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2.8 Male Reproductive System: Prostate Cancer Cheat Sheet (DRAFT) by

This is a draft cheat sheet. It is a work in progress and is not finished yet.

Radiation Therapy Options

Radiation therapy has been employed as the treatment of choice for several decades. As prostate cancer is highly sensitive to radiation, it is an approp­riate treatment of choice.
Most patients are diagnosed in the early/­cli­nically localised stage, which can be treated curatively with radiation therapy alone.
Innovative methods such as brachy­the­rapy, three dimens­ional conformal radiation therapy (3D-CRT), intensity modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT) are able to deliver very high tumour­icidal doses to the diseased prostate, with minimal side effects to the surrou­nding tissue.
Radiation therapy combined with hormonal treatment can be curative in locally advanced disease.
Radiation therapy is very effective in allevi­ating symptoms of metastatic prostate cancer (bone metast­ases, spinal cord compre­ssion, and bladder outlet obstru­ction).
External beam radiation therapy (EBRT), alone or in combin­ation with other treatment modali­ties, such as hormonal therapy or brachy­the­rapy, has become an altern­ative treatment to radical prosta­tectomy in patients with low-risk tumours. Yet the long natural history often observed in these patients makes an accurate assessment of the impact of any therapy on survival more difficult.
EBRT treatments are conven­tio­nally given from one or more fixed gantry angles. For deep seated targets with adjacent critical normal tissues such as prostate and its close proximity to the rectum, or where there is complex geometry, as many as 6-9 beams are utilised to optimise the geometric dose parame­ters.

Compli­cations and Toxicity

External beam RT is generally well-t­ole­rated; the most common side effects are: grades 1–2 acute rectal morbidity, tenesmus, diarrhoea, urinary symptoms (frequ­ency, dysuria, urgency, nocturia) requiring conser­vative medica­tion.
Serious persisting compli­cations that require corrective surgical interv­ention are rare.
Bladder Toxicity
Two major predicting factors for acute bladder toxicity: more than 30% of the bladder receiving doses of 65 Gy or higher and neoadj­uvant hormonal treatment (because of rapid volume shrinkage and more normal tissue exposed to irradi­ation).
In addition, the relative risk of developing late bladder compli­cations (bleeding, strict­ures) also increased as the percentage of the bladder receiving 65 Gy or more of radiation increased.
Rectal Toxicity
There is a signif­icant correl­ation between the percentage of the rectum treated to 70 Gy or higher and the likelihood of late rectal toxicity (bleeding, rectal wall ulcer, severe diarrhoea, incont­ine­nce).
Patients with more than 25% of the rectal wall treated to 70 Gy or a higher dose had a 37% risk of grade 2 rectal toxicity compared to 13% in patients who had less than 25% of the rectal wall exposed to this dose.
In recent years, the addition of a hydrogel 'spacer' placed between the prostate and rectum has helped to minimise dose to the rectal wall by displacing it outside the high-dose region. This has the potential to reduce radiation induced rectal toxicity, thus allowing dose escalation to occur to improve disease control.

Treatment

An important aspect of prostate EBRT and clinical quality assurance is treatment verifi­cation.
Verifi­cation procedures have been establ­ished that improved patient set-up accuracy, such as ultrasound locali­sation systems, kV and MV imaging systems, cone beam CT scanners, CT on rails and implanted gold seeds or fiducial markers.
These systems offer the possib­ility of visual­ising the prostate (or markers within the prostate) immedi­ately before treatment to assure optimal target positi­oning.
This procedure is called image-­guided radiot­herapy (IGRT). It is important to note that when consid­ering imaging protocols the following points are taken into account:
1. Dose received by the patient from imaging (this is often factored into the total dose delivered)
2. Time taken to acquire, assess and act on imaging results – the effect of this on the time the patient is on the treatment couch.
3. Will images be assessed before or after treatment – this is referred to as online or offline review.
4. Equipment and imaging options available
5. Overall, impact of imaging on achieving accurate, reprod­ucible treatment that allows or high dose to be delivered to the tumour with minimal impact on organs at risk
Specific to prostate patients it is important to ensure any patient prepar­ation instru­ctions for bladder and bowel must be strictly adhered to. Patients cannot be treated unless all conditions are the same as simula­tion.

Planning

A large number of randomised studies have demons­trated that radiot­herapy doses of </=70 Gy are less than ideal as curative prescr­iptions for the treatment of localised prostate cancers.
Most of these studies are based upon measures of freedom from bioche­mical failure and it should be noted that “no randomised study so far has demons­trated the survival benefit from dose escala­tion”
Dose and fracti­onation regimes
The dose fracti­onation regimes used for 3DCRT and IMRT/VMAT radical treatment of prostate cancers vary slightly.
Dose fracti­ona­tions are evidence based and may vary due to individual Radiation Oncolo­gists prefer­ences, actual treatment technique used (3DCRT or IMRT, and IGRT protocols) and individual patient variat­ions.
Volume and organ deline­ation
After patient simulation and acquis­ition of CT scans of the treatment area, the first stage of the planning process is to use the CT scans to delineate target structures as well as organs at risk.
There is convincing published evidence that favours the use of additional imaging modalities such as magnetic resonance imaging (MRI), as it provides superior soft tissue visual­isation compared to CT.
Compared to MRI, CT leads to a larger volume than that derived by MRI, which also facili­tates a more precise definition of the prostate apex.
Standard protocol for IGRT and IMRT prostate planning to delineate the following anatomical struct­ures:
1. Prostate
2. Seminal Vesicles or part thereof (this is a clinical decision).
3. Rectum - Some prescr­ibing RO’s prefers to mark the rectum and anal canal as one organ.
4. Bladder
5. Head & Neck of Femurs
Inter observer errors often occur in the deline­ation of the apex of the prostate – this is when one observer would delineate the apex of the prostate differ­ently to the next observer.
Contouring errors at the apex result in the overes­tim­ation of prostate volume in the vast majority of cases.
Once the prostate volume and OAR have been deline­ated, the addition of beams to the treatment plan can commence. The ICRU point for dosimetry is in the centre of the Planning Target Volume (PTV).

Limita­tions of CT for Prostate deline­ation

CT is able to differ­entiate various tissues solely on the basis of differ­ences of attenu­ation coeffi­cients.
Since the prostate, rectal and bladder wall, levator ani muscle, and penile bulb all have similar attenu­ation coeffi­cients they cannot be readily differ­ent­iated on CT.
Many clinical centres use CT/MRI fusion for radical treatment planning of prostate cancer protocols but the use of CT/MRI fusion will vary from one clinical centre to the next.
Some centres may use MRI for IMRT planning, while others may use it for dose escala­tion, or not at all. The soft tissue contrast of T2 weighted MRI images has been demons­trated to result in better definition of both prostate and critical struct­ures.

Simula­tion: Example

An example of a prostate simulation procedure that could be used for radical 3DCRT or IMRT/VMAT treatment:
Fiducial Gold seeds implanted under ultrasound guidance one week prior to CT.
Clinical centre protocol for bowel and/or bladder prepar­ation instru­ctions given to the patient prior to simulation appoin­tment.
Prior to CT establish if the patient has complied with the bowel and/or bladder prepar­ation instru­ctions.
Patient scanned supine using the stabil­isation devices as per the clinical centre protocol. These generally include some form of knee and foot stabil­isation devices.
Trans-­axial CT Data-Set acquired.
Scan from L5 to Perineum 2 - 5mm slices (centre dependent)
No contrast requested

Simula­tion: Bowel and bladder prepar­ation

The anatomical position of the prostate varies depending on bladder and bowel filling
Simulation imaging and treatment require patients to follow bowel and bladder prepar­ation protocols. Patients will receive instru­ctions on the prepar­ations and procedures required prior to their simulation appoin­tment.
Most clinical centres follow full bladder and empty bowel protocols during simulation and treatment.
Filling the bladder reduces the area of bladder that will fall within or close to high dose regions of the treatment volume.

Simula­tion: Stabil­isation and locali­sation

The standard radical set-up for prostate cancer radiation therapy includes placement of devices for the head, support for the pelvis region, the knees and feet.

Gold seed markers

Prostate Cancer Simulation

It is well establ­ished the prostate can move intern­ally, despite the body remaining completely still. Therefore, bony anatomy is not a reliable method of determ­ining precise prostate position.
Many clinical centres have an establ­ished gold seed or fiducial marker implan­tation programs, whereby 3 gold seeds or fiducial markers are implanted into the prostate prior to simula­tion.
A Urologist or Radiol­ogist inserts the fiducial markers using ultrasound guidance in a procedure similar to the prostate biopsy.
The fiducial markers are then visible on the CT and verifi­cation images to accurately localise the prostate and ensure treatment is delivered accura­tely, minimising dose to critical structures such as the bladder and rectum.
As with all radiation therapy treatment sites, the simulation procedure will be based on the same fundam­ental principles of collecting the required inform­ation and data to effect­ively reproduce the approp­riate treatment plan over the course of the patients treatment.

Brachy­therapy

Brachy­therapy (BT) can be used as mono-t­herapy, mainly for low-risk patients with smaller prostate volumes.
Combined EBRT, followed by a temporary brachy­therapy (BT) boost, is effective in low-risk patients (T2a, initial PSA <10 ng/ml, Gleason score<6), but these patients also do well with permanent brachy­therapy alone.
The greatest advantage of EBRT plus temporary BT (total dose of 20–25 Gy) seems to be in interm­ediate- and high-risk patients (T1b–T3b or PSA>10 ng/ml or Gleaso­n>6).
Common side effects: Transient urinary morbidity related to radiation induced urethritis (infla­mmation of the urethra) or prosta­titis (infla­mmation of the prostate gland)
Irritative and obstru­ctive lower urinary tract symptoms may develop over the first few weeks as a result of implant trauma.
These side effects are of a temporary nature. In addition to the urethral dose, the presence of obstru­ctive symptoms secondary to pre-ex­isting benign prostatic hypert­rophy before brachy­therapy has been correlated with an increased incidence of acute symptoms, including urinary retention.
Late side effects, such as incont­inence, chronic cystitis, urinary retention, dysuria, frequency and late grade 3 urinary compli­cat­ions, that require medical or surgical interv­ention may occur in approx­imately 2%–5% of patients.
Combined modality (with EBRT) can cause about 20% of patient’s grade 2 and 8% grade 3 toxicity.
Late rectal compli­cations, including proctitis with diarrhea, perineal pain, tenesmus, or rectal bleeding may occur in 2 – 19% of patients.

Volumetric Modulated Arc Therapy (VMAT)

VMAT is a type of intensity modulated radiation therapy (IMRT) treatment technique which can be delivered on a linear accele­rator and delivers the radiation therapy treatment using a rotational or arc geometry rather than several static beams.
There are three mechanical variable in VMAT delivery; gantry rotation, multi-leaf collimator (MLC) motion, and dose rate modulation
Both the MLC aperture and the dose rate can be simult­ane­ously adjusted in an arc of 360 degrees or less, whereas gantry speed is modulated as needed.
During a VMAT treatment, the Linear Accele­rator rotates around the patient while the radiation beam is shaped and reshaped as it is contin­uously delivered from virtually every angle in a revolu­tion.
During a VMAT treatment, specia­lised software algorithms will vary the three parameters simula­teo­usly; the speed of rotation around the patient, the shape of the MLC aperture, and the dose delivery rate.
The target volume dose does not change when using VMAT. The amount of scatter and leakage radiation dose to the rest of the body is reduced compared to conven­tional IMRT.
VMAT for prostate treatment and planning is more widely accepted in Australian clinical practice, many centres deliver 78Gy in 39 Fractions using.
For the treatment of prostate cancer, there is an involv­ement of tissues such as bone, rectum, and bladder, which all have different tissue hetero­gen­eities. Hence, it is important to have an accurate tissue hetero­geneity correction while calcul­ating dose in the situation when tissues of different densities are involved in the beam path.

3D Conformal Radiation Therapy (3DCRT)

A technique where the beams of radiation used in treatment are shaped to match the tumor.
Retros­pective dose escalation studies using 3DCRT provide clear evidence for a dose-r­esponse relati­onship in various subgroups of patients with prostate cancer.
The RTOG 9406 trial invest­igated changes in toxicity with increasing radiation doses. They report no signif­icant difference in acute and late toxicity up to the highest dose level of 79.2 Gy.
The vast majority of 3DCRT studies showed a direct relati­onship between high doses and no bioche­mical evidence of disease.

Anatomy

The prostate gland is positioned just below the base of the bladder and in front of the rectum.
In a young male the prostate weighs approx­imately 20 grams and is 3 x 4 x 2cm (often referred to as being the size and shape of a walnut or plum).
Through the prostate passes the prostatic urethra, which is covered by transi­tional epithe­lium. The prostate is divided into two lobes and is surrounded by a thin layer of fibrous tissue. Part of the venous drainage is to a plexus of veins lying in front of the vertebral bodies. This is possibly a reason why prostate cancer has a tendency to spread to the vertebrae.
In radiation therapy planning it is important to be able to identify the apex and the base of the prostate
Apex = inferior portion of prostate, continuous with striated sphincter.
Base = superior portion and continuous with bladder neck.
The growth and function of the prostate are controlled by hormones. Normal prostate function depends on several androgens, primarily testos­terone, which is produced by the testes.
The prostate is made up of thousands of tiny fluid-­pro­ducing glands. Specif­ically, the prostate is an exocrine gland.
Exocrine glands are so-called because they secrete through ducts to the outside of the body (or into a cavity that commun­icates with the outside). The fluid the prostate gland produces forms part of semen.
The prostate also produces a protein called Prostate Specific Antigen (PSA)
PSA is released with the ejacul­atory fluid and can also be traced in the blood stream. The testing of PSA levels in the blood is used to detect prostate cancer
In addition to the prostate's role in producing ejaculate, it also plays a part in contro­lling the flow of urine. The prostate wraps itself around the urethra as it passes from the bladder to the penis. Muscular fibres in the prostate contract to slow the flow of urine.

Hormonal options

Hormonal treatments are of benefit in the reduction of testos­terone circul­ating in the bloods­tream.
Mechan­isms:
Firstly is the removal of the testes;
Secondly the consum­ption of oral oestro­gens;
Thirdly through the admini­str­ation of monthly or three monthly inject­ions.
Early interv­ention with hormonal therapy reduces compli­cations of the disease such as pathol­ogical fractures, however it does not appear to improve survival. Hormonal treatment also has a role in reducing prostate volume before treatment (“down­siz­ing”), due to reduced benign prostate hyperp­lasia (BPH) of the gland.

Surgical options

Radical prosta­tectomy is an option when the tumour is still confined to the prostate, and the patient is medically fit.
This operation entails the removal of the entire prostate, including the capsule, a layer of the surrou­nding connective tissue, and the attached seminal vesicles.
The anatomical location of the prostate makes this procedure techni­cally challe­nging and nerve sparing to avoid compli­cations is an important issue.
Once the tumour has spread beyond the prostate and there are metast­ases, surgery is no longer an option. Side effects from this surgery include incont­inence and compro­mised potency. Improved surgical techniques have reduced the incidence of long term compli­cations from radical prosta­tec­tomy.
Transu­rethral resection of the prostate (TURP) involves removing tissue from the prostate with the use of an instrument inserted through the urethra. This surgical procedure is often done to relieve symptoms resulting from the tumour, and prior to other treatment. TURP may also be performed for patients who due to age or other illness are unable to have a radical prosta­tec­tomy.

Treatment summary

It is very difficult to find the optimum treatment for patients presenting with early prostate cancer, as the clinical behaviour of the disease can be quite unpred­ict­able.
The disease has a long natural history, and many patients survive 15 years or more after the diagnosis is establ­ished.
Treatment of patients using radiation when it is asympt­omatic may lead to toxicity of treatment, whilst no or under treatment can lead to morbidity or cancer related death.
This is a potent­ially curable disease, therefore it is a fine line to balance each patient indivi­dually.
There are five options available to patients currently:
1. watchful waiting
2. hormonal therapy
3. radical prostatectomy
4. radical external beam radiation therapy
5. radical brachy­therapy
- brachy­therapy seed implants
- high dose brachy­therapy
Patients who are expected to have a life expectancy of greater than 10 years will be offered radical treatment. In general, for patients who have a high PSA, Gleason score, and T stage, the greater the likelihood of tumour progre­ssion, and therefore the need for radical treatment.
Patients who are elderly and medically unfit with less aggressive histol­ogical features are managed with watchful waiting. They also have options of hormonal treatments and palliative radiot­herapy if and when the need arises.

TNM Staging: Metastases

TNM Staging: Nodes

TNM Staging: Stage extent

Gleason Score

Presen­tation and Workups

Screening
Prostate Specific Antigen (PSA) is a glycop­rotein that liquefies semen. The normal range of PSA is approx­imately 4ng/ml. Levels above this increases the risk. PSA levels increase propor­tio­nally to the volume of disease, and are a valuable tool to monitor response to treatment and develo­pment of metastatic disease.
Clinical presen­tation
Early prostatic cancer is usually asympt­omatic and can only be detected through a routine rectal examin­ation. As the prostate can undergo benign enlarg­ement, patients may experience increased frequency and difficulty in mictur­ition (ejection of urine).
Larger tumours can produce symptoms of: hesitancy; urgency; nocturia (urination at night); poor urine stream; dribbling and terminal haematuria (blood in urine).
Advanced disease can manifest itself as pain in the back, pelvis, shoulders and possibly over multiple bony sites. Occasi­onally patients may present with pathol­ogical fractures in the femurs.
Diagnostic workups and staging
Trans-­rectal ultrasound (TRUS) is helpful for defining the extent of local disease but is unable to assess lymph node size.
With rectal examin­ation exclus­ively, there is 50% unders­taging, and with ultrasound exclus­ively, unders­taging is 62%.
A bone scan to assess for bone metastasis should be part of the initial staging.
Computed Tomography (CT) scanning or Magnetic Resonance Imaging (MRI) can help evaluate the pelvic lymph nodes but have poor sensit­ivity and specif­icity
Acid phosph­atase levels directly correlate with the stage of prostate cancer. Because it is rarely elevated in organ-­con­fined disease, the acid phosph­atase is a good marker for extra-­cap­sular disease.
Pathol­ogical staging refers to histol­ogical examin­ation of the resected specimen after surgery. It is important for determ­ining prognosis and the need for more treatment after surgery. Surgical removal of the prostate, seminal vesicles and pelvic lymph nodes is required for complete pathol­ogical staging.
The extent of tumour is stratified to organ confined, specim­en-­con­fined, and margin negative or margin­-po­sitive disease. Histop­ath­ologic examin­ation of the malignant tissue and histop­ath­ologic growth patterns are used to determine grade (degree of biological aggres­siv­eness).
Because of the wide variab­ility of growth patterns, cell types, degree of anaplasia, and variation from one micros­copic field to another, a range of differ­ent­iation among the malignant tumours may be reported.
Gleason's score is used to report the degree of malignancy of prostate cancer. This system assigns histol­ogical grade to the predom­inant (primary grade) and the lesser (secondary grade) patterns of tumor on a scale of 1 to 5.
The grade numbers of the two patterns are added to obtain the Gleason score, which may range from 2 to 10. The lower the score, the better.
The major problem with the Gleason grading system is its reprod­uci­bility, which is only 80%.

Prognosis

The rate of tumour growth can vary from very slow to moderately rapid.
As it is often not diagnosed until a man is 70 years of age or older, the approach to treatment and thus prognosis is greatly influenced by the patient's age and coexistent medical problems. Men who are younger at the time of diagnosis are more likely to die of prostate cancer, and definitive treatment is important for them.
As with other cancers, survival is related to the extent of tumour dissem­ination and histol­ogical grade.
When confined to the gland, prostate cancer is frequently curable. Median survival is more than 5 years whether the cancer is treated or not.
When locally advanced, prostate cancer is rarely curable. Many patients will die of the cancer, but some may live for 5 years or longer with treatment.
If spread to distant organs has occurred, cure is not possible. Median survival in such cases is 1 to 3 years, and most such patients will die of their tumour.
Other factors influe­ncing prognosis are the: patient's age;
hormone status;
acid phosph­atase levels in the blood;
regional lymph node involvement;
bone scan results;
response to treatment.
As prostate cancer grows slowly at its onset, a diagnosis before spread beyond the gland would result in an excellent potential for survival with treatment. However, localised malignancy of the prostate is not easy to diagnose because it is charac­ter­ist­ically asympt­omatic.

Pathology and natural history

More than 95% of prostatic carcinomas arise in the glandular epithelium of the peripheral glands of the prostate and hence are classified as adenoc­arc­inomas. Other histol­ogies such as sarcomas, transi­tional, small and squamous cell carcinomas are rare.
Prostate carcinoma is more commonly found in the apex of the prostate, frequently involves the gland’s capsule and is also multif­ocal. This makes the removal by transu­rethral resection unfeas­ible.
The develo­pment of clinically signif­icant prostate cancer follows predic­table patterns. Although growing slowly at first, as time goes on and as the tumour mass becomes larger, prostatic tumours appear to progre­ssively dediff­ere­ntiate and become more aggres­sive. As the bulk of the tumour increases, there occurs extension to the capsule margins, through the capsule, and into the seminal vesicles, the neck of the bladder, and the pelvic lympha­tics. Rarely do prostate tumours cross the fascial space into the rectal wall.
Metastatic spread is both lymphatic and haemat­oge­nous.
The pelvic lymph nodes near the prostate are usually affected first by lymphatic spread, which is orderly. The next area of metastasis is to the lymph nodes around the arteries and veins leading to the legs and pelvic organs. Dissem­ination via the blood most frequently affects the bones, producing dense osteob­lastic metast­ases.
Liver involv­ement also occurs, but metastasis to the brain and other soft tissues is less common. 60% of men who die of prostate cancer have bone metastases (verte­brae, pelvis, femur, and ribs). Spinal involv­ement frequently extends into the epidural space and is a cause of extrinsic compre­ssion of the spinal cord that can result in leg weakness and can progress to parapl­egia.

Epidem­iology and aetiology

The exact aetiology of prostatic cancer is unknown. It commonly presents itself in the seventh and eighth decades and is rare under the age of 40 years. There are signif­icant differ­ences in incidences worldwide, with the highest risk of developing prostate cancer being in Sweden, followed by the United States and Europe. The lowest incidence is in Japan.
Many factors contribute to the develo­pment of prostate cancer­:diet (high fat consum­ption); genetics (risk increasing with positive family history); enviro­nmental factors (such as exposure to radiation, heavy metals and chemical fertil­isers); hormonal factors.
Orchid­ectomy or admini­str­ation of oestrogens may result in the shrinkage of the prostate gland in 80% of tumours.

Anatomy