Keywords

Hypofractionation in the radiotherapeutic management of endometrial cancer has an important but selective role, mainly in terms of postoperative vaginal cuff HDR brachytherapy . SBRT is used for oligometastatic disease, rarely as a boost technique with EBRT and for palliation. These data have mostly been reported from retrospective cohort studies that include other gynecological malignancies as discussed in the cervical cancer chapter. Surgery [total hysterectomy with bilateral salpingo-oophorectomy (BSO)] with or without nodal assessment (sentinel lymph node biopsy or nodal dissection) is the primary treatment of endometrial cancer. Recommendations for adjuvant radiotherapy are based on surgical pathology. Factors considered include depth of invasion, grade, lymphovascular space invasion, and nodal involvement. The use of postoperative vaginal cuff brachytherapy for high-intermediate-risk early-stage endometrial cancer is increasing in the recent years after reports indicating its efficacy in local control and favorable toxicity profile compared to pelvic EBRT.

1 Pearls

  • Uterine cancer is the most common gynecologic malignancy in the USA and the sixth most common cancer diagnosis in women worldwide.

  • Mostly diagnosed in postmenopausal women (median age 63 years); 4% of the women are younger than 40 years.

  • It is most common in white women followed by African-Americans, Hispanics, and Asian women. Notably, African-American women experience poorer prognosis, regardless of stage, pathology, socioeconomic status, and treatment.

  • Risk factors include excess (unopposed) estrogen exposure: early age at menarche, nulliparity, late age at menopause, obesity, estrogen-secreting tumors, tamoxifen therapy, and estrogen-progestin postmenopausal hormone therapy. Diabetes mellitus and high-fat diet are also considered risk factors.

  • Genetic predisposition: Lynch syndrome, BRCA1 mutation.

  • The most common presenting symptom is postmenopausal uterine bleeding (75–90%).

  • Most diagnoses occur at an early stage: disease confined to the uterus (67–80%), spread to regional lymph nodes and organs (21%), and distant metastases (12%).

  • Histology: Adenocarcinoma (i.e., endometrioid cancer) is the most common subtype (90–95%). Type 1 cancers (75–80%) are estrogen-dependent, low-grade, and uterus-confined cancers that typically occur in postmenopausal women and have favorable prognosis. Type 2 cancers (10–20%) are estrogen-independent, non-endometrioid (serous, clear cell, mixed histology, undifferentiated, carcinosarcoma) cancers with poorer prognosis. Uterine sarcoma ~ 5%.

  • Patterns of spread:

    • Local spread is through invasion of the myometrium or the cervix and less commonly to uterine serosa, parametria, or vagina.

    • Extrauterine spread of endometrioid cancer primarily occurs through lymphatic drainage to locoregional lymph nodes (pelvic, iliac, obturator, presacral, and para-aortic) and the adnexa.

    • Surgical series have described several pathologic risk factors for lymphatic spread including depth of invasion, tumor grade [1], tumor sizes [2], and lymphovascular space invasion (LVSI) [3].

    • Hematogenous dissemination to the lungs and liver is less common. Uterine sarcoma can spread to the lungs.

  • Medical workup:

    • Physical exam including a pelvic exam with speculum and bimanual examination. For women with postmenopausal vaginal bleeding, the American College of Obstetricians and Gynecologists recommends initial evaluation with either endometrial biopsy or transvaginal ultrasonography. Endometrial thickness of greater than 4 mm on ultrasound requires a biopsy. Non-diagnostic endometrial biopsy should be followed by dilation and curettage.

    • Laboratory tests: CBC, serum chemistries, LFTs, and renal function tests. CA-125 is optional for high-grade endometrioid histology, advanced stage, and serous or clear cell histology.

    • Though the majority of women diagnosed are postmenopausal, fertility consultation should be considered for patients of childbearing age.

  • Imaging studies:

    • For patients, who will have surgical staging and primary treatment, preoperative imaging is reserved for those with high-grade or non-endometrioid cell types or suspected advanced stage on clinical evaluation.

    • Suspected/gross cervical involvement: contrast abdomen and pelvis MRI is recommended to evaluate extent of disease.

    • Suspected extrauterine disease: MRI/CT/PET as clinically indicated.

  • Operable patients undergo initial hysterectomy (open, laparoscopic, or robotic) with BSO ± adjuvant treatment based on age, stage, and pathologic risk factors.

  • The highest-risk site of disease recurrence after surgery is at the vaginal cuff.

  • Adjuvant therapy primarily includes EBRT and/or vaginal brachytherapy (VBT) . Chemotherapy may be administered for advanced disease. Recent data showed that VBT is as effective as EBRT in reducing vaginal recurrences in select FIGO stage I intermediate- to high-intermediate-risk patients, who have a low risk of lymph node involvement [4].

  • Patients with FIGO stage II endometrial cancer may be candidates for VBT ± EBRT based on other pathologic risk factors.

  • Patients with FIGO stage III endometrial cancer typically receive chemotherapy with pelvic EBRT.

  • Medically inoperable patients with early-stage disease without risk factors per MRI (positive LN, deep myometrium involvement) can be treated by intracavitary brachytherapy alone or EBRT + brachytherapy [5]. Hormone therapy (either systemic or via a hormonal intrauterine device) alone can be considered for unfit patients [6].

  • Patients with unresectable disease (e.g., invasion of the vagina, bladder, rectum) or with extrauterine pelvis disease are candidates for EBRT + brachytherapy ± chemotherapy, or neoadjuvant chemotherapy or chemoradiotherapy followed by surgical resection or chemotherapy alone.

  • Treatment for locoregional recurrences is dependent on primary cancer treatment as well as site of recurrence. Patients without prior RT are treated with EBRT ± brachytherapy. Recurrences at the vaginal cuff are amenable to intracavitary or interstitial brachytherapy , while nodal or pelvic sidewall recurrences are typically treated with EBRT alone. Patients, who recur in or adjacent to a prior RT field, are treated with surgical exploration with resection ± intraoperative radiotherapy (IORT) and/or systemic therapy.

  • Limited nodal recurrence may be amenable to hypofractionated radiotherapy using SBRT with good efficacy and favorable toxicity in retrospective review [7] and in single-institution prospective evaluation [8], though further evaluation of this strategy may be warranted.

  • Regardless of tumor type, the estimated 5-year OS is 85–90% for stage I, 75–85% for stage II, 50–65% for stage III, and 20–25% for stage IV (FIGO 26th report).

2 AJCC and FIGO Staging

Primary tumor (T)

T category

FIGO stage

T criteria

TX

 

Primary tumor cannot be assessed

T0

 

No evidence of primary tumor

T1

I

Tumor confined to the corpus uteri, including endocervical glandular involvementa

 T1a

IA

Tumor limited to the endometrium or invading less than half the myometrium

 T1b

IB

Tumor invading one half or more of the myometrium

T2

II

Tumor invading the stromal connective tissue of the cervix but not extending beyond the uterus. Does NOT include endocervical glandular involvement

T3

III

Tumor involving serosa, adnexa, vagina, or parametrium

 T3a

IIIA

Tumor involving the serosa and/or adnexa (direct extension or metastasis)

 T3b

IIIB

Vaginal involvement (direct extension or metastasis) or parametrial involvement

T4

IVA

Tumor invading the bladder mucosa and/or bowel mucosa (bullous edema is not sufficient to classify a tumor as T4)

Regional lymph nodes (N)

N category

FIGO stage

N criteria

NX

 

Regional lymph nodes cannot be assessed

N0

 

No regional lymph node metastasis

N0(i+)

 

Isolated tumor cells in regional lymph node(s) no greater than 0.2 mm

N1

IIIC1

Regional lymph node metastasis to pelvic lymph node

 N1mi

IIIC1

Regional lymph node metastasis (greater than 0.2 mm but not greater than 2.0 mm in diameter) to pelvic lymph nodes

 N1a

IIIC1

Regional lymph node metastasis (greater than 2.0 mm in diameter) to pelvic lymph nodes

N2

IIIC2

Regional lymph node metastasis to Para-aortic lymph nodes, with or without positive pelvic lymph nodes

 N2mi

IIIC2

Regional lymph node metastasis (greater than 0.2 mm but not greater than 2.0 mm in diameter) to Para-aortic lymph nodes, with or without positive pelvic lymph nodes

 N2a

IIIC2

Regional lymph node metastasis (greater than 2.0 mm in diameter) to Para-aortic lymph nodes, with or without positive pelvic lymph nodes

Suffix (sn) is added to the N category when metastasis is identified only by sentinel lymph node biopsy

Distant metastasis (M)

M category

FIGO stage

M criteria

M0

 

No distant metastasis

M1

IVB

Distant metastasis (including metastasis to inguinal lymph nodes, intraperitoneal disease, lung, liver, or bone) (it excludes metastasis to pelvic or Para-aortic lymph nodes, vagina, uterine serosa, or adnexa)

Prognostic state groups

When T is…

And N is…

And M is…

Then the stage group is…

T1

N0

M0

I

T1a

N0

M0

IA

T1b

N0

M0

IB

T2

N0

M0

II

T3

N0

M0

III

T3a

N0

M0

IIIA

T3b

N0

M0

IIIB

T1-T3

N1/N1mi/N1a

M0

IIIC1

T1-T3

N2/N2mi/N2a

M0

IIIC2

T4

Any N

M0

IVA

Any T

Any N

M1

IVB

Histologic grade (G)

G

G definition

 GX

Grade cannot be assessed

 G1

Well differentiated

 G2

Moderately differentiated

 G3

Poorly differentiated or undifferentiated

Histopathology: Degree of differentiation

Cases or carcinoma of the corpus uteri should be grouped according to the degree of differentiation of the endometrioid adenocarcinoma

G

G definition

 G1

5% or less of nonsquamous or nonmorular solid growth pattern

 G2

6–50% of a nonsquamous or nonmorular solid growth pattern

 G3

More than 50% of a nonsquamous or nonmorular solid growth pattern. Papillary serous, clear cell, and carcinosarcoma are considered high grade

  1. NOTES on pathologic grading
  2. 1. Notable nuclear atypia exceeding that which is routinely expected for the architectural grade increases the tumor grade by 1 (i.e., 1 to 2 and 2 to 3)
  3. 2. Serous, clear cell, and mixed mesodermal tumors are high risk and considered grade 3
  4. Adenocarcinomas with benign squamous elements (squamous metaplasia) are graded according to the nuclear grade of the glandular component
  5. Used with permission of the American College of Surgeons, Chicago, Illinois. The original course for this information is the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing
  6. aEndometrial intraepithelial carcinoma (EIC) should be considered a T1 cancer

3 Patient Selection

Adjuvant setting (after hysterectomy/BSO) : FIGO stage I–II

  • Surgical pathology must be fully assessed to determine recommendations for adjuvant radiotherapy.

  • For patients with FIGO stage I endometrioid cancer, three risk factors are considered: high grade (grade 2–3), deep (>66%) myometrial invasion, and LVSI. Adjuvant treatment is recommended for patients with age <50 years with all three risk factors; 50–70 years with two risk factors; and 70 years and older with any one risk factor. These risk factors for recurrence were initially described in GOG 99 [9].

  • Low-risk patients, who do not meet the above criteria, need only close surveillance.

  • Patients meeting the above “high-intermediate”-risk criteria are recommended to receive adjuvant EBRT or VBT.

  • Many of these patients are candidates for VBT alone; however, some patients have substantial risk of occult nodal involvement (i.e., G3 disease with deep myometrial invasion, extensive LVSI) warranting EBRT to target the at-risk nodal basins in addition to the vaginal cuff.

  • Occasionally, a patient may have risk factors that warrant EBRT but have additional risk factors for recurrence at the vaginal cuff (positive surgical margins, FIGO stage II – cervical stromal invasion), and a VBT boost is administered.

  • Initiate brachytherapy after the vaginal cuff is healed, usually at least 4–6 weeks postsurgery (within 12 weeks postoperatively).

  • Brachytherapy dose depends on whether EBRT is indicated.

FIGO stage IIIC1/2

  • Patients with lymph node involvement will typically receive 6 cycles of chemotherapy and pelvic EBRT. EBRT will generally occur between cycles 3 and 4 of chemotherapy (“sandwich”) or after completion of chemotherapy. VBT boost may be warranted if there are additional risk factors for vaginal cuff recurrence.

Definitive radiotherapy in patients who are not surgical candidates:

  • Patients with early stage but medically inoperable disease are treated with EBRT and/or intracavitary brachytherapy or hormone therapy.

  • Patients with unresectable disease (e.g., invasion of the vagina, bladder, rectum) or extrauterine pelvic disease are candidates for EBRT + brachytherapy ± chemotherapy, chemoradiotherapy followed by surgical resection, neoadjuvant chemotherapy, or chemotherapy alone.

Recurrent disease:

  • Patients with recurrent disease should only be considered for surgery if gross tumor resection can be achieved [4, 6]. RT with curative intent is indicated in patients with isolated pelvic relapse after surgery alone for initial disease (no prior RT) [8].

  • Brachytherapy technique for vaginal cuff recurrence (intracavitary vs. interstitial) is based on the depth of vaginal wall invasion and the distribution of the disease. In cases of superficial (<5 mm) recurrences, VBT may be selected. For lesions invading ≥5 mm, VBT provides inadequate dose at depth compared with interstitial techniques [10,11,12,13]. For recurrences in the pelvic lymph nodes or pelvic sidewall not amenable for brachytherapy, EBRT is given with a boost to the region of gross involvement. SBRT can be considered for low volume recurrences.

4 Treatment Planning

Vaginal brachytherapy:

Timing

Brachytherapy should be started within 12 weeks after surgery. We recommend once weekly intracavitary brachytherapy if administered during EBRT. VBT can be administered twice weekly as a monotherapy or after EBRT completion

Analgesia

Consider premedication with anxiolytics, pain medication, or mild sedation [11]. However, these are often not necessary with VBT

Position

Dorsal lithotomy position

Pelvic exam

Perform a visual inspection and manual examination with care to ensure that the vaginal cuff is well healed and that there is no recurrence at the vaginal apex or vaginal cuff dehiscence. In a subset of patients, the placement of a vaginal applicator may be difficult (postoperative changes, pain, etc.)

Preparation and procedure

• Placement of a radiopaque marker at the vaginal cuff can assist in verifying that the applicator is in contact with the vaginal mucosa. Typically three markers are placed – One at the apex and two laterally

• A vaginal cylinder is commonly used for postoperative VBT. The choice of applicator depends on patient’s anatomy and physician’s experience. In many patients, the postoperative vagina is cylindrical, and it can be treated adequately with a properly sized vaginal cylinder. In some situations, ovoids may provide better dosimetry due to the remnants of the vaginal fornices. The applicator should be lubricated prior to placement. After placement of the applicator, a visual check is done to verify that the applicator is midline and not tilted laterally, anteriorly, or posteriorly

• The treatment target is the submucosal lymphatics of the vagina, and in most situations only the proximal vagina must be targeted [11, 14,15,16]. The proximal vagina is limited to the upper 1/3–1/2 of the vagina (upper 3–5 cm of the vagina) [11, 15]. Increased treatment length can result in increased toxicity

• To allow an optimal dose distribution, the vaginal mucosa needs to be in contact with the applicator surface (no air pockets). The ABS recommends use of the largest diameter cylinder that can comfortably fit into the apex of the vagina [6, 11] to reduce mucosal dose

Treatment planning

Treatment planning can be 2D (x-ray) and/or 3D (CT, MRI) based. For treatment planning optimization, points should be placed around both the apex and the lateral aspects of the applicator [11, 15]

Documentation

Documentation of brachytherapy is essential and should include the type of isotope and source; description of the target (including size and shape); prescription depth, target dose, dose per fraction, and the fractionation plan; the applicator type and size, and the treatment plan documentation (dose distribution to dose the target and OAR)

Intact uterus :

Timing

Brachytherapy should be started as soon as possible. We recommend once weekly intracavitary brachytherapy if administered during EBRT. Brachytherapy can be administered twice weekly as a monotherapy or after EBRT completion

Analgesia

Analgesia options include general, spinal, intravenous sedation and/or oral pain medication. Our practice is to use titrated doses of fentanyl, starting with 50 micrograms IV, and lorazepam with 1 mg IV, 20–30 min prior to start of the procedure

Position

Dorsal lithotomy position

Pelvic exam

Examination under anesthesia – a bimanual examination to document any residual nodularity, the cervix size and, the size of the vaginal fornices (i.e., disease extension/response to treatment). The uterus is sounded to aid in selection of the appropriate tandem applicator. Insertion of radiopaque markers in the cervix aids localization of the cervix on imaging. We generally avoid inserting the seed at 3, 6, 9, and 12 o’clock position on the cervical os so that the seeds are not masked by the applicator on AP and lateral orthogonal images

Procedure

• A Foley catheter is inserted into the bladder, and the balloon is inflated with dilute contrast

• Tandem and ovoids are commonly used for brachytherapy in this setting. Other applicators include tandem and ring applicator. Simon-Heyman capsules can be used to further distribute dose to the uterus

• After selection of appropriate applicators (including angle of the intrauterine tandem and size of ring or ovoids), cervical os is dilated to enable accommodation of Simon-Heyman capsules (if used). Ultrasound guidance can be used during applicator insertion to help guide dilation of the endocervical canal and evaluate placement of the uterine applicators. A tenaculum may be placed on the cervix to provide countertraction for placement of the intrauterine tandem. A ring or ovoids can be used if lateral cervical dosing is needed

• It is important that the tandem extends to the uterine fundus to ensure that the entire endometrial lining is treated

• Radiopaque vaginal packing is used to displace the bladder base anteriorly and the anterior rectal wall posteriorly away from the intracavitary applicator. Packing also serves to prevent the displacement of the tandem from the uterus and to secure the positioning of the entire applicator

• We do not routinely use a smit sleeve, but they can be useful for anatomically difficult implants

• Imaging (CT, MRI, plain radiographs) is done for each implant immediately following the placement of the applicator and is essential for treatment planning of each procedure

• 3D imaging allows for accurate contouring of the tumor, cervix, uterus, and OAR

Treatment planning

Treatment planning can be 2D (X-ray) and/or 3D (CT, MRI) based. Brachytherapy is prescribed to the uterine serosa

Documentation

Documentation of brachytherapy is essential and should include the type of isotope and source; description of the target (including size and shape), target dose, dose per fraction, and the fractionation plan; the applicator type and size and the treatment plan documentation (dose distribution to dose the target and OAR)

5 Common Dose/Fractionation Scheme

Vaginal brachytherapy alone:

  • At UNC, VBT is typically prescribed to a dose of 7 Gy at 0.5 cm depth × 3 fractions for VBT alone after hysterectomy. The goal is to achieve an LDR equivalent of 30 Gy at 0.5 cm depth and 65 Gy at the surface.

Common vaginal brachytherapy doses [ 11 , 15 ]

Dose and fractionation

Prescription depth

7 Gy × 3

0.5 cm depth

4 Gy × 6

Vaginal surface

6 Gy × 5

Vaginal surface

5.5 Gy × 4

0.5 cm depth

EBRT followed by vaginal brachytherapy :

  • If EBRT is given, the total dose is 45–50.4 Gy. Midline block (at ~40 Gy) can be used [11].

  • Involved unresected lymph nodes can be boosted during EBRT with 1.8 Gy daily fractions for a total of 59.4 Gy [11].

  • At UNC, VBT is typically prescribed to a dose of 5 Gy to the vaginal surface x 3 fractions when administered in conjunction with EBRT.

Common vaginal brachytherapy doses (combined with EBRT, 1.8 Gy × 25–33 fx) [6, 12]

Dose and fractionation

Prescription depth

5 Gy × 3

Vaginal surface or 0.5 cm depth

6 Gy × 2

Vaginal surface or 0.5 cm depth

6 Gy × 3

Vaginal surface

RT for inoperable patients:

Inoperable patients with stage I grade 1–2 endometrial cancer with minimal myometrial invasion can be treated with brachytherapy alone. All other patients should receive EBRT in conjunction with brachytherapy. The CTV encompassing the whole uterus extending to the serosal surface should receive an EQD2 of at least 48 Gy for tandem/ovoids (intracavitary brachytherapy alone) and at least 65 Gy for combination of EBRT plus VBT. A GTV may also be defined using T2-weighted MRI and may be prescribed a dose of ≥80 Gy [5].

Common brachytherapy doses (without EBRT) for inoperable endometrial cancer [ 5 ]

Fractionation prescribed to uterine serosa

EQD2(Gy) to the tumor (point A with α/β = 10 Gy)

6 Gy × 6

48

6.4 Gy × 6

52.5

7.3 Gy × 5

52.6

8.5 Gy × 4

52.4

Common brachytherapy doses (combined with EBRT, 1.8 Gy × 25 fx) [5].

Fractionation prescribed to uterine serosa

EQD2(Gy) to the tumor (point A with α/β = 10 Gy)

6.5 Gy × 3

71.1

5.2 Gy × 4

70.6

5 Gy × 5

75

6 Normal Tissue Tolerance

  • EBRT + VBT:

    • Upper vagina mucosa 150 Gy, mid-vagina mucosa 80–90 Gy, lower vagina mucosa 60–70 Gy. *NOTE: the proximal vagina is a target in VBT

    • Small bowel <45–50.5 Gy

    • Rectal point dose <70 Gy

    • Bladder <75 Gy

Dose constraints to organs at risk for brachytherapy

Organ at risk

Radiographic (ICRU point)

3D imaging (D2cc)

Bladder

5× < 3.7 Gy

<90 Gya

Rectum

5× < 3.7 Gy

<70–75 Gya

Sigmoid

–

<70–75 Gya

Ureters

–

<70 Gy

  1. aMax point dose defined as <0.035 cc

7 Patient Management Considerations

  • After completion of treatment, patients should be given a vaginal dilator to prevent scar tissue and adhesions within the vagina. Patients are instructed to place the dilator within the vagina for 10–15 min several times per week.

  • Acute toxicity

    Due to the conformal dosimetry of vaginal cuff brachytherapy, toxicity to bowel, bladder, and rectum are low. There are generally minimal acute toxicities during treatment with vaginal cuff brachytherapy alone.

  • Late toxicity

    Late toxicity is also rare with vaginal cuff brachytherapy alone. The most common side effect is stenosis and atrophy of the vagina, which can result in vaginal shortening or narrowing. Incidences of severe bowel, rectum, and bladder toxicity have been reported including rectovaginal fistula, radiation colitis or cystitis, and vaginal or bladder necrosis, but these reports are rare and appear to be more common when VBT is administered with EBRT.

8 Follow-Up

  • H&P including pelvic exam should be completed every 3–6 months for the first 2–3 years, then every 6 months for 5 years, and then annually.

  • Ca-125 is optional, useful for follow-up if preoperative level was elevated.

  • Imaging only if clinically indicated and/or if extrauterine spread was present at initial surgery.

9 Relevant Literature

PORTEC-1 and GOG-99, which established the role of postoperative EBRT (conventional fractionation), are outside the scope of this chapter.

Postoperative vaginal brachytherapy vs. vaginal brachytherapy + EBRT

Randomized control trials

Study

Arm 1: VBT alone

Arm 2: VBT + EBRT

Median follow-up

Outcomes

Onsrud (2013) [17]

Stage I

(n = 280)

60 Gy LDR

(n = 288)

60 Gy LDR + 40 Gy EBRT

20.5 years

Median OS

20.48 years (VBT) vs. 20.5 years (EBRT+VBT) (p = 0.186)

Aalders

(1980) [18]

Stage I

(n = 277)

60 Gy LDR

(n = 263)

60 Gy LDR + 40 Gy EBRT

3–10 years

5-year OS

91% (VBT) vs. 89% (EBRT+VBT) (p = NS)

Vaginal/pelvic recurrences

6.9% (VBT) vs. 1.9% (EBRT+VBT) (p < 0.01)

Grade 3+ toxicity

0.7% (VBT) vs. 1.1% (EBRT+VBT)

Sorbe

(2012) [19]

Stage I

(n = 263)

3 Gy × 6 fx (HDR)

5.9 Gy × 3 fx

(HDR) , or 20 Gy (LDR)

(n = 285)

VBT + 46 Gy EBRT

62 months

5-year OS

90% (VBT) vs. 89% (EBRT+VBT) (p = NS)

Pelvic recurrences

5.3% (VBT) vs. 0.4% (EBRT+VBT) (p < 0.001)

Vaginal recurrences

2.7% (VBT) vs. 1.9% (EBRT +VBT) (p = 0.55)

Grade 3 toxicity

0.8% (VBT) vs. 1.9% (EBRT+VBT)

Postoperative vaginal brachytherapy vs. EBRT

Randomized control trial

Study

Arm 1: VBT

Arm 2: EBRT

Median follow-up

Outcomes

Nout (2010) [20]

(PORTEC-2)

Stage I–II

(n = 213)

7 Gy × 3 fx at 0.5 cm (HDR) or 30 Gy at 0.5 cm (LDR)

(n = 214)

46 Gy EBRT

45 months

5-year OS

84.8% (VBT) vs. 79.6% (EBRT) (p = NS)

Pelvic recurrences

3.8% (VBT) vs. 0.5% (EBRT) (p = 0.02)

Vaginal recurrences

1.8% (VBT) vs. 1.6% (EBRT) (p = NS)

Grade 3 toxicity

<1% (VBT) vs. 3% (EBRT)

Selected studies of postoperative HDR-VBT alone

Study

Patients

Treatments

Median follow-up

Outcomes

Prospective

Sorbe (1990) [21]

Stage I

404

5.0 Gy × 6 fx

4.5 Gy × 6 fx

6.0 Gy × 5 fx

9.0 Gy × 4 fx

NA

5-year OS 92%

Pelvic/vaginal recurrences 1.7%

Vaginal recurrences 0.7%

Acute toxicity 30.9%, late toxicity 15.8%

The high-dose group 9 Gy × 4 had a higher rate and grade of late complications

Retrospective

Weiss (1998) [22]

Stage IA–II

122

7.0 Gy × 3 fx

25.6 months

Pelvic recurrence 4.1%

Vaginal recurrence 1.6%

Recurrence occurred in 3.8% of patients with moderate risk and in 20.5% of patients with high risk

No grade 3–4 toxicity

Petereit (1999) [23]

Stage IB

191

16.2 Gy × 2 fx prescribed to surface

38 months

4-year OS 95%

Pelvic recurrence 0.5%

Vaginal recurrence 0%

0.5% developed colo-vaginal fistula

4% asymptomatic vaginal cuff necrosis

Horowitz (2002) [24]

Stage IB–II

164

7 Gy × 3 fx at 0.5 cm

65 months

5-year OS 87%

Pelvic recurrence 0.6%

Vaginal recurrence 1.2%

No grade 3–4 toxicity

Alektiar (2005) [16]

Stage IB–IIB

382

6.0–7.0 Gy × 3 fx

48 months

5-year OS 93%

Pelvic recurrence 3%

Vaginal recurrence 0.8%

No grade 3–4 toxicity

Diavolitsis (2012) [25]

Stage IA

169

7.0 Gy × 3 fx

5.5 Gy × 4 fx

at 0.5 cm

103 months

5-year OS 95.5%

5-year RFS 94.4%

Pelvic recurrence 0.5%

Vaginal recurrence 0.5%

No grade 3–4 toxicity

Selected studies of postoperative pelvic EBRT and HDR -VBT

Study

Patients

Treatments

Median follow-up

Outcomes

Retrospective

Lybeert (1989) [26]

Stage I–IV

291

40 Gy EBRT + 5Gy × 4 fx at 0.5 cm HDR

NA

5-year RFS

Stage I:88%

Stage II:68%

Stage III/IV:50%

Pelvic recurrence 2.7%

Vaginal recurrence 2.7%

No grade 3–4 toxicity

Nori (1994) [27]

Stage I

300

40 Gy EBRT + 7Gy × 3 fx at 0.5 cm HDR

12 years

PFS 96.6%

Pelvic recurrence 0.3%

Vaginal recurrence 2%

No grade 3–4 toxicity

Algan (1996) [28]

Stage I/II

81

45 Gy EBRT + 4 Gy × 3 fx at 0.5 cm HDR

Or 30 Gy LDR to surface

NA

5-year OS 83%

Pelvic recurrence 3%

Vaginal recurrence 4%

Grade 3 toxicity 3%

Cannon (2009) [29]

Stage II

50

45–51 Gy EBRT + more than 4 different fractionations for HDR (most common 5 Gy × 5 fx or 7.8 Gy × 2 fx)

5.2 years

5-yearr OS 82%

5-year DFS 82%

Pelvic recurrence 4%

Vaginal recurrence 0%

Grade 3 toxicity 2%, grade 4 toxicity 2%