BACKGROUND: For patients with locally advanced cervical cancer (LACC) ineligible for concurrent chemotherapy, radiotherapy (RT) alone achieves complete response rate (CRR) \<70% and long-term locoregional control (LRC) \<62%. Hypofractionated (HF-)RT using older techniques results in comparable CRR and disease control, and low late toxicity rates (4-8%). Dose-adapted HF-RT using intensity-modulated radiotherapy (IMRT) with nodal simultaneous integrated boost (nSIB) could improve tumor control and toxicity.
GENERAL OBJECTIVE: To determine the effectiveness and safety of HF-RT with (or without) nSIB in LACC among patients who are chemo-ineligible.
PRIMARY OBJECTIVES:
Phase 1: To determine the maximum tolerated dose (MTD) for nSIB used in combination with pelvic HF-RT (2.67 Gray (Gy) x 15 fractions), using IMRT Phase 2: To assess the efficacy of HF-RT ± nSIB in terms of complete response rates at 3 months
SECONDARY OBJECTIVES:
To assess the efficacy of HF-RT ± nSIB in terms of progression free survival (PFS), locoregional PFS, distant metastasis free survival (DMFS), cervical cancer specific survival (CCSS), overall survival (OS)
To assess the acute and late toxicity of HF-RT ± nSIB, and patient-reported quality of life outcomes
EXPLORATORY OBJECTIVES:
To evaluate the predictive utility of clinical and dosimetric variables for tumor response/control and toxicity. Variables: age, performance status, T- and N-stage, T-score, histology, baseline hemoglobin, clinical target volume and organs-at-risk doses, overall treatment time
STUDY DESIGN:
Phase 1: Dose-escalation study (standard 3+3 design) Phase 2: Single-arm clinical trial (Simon's two-stage design)
STUDY TREATMENTS:
Pelvic HF-RT ± nSIB to 40 Gy in 15 fractions using IMRT, followed by brachytherapy (BRT) 6.5-7.5 Gy x 4 fractions using 2D or image-guided techniques
SAMPLE SIZE:
One-sided hypothesis testing. H0: CRR p0 ≤64%; H1: CRR p1 ≥84%. Simon 2 stage: First stage, n1=28 will be enrolled. If response (r1) ≤18, the study will be stopped for futility. Otherwise, second stage: n2=22, for a total of 50.
H0 will be rejected if r1+r2 ≥38, in 50 patients. This yields a type I error rate of 5% and power of 95% when the true response rate is ≥84%.
Accrual: Accounting for 10% attrition, a n=55 will be targeted. At a rate of 4-5 patients quarterly, accrual may take 33-42 months. The trial may be opened to other centers to accelerate accrual.
Females aged ≥18 years
Histologically confirmed cervical squamous, adeno-, or adenosquamous carcinoma
2018 Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) Stage IIIA-IIIC1, IVA
Pelvic nodal metastases (for the phase 1 cohorts)
Other histology (small cell, neuroendocrine, lymphoma, sarcoma, etc.)
2018 FIGO Stage IIIC2 (para-aortic nodal metastases)
Clinical and/or radiologic evidence of metastatic disease
History of another malignancy except for the following: malignancy treated with curative intent and with no known active disease ≥5 years and of low potential risk for recurrence; adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; adequately treated carcinoma-in-situ without evidence of disease
Single group
Hypofractionation
RadiationPhase 1 (Dose Escalation Study): Pelvic hypofractionated radiotherapy (40 Gy over 15 daily fractions) with nSIB 45 Gy (first dose level) and 48 Gy (second dose level); to be followed by brachytherapy (6.5-7.5 Gy x 4 fractions) Phase 2 (Efficacy Study): Pelvic hypofractionated radiotherapy (40 Gy over 15 daily fractions) with (or without) nSIB 45-48 Gy (depending on phase 1 results); to be followed by brachytherapy (6.5-7.5 Gy x 4 fractions)
Maximum tolerated dose (for phase 1)
The highest dose studied for which the incidence of dose-limiting toxicity was less than 33%
Complete response rate (for phase 2)
Proportion of treated patients with disappearance of all lesions on clinical and radiologic examination
Progression-free survival
Time from date of enrolment to date of progression, date of death from any cause, or date of last follow-up, whichever occurs first
Locoregional progression-free survival
Time from date of enrolment to date of locoregional progression, date of death from any cause, or date of last follow-up, whichever occurs first
Metastasis-free survival
Time from date of enrolment to date of development of metastasis, date of death from any cause, or date of last follow-up, whichever occurs first
Cervical cancer-specific survival
Time from date of enrolment to date of death attributed to cervical cancer, or date of last-follow-up, whichever occurs first
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University of Santo Tomas Hospital, Philippines
Lead sponsor
Philippine Council for Health Research & Development
Collaborator
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