Delays in Cervical Cancer Treatment Initiation for Patients Living With or Without HIV in Botswana: An Observational Cohort Analysis (2015-2019).

PURPOSE: To assess delays in treatment initiation of chemoradiation or radiation alone for patients with advanced stage cervical cancer in Botswana. METHODS AND MATERIALS: Females with locally advanced cervical cancer (stages IB2-IVB) were prospectively enrolled in an observational cohort study from 2015 to 2019. We evaluated delays at 30, 60, 90, 120, 150, and 180 or greater days between the date of diagnosis and treatment initiation. Factors associated with overall survival were modeled with multivariable Cox proportional hazards regression (aHR). Associations between delays in cervical cancer treatment initiation were evaluated via univariable logistic regression. RESULTS: Among the 556 patients included (median age = 47.9 years), 386 (69.4%) were females living with HIV with a median CD4 count of 448.0 cells/µL (IQR, 283.0-647.5 cells/µL) at diagnosis. Most patients had stages 2 (38.1%) or 3 (34.5%) cervical cancer. Early-stage patients experienced longer delays in treatment initiation compared to late-stage patients (P = .033). Early-stage patients with delays ≥90 days and pathology diagnosis between 2016 and 2019 (aHR, 0.34; P < .001) versus <90 days had a decreased risk of mortality, and those with delays ≥90 days and pathology diagnosis before 2016 (aHR, 5.67; P = .022) versus <90 days had an increased risk of mortality. Late-stage patients with delays ≥120 days and pathology diagnosis between 2018 and 2019 (aHR, 1.98; P = .025) versus <120 days had an increased risk of mortality. Early-stage patients with pathology diagnosis between 2016 and 2019 (odds ratio, 2.32; P = .043) versus before 2016 were more likely to experience delays ≥90 days, and late-stage patients who traveled >100 km to the treatment facility (odds ratio, 2.83; P < .001) versus <100 km were more likely to experience delays ≥120 days. CONCLUSIONS: Delays in care are common in Botswana, particularly for those living farther from the treatment clinic and at advanced stages. This paper is among the first to show an association between treatment delays and worsened overall survival at advanced stages of cervical cancer, highlighting the need for interventions to help patients receive timely care in global settings.

Significance of HIV status in cervical cancer patients receiving curative chemoradiation therapy, definitive radiation alone, or palliative radiation in Botswana.

BACKGROUND: Cervical cancer associated with human papillomavirus has the highest cancer incidence and mortality for women in Botswana because of a high HIV prevalence and limited screening. This study investigates the significance of HIV on the overall survival (OS) of patients with locally advanced cervical cancer by various treatment categories (curative chemoradiation, definitive radiation [RT] alone, or palliative RT alone). METHODS: This study included patients diagnosed with cervical cancer between 2013 and 2020, prospectively enrolled in the Botswana Prospective Cancer Cohort. OS based on HIV status and completion of planned treatment regimen was estimated by the Kaplan-Meier method. Comparisons of 2-year OS by HIV status was performed by the log-rank test, univariate and multivariable Cox analyses adjusting for cancer stage, RT dose, number of chemotherapy cycles, and baseline hemoglobin levels. RESULTS: Of 1131 patients diagnosed with stage IB-IVB cervical cancer, 69.8% were women living with HIV (n = 789). For patients receiving curative chemoradiation, HIV status was not significantly associated with OS in unadjusted (p = .987) and adjusted (p = .578) analyses. For RT only treatment and definitive (high-dose) RT alone, HIV status was significantly associated with OS in unadjusted analysis (HR = 1.77, p = .002; HR = 1.95, p = .014), but not in adjusted analysis (p = .227, p = .73). For patients receiving palliative (low-dose) RT, HIV status was not associated with OS in unadjusted (p = .835) or adjusted analysis (p = .359). CONCLUSIONS: In Botswana, a resource-limited setting, HIV status had no significant effect on 2-year OS in patients with cervical cancer with well-managed HIV receiving chemoradiation, RT alone, or palliative RT. This demonstrates that patients living with HIV receiving antiretroviral treatment can receive clinically appropriate treatment with no evidence that HIV may lead to poorer outcomes.

Surgery of the primary tumor in patients with de novo metastatic breast cancer: a nationwide population-based retrospective cohort study in Belgium.

PURPOSE: We aimed to assess the impact of surgery of primary tumor in overall survival (OS) of women with de novo metastatic breast cancer. METHODS: Nationwide, population-based retrospective cohort study of women diagnosed with de novo metastatic breast cancer in Belgium, between Jan/2010-Dec/2014. Data was obtained from the Belgian Cancer Registry and administrative databases. "Surgery" group was defined by surgery of primary tumor up to nine months after diagnosis. We excluded women who did not receive systemic treatment or did not complete nine months follow-up after diagnosis. All the subsequent analyses reporting on overall survival and the stratified outcome analyses were performed based on this nine-month landmark cohort. OS was estimated using Kaplan-Meier method and compared using adjusted Cox proportional hazards models controlling for confounders with 95% confidence intervals (CI). We performed a stratified analysis according to surgery timing and a propensity score matching analysis. RESULTS: 1985 patients, 534 (26.9%) in the "Surgery" and 1451 (73.1%) in the "No Surgery" group. Patients undergoing surgery were younger (p < 0.001), had better performance status (PS) (p < 0.001), and higher proportion of HER2-positive and triple-negative breast cancer (p = 0.012). Median follow-up was 86.0 months (82.6-88.5). Median OS was 60.1 months (57.1-68.2) in the "Surgery" vs. 41.9 months (39.8-44.2) in the "No Surgery" group (adjusted HR 0.56; 0.49-0.64). OS was similar when surgery was performed upfront or after systemic treatment. Propensity score matching analysis confirmed the same findings. CONCLUSION: Among patients receiving systemic treatment for de novo metastatic breast cancer and surviving nine months or more, those who received surgery of the primary tumor within nine months of diagnosis have longer subsequent survival than those who did not.

Paclitaxel plus Eftilagimod Alpha, a Soluble LAG-3 Protein, in Metastatic, HR+ Breast Cancer: Results from AIPAC, a Randomized, Placebo Controlled Phase IIb Trial.

PURPOSE: Eftilagimod alpha (efti), a soluble lymphocyte activation gene (LAG-3) protein and MHC class II agonist, enhances innate and adaptive immunity. Active Immunotherapy PAClitaxel (AIPAC) evaluated safety and efficacy of efti plus paclitaxel in patients with predominantly endocrine-resistant, hormone receptor-positive, HER2-negative metastatic breast cancer (ET-resistant HR+ HER2- MBC). PATIENTS AND METHODS: Women with HR+ HER2- MBC were randomized 1:1 to weekly intravenous paclitaxel (80 mg/m2) and subcutaneous efti (30 mg) or placebo every 2 weeks for six 4-week cycles, then monthly subcutaneous efti (30 mg) or placebo maintenance. Primary endpoint was progression-free survival (PFS) by blinded independent central review. Secondary endpoints included overall survival (OS), safety/tolerability, pharmacokinetics/pharmacodynamics, and quality of life. Exploratory endpoints included cellular biomarkers. RESULTS: 114 patients received efti and 112 patients received placebo. Median age was 60 years (91.6% visceral disease, 84.1% ET-resistant, 44.2% with previous CDK4/6 inhibitor treatment). Median PFS at 7.3 months was similar for efti and placebo. Median OS was not significantly improved for efti (20.4 vs. 17.5 months; HR, 0.88; P = 0.197) but became significant for predefined exploratory subgroups. EORTC QLQC30-B23 global health status was sustained for efti but deteriorated for placebo. Efti increased absolute lymphocyte, monocyte and secondary target cell (CD4, CD8) counts, plasma IFNγ and CXCL10 levels. CONCLUSIONS: Although the primary endpoint, PFS, was not met, AIPAC confirmed expected pharmacodynamic effects and demonstrated excellent safety profile for efti. OS was not significantly improved globally (2.9-month difference), but was significantly improved in exploratory biomarker subgroups, warranting further studies to clarify efti's role in patients with ET-resistant HER2- MBC.

Breast cancer patient experiences in the Botswana health system: Is it time for patient navigators?

BACKGROUND: New models of care are required to support women with breast cancer due to rising incidence and mortality in sub-Saharan Africa (SSA). This study gives voice to the experiences of advanced-stage breast cancer patients in the Botswana healthcare system, to guide improved service provision and the potential utility of patient navigator (PN) programs. METHODS: focus group discussions (FGD) were conducted with advanced-stage breast cancer patients recruited from the oncology ward of the public Princess Marina Hospital located in Gaborone, Botswana. RESULTS: FGDs included 7 female breast cancer patients and their 7 caregivers (2 male and 5 females). Findings fell into the following themes: experiences with cancer diagnosis, experiences with treatment, roles of caregivers, information needs, views on cancer resources, and attitudes towards cancer research. The study identified several barriers across the cascade of care for breast cancer patients in the Botswana health system. These correspond to challenges with timely diagnosis and comprehensive management and highlight community level barriers to achieving the targets of the WHO Global Breast Cancer initiative (GBCI). CONCLUSION: The study findings suggest PN programs have the potential to bridge barriers identified in the Botswana healthcare system by improving communication, meeting information needs, providing emotional or practical support, and by addressing logistical barriers to cancer diagnosis and treatment in Botswana.

Benchmarking of the Cervical Cancer Care Cascade and Survival Outcomes After Radiation Treatment in a Low- and Middle-Income Country Setting.

PURPOSE: Timely radiation treatment (RT) is critical in cervical cancer treatment, but patients in low- and middle-income countries (LMICs) in sub-Saharan Africa often face barriers that delay care. Time to care was benchmarked in a multidisciplinary team (MDT) setting in Botswana. METHODS: Time intervals between steps in care were recorded for 230 patients reviewed at MDT between January 2016 and July 2018. Associations between RT delay and overall survival (OS) were evaluated using Kaplan-Meier curves and multivariable Cox proportional hazards models. RESULTS: For patients who received RT (n = 187; 81.3%), the median biopsy to pathology reporting interval was 25 (IQR, 19-36) days and was 57 (IQR, 28-68) days for patients who did not (P = .003). Intervals in care did not differ between patients who did and did not receive RT. Among treated patients, the uppermost quartile interval from pathology reporting to RT initiation was ≥111 days and that from RT simulation to initiation was ≥12 days. Among patients receiving a RT dose of ≥65 Gy (n = 100), the delay from RT simulation to initiation of >12 days was associated with worse median OS (2.0 v 4.6 years; P = .048); this association trended toward, although did not meet, statistical significance on multivariable analysis (hazard ratio, 2.35; 95% CI, 0.95 to 5.85; P = .07). CONCLUSION: The MDT-coordinated care model allows for systematic benchmarking of the patient treatment cascade. Barriers to timely treatment exist for this cohort in Botswana, and RT delay may be associated with OS of patients receiving curative treatment. Interventions to accelerate the timing of the radiation oncology care cascade may improve clinical outcomes in this LMIC setting.

Patterns of care and outcomes for endometrial and ovarian cancers in botswana 2015-2021.

Purpose: Endometrial and ovarian cancers are leading causes of cancer death among women. However, there is little data on these patients from low- and middle-income countries including Botswana, a country in sub-Saharan Africa. This study reports data on demographics, treatment, and outcomes for patients with endometrial and ovarian cancer in Botswana. Methods: This prospective cohort study included all prospectively enrolled patients with endometrial or ovarian cancer who presented to Princess Marina or Gaborone Private Hospital between May 2015 and May 2021. Demographic, treatment, and survival data were analyzed. Results: 99 patients with endometrial and 38 patients with ovarian cancer were included. Median age at diagnosis was 64 for patients with endometrial cancer and 57 for patients with ovarian cancer. Just over half of patients with endometrial cancer (52.6%) presented with FIGO stages I and II, whereas most patients with ovarian cancer (65.8%) presented with stages III and IV. 24.2% of patients with endometrial cancer received chemotherapy, 32.3% received radiotherapy, 74.7% received surgical treatment, and 16.2% received no treatment; of patients with ovarian cancer, 42.1% received chemotherapy, 2.6% received radiotherapy, 52.6% received surgical treatment, and 31.6% of patients received no treatment. 1-and 2-year overall survival probabilities were 76.9% and 59.7% for patients with endometrial cancer and 62.8% and 43.7% for patients with ovarian cancer, respectively. Conclusion: This study demonstrates that a large proportion of patients with ovarian and endometrial cancer in Botswana are diagnosed at an advanced stage, and many do not receive standard-of-care treatment. Further inquiry is required to characterize challenges to diagnosis and treatment of ovarian and endometrial cancers in Botswana.

Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer (OVHIPEC-1): final survival analysis of a randomised, controlled, phase 3 trial.

BACKGROUND: The OVHIPEC-1 trial previously showed that the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery resulted in improved progression-free and overall survival compared with cytoreductive surgery alone at 4·7 years of follow-up in patients with stage III epithelial ovarian cancer who were ineligible for primary cytoreduction. We report the final survival outcomes after 10 years of follow-up. METHODS: In this open-label, randomised, controlled, phase 3 trial, patients with primary epithelial stage III ovarian cancer were recruited at eight HIPEC centres in the Netherlands and Belgium. Patients were eligible if they were aged 18-76 years, had not progressed during at least three cycles of neoadjuvant carboplatin plus paclitaxel, had a WHO performance status score of 0-2, normal blood counts, and adequate renal function. Patients were randomly assigned (1:1) to undergo interval cytoreductive surgery without HIPEC (surgery group) or with HIPEC (100 mg/m2 cisplatin; surgery-plus-HIPEC group). Randomisation was done centrally by minimisation with a masked web-based allocation procedure at the time of surgery when residual disease smaller than 10 mm diameter was anticipated, and was stratified by institution, previous suboptimal cytoreductive surgery, and number of abdominal regions involved. The primary endpoint was progression-free survival and a secondary endpoint was overall survival, analysed in the intention-to-treat population (ie, all randomly assigned patients). This study is registered with ClinicalTrials.gov, NCT00426257, and is closed. FINDINGS: Between April 1, 2007, and April 30, 2016, 245 patients were enrolled and followed up for a median of 10·1 years (95% CI 8·4-12·9) in the surgery group (n=123) and 10·4 years (95% CI 9·5-13·3) in the surgery-plus-HIPEC group (n=122). Recurrence, progression, or death occurred in 114 (93%) patients in the surgery group (median progression-free survival 10·7 months [95% CI 9·6-12·0]) and 109 (89%) patients in the surgery-plus-HIPEC group (14·3 months [12·0-18·5]; hazard ratio [HR] 0·63 [95% CI 0·48-0·83], stratified log-rank p=0·0008). Death occurred in 108 (88%) patients in the surgery group (median overall survival 33·3 months [95% CI 29·0-39·1]) and 100 (82%) patients in the surgery-plus-HIPEC group (44·9 months [95% CI 38·6-55·1]; HR 0·70 [95% CI 0·53-0·92], stratified log-rank p=0·011). INTERPRETATION: These updated survival results confirm the long-term survival benefit of HIPEC in patients with primary stage III epithelial ovarian cancer undergoing interval cytoreductive surgery. FUNDING: Dutch Cancer Foundation (KWF Kankerbestrijding).

Molecular Results and Potential Biomarkers Identified from the Phase 3 MILO/ENGOT-ov11 Study of Binimetinib versus Physician Choice of Chemotherapy in Recurrent Low-Grade Serous Ovarian Cancer.

PURPOSE: We present the results of a post hoc tumor tissue analysis from the phase 3 MILO/ENGOT-ov11 study (NCT01849874). PATIENTS AND METHODS: Mutation/copy-number analysis was performed on tissue obtained pre-randomization. The Kaplan-Meier method was used to estimate progression-free survival (PFS). Unbiased univariate analysis, Cox regression, and binary logistic regression were used to test associations between mutation status and outcomes, including PFS and binary response by local RECIST 1.1. RESULTS: MILO/ENGOT-ov11 enrolled 341 patients, ranging in age from 22 to 79, from June, 2013 to April, 2016. Patients were randomized 2:1 to binimetinib or physician's choice of chemotherapy (PCC). The most commonly altered gene was KRAS (33%). In 135 patients treated with binimetinib with response rate (RR) data, other detected MAPK pathway alterations included: NRAS (n = 11, 8.1%), BRAF V600E (n = 8, 5.9%), RAF1 (n = 2, 1.5%), and NF1 (n = 7, 5.2%). In those with and without MAPK pathway alterations, the RRs with binimetinib were 41% and 13%, respectively. PFS was significantly longer in patients with, compared with those without, MAPK pathway alterations treated with binimetinib [HR, 0.5; 95% confidence interval (CI) 0.31-0.79]. There was a nonsignificant trend toward PFS improvement in PCC-treated patients with MAPK pathway alterations compared with those without (HR, 0.82; 95% CI, 0.43-1.59). CONCLUSIONS: Although this hypothesis-generating analysis is limited by multiple testing, higher RRs and longer PFS were seen in patients with low-grade serous ovarian cancer (LGSOC) treated with binimetinib, and to a lesser extent in those treated with PCC, who harbored MAPK pathway alterations. Somatic tumor testing should be routinely considered in patients with LGSOC and used as a future stratification factor.

A Multi-Institutional Study of Barriers to Cervical Cancer Care in Sub-Saharan Africa.

Purpose: The global rise in cancer incidence has been accompanied by disproportionately high morbidity and mortality rates in low- and middle-income countries. Many patients who are offered potentially curative treatment for cervical cancer in low- and middle-income countries never return to start treatment for reasons that are poorly documented and little understood. We investigated the interplay of sociodemographic, financial, and geographic factors as barriers to care among such patients in Botswana and Zimbabwe. Methods and Materials: Patients seen in consultation between 2019 and 2021 who were >3 months late for an appointment to initiate definitive treatment were contacted via telephone and invited to complete a survey. Afterward, an intervention connected patients with resources and counseling to return for treatment. Follow-up data were collected 3 months later to ascertain the outcomes of the intervention. Fisher exact tests analyzed the relationship between the putative number and types of barriers and demographics. Results: We recruited 40 women who initially presented for oncology care but did not return for treatment at [Princess Marina Hospital] in Botswana (n = 20) and [Parirenyatwa General Hospital] in Zimbabwe (n = 20) to complete the survey. Overall, married women experienced more barriers than unmarried women (P < .001), and unemployed women were 10 times more likely to report a financial barrier than employed women (P = .02). In Zimbabwe, financial barriers and belief-associated barriers (eg, fear of treatment) were reported. In Botswana, many patients noted scheduling obstacles associated with administrative delays and COVID-19. At follow-up, 16 Botswana patients and 4 Zimbabwe patients had returned for treatment. Conclusions: Financial and belief barriers identified in Zimbabwe showcase the importance of targeting cost and health literacy to reduce apprehensions. In Botswana, administrative challenges could be addressed with patient navigation. Improving our understanding of the specific barriers to cancer care could enable us to help patients who might otherwise default.

Analysis of Cancer Research Projects in Sub-Saharan Africa: A Quantitative Perspective on Unmet Needs and Opportunities.

PURPOSE: To evaluate the scope and types of cancer research projects in sub-Saharan Africa (SSA) to identify research gaps and inform future efforts. METHODS: This retrospective observational study summarized information on cancer research projects in SSA from the International Cancer Research Partnership (ICRP) between 2015 and 2020, alongside 2020 cancer incidence and mortality data from the Global Cancer Observatory. SSA cancer research projects were identified as led by investigators in SSA countries, or by investigators in non-SSA countries with collaborators in SSA, or in database keyword searches. Projects from the Coalition for Implementation Research in Global Oncology (CIRGO) were also summarized. RESULTS: A total of 1,846 projects were identified from the ICRP database, funded by 34 organizations in seven countries (only one, Cancer Association of South Africa, based in SSA); only 156 (8%) were led by SSA-based investigators. Most projects focused on virally induced cancers (57%). Across all cancer types, projects were most frequently related to cervical cancer (24%), Kaposi sarcoma (15%), breast cancer (10%), or non-Hodgkin lymphoma (10%). Gaps were observed for several cancers with higher incidence/mortality burden in SSA; for example, prostate cancer accounted for only 4% of projects but 8% of cancer-related deaths and 10% of new cases. Approximately 26% were dedicated to etiology. Treatment-related research declined over the study period (14%-7% of all projects), while projects related to prevention (15%-20%) and diagnosis/prognosis (15%-29%) increased. Fifteen CIRGO projects were identified; seven were relevant across multiple cancer types, and 12 focused either wholly or partially on cancer control (representing 50% of the total research effort). CONCLUSION: This analysis shows notable discrepancies between cancer burden and research projects and identifies opportunities for future strategic investments in cancer care in SSA.

Advancing oncology drug therapies for sub-Saharan Africa.

Cancer incidence is rising across sub-Saharan Africa (SSA), and is often characterized by late-stage presentation, early age of onset and poor survival. While a number of oncology drugs are now improving the length and quality of life for cancer patients in high-income countries, significant disparities in access to a range of oncology therapeutics exist for SSA. A number of challenges to drug access such as drug costs, lack of infrastructure and trained personnel must be urgently addressed to advance oncology therapies for SSA. We present a review of selected oncology drug therapies that are likely to benefit cancer patients with a focus on common malignancies in SSA. We collate available data from seminal clinical trials in high-income countries to highlight the potential for these therapeutics to improve cancer outcomes. In addition, we discuss the need to ensure access to drugs within the WHO Model List of Essential Medicines and highlight therapeutics that require consideration. Available and active oncology clinical trials in the region is tabulated, demonstrating the significant gaps in access to oncology drug trials across much of the region. We issue an urgent call to action to address drug access due to the predicted rise in cancer burden in the region in coming years.

Bibliometric analysis of cancer research outputs in Botswana between 2009 and 2021.

INTRODUCTION: Cancer research is critical for cancer control policies; however, the state of cancer research activities in Botswana is largely unknown. The goal of this review was to describe trends and patterns of cancer research outputs in Botswana. METHODS: PubMed, Web of Science, EBSCOhost, African Journals Online, and African Index Medicus databases were systematically searched for peer-reviewed, primary cancer-related research articles published on the Botswana population or by Botswana institutions between January 2009 and June 2021. RESULTS: Of the 86 publications included, 39 (45 %) were about cervical cancer, followed by breast cancer (10 %) and Kaposi sarcoma (7 %). The remainder (27 %) were not focused on any specific cancer type. The research activities were skewed towards three main areas of scientific interest: early detection, diagnosis, and prognosis; cancer control, survivorship, and outcomes; and treatment. Botswana was represented by authors in the first (54 %), last (53 %), and any authorship (53 %) positions. The United States of America had the strongest collaborative partnerships with Botswana, followed by the United Kingdom and South Africa. The majority of funding institutions were American (76 %) and the National Institutes of Health was the most mentioned funding organization, accounting for 33 % of all financial acknowledgments. Only 9 % of the funding acknowledgments came from Botswana. CONCLUSION AND POLICY SUMMARY: Although cancer research in Botswana is expanding because of substantial foreign assistance, it is also hampered by a lack of local funding, minimal participation by Botswana-affiliated researchers, and research that is not aligned with disease burden. Our study highlights the need to strengthen local research capacity in Botswana.

Cervical cancer screening in HIV-endemic countries: An urgent call for guideline change.

Women living with HIV (WLWH) are at an increased risk of developing HPV-related high grade cervical dysplasia and cervical cancer. Prior World Health Organization (WHO) screening guidelines recommended starting screening at age 30. We assessed characteristics of women diagnosed with cervical cancer to further inform and refine screening guidelines. We prospectively enrolled women diagnosed with cervical cancer from January 2015 to March 2020 at two tertiary hospitals in Gaborone, Botswana. We performed chi-square and ANOVA analyses to evaluate the association between age upon diagnosis and HIV status, CD4 count, viral load, and other sociodemographic and clinical factors. Data were available for 1130 women who were diagnosed with cervical cancer and 69.3% were WLWH. The median age overall was 47.9 (IQR 41.2-59.1), 44.6 IQR: 39.8 - 50.9) among WLWH, and 61.2 (IQR 48.6-69.3) among women living without HIV. There were 1.3% of women aged <30 years old, 19.1% were 30-39 and 37.2% were 40-49. Overall, 20.4% (n = 231) of cancers were in women <40 years. Age of cervical cancer diagnosis is younger in countries with higher HIV prevalence, like Botswana. Approximately 20% of the patients presented with cancer at <40 years of age and would have likely benefited from screening 10 years prior to cancer diagnosis to provide an opportunity for detection and treatment of pre-invasive disease.

Pembrolizumab, radiotherapy, and an immunomodulatory five-drug cocktail in pretreated patients with persistent, recurrent, or metastatic cervical or endometrial carcinoma: Results of the phase II PRIMMO study.

A phase II study (PRIMMO) of patients with pretreated persistent/recurrent/metastatic cervical or endometrial cancer is presented. Patients received an immunomodulatory five-drug cocktail (IDC) consisting of low-dose cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin starting 2 weeks before radioimmunotherapy. Pembrolizumab was administered three-weekly from day 15 onwards; one of the tumor lesions was irradiated (8Gyx3) on days 15, 17, and 19. The primary endpoint was the objective response rate per immune-related response criteria (irORR) at week 26 (a lower bound of the 90% confidence interval [CI] of > 10% was considered efficacious). The prespecified 43 patients (cervical, n = 18; endometrial, n = 25) were enrolled. The irORR was 11.1% (90% CI 2.0-31.0) in cervical cancer and 12.0% (90% CI 3.4-28.2) in endometrial cancer. Median duration of response was not reached in both cohorts. Median interval-censored progression-free survival was 4.1 weeks (95% CI 4.1-25.7) in cervical cancer and 3.6 weeks (95% CI 3.6-15.4) in endometrial cancer; median overall survival was 39.6 weeks (95% CI 15.0-67.0) and 37.4 weeks (95% CI 19.0-50.3), respectively. Grade ≥ 3 treatment-related adverse events were reported in 10 (55.6%) cervical cancer patients and 9 (36.0%) endometrial cancer patients. Health-related quality of life was generally stable over time. Responders had a significantly higher proportion of peripheral T cells when compared to nonresponders (p = 0.013). In conclusion, PRIMMO did not meet its primary objective in both cohorts; pembrolizumab, radiotherapy, and an IDC had modest but durable antitumor activity with acceptable but not negligible toxicity.Trial registration ClinicalTrials.gov (identifier NCT03192059) and EudraCT Registry (number 2016-001569-97).

Distance to Multidisciplinary Team Clinic in Gaborone, Botswana, and Stage at Cervical Cancer Presentation for Women Living With and Without HIV.

PURPOSE: Cervical cancer is the leading cause of cancer death for women in Botswana. Barriers in access to cancer care can lead to later stages at diagnosis and increased mortality. This study evaluated access, defined as travel time from a patient's residential village to a multidisciplinary team clinic in Gaborone, with stage of cervical cancer at presentation. In addition, because of the high HIV prevalence in Botswana, we explored the association between travel time and HIV status. METHODS: Eligible patients with cervical cancer presenting to the multidisciplinary team between 2015 and 2020 were included. Data were abstracted from questionnaires and hospital records. Google Maps was used to calculate travel time. Multinomial regression was used to examine travel time and cancer stage, and multivariable logistic regression was used to investigate travel time and HIV status. RESULTS: We identified 959 patients with cervical cancer of which 70.1% were women living with HIV. The median travel time was approximately 2 hours. Using a reference group of stage I disease and a travel time of < 1 hour, the odds of presenting with stage II increased for patients traveling 3-5 hours (adjusted odds ratio [OR], 2.00; 95% CI, 1.14 to 3.52) and > 5 hours (OR, 2.19; 95% CI, 1.15 to 4.19). There were no significant associations for stage III. For stage IV disease, the odds were increased for patients traveling 3-5 hours (OR, 2.93; 95% CI, 1.26 to 6.79) and > 5 hours (adjusted OR, 4.05; 95% CI, 1.62 to 10.10). In addition, the odds of patients presenting living with HIV increased with increasing travel time (trend test = 0.004). CONCLUSION: This study identified two potential factors, travel time and HIV status, that influence access to comprehensive cervical cancer care in Botswana.

Stage and outcomes of invasive cervical cancer patients in Botswana: A prospective cohort study from 2013 to 2020.

Objective: To present the stage distribution, patterns of care, and outcomes of patients from Botswana with invasive cervical cancer, living with or without HIV. Methods: Between 2013 and 2020, women with cervical cancer were prospectively enrolled in an observational cohort study. Results: A total of 1,043 patients were enrolled; 69% were women living with HIV. The median age of the cohort was 47 years (interquartile range [IQR] 40-58 years), with women living with HIV presenting at a younger age compared to women without HIV (44 versus 61 years, p < 0.001). Among women living with HIV, the median CD4 count at the time of cancer diagnosis was 429.5 cells/µL (IQR 240-619.5 cells/µL), 13% had a detectable viral load, and 95% were on antiretroviral therapy. In regard to treatment, 6% (n = 58) underwent surgery, 33% (n = 341) received radiation therapy, 51% (n = 531) received chemoradiation, and 7% (n = 76) did not receive treatment. Stage distribution in the cohort was as follows: I 17% (n = 173), II 37% (n = 388), III 35% (n = 368), and IV 8% (n = 88). For all patients, 2-year OS was 67%. In multivariable Cox regression, worse OS was associated with stage: II (HR 1.91, p = 0.007), III (HR 3.99, p < 0.001), and IV (HR 5.06, p < 0.001) compared to stage I. Improved OS was associated with hemoglobin > 10 g/dL (HR 0.51, p < 0.001) compared to Hb ≤ 10 g/dL. Conclusions: Among women in Botswana with cervical cancer, most patients presented with stage II or III disease warranting radiation therapy or chemoradiation. While two-thirds of cervical cancer patients were women living with HIV, HIV did not impact OS.

Dynamic alterations of immunosenescence-related genes in older women with breast cancer receiving chemotherapy: A prospective study.

BACKGROUND: The exact impact of chemotherapy on the immune system of older patients with breast cancer is not well known. A longitudinal study was performed investigating the evolution of the blood immune profile during and after chemotherapy in this population. PATIENTS AND METHODS: The study included 39 patients receiving adjuvant chemotherapy (chemotherapy group, CTG) and 32 patients receiving only hormone therapy (control group, CG). A 10-gene panel associated with immunosenescence was measured in peripheral blood mononuclear cells (PBMC) before (T1), at 3 months (T2) and at 12 months (T3) after initiation of adjuvant therapy. Nutrition status was assessed by using a mini nutritional assessment scale. Linear mixed model analyses were performed for trajectory evolution, with or without adjusting for age, tumor stage, breast cancer phenotype, and/or corresponding baseline gene levels. RESULTS: Six genes relating to T cell activation (CD28, CD27, CD86, LCK, GRAP, LRRN3), and two genes relating to oxidative stress (PRDX6, HMOX1) exhibited a significant group-by-time effect, even after adjusting covariates(p≤ 0.01). In CTG, the T cell activation genes substantially declined from T1 to T2 and bounced back to a level higher than baseline at T3 (p<0.03), which was not observed in CG (p>0.26). Patients with malnutrition detected at T1 experienced more pronounced perturbation regarding CD27, LCK, CD69, VAMP5, and LRRN3 (p<0.05). CONCLUSION: Chemotherapy leads to transient perturbation of immune-related gene expression and potentially stimulates immunity in the long term. Well-nourished patients experience less impact of chemotherapy on immune-related gene expression profiles.

Patient perspectives on delays in cervical cancer screening and follow-up care in Botswana: a mixed methods study.

BACKGROUND: Delays in screening and timely diagnosis contribute significantly to global disparities in cervical cancer mortality in Botswana and other low- and middle-income countries, particularly those with high rates of HIV. Little is known about the modifiable factors shaping these delays from the perspectives of women themselves and how these perspectives may differ between those living with and without HIV. METHODS: From March-May 2019, we conducted a concurrent, mixed methods study of women receiving treatment for cervical cancer at a multidisciplinary oncology clinic in Botswana. Enrolled participants completed a one-time, concurrent semi-structured interview and structured questionnaire assessing patient characteristics, screening and HIV-related beliefs and knowledge, and barriers and facilitators to screening and follow-up care. Qualitative data were analyzed using directed content analysis guided by the Model of Pathways to Treatment and triangulated with quantitative questionnaire data to identify areas of convergence and divergence. Fisher's exact tests were used to explore associations between questionnaire data (e.g., screening knowledge) and HIV status. RESULTS: Forty-two women enrolled in the study, 64% of whom were living with HIV and 26% were diagnosed with stage III cervical cancer. Median age was 45 years (IQR 54-67) in those living with HIV and 64 years (IQR 42-53) in those living without. Overall screening rates before symptomatic disease were low (24%). Median time from most proximal screen to diagnosis was 52 median days (IQR 15-176), with no significant differences by HIV status. General screening knowledge was higher among those living with HIV versus those without (100% vs 73%; p < 0.05), but knowledge about HPV and other risk factors was low in both groups. Similar to questionnaire results, qualitative results indicate limited awareness of the need to be screened prior to symptoms as a central barrier to timely screening. Some participants also noted that delays in the receipt of screening results and fear also contributed to treatment delays. However, many participants also described myriad sources of social and tangible support that helped them to overcome some of these challenges. CONCLUSION: Interventions focused on increasing routine screening and supporting timely awareness and access to care are needed to reduce global disparities in cervical cancer.