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Prostate adenocarcinoma definitive EBRT conventional intermediate-risk

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  • Intact prostate.
  • Life expectancy >5 years.

Cautions

  • Previous high dose radiation to the pelvis.
  • Poor urinary and bowel function.
  • Radiosensitising medications (e.g. methotrexate).
  • Inflammatory bowel disease and/or history of adhesions/bowel obstruction.
  • Bilateral hip replacement.
  • Non-rheumatoid collagen vascular disorders.

Notes

  • Consider offering active surveillance to patients with favourable intermediate-risk prostate cancer.
  • If the patient has recently undergone a transurethral resection of the prostate (TURP) wait 8-12 weeks until urinary function has stabilised, before commencing radiation therapy.
  • If inserting fiducial markers, ensure insertion is more than 5 days prior to planning CT.
  • Optional use of hydrogel spacer.r Caution where posterior extracapsular extension is present.

Androgen deprivation therapy (ADT)

  • Consideration should be given to the addition of 4-6 months of neoadjuvant androgen deprivation therapy, particularly in unfavourable intermediate-risk prostate cancer. Link to Medical oncology urogenital protocols.
  • Risk factors should be considered in relation to individual co-morbidities.
Simulation Options Notes
Position
  • Supine.
  
Arm/leg/head/neck/shoulder position
  • Arms on chest.
  
Immobilisation and supports
  • Neck support.
  • Knee supports.
  • Ankle supports.
  • Vacbag (optional).
  
Organ pre-requisites
  • Bladder comfortably full.
  • Rectum empty.
 Bladder and rectal filling should be consistent between CT and simulation and daily treatment delivery.
Contrast
  • N/A
  
Radiopaque markers
  • Fiducials (optional).
  
Bolus
  • N/A
  
Other imaging
  • MRI.
  • PSMA-PET (optional).
 Consider MRI to assist with the delineation of the CTV, particularly in the presence of hip prosthesis and when hydrogel is used.
CT acquisition
  • 3D CT.

Scan from L3/L4 to 1.5 cm below ischial tuberosities. Upper level may be extended superiorly if nodal treatment is indicated.
Medications
  • N/A
  
Phase Target area Dose prescription Prescription point/ volume Beam type Beam energy Dose/# Fractions Scheduling
#/day #/fortnight
IMRT/VMAT - Single phase
1 Prostate + proximal seminal vesicles (no nodes)*

78-81 Gy

 ICRU 62/83 Photons 6-18 MV 1.8-2 Gy 39-45 1 9-10

Prescription notes

  • *Elective nodal irradiation may be considered in patients with unfavourable intermediate-risk prostate cancer, based on assessment of risk factors. Although there is no randomised evidence that treating the pelvic lymph nodes is superior to not treating nodes, a significant proportion of randomised trials including patients with intermediate and high-risk prostate cancer included nodal irradiation. EQD2 ~45-50 Gy is recommended for nodal volumes.
  • Dose prescriptions of 78 Gy EQD2, or slightly higher, are favoured if they can be delivered safely using IGRT and/or IMRT techniques and DVH constraints can be met. 
  • Lower doses of 73.8-74 Gy EQD2, can be considered for patients where tolerability of treatment is a concern.
  • If delivering doses less than 73.8 Gy EQD2, neoadjuvant or adjuvant hormone therapy is recommended to compensate for the lower radiation dose.
Phase 1
GTV
  • Prostate.
CTVProstate + proximal SV
  • Prostate + proximal seminal vesicles.
PTV
  • CTV + 0.5-0.8 cm margin. Smaller margins can be used depending on departmental protocol/imaging.
Nodal volumes (if treated)
CTV
  • For information on target nodal regions, refer to the NRG Oncology Updated International Consensus Atlas on Pelvic Lymph Node Volumes for Intact and Post-operative prostate cancer.r
PTV
  • CTV + 0.5-0.8 cm margin.

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

Target volume guides

  • FROGG consensus guidelines for definitive EBRT in prostate adenocarcinoma.r
  • Radiographic and anatomic basis for prostate contouring errors and methods to improve
    prostate contouring accuracy.r
  • ESTRO ACROP consensus guidelines of localised prostate cancer.r
  • NRG oncology updated international consensus atlas on pelvic lymph node volumes for intact and post-operative prostate cancer.r
Organ Constraint Additional information
Rectum Ideal:
  • V40 Gy <35%r
  • V65 Gy <17%r
  • V75 Gy <10%
Acceptable:r
  • V50 Gy <50%
  • V60 Gy <35%
  • V65 Gy <25%
  • V70 Gy <20%
  • V75 Gy <15%
  
Bladder

Ideal:r

  • V40 Gy <50%
  • V65 Gy <25%

Acceptable:​rr

  • V65 Gy <50%
  • V70 Gy <35%
  • V75 Gy <25%
  • V80 Gy <15%
  
Femoral heads 

Ideal:r

  • V50 Gy <5%

Acceptable:r

  • V35 Gy <100%
  • V45 Gy <60%
  • V60 Gy <30%
  
Penile bulb
  • Mean dose <52.5 Gyrr

Tolerance of the penile bulb and crura is not well established. Benefit versus risk of geographical miss has not been conclusively quantified.

Penile bulb constraints should not compromise coverage of the PTV. 

Contouring of the penile bulb is best achieved using MRI.
Small bowel - individual loops
  • Minimise dose where possible.
  • Avoid dosimetric hotspots in loops of the small bowel.
  • Guide D1 cc <54 Gy EQD2.
  • Peritoneal cavity V45 Gy <195 cc.r

Be aware of the location of small bowel when determining volumes. Small bowel should be contoured in proximity to PTV.
Large bowel
  • Avoid dosimetric hotspots in the large bowel.

There are no clear guidelines however departments may choose to use the constraints for rectum or small bowel for large bowel.

Caution should be exercised in the presence of diverticular disease.

OAR notes

Modality Frequency Match point
  • kV planar

OR

  • MV planar

OR

  • CBCT.
  • Daily.
  • Fiducial markers.
  • On CBCT: check soft tissue alignment.

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

The side effects listed below are not a complete list of all possible side effects for this treatment and should only be used as a guide.

Acute: Short term side effects during or within a few weeks post radiation therapy (usually temporary)
Fatigue

Read more about fatigue.
Proctitis

Including diarrhoea, increased bowel frequency, rectal urgency, pain and bleeding.

Read more about proctitis.
Enteritis
Irritative or obstructive urinary symptoms

Bladder spasms, dysuria, nocturia, frequency, incontinence, urgency, retention.
Cystitis

Read more about cystitis.

Late: Long term side effects - months to years post radiation therapy (may be permanent)
Proctitis

Read more about proctitis.
Small bowel toxicity

Including obstruction and perforation.
Urethral stricture
Cystitis/urethritis
Sexual dysfunction - male

Including erectile dysfunction, impotence, dry/painful ejaculation and haematospermia. Patients should be offered sexual counselling to manage potential late effects related to sexual function.
Impaired fertility or infertility

Fertility preservation should be discussed prior to commencement of treatment.

Read more about the effect of cancer treatment on fertility.
Insufficiency fracture
Second malignancy
Source Study & year published Supports use
Yes/No/NA		 Is the radiation dose and fractionation consistent with the protocol? Comments
Meta-analysis Zaorsky et al. 2018r Yes Yes Supports use of dose escalated radiation therapy to prevent biochemical failure in low and intermediate-risk prostate cancer patients.
Viani et al. 2009r Yes Yes

Supports use of high dose radiation therapy (HDRT) to prevent biochemical failure in low, intermediate and high-risk prostate cancer patients.
Phase III trials Bolla et al. 2016r Yes

Range of doses:

70 Gy/74 Gy/78 Gy

  

Denham et al. 2014r 

TROG 03.04 RADAR

 Yes

Range of doses:

66 Gy/ 70 Gy/ 74 Gy

  

Denham et al. 2011r

TROG 96.10

 Yes

No

66 Gy to prostate/SV

  
Kuban et al. 2008r & 2011r Yes

Yes

70 Gy vs 78 Gy

 Modest escalation in radiation therapy dose improved freedom from biochemical and clinical failure, with the largest benefit in prostate cancer patients with PSA >10 ng/ml (78% for 78 Gy vs 39% for 70 Gy; p = 0.001).
Zelefsky et al. 2008r Yes

Yes

Dose range:

66-86 Gy

 Significant improvements were observed with higher doses for patients with intermediate and high-risk features. For intermediate-risk features, multivariate analysis showed that radiation dose was an important predictor for improved PSA relapse-free survival (p <0.0001) and improved distant metastases-free survival (p = 0.04).

D'Amico et al. 2008r

Dana Faber Trial

 Yes

Yes

70 Gy vs 80 Gy

  
Peeters et al. 2006r Yes

Yes

68 Gy vs 78 Gy

  

Roach et al. 2003r

RTOG 94.13

 Yes

Yes

68 Gy vs 78 Gy

  
Guidelines Date published/revised Supports use Is the dose and regimen consistent with the protocol? Comments
NCCN V2.2020r Yes Yes  
EAU 2019r Yes Yes  
AUA-ASTRO-SUO 2017r Yes Yes  

 

Efficacy

Dose Escalation

Meta-analyses have demonstrated a dose-response relationship for prostate cancer and biochemical control.rr The Zaorksy meta-analysis of 12 randomised trials, including 6884 patients treated with EBRT, showed increasing biologically equivalent dose was associated with a 7.2% improvement in 10-year freedom from biochemical failure, for men with intermediate-risk prostate cancer. However, dose escalation has not been shown in any prospective studies to improve prostate cancer-specific survival or overall survival.

Evidence supporting moderate hypofractionation for intermediate-risk prostate cancer is not discussed within this protocol, but can be found in the evidence and efficacy sections of ID 3370 Prostate adenocarcinoma definitive EBRT hypofractionation.

Androgen Deprivation Therapy

Multiple randomised trials have demonstrated an improvement in disease outcomes when short-term ADT (4-6 months) was given in addition to radiation therapy.

  • In RTOG 9408, 1979 patients (mainly low and intermediate-risk) were randomised to 66.6 Gy radiation therapy with or without 4 months of ADT (ADT commencing 2 months before radiation therapy). At a median follow-up of 9.1 years there was a benefit for short-term ADT and radiation therapy in 10-year overall survival (62% vs 57%, p = 0.03), disease-specific mortality (8% vs 4%, p = 0.001) and incidence of distant metastases.r
  • D'Amico published a small study of 206 patients (75% with intermediate-risk disease) randomised to 70 Gy 3D CRT plus 6 months ADT.r The addition of ADT resulted in significantly higher overall survival and prostate cancer-specific survival, compared to radiation alone. 8-year overall survival rates were 74% (95% CI:64-82%) for radiation therapy plus ADT vs 61% (95% CI:49-71%) for radiation therapy alone.

The trials above used lower radiation doses than what is considered standard in contemporary practice. EORTC 22991 was a randomised study of 819 patients with intermediate (75%) or high-risk (25%) prostate cancer, comparing radiation therapy alone to radiation therapy plus 6 months ADT.r The radiation doses prescribed were 70 Gy, 74 Gy or 78 Gy, and ADT was given during and following radiation. After a median follow-up of 7.2 years, the addition of ADT to radiation therapy improved biochemical progression-free survival, compared to radiation alone (HR = 0.52, CI:0.41-0.66, p <0.001). Improvement in clinical progression-free survival was also statistically significant, 88.7% with radiation plus ADT vs 80.8% with radiation alone (HR = 0.63, 95% CI:0.48-0.84, p = 0.001). Overall survival data are not yet mature. In exploratory analysis, there was no statistically significant interaction between treatment effect and radiation dose.

In a network meta-analysis of 6 randomised trials comparing radiation therapy with or without ADT in 4663 men, the addition of ADT improved overall survival (HR = 0.70, 95% CI:0.62-0.81).r This analysis was repeated as a sensitivity analysis of the subset of randomised trials, treating mostly men with intermediate-risk prostate cancer, and found similar estimates (HR = 0.73, 95% CI:0.51-1.04).

Some patients may have a very small benefit from the addition of ADT. The risks versus benefits should be considered on an individual patient basis. For further information related to ADT agents and toxicities refer to eviQ medical oncology for urogenital cancers.

Toxicity

A summary of the most clinically significant toxicities associated with this protocol are included in the table below:

Toxicity Study/Year Incidence of event or % Comment
Early and late (hypofractionation) Refer to the evidence and toxicity sections of ID 3370 - Prostate adenocarcinoma definitive EBRT hypofractionation.
Gastrointestinal

Aluwini et al. 2016r 

HYPRO

3-year cumulative incidence:

Grade ≥3 = 2.6%  

 Data for conventional/standard arm: 78 Gy/39 fx.

Catton et al. 2017r

PROFIT

Incidence Grade ≥3 = 3%

Median follow-up of 6 years.
Genitourinary

Aluwini et al. 2016r 

HYPRO

3-year cumulative incidence:

Grade ≥3 = 12.9%

 Data for conventional/standard arm: 78 Gy/39 fx.

Catton et al. 2017r

PROFIT

Incidence Grade ≥3 = 3%

Median follow-up of 6 years.
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Version 5

Date Summary of changes
8/04/2021

Reviewed online and at urogenital RCM 15/10/2020. Approved and published to eviQ. Review in 2 years.

Version 4

Date Summary of changes
9/06/2009 Approved on CI-SCaT. Previous CI-SCaT ID : 02-1183.
20/08/2009 Reviewed and transferred to eviQ.
15/12/2010 Integrated boost doses added.
30/06/2014

Biennial review and updated with the following changes:

  • Conventional added into the title to distinguish between hypofractionated protocols in the future
  • Review Group 2
30/04/2017

Protocol reviewed at August 2016 RCM.
Approved and published to eviQ.
Review group 2.
31/05/2017 Transferred to new eviQ website.

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/234

25 Jun 2021