Gynaecological endometrium definitive EBRT with or without chemotherapy

• Endometrial cancer including endometrioid adenocarcinoma, serous carcinoma, clear cell carcinoma and carcinosarcoma, undifferentiated.
• FIGO stage I - IVA.
• Patient that declines surgery or is medically inoperable (deemed high-risk by surgical and anaesthetic teams at a tertiary centre).

• ECOG 0-2.

Cautions

• Non-rheumatoid collagen vascular disorders.

• Inflammatory bowel disease and/or history of adhesions/bowel obstruction.

• Renal transplant and horseshoe kidney.

• Prior radiation therapy to the pelvis.

Exclusions

• Patients not eligible for brachytherapy boost.

• Pregnancy.

• EBRT with brachytherapy boost +/- systemic therapy is the preferred treatment approach for definitive treatment for endometrial cancer.       
• Patients should receive brachytherapy boost at the completion of EBRT.

• Current smokers should be referred to a smoking cessation program.

 Sequential prescription

 Simultaneous integrated boost (SIB) prescription

*55-60 Gy EQD2.

Prescription notes

• High dose rate (HDR) brachytherapy boost must follow this protocol. For brachytherapy protocol information see endometrium definitive brachytherapy boost (ID 3747) protocol.

The use of IMRT/VMAT techniques to minimise OAR toxicity is recommended.^rr

Margin ranges have been agreed by the Radiation Oncology reference committee and reflect safe clinical practice.

Target volume notes

• For additional information on volumes refer to Schwarz et al. 2015.^r

Recommended contouring guidelines

• NRG Oncology/RTOG Consensus Guidelines for Delineation of Clinical Target Volume for Intensity Modulated Pelvic Radiation Therapy in Postoperative Treatment of Endometrial and Cervical Cancer: An Update opens in a new tab or window.^r

• Lim et al. 2011 provide guidelines for:^r
  • contouring of target volumes on MRI, most of which can be extrapolated to CT.
  • delineation of CTV for IMRT pelvic radiation therapy for definitive treatment of cervix cancer.

• Taylor et al. 2007 provide guidelines for defining nodal regions in the pelvis.​^r

• Japan Clinical Oncology Group (JCOG) provide consensus-based guidelines for defining CTV.^r

OAR notes

Recommended contouring guidelines

• Suggested contouring atlas are available at NRG oncology - Gynaecologic Cancer Atlases, Templates, & Tools opens in a new tab or window.

Target verification recommendations reflect the minimum imaging required for the safe delivery of this protocol.

Efficacy

The incidence of endometrial cancer is growing and is the second most commonly diagnosed gynaecological malignancy worldwide.^r 

The standard of care for endometrial cancer in high-intermediate-risk disease is surgery followed by adjuvant radiation therapy (RT). In high-risk disease the addition of concurrent adjuvant chemotherapy is appropriate.^rr A small percentage (<5% to up to 10%) of patients are deemed inoperable due to medical co-morbidities.^rr Primary RT with curative intent is reserved for patients in this setting. Local control can be achieved by a combination of external beam radiation therapy (EBRT) and intra-cavitary high dose rate (HDR) brachytherapy or HDR brachytherapy alone. Pelvic external beam RT treats areas at risk for locoregional spread and with the aim of cytoreduction of bulkier tumours prior to brachytherapy treatment.

A search of the literature did not find strong (level 1) evidence to support the use of definitive RT in the treatment of inoperable endometrial cancer. For patients with extrauterine spread (stage II or III) or bulky stage 1 disease a combination of external beam radiation therapy to the whole pelvis and brachytherapy is recommended.^r Early-stage disease can be treated with brachytherapy alone and is covered in ID 3747: Gynaecological endometrium definitive HDR brachytherapy alone or boost. 

There are several retrospective and observational studies describing the use of definitive EBRT and brachytherapy for inoperable endometrial cancer. A selection of the most recent and pertinent studies is outlined in the above  evidence table. Dose fractionations are highly variable and often patient specific but in the majority of cases the EBRT doses ranges from 45 Gy in 25 fractions to  50.4Gy in 28 fractions with some studies utilising higher doses (up to 59 Gy) for gross nodal disease with sequential or simultaneous integrated boost techniques.

There is large variability in the outcome measures reported in this cohort largely due to the heterogeneity of patients included. Local control rates ranged between 81-100% at 2-4 years for stages I-III. Cause specific survival (CSS) and overall survival (OS) at 5 years ranged similarly from 71%- 93%.^rrrrrrr As expected, outcomes for high-risk histological subtypes, where reported as worse than low risk disease.

For patients unable to undergo brachytherapy there is limited evidence to guide management. Evidence for high dose EBRT is lacking. Consideration can be given to a stereotactic body RT (SBRT) boost in lieu of brachytherapy in select cases. Kemmerer et al. reported comparable outcomes to EBRT + brachytherapy using a SBRT boost technique sequentially to conventional EBRT.^r This approach can be considered on a case-by-case basis with input from a specialist multidisciplinary team (MDT).

There is no level 1 evidence to guide the use of systemic therapy in the medically inoperable setting, with the above studies employing various uses and sequencing of chemotherapy. Extrapolating from the cervical cancer literature and given the inferior outcomes of these patients, especially in the high-risk histological subgroups, consideration should be given for radiosensitising chemotherapy given concurrently with definitive RT, if tolerated by the patient, as there may be a potential benefit.^r However, the same medical reasons that preclude surgery in these patients may also preclude systemic therapy.

Toxicity

The table below provides a summary of the most clinically relevant toxicities linked to this protocol. Overall, the rates of acute and late toxicity are similar to those observed in data for more common uses of definitive and adjuvant pelvic radiation therapy for gynaecological malignancies.