Surbhi Grover

Cervical and Tumor-Associated Microbiomes in Botswana Women With and Without HIV With Carcinoma of the Cervix Before and After Definitive Chemoradiation

PURPOSE Cervical cancer remains a significant public health concern globally and particularly in sub-Saharan Africa, where high rates of HIV infection exacerbate cervical cancer incidence. Understanding the cervical microbiome and its role in cancer progression is essential, especially in regions where both cervical cancer incidence and HIV prevalence are high. This study aimed to characterize the cervical microbiome in women living with HIV (WLWH) and HIV-negative women with squamous cell carcinoma of the cervix in Botswana, compare the microbiome between before and after chemoradiation therapy (CRT) in WLWH, and assess the prognostic value of specific microbial taxa for overall survival (OS) in WLWH. PATIENTS AND METHODS Cervical samples were collected from women with cervical cancer presenting to one hospital in 2018-2019. Patients' clinical data, including HIV status, were recorded. Microbial composition was analyzed using 16S rRNA gene sequencing. Microbiome diversity and composition were evaluated using alpha and beta diversity metrics. Differential microbial abundance was analyzed using linear discriminant analysis effect size. The association between microbial taxa and OS was explored using Cox proportional hazards regression. RESULTS WLWH (n = 42) had a significantly lower Pielou evenness index than HIV-negative women (n = 11; 0.6 v 0.7, P = .02), suggesting a more imbalanced microbiome in WLWH. WLWH had higher levels of Parvimonas and members of the Corynebacteriaceae and Micrococcaceae families, suggesting a shift toward a more pathogenic microbiome. In WLWH, CRT did not significantly alter overall microbial diversity. However, Lactobacillus and Sutterella were enriched before treatment, reflecting a less pathogenic microbiome, whereas Ruminococcus and Phascolarctobacterium and the families Caulobacterales and Flavobacteriia were enriched after treatment, reflecting microbial adaptations to the altered immune and treatment environment. Notably, higher levels of Flavobacteriia after CRT were independently associated with worse OS in WLWH. CONCLUSION Microbiome profiles differ between WLWH and HIV-negative women with cervical cancer in Botswana. The microbiome might have prognostic significance. Future research is needed to better understand the significance of the microbiota in cervical cancer progression and treatment outcomes and the potential role of microbiome-targeted interventions.

Overcoming Logistical Barriers to Conducting Collaborative Clinical Research Between a High-Income Country and a Low- and Middle-Income Country

PURPOSE Building equitable research collaborations between high-income countries (HICs) and low- and middle-income countries (LMICs) requires effective coordination among international ethical review committees, which is often logistically challenging. This case report presents the insights gained when acquiring ethical approval for a cervical cancer research program conducted jointly by the University of Pennsylvania and the University of Botswana. METHODS We conducted a descriptive case study of the Ipabalele project, a 6-year HIC-LMIC partnership involving three complex research protocols that required approvals by multiple distinct ethical bodies. We analyzed various challenges affecting review procedures, timelines, and staffing. We then documented strategies employed in Ipabalele and other global initiatives to strengthen ethical review processes and build research capacity in LMICs. RESULTS In Ipabalele, ethical approvals were initially delayed by 2 years because of fragmented review processes with variable timelines and conflicting recommendations. Innovations to the process included centralizing institutional review board oversight within Botswana, implementing joint virtual meetings among review bodies, enhancing digital infrastructure, and streamlining research staffing and communication. CONCLUSION By providing practical strategies, this study highlights how empowered local leadership, centralized review processes, joint review mechanisms, and intentional capacity building can overcome logistical barriers in multinational ethical review.

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

ABSTRACTBACKGROUNDCervical 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).METHODSThis 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.RESULTSOf 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).CONCLUSIONSIn 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.

Human papillomavirus genotypes in women with invasive cervical cancer with and without human immunodeficiency virus infection in Botswana

Cervical cancer remains a significant cause of morbidity and mortality in women worldwide and is the leading cause of cancer‐related death in Botswana. It is well established that women with HIV have a higher risk of persistent HPV infection leading to cervical cancer. We assessed HPV prevalence and genotype distribution in 126 tissue specimens from confirmed invasive cervical cancer cases using Abbott real‐time PCR assay. Overall, 88 (69.8%) women were HIV‐infected. Fifty‐seven (64.8%) of the HIV‐infected women had a baseline CD4+ count ≥350 cells/μl, and 82 (93.2%) were on antiretroviral therapy at the time of cervical cancer diagnosis. The median age of HIV‐infected patients was significantly younger than that of HIV‐uninfected patients (p < 0.001). HPV DNA was detected in all of 126 (100%) of tissues analyzed in our study. The HPV genotypes identified included the HPV‐16 (75.4%), HPV‐18 (28.6%) and other high‐risk (hr) HPV genotypes (16.7%). HIV infection was positively associated with the presence of the HPV‐16 genotype (p = 0.036), but not with HPV‐18 or with other high‐risk (hr)‐HPV genotypes. Thirty‐three percent of the patients had multiple hr‐HPV genotypes, with higher rates in HIV‐infected women. These results highlight the importance and potential impact of large‐scale HPV vaccination programs covering HPV‐16 and HPV‐18 genotypes in countries like Botswana with high burden of HIV infection.

Cervical Cancer Treatment in HIV-Positive Patients: A Survey of Treatment Practices in India

PURPOSE Chemoradiation remains a challenge in women living with HIV (WLWH) and cervical cancer primarily because of concerns regarding immune status. With limited literature available to help guide the management of these patients, clinical practices among oncologists are variable across India. Hence, we conducted a survey among radiation oncologists in India to assess the patterns of current practices of treating cervical cancer with chemoradiation in WLWH. MATERIALS AND METHODS A questionnaire consisting of 12 questions related to the treatment of cervical cancer in WLWH was distributed to radiation oncologists at two national conferences in India. RESULTS The questionnaire was distributed to 105 radiation oncologists, and 90 (85.7%) responses were received. 95.5% of respondents reported that patients with advanced cervical cancer constituted the majority of their practice. Chemoradiation was reported as the most common modality of planned treatment. Ninety-four percentage of respondents reported that they referred patients to an antiretroviral therapy clinic before starting definitive treatment. The majority of respondents (68%) do not plan for concurrent chemotherapy if CD4 counts were < 200 cells/mm3. As many as 50% of respondents reported that they would only start antiretroviral therapy when CD4 counts drop. Poor social support (37.6%), concurrent infections during treatment (28.2%), acute toxicities (21.2%), and poor nutrition (13%) were cited as the most common reasons for treatment interruption in cervical cancer patients with HIV. CONCLUSION This survey highlights the prevalent inconsistencies in treatment protocols employed by radiation oncologists in India for the management of locally advanced cervical cancer in WLWH. It also reflects the need for social and nutritional support to help improve compliance and thereby improve outcomes in these patients.

Improving cervical cancer survival–A multifaceted strategy to sustain progress for this global problem

AbstractCervical cancer is associated with profound socioeconomic and racial disparities in incidence, mortality, morbidity, and years of life lost. The last standard‐of‐care treatment innovation for locally advanced cervical cancer occurred in 1999, when cisplatin chemotherapy was added to pelvic radiation therapy (chemoradiation therapy). Chemoradiation therapy is associated with a 30%–50% failure rate, and there is currently no cure for recurrent or metastatic disease. The enormity of the worldwide clinical problem of cervical cancer morbidity and mortality as well as the egregiously unchanged mortality rate over the last several decades are recognized by the National Institutes of Health as urgent priorities. This is reflected within the Office of Research on Women's Health effort to advance National Institutes of Health research on the health of women, as highlighted in a recent symposium. In the current review, the authors address the state of the science and opportunities to improve cervical cancer survival with an emphasis on improving access, using technology in innovative and widely implementable ways, and improving current understanding of cervical cancer biology.Lay summary Cervical cancer is associated with profound socioeconomic and racial disparities in incidence, mortality, morbidity, and years of life lost. In this review, the state of the science and opportunities to improve cervical cancer survival are presented with an emphasis on improving access, using technology in innovative and widely implementable ways, and improving current understanding of cervical cancer biology.

Outcomes of Cervical Cancer in HIV-Positive Women Treated With Radiotherapy at a Tertiary Care Center in India

PURPOSE There are limited data on management of cervical cancer in women living with HIV in the modern antiretroviral therapy era. The study aimed to evaluate outcomes and toxicities of these patients treated with radiotherapy. MATERIALS AND METHODS A retrospective analysis of HIV-positive cervical cancer patients treated with radiotherapy between 2011 and 2018 was conducted at a tertiary care center in India. RESULTS Eighty-two HIV-positive cervical cancer patients treated with radiotherapy were identified. Their median age was 45 years. Seventy-four (90%) patients received radiotherapy with curative-intent and eight patients received palliative radiotherapy. Median CD4 count at the start of treatment was 342 cells/mm3 (interquartile range: 241-531). Among patients planned for definitive radiotherapy, concurrent cisplatin was planned in 52 (70%) patients with a median of four chemotherapy cycles, and 81% (n = 60) patients received brachytherapy. Among patients who received brachytherapy, the median prescription dose was 80 Gy. Seventy-seven patients completed their prescribed treatment. At a median follow-up of 37 months, 3-year disease-free survival of patients planned with curative-intent was 54%. On multivariate analysis, treatment completion was associated with favorable disease-free survival. Grade III/IV acute gastrointestinal toxicity was seen in five (6.8%) patients, whereas 30% patients had grade III/IV acute hematologic toxicity. All these patients completed their planned radiotherapy with good supportive care. CONCLUSION Standard treatment of chemoradiation should be planned in women living with HIV with well-managed HIV presenting with locally advanced cervical cancer. Our study highlights the need for optimal management of these patients by a multidisciplinary team with intensive supportive care to ensure completion of planned treatment to achieve better outcomes.

Mapping of Radiation Oncology and Gynecologic Oncology Services Available to Treat the Growing Burden of Cervical Cancer in Africa

To meet the demand for cervical cancer care in Africa, access to surgical and radiation therapy services needs to be understood. We thus mapped the availability of gynecologic and radiation therapy equipment and staffing for treating cervical cancer. We collected data on gynecologic and radiation oncology staffing, equipment, and infrastructure capacities across Africa. Data was obtained from February to July 2021 through collaboration with international partners using Research Electronic Data Capture. Cancer incidence was taken from the International Agency for Research on Cancer's GLOBOCAN 2020 database. Treatment capacity, including the numbers of radiation oncologists, radiation therapists, physicists, gynecologic oncologists, and hospitals performing gynecologic surgeries, was calculated per 1000 cervical cancer cases. Adequate capacity was defined as 2 radiation oncologists and 2 gynecologic oncologists per 1000 cervical cancer cases. Forty-three of 54 African countries (79.6%) responded, and data were not reported for 11 countries (20.4%). Respondents from 31 countries (57.4%) reported access to specialist gynecologic oncology services, but staffing was adequate in only 11 countries (20.4%). Six countries (11%) reported that generalist obstetrician-gynecologists perform radical hysterectomies. Radiation oncologist access was available in 39 countries (72.2%), but staffing was adequate in only 16 countries (29.6%). Six countries (11%) had adequate staffing for both gynecologic and radiation oncology; 7 countries (13%) had no radiation or gynecologic oncologists. Access to external beam radiation therapy was available in 31 countries (57.4%), and access to brachytherapy was available in 25 countries (46.3%). The number of countries with training programs in gynecologic oncology, radiation oncology, medical physics, and radiation therapy were 14 (26%), 16 (30%), 11 (20%), and 17 (31%), respectively. We identified areas needing comprehensive cervical cancer care infrastructure, human resources, and training programs. There are major gaps in access to radiation oncologists and trained gynecologic oncologists in Africa.

Expanding Cervical Cancer Screening in Mozambique: Challenges Associated With Diagnosing and Treating Cervical Cancer

PURPOSE Mozambique has one of the highest burdens of cervical cancer globally. Treatment options are few as most women present with advanced disease, and there are limited trained health professionals and health care resources. The objective of this study was to describe the outcomes of women diagnosed with invasive cancer as part of the Mozambican women undergoing cervical cancer screening with human papillomavirus (HPV) testing in conjunction with family planning services (MULHER) study. MATERIALS AND METHODS Women age 30-49 years were prospectively enrolled in the MULHER study and offered screening with primary HPV testing followed by treatment of screen-positive women with thermal ablation or excision as appropriate. Women with cervical examination findings suspicious for cancer were referred to one of the three gynecologic oncologists in the country. RESULTS Between January 2020 and January 2023, 9,014 women underwent cervical cancer screening and 30 women were diagnosed with cervical cancer. In this cohort, four patients (13.3%) had early-stage disease, 18 (60.0%) had locally advanced disease, one (3.3%) had distant metastatic disease, and seven (23.3%) did not have staging information available. Five patients (16.6%) died without receiving oncologic treatment, and seven patients (23.3%) are still awaiting treatment. Of the remaining 18 patients, three (17.6%) underwent surgery and four (23.5%) received radiotherapy. Eleven (36.7%) patients received only chemotherapy. CONCLUSION As cervical screening programs are implemented in low-resource settings, there will likely be an increase in the number of women diagnosed with invasive cervical cancer. Our results in Mozambique demonstrate the need to increase access to advanced surgery, radiation, and palliative care services.

Feasibility and Clinical Acceptability of Automation-Assisted 3D Conformal Radiotherapy Planning for Patients With Cervical Cancer in a Resource-Constrained Setting

Automation may enable high-quality cervical cancer radiation on shorter treatment planning timelines.

Impact of the COVID-19 Pandemic on Cervical Cancer Treatment Delays in Botswana

PURPOSE Although the majority of cervical cancer cases are in sub-Saharan Africa, little is known regarding how the COVID-19 pandemic affected cancer care in this context. Drawing from robust longitudinal data, this study aimed to assess cervical cancer treatment patterns in Botswana before and during the pandemic. METHODS Longitudinal clinical and patient-reported data from a cohort of over 1,000 patients seen at a gynecologic oncology multidisciplinary team clinic in Botswana were used to evaluate treatment initiation patterns before (April 2018-December 2019) and during (April 2020-December 2021) the pandemic. The primary outcome was timeliness of treatment, defined as the number of days between the patient's first clinic visit and treatment initiation date, and categorized as timely (≤30 days), delayed (>30 days), or no treatment. The primary exposure was time of visit (pre–COVID-19 v COVID-19), defined by the month of the clinic visit. RESULTS Of the 559 patients with cervical cancer diagnosed during the study period, 336 were seen pre–COVID-19, and 223 were seen during the COVID-19 period. During the pandemic, a higher proportion of patients experienced treatment delays (66.4%) or received no treatment (24.2%), compared with the pre–COVID-19 period (35.7% and 9.8%, respectively; P < .001). Multivariable regression models indicated that patients seen during the pandemic were 10 times more likely to experience treatment delays (adjusted odds ratio [aOR], 10.01 [95% CI, 5.69 to 17.62]) and 14 times more likely to receive no treatment (aOR, 14.16 [95% CI, 7.14 to 28.10]). CONCLUSION The pandemic exacerbated treatment delays for patients with cervical cancer in Botswana. There is a need for evidence-based strategies to address these treatment delays, considering the disproportionate burden of disease and persistent disparities in access to care in Botswana and other low- and middle-income countries.

Cervical cancer treatment outcomes and survival in Botswana by human immunodeficiency virus status: Ipabalele study results

Abstract Background Cervical cancer is a leading morbidity/mortality cause, frequently co-occurring with human immunodeficiency virus (HIV) positivity, in Botswana. We examined long-term outcomes for Ipabalele study participants receiving curative chemoradiation for locally advanced cervical cancer (2015-2019) by HIV status. Methods Clinical and outcome data were collected at baseline, treatment completion, and 3 months thereafter. Patients were followed for up to 5 years. Overall survival (OS) was evaluated using Kaplan-Meier curves and Cox regression. Results The cohort comprised 295 patients (73.8% with HIV, younger at diagnosis [P < .001]) followed for a median of 44.2 months. Complete response was seen in 217/278 (76.1%) patients. Two- and 5-year OS rates were 73.4% and 59.9%, respectively, with no difference by HIV status. OS was associated negatively with advanced disease stage (III: hazard ratio [HR] 13.23, P < .001; IV: HR 7.8, P = .008) and positively with increased radiation (HR 0.977, P = .0005) and chemotherapy (HR 0.85, P = .005). Clinical response was associated negatively with advanced disease (IV: HR 0.113, P = .002) and positively with increased radiation (P = .009). Toxicity did not differ by HIV status. The most common grade-≥-2 non-hematological and hematological toxicities were radiation dermatitis (39.8%) and reduced white blood cell count (66.05%), respectively. Conclusions In this cervical cancer cohort with good HIV status control, treatment outcomes and OS were associated with disease and treatment factors, not the HIV status. Early screening and education regarding treatment protocols are crucial to improve cervical cancer outcomes in Botswana.

Patients with Cervical Cancer with and without HIV Infection Have Unique T-cell Activation Profiles despite Similar Survival Outcomes after Chemoradiation

Abstract The global burden of cervical cancer is highest in low- and middle-income countries. Women living with human immunodeficiency virus (HIV) infection are particularly affected by cervical cancer despite availability and adherence to antiretroviral therapy. Immune profile correlates of survival and treatment response have not been widely explored in patients with and without HIV infection. This study recruited women with cervical cancer undergoing definitive chemoradiation (CRT) in Botswana. Clinical characteristics and blood samples were collected. Flow cytometry was performed on samples prior to initiation, at completion, and 3 months after CRT. Logistic regression analysis identified immune markers that differed by HIV status and correlated with overall survival (OS). The study enrolled 131 consecutive women (HIV+ N = 89 and HIV− N = 42). From initiation to 3 months after CRT, a significant decrease in CD4 frequency (72%–60.55%, P < 0.001) and an increase in CD8 frequency (20.9%–31.5%, P < 0.001) were seen in women without HIV, whereas no significant changes in CD4 frequency (52.5%–50.9%) or CD8 frequency (39.9%–41.4%) were observed in those with HIV. Peripheral T cells underwent similar activation across the cohort regardless of HIV status. Improved OS was associated with reduced frequency of IL-2–expressing CD4 T-cell subsets. In women living with HIV, enhanced OS was associated with the presence of proinflammatory CD8 T cells. CRT induces peripheral T-cell activation and distinct cytokine profiles that differ by HIV status. Despite similar OS, HIV infection may differentially affect immune response to CRT in women with well-managed HIV. Significance: Chemoradiation affects the immune system of patients with cervical cancer with well-controlled HIV infection differently than those without HIV, yet their survival does not differ. This finding is an important step in understanding how management of HIV infection can modify cancer outcomes, particularly in settings with a high burden of HIV.

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

Delays in care for patients with cervical cancer in Botswana can be benchmarked using a multidisciplinary clinic model.