Part of the “Enhancing Prostate Cancer Care” MOOC

Catherine HolbornSenior Lecturer in Radiotherapy & Oncology

Sheffield Hallam University

Aim of the presentation

To provide an overview of the key aspects of radical radiotherapy in the radical treatment of localised and locally advanced prostate cancer

This supplements the information already provided on the overall management of prostate cancer and the role of the main radical treatment options (surgery and radiotherapy)

What is Radiotherapy?Radiotherapy is the use of ionising radiation to primarily treat

cancer.Ionising radiation causes breaks in a cell’s DNA. This affects

the cell’s function and ability to divide, causing cell death.There are two main types.External Beam Radiotherapy (EBRT)

Uses high energy x-rays (photons). A series of carefully planned photon beams, of varying sizes and multiple angles, are directed from an external source into the patient

Brachytherapy (internal treatment)A radioactive source is placed inside the body (temporarily or

permanently). Sources used for prostate brachytherapy emit gamma rays that go on to damage the cell’s DNA

Aim of RadiotherapyThe main aim of radiotherapy is to maximise the ‘therapeutic

ratio’.To deliver a high dose to the ‘target’ and maximise disease

control, whilst still keeping the dose to the normal tissue and surrounding organs at risk(OAR) as low as possible, minimising treatment related side effects and complications.

The main OAR during prostate radiotherapy are the rectum and bladder . For external beam the dose to the femoral heads is also assessed. The penile bulb may also be identified during the planning stage. For brachytherapy, the urethra is an OAR to which the dose must be minimised.

ConsiderationsFor men with localised prostate cancer, surgery is a treatment option

alongside radiotherapy. A number of factors may influence their final decision

Side effects are covered in a separate presentation. What else may be a consideration?General health/suitability for general anaesthetic (brachytherapy)Avoid risks of major operationPSA levels fall gradually (for up to 2 years). Some men may experience PSA 'bounce'

which can be worrying (increased amounts leak into bloodstream as a result of prostate cell death and altered vascular permeability)

Daily treatments (usually Mon-Fri) for approx. 6-8 weeks are required Inflammatory bowel disease is a contraindication (external beam)Salvage surgery is difficult after RT. RT may not be possible if previous radical RT has been received e.g. for another pelvic

cancer

• There are a number of steps that are taken as part of the radiotherapy process, that help to maximise the therapeutic ratio• The key stages of the radiotherapy process are:

• Localisation• Planning• Treatment delivery and verification

• The next few slides provide an overview of these stages

LocalisationA CT scan is taken with the man in the intended treatment

positionThe pelvic CT slices/cross sectional images are later viewed by

the clinicianThey outline the intended target and OAR on each of these

slicesAn advance in this area is the additional use of an MRI scan, to

improve the visualisation of these structures and the accuracy of the outline

CT alone tends to cause an overestimation of the true prostate gland size, meaning the target may encompass more normal tissue than necessary, potentially increasing side effects

The target outlined will depend on the risk/stage of the prostate cancer

Prostate Outlining (CT left, MRI right)

Rectum = red Prostate = blue Base of bladder = yellow

The prostate target volumeLow risk disease = prostate gland only (low risk of spread to the seminal

vesicles) Although, the prostate outline (especially with a safety margin applied)

may include some of the proximal half of the seminal vesicles anyway Intermediate and high risk disease = very likely to include the prostate +

seminal vesicles The proximal half should always be included. It is debateable whether the

whole seminal vesicle volume needs to be included. Doing this increases the amount of rectal volume in close proximity to the target/high dose region

Inclusion of pelvic lymph nodes is more debateable. The benefits of treating any cancer that may be present within these, must be weighed against the potential increased risk of toxicity from treating a larger radiation field In the recent PRO7 trial, which demonstrated the benefits of adding

androgen deprivation to radical radiotherapy for men with high risk localised and locally advanced disease, the pelvic lymph nodes were treated

The Planning Target Volume (PTV)A small ‘safety’ margin is added to the clinical target volume to

create the PTV.The margin accounts for any movement of the patient, or internal

organs, that might occur and change the position of the target, from when it was originally planned.

The size will vary across institutions, depending on local techniques used that help to minimise any changes in position; it tends to be 3-8mm (3-5mm posteriorly where it overlaps with the rectum)

The margin ensures that the high dose planned to the target, is still delivered to the target; HOWEVER, this is essentially a margin of normal tissue and so should be minimised as much as possible.

This means that we must keep the patient and the internal organs as stationary as possible.

Immobilisation and image guidance are very important!

EBRT dose prescribedConventional treatment is delivered in a series of daily

doses (called fractions #), usually Monday to Friday, until the prescribed total dose is reached.

It is well documented that EBRT as a definitive/primary treatment should deliver a minimum dose of 74Gy in 37 # to the prostate.

Rectal dose/toxicity is a concern though, given it’s relatively low tolerance dose and close proximity to the prostate gland. The anterior rectal wall will be included in, or very close to, the PTV. The dose to this region needs to be minimised as much as possible.

Minimising rectal doseUsing MR images as well as CT to outline the target will help to avoid an

over-estimation of prostate gland size.With 3D planning techniques (considered the minimum standard), the

whole target volume can be viewed in all directions and radiation beams can be created that closely match it’s size and shape.

Intensity Modulated Radiotherapy (IMRT) is a more advanced planning technique which varies the radiation intensity across each beam, and can shape the dose delivered even more precisely to the target.

When treating the seminal vesicles, more of the rectal volume is at risk. A phased technique (sequential delivery of different plans) can be used to limit the dose to the rectum. The prostate + seminal vesicles are treated first to a slightly lower dose, and then a second plan focuses on the prostate only, boosting the dose to 74Gy or possibly higher.

An advantage of IMRT is that this variation in dose across the prostate and seminal vesicles, can be delivered simultaneously. Only one plan is required

IMRT basic illustration: varying beam intensities build up the dose to the prostate/seminal vesicles, as the machine moves around the patient to differing positions, intensity is always lowest (blue) in the path of the rectum

Different types of IMRTStatic IMRT

Uses a fixed number of intensity modulated beams, delivering treatment from a series of specific angles/ directions

VMAT Volumetric Intensity Modulated Arc TherapyNo fixed beam angles. The beam intensity changes as the machine

moves/arcs around the patient (at a fixed or variable speed)Tomotherapy

Treatment is delivered in intensity modulated ‘slices’ across the planned volume

Most common form Helical Tomotherapy. The slices are delivered as the couch moves continuously through the machine (looks like a CT scanner)

Minimising rectal dose cont…Good immobilisation and image guidance techniques

on the treatment unit ensure the treatment plan is delivered as intended

The PTV margin can also be kept small, encroaching less on the rectum, if daily accuracy is high

Patient immobilisationAs much as possible, the patient and internal target

position should be the same each day for treatment, and the same as when the treatment was originally planned

To immobilise the patient, external positioning devices are used to stabilise the legs and/or pelvis (used at both the planning and treatment appointments)

See next slides (other centres might use a device that attaches over the pelvis)

Treatment room (conventional linear accelerator) with leg immobilisation devices

Image courtesy of Radiotherapy Centre at Nottingham City Hospital

Treatment room (Tomotherapy) with leg immobilisation devices

Stabilising the prostate positionChanges in rectal and bladder volume can also alter the

position of the prostateTo reproduce the same internal position, men may be

asked to empty their bowels prior to each treatment and ensure they have a full bladder

Some departments may ask for an empty bladder but this is less common. The full bladder is thought to keep areas of normal tissue e.g. the small bowel, further away from the higher target dose

Some centres (not common in the UK) might use a 'rectal balloon' to stabilise the position of the prostate

Why image guidance?The PTV margin accounts for the typical errors/changes in

position that are known to occur, when using the specific set up used locally for a particular patient group i.e. prostate cancer patients

However, individual patients may display positional errors/changes that are greater than this safety margin

In these instances, the treatment couch that the patient is lying on, can be moved, thus altering the patient position and bringing the target back in alignment with the treatment beam

Image Guided Radiotherapy (IGRT) on the treatment unit is used to assess how much a patient/target has moved, relative to the original planned target position

Methods of image guidanceImage guidance protocols vary across radiotherapy departmentsThe type of imaging modality used

Images that show the position of the prostate directly, as opposed to plain x-rays showing only bony anatomy, are considered the gold standard

CT based imaging modalities are increasingly commonA few implanted markers in the prostate could also be used, which can

be visualised on plain x-rays or CT imagesUltrasound has been researched but not commonly used

The frequency of imagingDaily imaging allows for all daily variations to be corrected, if needed Imaging for the first 1-5 days, allows the ‘average’ positional change,

compared to the original planned position, to be calculated and corrected if needed. It also allows assessment of the daily variation around this. If this is large, daily imaging may continue. Alternatively, a weekly imaging check may then occur.

Effect of an empty bladder (seen on cone beam CT images): the shift anteriorly would have moved the rectum into the higher dose region planned for the prostate/seminal vesicles (planned blue/red outlines) and the seminal vesicles into the lower dose region where the bladder originally was (planned green outline).

Rectum and SVs shifted anteriorly

Hypo-fractionationConventional doses are delivered in 2Gy per fraction. The alpha-

beta (α/β) ratio is a measure of radio sensitivity to fraction size. In comparison to many other cancers, prostate cancer is thought to have a relatively low α/β ratio (1.5-3.0) and this implies that a larger dose per fraction will increase its sensitivity/have a greater radiobiological effect.

This is called hypo-fractionation It’s use has gained momentum in the advent of IMRT and IGRT,

which can more effectively and accurately deliver these higher daily doses to the target.

The CHHiP trial investigated the benefits of hypo-fractionation. As you will see from the next slide. One obvious benefit for the man is the reduction in overall treatment time!

Conventional or Hypo-fractionated High Dose Intensity Modulated Radiotherapy (CHHiP) trial for Prostate Cancer

T1B - T3A N0 M0

Risk of SV involv ≤30%

PSA ≤30ng/ml

Conventional 74Gy 37F 7.5 wks

HypofractionationSchedule 1:

57Gy 19F 3.8 wks

Hypofractionation Schedule 2:

60Gy 20F 4.0 wks

Stereotactic Ablative Radiotherapy (SABR)This is not a common/routine treatment as yetResearch is ongoing and long term outcome data is sparseSABR involves the delivery of large, ablative doses per fraction, over

only a few fractionsFor example: 35-36Gy in 5#A very high degree of accuracy is required. Robust immobilisation and daily image guidance essential.This may involve an initial image to measure any error and make

corrections, a second image to verify this altered position and a third image at the end of the treatment to monitor if any movement is occurring during treatment.

Some centres may even use tracking software to monitor movement of the target in real time, as the treatment is being delivered. The ultimate form of image guidance would then involve ‘gating’ the treatment alongside this tracking.

Key principles and practice

BrachytherapyThe direct insertion of radioactive sources, either permanent

(low dose rate-LDR) or temporary (high dose rate-HDR), into the prostate gland

Brachytherapy is known for it’s rapid dose fall off away from the source and as such it is a highly conformal treatment, minimising the dose to the surrounding normal tissue

Not currently recommended as a monotherapy for high risk, bulkier disease. With the rapid dose fall off, the dose delivered may not be sufficient to cover all areas of spread.

It could however be used as a boost (most likely HDR), in combination with EBRT (this may be considered for men with intermediate risk disease as well)

LDR and HDRLDR (Low Dose Rate) involves the permanent

implantation of Iodine125 and Palladium103 seeds.

HDR (High Dose Rate) is delivered using a temporary implant. Plastic or metal tube applicators are inserted into the prostate and (when ready for treatment delivery) are connected to a machine that remotely loads the radioactive source into the prostate (via the applicators). The source used is Iridium192, delivering the radiation in a matter of a few seconds as it passes through the tube within the prostate

LDRUsed for low and selected intermediate risk, localised prostate

cancer patientsLarger prostate volumes >50-60cc can be difficult to treat/access

due to pubic arch interference and also are at a higher risk of acute urinary retention post implant

Men with existing urinary symptoms are also at risk of more severe urinary morbidity.

An IPSS (International Prostate Symptom Score) of >20 is associated with a 30-40% risk of acute urinary retention and sustained urethritis. An IPSS of <15 is typical in terms of eligibility for treatment

Previous TURP (trans-urethral resection of the prostate) e.g. for benign disease, would also be a contraindication

HDRCan also be used for intermediate or high risk localised diseaseFor men with early T3a, the disease extension should be minimal As previously noted, HDR as a monotherapy may not be

recommended unless as part of a research trialFor higher risk disease it is likely to be combined with EBRT

(which also allows treatment of pelvic lymph nodes, as well as extra prostatic extension, that brachytherapy may not sufficiently treat)

Similar to LDR, men should have an IPSS ≤ 15 and shouldn’t have had a TURP within 6 months

Prostate volume is less of an issue as the more flexible catheters can more easily manoeuvre around the pubic arch and they can be placed in the periphery of the prostate to help treat larger glands, and also as indicated above extra-capsular spread.

Precautions and preparationMen may be asked to stop taking any blood

thinning or anti-coagulant medication such as aspirin or warfarin.

Men may be given a bowel enema to improve the ultrasound image and visibility of structures

Localisation and planningA Trans-Rectal Ultrasound (TRUS) is taken to assess the prostate

volume, and in the case of HDR, guide the insertion of the catheters. Other images may also be taken e.g. CT, to aid the planning.

Images are then sent to a specialist computer for planningThe program plans the number of seeds that will be needed and at

what locations (LDR), or how long the source needs to stay in each catheter (HDR)

Clinicians generally aim to achieve a uniform distribution of dose throughout the prostate. Some may place more seeds/dose nearer the peripheral zone. Dose to the urethra must be limited as much as possible

Localisation and planning may be completed at a separate visit for LDR, or the seed/source insertion can be undertaken immediately after planning (like with HDR). Intra-operative, real time planning, as the seeds are inserted, is also possible.

LDR seed insertionDone under TRUS guidanceMost commonly under general anaestheticBowel prep may again be usedA urinary catheter may also be used to help to highlight the

position of the urethraThe position/shape of the prostate must be matched to that

achieved at the pre-implant Prostate Volume Study (PVS) if this were conducted at a separate visit

A template attached on top of the ultrasound probe is used to guide the needles through the perineum into the prostate. The brachytherapy plan identifies where on the template, to insert the needles and to what depth

Post-implantA post implant CT/MRI is taken to verify the position of

the seeds (LDR) approx. 4-6 weeks after implant

Post-implant precautionsBecause of the low dose rate from the LDR seeds, men are

not radioactive as such but should limit the time spent sitting very close to pregnant women or young children for the first two months

Sexual intercourse can resume approx. 1 month after treatment. It is rare, but an individual seed could migrate outside of the prostate and can be passed in the urine or when they ejaculate. Men should wear a condom for the first few weeks.

‘Stranded’ seeds reduce the chances of migration. Research is ongoing regarding the dosimetry and outcomes achievable with these

You may want to review the articles included in the journals provided as part of the MOOC.

Many of these relate to issues/points highlighted in this presentation and reading these may help to enhance your knowledge of radiotherapy technique and the research being carried out in this field.