This phase II trial compares the effect of hypofractionated radiotherapy (HFRT) to conventional fractionated radiotherapy (CFRT) when given in combination with cisplatin and brachytherapy in patients with stage IB3, II, or III cervical cancer. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill tumor cells and shrink tumors. CFRT delivers the total dose of radiation over the amount of time according to standard practice. HFRT delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. HFRT shortens treatment duration and may reduce costs and may improve the completion rates. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of tumor cells. Brachytherapy, also known as internal radiation therapy, uses radioactive material placed directly into or near a tumor to kill tumor cells. HFRT may be safe, tolerable, and/or as effective as CFRT when given in combination with cisplatin and brachytherapy in treating patients with stage IB3, II or III cervical cancer.
Females aged 18 years or older
Histologically confirmed squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the uterine cervix without prior treatment
Federation of Gynecology and Obstetrics (FIGO) 2018 stage IB3, IIA, IIB, IIIA, IIIB, or IIIC
Able to provide written informed consent in English, Luganda, Runyankole, or Lango
Prior hysterectomy. Women with previous total or subtotal hysterectomy have no cervix, and hence the anatomical changes have an impact on the radiotherapy field, and dose prescriptions because they tend to have a higher risk for bowel toxicity from pelvic radiotherapy. Therefore, these women will be excluded due to the likely impact on the results of our study intervention
Clinical and/or radiological evidence of distant metastases
Prior pelvic or abdominal radiotherapy
Presence of bilateral hip prosthesis that could interfere with radiotherapy treatment
Parallel
Hypofractionated Radiation Therapy
RadiationUndergoing HFRT - The prescription dose will be 40 Gy in 16 fractions (2.5 Gy/fraction) to the entire pelvis, with concurrent integrated nodal boost at 3.0 Gy per fraction (48 Gy) to involved (positive) pelvic nodes, delivered once a day, Monday through Friday, 5 fractions per week, using volumetric modulated arc therapy (VMAT).
Conventional Fractionated Radiotherapy
RadiationUndergoing CFRT
Cisplatin
DrugUndergoing Cisplatin
High-Dose Rate Brachytherapy
RadiationUndergoing HDR Brachytherapy
External Beam Radiotherapy Boost
RadiationUndergoing external beam radiotherapy boost
Computed Tomography
Procedure/SurgeryUndergoing CT scan
Biospecimen Collection
Procedure/SurgeryUndergoing blood sample collection
Questionnaire and Physical Exam
Other interventionAncillary Studies
Incidence of adverse events (AEs)
It will be categorized into 5 grades. The Conchran-Mantel-Haenszel test will be used to compare differences in the grades of AEs between patients who will receive hypofractionated radiotherapy versus conventional fractionated radiotherapy by stratifying for HIV status. A p-value of \< 5% will be regarded as significant.
Incidence of grade 3 or greater radiotherapy-related gastrointestinal or genitourinary AEs
Will compare the proportion of patients between the hypofractionated radiotherapy and conventional fractionated radiotherapy using a risk difference approach, and the 95% confidence interval (CI) for the difference in proportion will be estimated using the Farrington-Manning test. Non-inferiority will be determined when the upper bound of a two-sided 95% CI is less than 10%.
Local control (complete remission, stable disease, and partial response) rate
Will be compared using means, medians, standard deviations, and ranges for continuous variables and frequencies and percentages for categorical variables. Differences in local control for each treatment group and the 95% CI will be calculated using the Chi-square test or Fisher's exact test. Data on tumor sizes that are normally distributed will be presented as means and standard deviations with 95% CI. The log-rank test will be used to compare the local control rates. The mean difference between groups will be calculated using an independent T-test for normally distributed data. Will compare the proportion between arms using a risk difference approach and the 95% CI, the difference in proportion will be estimated using the Farrington-Manning test. Non-inferiority will be determined when the upper bound of a two-sided 95% Confidence interval is less than 10%.
Cervical cancer-specific survival
Will be estimated for both groups using the Kaplan-Meier method. Non-inferiority will be declared when the upper bound of the two-sided 95% CI hazard ratio is less than 1.1. Multivariable Regression analysis will be used to estimate the association between the treatment arm and local control while adjusting for potential confounders such as age, stage, and hemoglobin level.
Progression-free survival (PFS)
Will be computed using the Kaplan-Meier survival curves, describing the median PFS and its 95% CI.
Squamous cell carcinoma antigen (SCC-Ag)
It will be assessed using an enzyme-linked immunosorbent assay. A "positive biochemical response" is defined as a decrease in SCC-Ag levels after treatment, whereas a "negative biochemical response" is defined as an increase in SCC-Ag levels after treatment based on an increase in SCC-Ag values exceeding 1 ng/mL. Will be presented as means, medians, standard deviations, and ranges. Differences in SCC-Ag levels at the end of treatment between groups and the 95% CI will be calculated. A multivariable linear regression model will be used to adjust SCC-Ag levels for the cancer stage.
Association of SCC-Ag levels and PFS
The Pearson or Spearman correlation coefficients will be used to estimate the association between stage-adjusted SCC-Ag levels and PFS. Cox proportional hazards regression models will be used to determine the correlation between stage-adjusted SCC-Ag levels and PFS.
Health-related quality of life (costs of healthcare)
The total cost per patient, the differences between the costs in the two arms, and the 95% CI will be calculated. The volume of resources and costs will mainly be reported as mean values with standard deviations and mean differences with 95% CI using an independent student t-test. All analysis will be conducted using Stata version 16.0.
Patient-reported outcomes and quality of life
Will be calculated, and reported in mean scores, with standard deviation and/or 95% CI. The mean score will be compared between arms with Welch's t-test.
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Uganda Cancer Institute
Lead sponsor
Varian Medical Systems
Collaborator
Fogarty International Center of the National Institute of Health
Collaborator
