32Radiotherapy dose fractionation Third edition

Gynaecological

cancers

Cervix cancer

Background

Patients presenting with small volume International Federation of Gynaecologists

and Obstetricians (FIGO) stage IB1 and IIA disease can be treated either by radical

hysterectomy and lymphadenectomy or radical radiotherapy as primary procedures. The

two approaches have equivalent survival rates (Level 1b).

1,2

The combination of surgery and radiotherapy increases morbidity and should be avoided

if possible.

1,3

Postoperative chemoradiotherapy is indicated for patients with poor

prognostic features discovered at surgery (positive nodes, positive margins or extensive

lymphovascular space involvement) (Level 1b).

2–4

Local control and survival are increased by the addition of concomitant chemotherapy in

all stages, although the benet may be smaller when only one node is positive or when the

tumour size is <2 centimetres (cm) (Level 1b).

2–11

Randomised studies of radiotherapy have used fractionation regimens of 40–50.4 Gray (Gy)

in daily 1.8–2 Gy fractions over 4–5.5 weeks (Level 1b).

1–3,12,13

Both early and late toxicity are

increased when chemotherapy is added (Level 1b).

2,12,14

Overall treatment time, including intracavitary brachytherapy (ICBT), should not exceed 56

days for squamous carcinoma (Level 1b).

2,15–19

Haemoglobin levels during treatment are

prognostic, with the best outcomes in those whose haemoglobin remains greater than 12

grams per decilitre (g/dl) throughout treatment (Level 2b).

2,20

Small-volume parametrial disease can be often be encompassed within the brachytherapy

dose-envelope using a combination of interstitial and intracavitary brachytherapy (ISBT

and ICBT) (Level 2b).

Alternatively, a simultaneous integrated intensity-modulated

radiotherapy (IMRT) planned external beam radiotherapy (EBRT) boost can be considered

(Level 2b).

Boosting parametrial disease conventionally with three-dimensional conformal

radiotherapy (3D-CRT) or parallel opposed elds with midline blocking does not usually

allow organs at risk (OAR) constraints to be met and is not recommended (Level 1b).

2,21,22

Evidence from cohort series supports the use of image-guided brachytherapy (IGBT) to

reduce late toxicities and facilitate delivery of >80–85 Gy (combined external beam and

brachytherapy equivalent dose in 2 Gy per fraction [EQD2]).

23,24

Dose constraints to OARs

have been published based on organ volume rather than point doses (Level 2b).

2,25

These

doses can only be achieved within normal tissue constraints when doses of <50 Gy are

delivered by external beam radiotherapy.

Currently, there is no evidence of improvements in survival to support the routine use of

neoadjuvant or adjuvant chemotherapy in addition to primary chemoradiotherapy. This

question is being addressed by two international trials: Cisplatin and Radiation Therapy

with or without Carboplatin and Paclitaxel in Patients with Locally Advanced Cervical

Cancer (OUTBACK) and Induction Chemotherapy Plus Chemoradiation as First Line

Treatment for Locally Advanced Cervical Cancer (INTERLACE).

26,27

Treatment technique

The planning target volume (PTV) for treating pelvic malignancy normally encompasses the

lymphatic drainage of the true pelvis and may be extended further, depending on the extent

and type of malignancy, to include the para-aortic nodes, the inguinal nodes or the vagina.

33Radiotherapy dose fractionation Third edition

Nodal atlases have been developed to assist in the outlining of the female pelvis.

29,30

Signicantly less toxicity is seen if EBRT is delivered using IMRT or volumetric-modulated

arc therapy (VMAT) rather than 3D-CRT (Level 2b).

2,31

Recommendations

Post-operative external beam:

40 Gy in 20 fractions over 4 weeks (Grade A)

45 Gy in 25 fractions over 5 weeks (Grade A)

50 Gy in 25 fractions over 5 weeks (Grade A)

50.4 Gy in 28 fractions over 5.5 weeks (Grade A)

Delivered with weekly concurrent cisplatin 40 milligrams per metre squared (mg/m

)

(Grade A)

Denitive primary treatment

External beam radiotherapy:

40 Gy in 20 fractions over 4 weeks (Grade A)

45 Gy in 25 fractions over 5 weeks (Grade A)

50 Gy in 25 fractions over 5 weeks (Grade A)

50.4 Gy in 28 fractions over 5.5 weeks (Grade A)

Delivered with weekly concurrent cisplatin 40 mg/m

(Grade A)

Involved pelvic and para-aortic lymph nodes should receive:

57–60 Gy in 28 fractions over 5.5 week using a simultaneous integrated boost (Grade C)

Parametrial disease that cannot be encompassed by ICBT and ISBT may receive:

57–60 Gy in 25–28 fractions over 5–5.5 weeks

65 Gy in 28 fractions over 5.5 weeks using a simultaneous integrated boost (Grade C)

EBRT should be followed by image-guided brachytherapy so that a total dose of

80–85 Gy EQD2 is delivered to the high-risk clinical target volume (CTV) (Level 2b).

This is achieved with:

45 Gy in 25 fractions over 5 weeks external beam followed by high-dose rate (HDR) 28

Gy in 4 fractions (Grade B)

Other fractionation schedules in use for brachytherapy after the external beam

schedules given above are:

HDR: 6–7.5 Gy per fraction for 3–5 fractions (Grade C)

Pulsed dose rate (PDR): 17 Gy per fraction at 1 Gy per hour for 2 fractions, 7–10 days

apart (Grade C)

Overall treatment time, including brachytherapy should be no more than 56

days for squamous cancers (Level 1b)

The types of evidence and the grading of recommendations used within this review are based on

those proposed by the Oxford Centre for Evidence-based medicine.

34Radiotherapy dose fractionation Third edition

Endometrial cancer

Adjuvant therapy in operable disease

The majority of patients present with organ-conned disease and surgery is the

primarytreatment.

Trials of pelvic radiotherapy consistently show a reduction in local recurrences but no

overall survival benet.

32–37

The Vaginal Brachytherapy Versus Pelvic External Beam

Radiotherapy for Patients with Endometrial Cancer of High–Intermediate Risk (PORTEC

2) trial showed equivalent outcome for patients with some intermediate risk features who

received either adjuvant vaginal brachytherapy (VBT) or external beam radiotherapy.

The long-term pelvic side-eects in the brachytherapy group were less than with external

beam. The PORTEC 3 trial has investigated the benet of concurrent chemoradiotherapy

and adjuvant chemotherapy compared to adjuvant radiotherapy alone, which has been the

current standard of care. This shows an advantage for the combined approach in stage III

patients after hysterectomy.

36,37

Recommendations

High-risk patients

Postoperative adjuvant external beam radiotherapy:

46 Gy in 23 fractions over 4.5 weeks (Grade A)

48.6 Gy in 27 fractions over 5.5 weeks (Grade A)

Other schedules in use include 45 Gy in 25 fractions (Grade D) and 50.4 Gy in 28

fractions (Grade D)

Stage III patients should receive chemoradiation with cisplantin followed by adjuvant

carboplantin and paclitaxel (Grade A)

Vault brachytherapy may follow the above schedules in patients with cervical

involvement although there is no strong evidence base for this practice:

HDR: 8 Gy at 5 milimetres (mm) in 2 fractions (Level 1b)

PDR: 19 Gy at 5 mm at 1 Gy per hour given in 1 fraction (Level 1b)

Intermediate risk patients

Vaginal vault brachytherapy:

HDR:

21 Gy at 5mm in 3 fractions over 3 weeks (Grade A)

12–30 Gy at 5 mm in 3–8 fractions (Grade C)

PDR: 28 Gy at 5 mm in 1 Gy pulse per hour given in 2 fractions delivered in 7–10 days

(Level 1b)

The types of evidence and the grading of recommendations used within this review are based on

those proposed by the Oxford Centre for Evidence-based medicine.

35Radiotherapy dose fractionation Third edition

Denitive radiotherapy for inoperable disease

Endometrial carcinoma may be inoperable because of medical co-morbidity or advanced

disease stage. Accurate staging can be achieved using magnetic resonance imaging (MRI).

Radiotherapy can control stage I and II disease and may have a role in more advanced

cases (Level 2a).

38,39

Recommendations

Brachytherapy alone

HDR:

36 Gy in 5 fractions (Grade C) prescribed to the uterine serosa

37.5 Gy in 6 fractions (Grade C) prescribed to the uterine serosa

Combination therapy

External beam:

45 Gy in 25 fractions over 5 weeks (Grade C)

50 Gy in 25 fractions over 5 weeks (Grade C)

Brachytherapy:

HDR:

28 Gy in 4 fractions (Grade C) prescribed to the uterine serosa

25 Gy in 5 fractions (Grade C) prescribed to the uterine serosa

The types of evidence and the grading of recommendations used within this review are based on

those proposed by the Oxford Centre for Evidence-based medicine.

Endometrial carcinoma: salvage

Recurrent uterine corpus carcinoma in a previously unirradiated pelvis can be treated,

and sometimes salvaged, with radiotherapy (external beam alone, external beam

combined with brachytherapy or brachytherapy alone). Data of any sort are sparse, with no

randomised trials. Doses of greater than 60 Gy EQD2 including brachytherapy should be

delivered, provided rectal and bladder constraints are respected (Level 2c).

40,41

Vulva

Adjuvant therapy in operable disease

For those with operable vulval cancer, surgical resection of the primary with inguinal

lymphadenectomy remains the treatment of choice.

Adjuvant radiotherapy may be considered for those with incomplete resection, two or

more positive lymph nodes or any extracapsular spread. Concurrent chemotherapy with

cisplatin is used, but without a strong evidence base to support it (Grade C).

The Gronigen

International Study on Sentinel Nodes in Vulvar Cancer (GROINSS – II) study is comparing

surgery with either denitive radical radiotherapy or radical chemoradiotherapy where

sentinel lymph node metastases <2 mm are detected.

36Radiotherapy dose fractionation Third edition

Recommendation

Postoperative radiotherapy to vulva, pelvic and inguinal nodes:

45 Gy in 25 fractions over 5 weeks (Grade C)

50 Gy in 25 fractions over 5 weeks (Grade C)

The types of evidence and the grading of recommendations used within this review are based on

those proposed by the Oxford Centre for Evidence-based medicine.

Inoperable vulval carcinoma

Data in this area are sparse with no randomised studies. Potential therapeutic options

include denitive chemo-radiotherapy, treating the primary and nodes. Consideration

should then be given to surgical removal of residual disease or a second phase of

radiotherapy with electrons or brachytherapy.

Recommendation

Inoperable vulval cancer:

45 Gy in 25 fractions over 5 weeks (Grade C)

50 Gy in 25 fractions over 5 weeks (Grade C)

50.4 Gy in 28 fractions over 5.5 weeks (Grade C)

External beam radiotherapy may be given with weekly cisplatin 40 mg/m

(Grade C)

The primary and involved nodes should be boosted using electrons,

simultaneous integrated boost (SIB) with IMRT or brachytherapy to deliver a

total dose of 60–65 Gy EQD2 (Grade C)

The types of evidence and the grading of recommendations used within this review are based on

those proposed by the Oxford Centre for Evidence-based medicine.

Vaginal carcinoma

The rarity of vaginal carcinoma has led to therapy recommendations being derived from

single institution series accrued over many years and extrapolation from cervical carcinoma

data with no randomised trials. Therapy with EBRT in combination with either ISBT or ICBT

is accepted practice with doses of between 70–80 Gy EQD2 appearing to confer survival

advantage (Level 4).

The addition of concurrent chemotherapy appears to deliver a

survival advantage (Level 4).

Recommendation

Denitive therapy of vaginal carcinoma:

45–50 Gy in 25 fractions over 5 weeks (Grade C)

Followed by ISBT or ICBT HDR 18.75–20 Gy in 5 fractions (Grade C)

The types of evidence and the grading of recommendations used within this review are based on

those proposed by the Oxford Centre for Evidence-based medicine.

37Radiotherapy dose fractionation Third edition

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