Radiotherapy for Gynecologic Cancer With Up to 10 Active Metastatic Lesions

OLIGYNE-10 RT is an investigator-initiated, international, multicenter, noninterventional master registry. All treatment decisions remain with the treating clinical teams. Qualifying radiotherapy may include stereotactic radiotherapy, other external beam techniques, brachytherapy, proton therapy, reirradiation, or qualifying combinations. Surgery, thermal ablation, and systemic treatment may be part of a combined strategy, but treatment without qualifying radiotherapy does not establish eligibility for the radiotherapy-treated core cohort.

Participants are enrolled consecutively: all patients meeting eligibility criteria at participating centers during the applicable enrollment period are included.

Data acquisition combines historical retrospective records, ambispective routine-care follow-up, and prospective enrollment. Prospective participants provide written informed consent before the first qualifying radiotherapy fraction or brachytherapy application. Inclusion in the radiotherapy-treated core cohort requires delivery of at least one qualifying fraction or application. The registry distinguishes screening from the treated analysis population.

Imaging-based stratification separates classical oligometastatic disease with 1 to 5 active metastatic lesions from an extended, hypothesis-generating group with 6 to 10 lesions confirmed by qualifying FDG PET/CT or FDG PET/MRI. Cases with 6 to 10 lesions assessed without qualifying PET are considered only in a separate exploratory module and are not pooled with the extended PET cohort in the main analysis. Polymetastatic progression thresholds refer to the total active metastatic burden, not only the number of newly detected lesions.

The date of qualifying oligometastatic disease assessment (T0-OMD), the first qualifying radiotherapy fraction or brachytherapy application in the index episode (T0-RT), and lesion-specific treatment dates are recorded separately. Clinical scenarios, imaging, tumor characteristics, radiotherapy technique and dosimetry, systemic treatment strategy, treatment completeness, response, progression, adverse events, subsequent treatments, and vital status are collected. Data windows harmonize available routine-care information and do not mandate additional clinical visits or scans.

Analyses will account for the primary cancer, histology and molecular characteristics, oligometastatic disease scenario, disease burden, imaging, treatment context, and center. Historical and prospective cohorts will initially be reported separately for endpoints sensitive to documentation quality. Time-to-event, competing-risk, multivariable, multistate, propensity-score, landmark, and time-dependent analyses may be used as appropriate. Comparisons of systemic treatment strategies are observational and will be interpreted with consideration of confounding by indication.

Optional patient-reported outcome and translational modules require the applicable consent and separate approvals. The core registry does not mandate additional biospecimen collection or research imaging. Direct patient identifiers are not transferred to the central registry database; analyses and publications use pseudonymized or aggregate information.

• Routine-care metastasis-directed radiotherapy (Radiation): Qualifying radiotherapy delivered as routine clinical care to at least one active metastatic lesion, with radical, consolidative, or metastasis-directed intent for durable local control. Eligible modalities include SBRT/SABR, stereotactic or hypofractionated external beam radiotherapy, conventional metastasis-directed external beam radiotherapy, brachytherapy, proton therapy, and qualifying combinations. Reirradiation is permitted. The treating team determines the indication, technique, dose, fractionation, target selection, treatment sequence, and any systemic treatment. The registry observes and records care; it does not assign or randomize treatment, prescribe a dose, or mandate additional imaging, visits, or other clinical procedures.

Primary outcomes

• Radiographic progression-free survival (rPFS) [From the first qualifying radiotherapy fraction or brachytherapy application (T0-RT), assessed for up to 5 years.]: Time from T0-RT to first radiographic progression at any site or death from any cause. Participants without an event are censored at the last reliable radiographic assessment. Clinical progression without imaging is recorded separately and considered in sensitivity analyses.

Secondary outcomes

• Polymetastatic progression-free survival: classical threshold (PMFS-C5) [From the first qualifying radiotherapy fraction or brachytherapy application (T0-RT), assessed for up to 5 years.]: Time from T0-RT to more than 5 total active metastatic lesions, diffuse or uncountable disease, or death. Evaluated only in participants with 1-5 active metastatic lesions at T0-OMD. The threshold uses total active metastatic burden, not only newly detected lesions.
• Polymetastatic progression-free survival: extended threshold (PMFS-E10) [From the first qualifying radiotherapy fraction or brachytherapy application (T0-RT), assessed for up to 5 years.]: Time from T0-RT to more than 10 total active metastatic lesions, diffuse or uncountable disease, or death. Evaluated in the PET-defined cohort with 1-10 lesions. PMD-E10 status is indeterminate when follow-up imaging cannot assess the threshold, unless more than 10 lesions or diffuse disease is unequivocal.
• Time to loss of the oligometastatic state (TLOMS) [From the first qualifying radiotherapy fraction or brachytherapy application (T0-RT), assessed for up to 5 years.]: Time from T0-RT to loss of the oligometastatic state through progression to the applicable polymetastatic threshold or diffuse disease. Death is treated as a competing event in the disease-state estimand.
• Systemic therapy start or switch-free survival (SST-FS) [From the first qualifying radiotherapy fraction or brachytherapy application (T0-RT), assessed for up to 5 years.]: Time from T0-RT to initiation of systemic anticancer treatment, a change in treatment line, escalation of the systemic strategy, or death. Event rules depend on the baseline systemic-treatment setting.
• Overall survival (OS) [From the first qualifying radiotherapy fraction or brachytherapy application (T0-RT), assessed for up to 5 years.]: Time from T0-RT to death from any cause.
• Treated-lesion local control [From the first radiotherapy fraction or brachytherapy application to each lesion, assessed for up to 5 years.]: Time from the first radiotherapy fraction or brachytherapy application to the individual lesion to unequivocal in-field progression. Death without lesion progression is treated as a competing event. Lesions are assessed individually.
• Pattern of first progression [At first progression after T0-RT, during follow-up of up to 5 years.]: Description of first progression by anatomical site, number of active lesions, detection modality, local feasibility of subsequent metastasis-directed therapy, and oligometastatic or polymetastatic disease status.
• Systemic therapy-free survival (STFS) [From the first qualifying radiotherapy fraction or brachytherapy application (T0-RT), assessed for up to 5 years.]: Among participants without active systemic treatment at T0-RT, time to initiation of any systemic anticancer treatment or death.
• Time to next systemic therapy line (TTNSL) [From the first qualifying radiotherapy fraction or brachytherapy application (T0-RT), assessed for up to 5 years.]: Time from T0-RT to the first new systemic treatment line after the index strategy. Continuation of a regimen started as part of the index strategy is not an event until treatment is changed or escalated.
• Time to initiation or change of cytotoxic chemotherapy (CFS) [From the first qualifying radiotherapy fraction or brachytherapy application (T0-RT), assessed for up to 5 years.]: Time from T0-RT to initiation or change of cytotoxic chemotherapy. Continuation of non-cytotoxic treatment is not an event.
• Maintenance treatment strategy preservation interval (MTPI) [From the first qualifying radiotherapy fraction or brachytherapy application (T0-RT), assessed for up to 5 years.]: Among participants receiving maintenance or continuing therapy, time from T0-RT to permanent discontinuation, escalation or change of that strategy because of progression, an adverse event or a clinical decision. A temporary hold followed by resumption of the same therapy is not an event.
• Time to subsequent metastasis-directed therapy (TTMDT) [From the first qualifying radiotherapy fraction or brachytherapy application (T0-RT), assessed for up to 5 years.]: Time from T0-RT to subsequent metastasis-directed treatment, particularly a subsequent course of radiotherapy.
• Complete response of treated lesions [Approximately 3 months (±6 weeks) and 6 months (±8 weeks) after completion of index radiotherapy.]: Complete response assessed separately for treated lesions at approximately 3 and 6 months after completion of radiotherapy, according to local practice, preferably RECIST 1.1, supplemented by metabolic criteria when PET is used.
• Patient-level complete response [Approximately 3 months (±6 weeks) and 6 months (±8 weeks) after completion of index radiotherapy.]: Complete response at participant level assessed at approximately 3 and 6 months after completion of radiotherapy, according to local practice, preferably RECIST 1.1, supplemented by metabolic criteria when PET is used.
• Acute adverse events [From initiation of radiotherapy through 90 days after completion of index radiotherapy.]: Acute adverse events characterized by term, grade, dates, seriousness, attribution, intervention, hospitalization, treatment interruption and outcome. Baseline events are recorded separately. CTCAE v6.0 is used for prospectively collected data; historical data retain the source version and are mapped only when reliable.
• Late adverse events [More than 90 days after completion of index radiotherapy, assessed during follow-up of up to 5 years.]: Adverse events occurring more than 90 days after completion of radiotherapy, characterized by term, grade, dates, seriousness, attribution, intervention and outcome. CTCAE v6.0 is used for prospectively collected data; historical data retain the source version and are mapped only when reliable.
• PET-associated disease-burden reclassification [At baseline, using CT/MRI and FDG-PET performed no more than 28 days apart, without intervening treatment that changes disease burden.]: Reclassification of the number of active metastatic lesions between 1-5, 6-10, and more than 10 or diffuse-disease categories after incorporating FDG-PET. Paired CT/MRI-PET comparisons require scans no more than 28 days apart without intervening treatment that changes disease burden.
• PET-associated management change [During qualifying baseline staging and planning for the index radiotherapy strategy.]: PET-associated changes in eligibility, treatment intent, target selection, radiation fields or systemic-treatment strategy for the index episode.
• Discordance between conventional imaging and FDG-PET [At baseline, using CT/MRI and FDG-PET performed no more than 28 days apart, without intervening treatment that changes disease burden.]: Differences between CT/MRI and FDG-PET in the number and anatomical location of active metastatic lesions, assessed in the paired-imaging population.
• Distant disease progression-free interval [From T0-RT, assessed for up to 5 years.]: Time from T0-RT to the first radiographically documented new lesion or unequivocal progression of an existing lesion outside the prespecified disease-specific locoregional compartment. This includes progression of distant metastases present at baseline. Compartments are defined relative to the primary tumor, independently of the radiation fields.
• Locoregional disease progression-free interval [From T0-RT, assessed for up to 5 years.]: Time from T0-RT to the first radiographically documented new lesion or unequivocal progression within the primary tumor or operative bed and the regional nodal basins prespecified for the primary gynecological site. Locoregional status is anatomical and is not defined by whether a lesion lies within a radiation field.
• Time to deterioration in EORTC QLQ-C30 global health status/quality of life [From T0-RT, assessed in the approved PRO module for up to 5 years.]: Only where the optional PRO module has been approved and activated, and the required participant consent has been obtained, time from T0-RT to the first observed decrease of at least 10 points from a valid pre-radiotherapy baseline in the EORTC QLQ-C30 Global Health Status/QoL scale (items 29-30; range 0-100; higher scores indicate better health/QoL). The event date is the questionnaire date; confirmation at a later assessment is not required.
• Change in EORTC QLQ-C30 global health status/quality of life [Baseline before radiotherapy and approximately 3 months (±6 weeks) and 6 months (±8 weeks) after completion of index radiotherapy.]: Only where the optional PRO module has been approved and activated, and the required participant consent has been obtained, mean change from a valid pre-radiotherapy baseline in the EORTC QLQ-C30 Global Health Status/QoL scale (items 29-30; range 0-100), assessed separately at approximately 3 and 6 months after completion of radiotherapy. Positive change indicates improvement and negative change indicates deterioration. No binary preservation threshold is applied.
• Patient-reported general pain and fatigue using PRO-CTCAE [Baseline before radiotherapy and approximately 3 months (±6 weeks) and 6 months (±8 weeks) after completion of index radiotherapy; each questionnaire uses a 7-day recall.]: Only where the optional PRO module has been approved and activated, and the required participant consent has been obtained, response-category distributions and changes from pre-radiotherapy baseline are reported separately for General pain frequency, severity and interference, and Fatigue severity and interference, using the five corresponding PRO-CTCAE items with a 7-day recall. No combined score, CTCAE-grade conversion or clinically meaningful responder threshold is used.
• Unplanned hospital and urgent-care use during the first 180 days [The first 180 calendar days beginning on T0-RT (day 0 through day 179).]: During the first 180 calendar days beginning on T0-RT, report separately per participant the number of unplanned inpatient admission episodes, urgent or unscheduled visits, and unique days spent in unplanned inpatient care. Transfers during one continuous inpatient stay do not constitute a new admission. Components are not combined into a single score.
• Days alive and out of hospital during the first 180 days (DAOH-180) [The first 180 calendar days beginning on T0-RT (day 0 through day 179).]: Number of calendar days alive and not in inpatient care during days 0-179 beginning on T0-RT; range 0-180. Both planned and unplanned inpatient stays count as hospital days. A day with any inpatient care counts once; outpatient-only visits do not subtract a day. The date of death and subsequent days contribute zero. A value is calculated only when vital status and inpatient dates are adequately documented.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Age at least 18 years at the reference eligibility date: at signing of consent/prospective enrollment, or at T0-RT for historical and ambispective cohorts.
* Histologically confirmed primary gynecologic malignancy. Biopsy of every metastatic lesion is not required if its nature is unequivocal clinically and on imaging, or confirmed by the multidisciplinary team.
* One to 10 active metastatic lesions at the qualifying assessment, subject to the protocol imaging strata. The extended PET core cohort with 6-10 lesions requires qualifying FDG PET/CT or FDG PET/MRI.
* For the RT-treated core population: receipt of at least one qualifying radiotherapy fraction or brachytherapy application to an active metastatic lesion, with radical, consolidative or metastasis-directed intent. Before RT starts, only screening registration is possible.
* Availability of T0-OMD, T0-RT, lesion number and location, and systemic strategy data; for historical cohorts, at least one follow-up outcome or vital-status observation.
* For the prospective cohort: ability to provide informed consent and a signed consent form before the first qualifying radiotherapy fraction or brachytherapy application.

Exclusion Criteria:

* No confirmed gynecologic malignancy.
* Surgery, ablation or systemic therapy alone without qualifying radiotherapy to a metastatic lesion.
* Radiotherapy solely for symptom relief without intent to achieve durable control of the treated lesion, if it does not meet the MDT criteria specified in the analysis plan.
* More than 10 active metastatic lesions or diffuse/uncountable disease at T0-OMD, for the core analysis.
* A prospective case with 6-10 lesions without qualifying FDG PET/CT or FDG PET/MRI cannot enter the extended PET core cohort. It may enter only a separate exploratory module if otherwise eligible.
* Lack of minimum data that prevents determination of eligibility, T0-RT or outcome.
* No informed consent in the prospective cohort.

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• Mateusz Bilski, MD, PhD, Principal investigator, Affidea NU-MED Centrum Diagnostyki i Terapii Onkologicznej, Zamosc, Poland