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Table 1 Table of evidence

From: Treatment of pre- and confirmed cervical cancer in HIV-seropositive women from developing countries: a systematic review

First author & publication yearStudy typePurposePopulation & ageCountryStage of cancerTreatment methodOutcome(s)ResultsAuthors’ ConclusionsQuality score
Simonds et al.,
2012 [20]
Retrospective cohort studyTo compare the clinical characteristics, radiation, and chemotherapy treatments, outcomes in a cohort of HIV-positive and HIV-negative women with cervical cancer59 HIV-positive (median age 41 years) and 324 HIV-negative (median age of 50 years) patientsSouth AfricaIBi–IIIBRadiation and chemotherapyChemotherapy cycles, response at time of brachytherapy, and 6-week follow-up88.1% of HIV-positive patients presented with IIIB disease compared to 65.7% of HIV-negative patients (p = 0.009). 79.7% HIV-positive and 89.8% HIV-negative patients completed radiation dose of 68 Gy EBRT and HDR brachytherapy (p = 0.03). For concurrent chemotherapy, 53.1% HIV-positive and 74.6% HIV-negative patients completed four or more weekly cycles of platinum-based treatment.
At 6 weeks, poor response was associated with stage IIIB disease (OR = 2.39, 95% CI 1.45–3.96) and receiving less than 68 Gy EQD2 radiation (OR = 3.14, 95% CI 1.24–794).
Good medical care of HIV-positive patients can enable patients to complete treatment for locally advanced cervical cancer and might improve response to treatment.Moderate
Shrivastava et al., 2005 [21]Retrospective reviewTo determine the effect of radiotherapy in HIV seropositive cervical cancer patients, tumour response and toxicity, and compliance of patients to the treatment.42 HIV seropositive patients, mean age of 41 yearsIndiaIIIB–IVARadiotherapyAge and symptoms of presentation, clinical stage, response, compliance, and tolerance to radiotherapyAll patients presented with the symptoms of cervical disease. Of these patients 31 (74%) patients had ‘Karnofsky Performance Scale’ (KPS) more than 80%. Twenty-one (50%) of the patients were of stage IIIb–IVa. Thirty-two (76%) were started on radiotherapy with radical intent. Compliance to radiotherapy was poor with 24% patients discontinuing after few fractions of radiotherapy. Seven (17%) patients were given palliative radiotherapy. Twenty-two patients completed prescribed radical radiotherapy and 50% of these achieved complete response. Grade III–IV acute gastrointestinal toxicity was seen in 14% of the patients, and grade III acute skin toxicity was seen in 27% of patients, leading to treatment delays. There was good relief of symptoms in patients treated with palliative intent.Radiotherapy is effective in this set of patients. Palliative fractionation schedules are effective for patients with poor performance status and locally advanced cancers in relieving the symptoms related to carcinoma cervix. An emphasis should be given to the increased acute mucosal and skin toxicity and to improving compliance and clinical outcome of these patients.Low
Gichangi et al., 2006 [22]Prospective cohort studyTo determine the impact of HIV infection on acute morbidity and pelvic tumour control following external beam radiotherapy (EBRT) for cervical cancer218 patients, 20% of them HIV-positiveKenya RadiotherapyAcute treatment toxicity and pelvic tumour controlOverall, 53.4% of the patients had radiation-related acute toxicity (grade 3–4). HIV infection was associated with a 7-fold higher risk of multisystem toxicity: skin, gastrointestinal tract (GIT), and genitourinary tract (GUT) systems. It was also an independent risk factor for treatment interruptions (adjusted relative risk 2.2). About 19% of the patients had residual tumour at 4 and 7 months post-EBRT. HIV infection was independently and significantly associated with 6-fold higher risk of residual tumour post-EBRT. The hazard ratio of having residual tumour after initial EBRT was 3.1-times larger for HIV-positive than for HIV-negative patients (p = 0.014).HIV is associated with increased risk of multisystem radiation-related toxicity; treatment interruptions and pelvic failure (residual tumour) following EBRT. HIV infection is an adverse prognostic factor for outcome of cervical cancer treatment.Moderate
Mdletshe et al., 2016 [23]Prospective quantitative comparative studyTo evaluate in detail treatment response, its toxicities and compliance of HIV-positive women to radical combination therapy (radiotherapy with chemotherapy)55 HIV-positive (median age of 40 years) and 55 HIV-negative (median age of 55 years) patients with performance status ECOG I & IIZambiaIB2–IIIBCombination of radiotherapy and chemotherapy given concurrentlyAcute reactions to radical chemo-radiation and toxicityAll participants completed EBR and HDR as prescribed.
Average EBR dose delivered was 48 Gy, and the difference in dose received was significant with regard to HIV status (p = 0.022).
58% of HIV-positive were treated with 6.5 Gy × 4 brachytherapy fractions as compared to 58% HIV-negative patients treated with 8 Gy × 3 fractions.
There were no statistically significant differences in toxicity between HIV-positive and HIV-negative patients with regard to skin, GIT system, GU system, and haemopoietic system.
Radical chemo-radiation in conventional doses was safely tolerated by a well-selected cervical cancer HIV-positive group on HAART and could be considered suitable for similar patients.Moderate
Boupaijit and Suprasert, 2016 [24]Retrospective studyTo evaluate the survival outcomes of chemotherapy and the prognostic factors in this setting173 patients (mean age of 50.9 year), with 4.1% of them HIV-positiveThailandIVBChemotherapySurvival outcomes and prognostic factorsMedian overall survival of all studied patients was 13.2 months.
Only a recurrence-free interval of less than 12 months was an independent prognostic factor for survival outcome
Chemotherapy treatment for advanced and recurrent cervical cancer patients showed modest efficacy with a shorter recurrence-free survival less than 12 months as a significant poor prognosis factorModerate
Ferreira et al., 2017 [25]Cohort studyTo assess mortality, treatment response, and relapse among HIV-infected and HIV-uninfected women with cervical cancer in Rio de Janeiro, Brazil87 HIV-infected and 336 HIV-uninfected women with cervical cancerBrazilIA/IB1, IB2/II, III, IVA/IVB28% treated with surgery, 23% with radiation, 30% with chemo-radiation, and 36% received additional brachytherapyMortality, treatment response and relapse70% HIV-infected women and 76% HIV-uninfected women completed recommended treatment.
58  HIV-infected and 176 HIV-uninfected women died. Among HIV-infected women, overall mortality was 324 per 1000 person-years, with 82% of deaths due to cancer. Among HIV-uninfected women, overall mortality was 209 per 1000 person-years, with 93% of deaths from cancer.
Among 222 patients treated with radiotherapy, HIV-infected had similar response rates to initial cancer therapy as HIV-uninfected women (HR 0.98, 95% CI 0.58–1.66). However, among women who were treated and had a complete response, HIV was associated with elevated risk of subsequent relapse (HR 3.60, 95% CI 1.86–6.98, adjusted for clinical stage)
HIV infection was not associated with initial treatment response or early mortality, but relapse after attaining a complete response and late mortality were increased in those with HIV.
There is a role for an intact immune system in control of residual tumour burden among treated cervical cancer patients
Moderate
Moodley, 2017 [26]Case studiesTo present radical hysterectomy experience to inform management of early-stage invasive cervical cancer18-year-old nulliparous, 36-year-old primiparous, and 39-year-old para 2 HIV-positive womenSouth AfricaDifferentiated squamous cell carcinoma (LVSI)Surgery (radical hysterectomy)Management outcomes after radical hysterectomyAll three made uneventful postoperative recoveries and all vaginal vault cytologic smears have been negative. The 18-year-old is well 6 years postsurgery as are the 36- and 39-year-olds at 3 years follow-up visits.
The 39-year-old patient needed ureteric re-implantation due to ureteric stricture, which could occur as a recognised complication even in HIV
Non-infected patients.
With reasonable levels of immunosuppression, management of HIV-positive women with early cervical cancer with radical hysterectomy can produce reasonable outcomes and survival.Low
Kietpeerakool et al. 2006 [27]Retrospective cohort studyTo evaluate the treatment outcomes and complications in human immunodeficiency virus (HIV)-infected women undergoing loop electrosurgical excision procedure (LEEP) for cervical neoplasia60 HIV-infected (mean age of 35.9 years) and 61 HIV-negative (mean age of 40.1 years) women with cervical neoplasiaThailandLSIL–HSILLEEPLEEP treatment outcomes and complications in HIV-positive women97.1% and 88% of HIV-positive women were disease-free at 6 and 12 months, respectively after LEEP.
1.7% had severe intraoperative haemorrhage, 5% had early and late postoperative haemorrhage, 11.7% had localised infection of the cervix and 3.3% developed cervical stenosis at 6 months after LEEP.
No significant difference in overall complications (p = 0.24) between HIV-positive and HIV-negative patients.
LEEP appears to be safe and effective in HIV-infected women.Moderate
Firnhaber et al. 2017 [28]Randomised controlled trialTo compare cervical cryotherapy to observation in HIV-infected women with CIN1 on histology202 HIV-positive women (median age of 37.9 years) with CIN1South AfricaCIN1CryotherapyCIN2/3 by histology at month 12. Regression of cervical histology to no evidence of NILMCIN2/3 at month 12, occurred in 2 of 99 (2%) women in the cryotherapy arm as compared with 15 of 103 (15%) women in the no treatment arm [86% risk reduction, 95% confidence interval (CI) 61 to 97%; p = 0.0016].
No cervical cancers in both arms. Forty of 99 (40%) women in the cryotherapy group experienced regression as compared 14 of 103 (14%) women in the no treatment group (69% reduced regression, 95% CI 58% to 83%, p<0.0001).
Treating CIN1 with cryotherapy reduces progression to CIN2/3. The benefit was exclusively among those with hrHPV. Cryotherapy was safe in this population with no serious adverse events.High
Woo et al., 2011 [29]Prospective cohort studyTo estimate the safety, tolerability, and acceptability of loop electrosurgical excision procedure (LEEP) for cervical intraepithelial neoplasia (CIN 2/3) in HIV-positive women180 HIV-positive womenKenyaCIN2/3LEEPSafety, tolerability and acceptability of LEEP after 4 weeks post-procedure179 (99%) reported “very mild” to mild symptoms, while 1 (n = 1%) participant described the symptoms as moderate.
Mean CD4+ count was significantly higher among women who reported any symptoms compared to women who reported no symptoms post LEEP (419 cells/mm3 vs. 349 cells/mm3, p < 0.05)
Only 16% (CI 11–22%, n = 29) of women reported early resumption of intercourse prior to their 4-week follow-up visit
LEEP performed by clinical officers was well-accepted by HIV positive women and appears safe, resulting in minimal side effects, even among women with early resumption of intercourseModerate
Kietpeerakool et al., 2006 [27]Prospective studyTo assess outcome in HIV-positive women undergoing the loop electrosurgical excision procedure (LEEP)70 HIV-positive (mean age of 37.5) and 719 HIV-negative (mean age 45.8) women.ThailandCIN1/2/3, IA1-IB1LEEPSafety of LEEP among HIV-positive patientsHIV infection was not significantly associated with the incidence of LEEP complications (adjusted odds ratio, 0.41; 95% CI, 0.15–1.15; p = 0.10).
There were no statistically significant differences in operative time, size of excised specimens, incidence of 2 or more passes of the loop, or use of Monsel paste between the 2 groups.
There was a higher prevalence of LEEP margin involvement in the HIV-positive than in the HIV-negative group (60.0% vs 49.4%).
LEEP is safe in HIV-infected women with cervical neoplasia treated in outpatient settings, and when technically possible, a repeat intervention is safe, with an acceptable success rate, even though HIV-infected women have a higher risk of resection margin involvement.Moderate
Einstein et al., 2019 [30]Randomised controlledTo determine the feasibility, safety, and tolerability of concomitant chemoradiotherapy administered at standard doses in HIV-infected women with locally advanced cervical cancer (LACC) receiving antiretroviral therapy (ART).38 HIV-seropositive women over 18 years oldSub-Saharan AfricaLACCConcomitant chemoradiotherapyFeasibility, safety, and tolerability of concomitant chemoradiotherapy administered at standard dosesSixty-four women were screened at two sites in sub-Saharan Africa, of whom 40 eligible participants were enrolled, for a screening ratio of 1.60. Of the 38 eligible participants who initiated study treatment, 31 (82%) completed treatment. By the 12-month follow-up visit, 7 women had died of disease and 29 of 31 (94%) returned for follow-up. One-year progression-free survival was 76.3% (95% CI, 59.4–86.9%), and did not significantly differ according to stage at entry (p = 0.581). Participant-reported adherence to ART was high; by 12 months, 93% of participants had an undetectable viral load. The most common grade 3 or 4 adverse event was decreased lymphocyte count that affected all treated participants. Non-hematologic serious adverse events were similar to those observed in women with LACC without HIV infection.The majority of HIV-infected women with LACC can complete concomitant chemoradiotherapy with the same cisplatin dose used in HIV-uninfected women with comparable tolerability and high ART adherence while on treatment.High
Smith et al., 2017 [31]Randomised controlled trialTo identify effective treatment methods for high-grade cervical precursors among HIV-seropositive women by comparing the difference in the efficacy of loop electrosurgical excision procedure vs cryotherapy for the treatment of high-grade cervical intraepithelial neoplasia (grade ≥ 2)166 HIV-seropositive women aged 18–65 yearsSouth AfricaCIN2+Cryotherapy vs LEEPEfficacy of LEEP and cryotherapyCumulative cervical intraepithelial neoplasia grade ≥ 2 incidence was higher for cryotherapy (24.3%; 95% confidence interval, 16.1–35.8) than LEEP at 6 months (10.8%; 95% confidence interval, 5.7–19.8) (p = .02), although by 12 months, the difference was not significant (27.2%; 95% confidence interval, 18.5–38.9 vs 18.5%; 95% confidence interval, 11.6–28.8, p = .21). Cumulative cervical intraepithelial neoplasia grade ≥ 1 incidence for cryotherapy (89.2%; 95% confidence interval, 80.9–94.9) did not differ from LEEP (78.3%; 95% confidence interval, 68.9–86.4) at 6 months (p = .06); cumulative cervical intraepithelial neoplasia grade ≥ 1 incidence by 12 months was higher for cryotherapy (98.5%; 95% confidence interval, 92.7–99.8) than LEEP (89.8%; 95% confidence interval, 82.1–95.2) (p = .02). Cumulative high-grade cytology incidence was higher for cryotherapy (41.9%) than LEEP at 6 months (18.1%, p < .01) and 12 months (44.8% vs 19.4%, p < .001). Cumulative incidence of low-grade cytology or greater in cryotherapy (90.5%) did not differ from LEEP at 6 months (80.7%, p = .08); by 12 months, cumulative incidence of low-grade cytology or greater was higher in cryotherapy (100%) than LEEP (94.8%, p = .03).Both treatments appeared effective in reducing cervical intraepithelial neoplasia grade ≥ 2 by > 70% by 12 months. The difference in cumulative cervical intraepithelial neoplasia grade ≥ 2 incidence between the 2 treatment methods by 12 months was not statistically significant. Relatively high cervical intraepithelial neoplasia grade ≥ 2 recurrence rates, indicating treatment failure, were observed in both treatment arms by 12 months. A different treatment protocol should be considered to optimally treat cervical intraepithelial neoplasia grade ≥ 2 in HIV-seropositive womenHigh
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