 production and local T helper type 17 cells.

T helper type 17 (Th17) cells play an important role in immunity to fungal and bacterial pathogens, although their role in the female genital tract, where exposure to these pathogens is common, is not well understood. We investigated the relationship between female genital tract infections, cervicovaginal interleukin-17 (IL-17) concentrations and Th17 cell frequencies. Forty-two cytokines were measured in cervicovaginal lavages from HIV-uninfected and HIV-infected women. Frequencies of Th17 cells (CD3(+) CD4(+) IL-17a(+)) were evaluated in cervical cytobrushes and blood by flow cytometry. Women were screened for Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, Trichomonas vaginalis and herpes simplex virus 2 by PCR, and candidal infections and bacterial vaginosis by Gram stain. Women with bacterial sexually transmitted infections (STIs), specifically chlamydia and gonorrhoea, had higher genital IL-17 concentrations than women with no STI, whereas women with candidal pseudohyphae/spores had lower IL-17 concentrations compared with women without candidal infections. Viral STIs (herpes simplex virus 2 and HIV) were not associated with significant changes in genital IL-17 concentrations. Genital IL-17 concentrations correlated strongly with other inflammatory cytokines and growth factors. Although Th17 cells were depleted from blood during HIV infection, cervical Th17 cell frequencies were similar in HIV-uninfected and HIV-infected women. Cervical Th17 cell frequencies were also not associated with STIs or candida, although few women had a STI. These findings suggest that IL-17 production in the female genital tract is induced in response to bacterial but not viral STIs. Decreased IL-17 associated with candidal infections suggests that candida may actively suppress IL-17 production or women with dampened IL-17 responses may be more susceptible to candidal outgrowth.

Control of cancer of the cervix in low- and middle-income countries.

Cervical cancer is the fourth most common cancer among women globally but the second most common in Sub-Saharan Africa (SSA). The high burden of cervical cancer in developing countries reflects the absence of cervical cancer prevention programs. The majority of the incident cases and deaths from cervical cancer, greater than 85%, occur in developing countries, where resources for early detection and treatment are severely limited. Survival from cancer in Africa is very poor due to late presentation and lack of access to effective treatment. Radiation, chemotherapy, and surgical oncology are not available in many parts of SSA. It is estimated that by 2030 cancer will affect much larger numbers of people living in low- and middle-income countries. Very few, if any, are prepared for or have sufficient health care infrastructure to provide acceptable services. It is imperative that governments in low- and middle-income countries pay urgent attention to the problem by developing National Cancer Control Programs, which should include population-based registries and data collection systems that allow an accurate evaluation of the burden of disease and hence resources required to meet it.

Human papillomavirus prevalence and type distribution in invasive cervical cancer in sub-Saharan Africa.

In sub-Saharan Africa, invasive cervical cancer (ICC) incidence and mortality are among the highest in the world. This cross-sectional epidemiological study assessed human papillomavirus (HPV) prevalence and type distribution in women with ICC in Ghana, Nigeria, and South Africa. Cervical biopsy specimens were obtained from women aged ≥ 21 years with lesions clinically suggestive of ICC. Histopathological diagnosis of ICC was determined by light microscopy examination of hematoxylin and eosin stained sections of paraffin-embedded cervical specimens; samples with a confirmed histopathological diagnosis underwent HPV DNA testing by polymerase chain reaction. HPV-positive specimens were typed by reverse hybridization line probe assay. Between October 2007 and March 2010, cervical specimens from 659 women were collected (167 in Ghana, 192 in Nigeria and 300 in South Africa); 570 cases were histologically confirmed as ICC. The tumor type was identified in 551/570 women with ICC; squamous cell carcinoma was observed in 476/570 (83.5%) cases. The HPV-positivity rate in ICC cases was 90.4% (515/570). In ICC cases with single HPV infection (447/515 [86.8%]), the most commonly detected HPV types were HPV16 (51.2%), HPV18 (17.2%), HPV35 (8.7%), HPV45 (7.4%), HPV33 (4.0%) and HPV52 (2.2%). The prevalence of single and multiple HPV infections seemed higher among HIV-positive women and HPV type distribution appeared to differ according to tumor type and HIV status. In conclusion, HPV16, 18, 45 and 35 were the most common HPV types in sub-Saharan African women with ICC and HPV infections were more common in HIV-positive women.

Altered phenotype and function of NK cells infiltrating human papillomavirus (HPV)-associated genital warts during HIV infection.

HIV-infected individuals experience more persistent HPV infections and are less likely to resolve genital warts. This study compared phenotype and functions of NK and T cells from genital warts and blood from 67 women. We compared in vitro functional responses of NK and T cells by multiparametric flow cytometry. HIV+ women had significantly lower frequencies of CD4 T cells in warts (p = 0.001) and blood (p = 0.001). While the distribution of NK cell subsets was similar, HIV+ women tended to have lower frequencies of CD56(Dim) NK cells in both blood (p = 0.0001) and warts (p = 0.006) than HIV- women. Wart NK cells from HIV+ women expressed significantly lower CD107a and produced IFN-γ. HAART status was not associated with differences in NK cell functionality. We conclude that wart NK cells from HIV+ women have defects in their ability to degranulate and/or secrete IFN-γ, which may provide insights into why HIV+ women fail to spontaneously resolve genital warts.

Challenges and opportunities in cancer control in Africa: a perspective from the African Organisation for Research and Training in Cancer.

Sub-Saharan Africa has a disproportionate burden of disease and faces a major public-health challenge from non-communicable diseases. Although infectious diseases continue to afflict Africa, the proportion of the overall disease burden in sub-Saharan Africa attributable to cancer is rising. The region is predicted to have a greater than 85% increase in cancer burden by 2030. Approaches to minimise the burden of cancer in sub-Saharan Africa in the past few years have had little success because of low awareness of the cancer burden and a poor understanding of the potential for cancer prevention. Success will not be easy, and will need partnerships and bridges to be built across countries, economies, and professions. A strategic approach to cancer control in sub-Saharan Africa is needed to build on what works there and what is unique to the region. It should ideally be situated within strong, robust, and sustainable health-care systems that offer quality health care to all people, irrespective of their social or economic standing. However, to achieve this will need new leadership, critical thinking, investment, and understanding. We discuss the present situation in sub-Saharan Africa and propose ideas to advance cancer control in the region, including the areas of cancer awareness, advocacy, research, workforce, care, training, and funding.

Treatment of cancer in sub-Saharan Africa.

Cancer is rapidly becoming a public health crisis in low-income and middle-income countries. In sub-Saharan Africa, patients often present with advanced disease. Little health-care infrastructure exists, and few personnel are available for the care of patients. Surgeons are often central to cancer care in the region, since they can be the only physician a patient sees for diagnosis, treatment (including chemotherapy), and palliative care. Poor access to surgical care is a major impediment to cancer care in sub-Saharan Africa. Additional obstacles include the cost of oncological care, poor infrastructure, and the scarcity of medical oncologists, pathologists, radiation oncologists, and other health-care workers who are needed for cancer care. We describe treatment options for patients with cancer in sub-Saharan Africa, with a focus on the role of surgery in relation to medical and radiation oncology, and argue that surgery must be included in public health efforts to improve cancer care in the region.

HIV-specific T-cell responses detected in the genital tract of chronically HIV-infected women are largely monofunctional.

HIV-specific T cells that produce interferon-γ (IFN-γ) are present in the genital tract of HIV-infected women although these do not provide protection against genital HIV shedding. Because polyfunctional HIV-specific T cells have been implicated in better HIV control than those with a single function, this study aimed to investigate whether polyfunctional T cells were present at the female genital mucosa. Cervical cytobrush-derived T cells were obtained from chronically HIV-infected women and compared with blood. CD3(+) T cells from both compartments were expanded with Dynal anti-CD3/CD28 expander beads for 14 days and flow cytometry was used to evaluate four T-cell functions (CD107a, IFN-γ, tumour necrosis factor-α and macrophage inflammatory protein-1ß) from 16 women. The majority of Gag-specific T-cell responses in the female genital tract were monofunctional, although low frequencies of HIV Gag-specific polyfunctional CD8(+) T cells were detected at the cervix in 81·3% (13/16) of women. The ability of CD8(+) T cells at both the cervix and in blood to express CD107a and to exhibit polyfunctional responses (two or more functions) following Gag stimulation was inversely associated with plasma viral load and positively associated with blood CD4 counts, suggesting that clinical status impacted on the functionality of HIV-specific T cells at the mucosa, in a similar way to blood. HIV Gag-specific cervical T cells were largely monofunctional. Polyfunctional T cells were detected at the cervix in women with high blood CD4 count and low plasma viral load but these did not protect from HIV genital shedding.