PROSTATE CANCER

It is based on risk categorization
Low Risk: T1-T2 and Gleason Score 2-6 and PSA <10ng/ml
Intermediate risk : T2b-T2c or GS 7 or PSA 10-20ng/ml
High Risk: T3a or GS 8-10, or PSA >20ng/ml
Very High risk: T3b- T4

Treatment Recommendations

Low Risk: T1-T2a and Gleason Score 2-6 and PSA <10ng/ml	For life expectancy < 10 yrs	Active survillence Or RT (3D CRT/IMRT with IGRT or Brachytherapy)
	For life expectancy >= 10 yrs	Active survillence Or RT (3D CRT/IMRT with IGRT or Brachytherapy) Or Surgery +RT
Intermediate risk: T2b, Gleason Score 7, PSA 10-20	For life expectancy < 10 yrs	Expectant management or RT + Short term hormonal treatment (4-6 months) Or Surgery
	For life expectancy >= 10 yrs	RT + Short term hormonal treatment (4-6 months) ( preferred), Or Surgery + adjuvant RT +/- short term HT (preferred)
High Risk: T3a, GS 8-10, or PSA >20	Long term hormonal treatment (2-3 yrs) + RT (3D CRT or IMRT with IGRT) OR RT + Short term hormonal treatment (4-6 months) in selected patients with a single adverse high risk factor
Locally advanced Very High risk: T3b- T4	Definitive RT + Short term hormonal treatment (4-6 months) Or Long term hormonal treatment (2-3yrs) alone
Metastatic disease	Androgen ablation +/- palliative RT +/- bisphosphonates. For Hormone refractory disease, Chemotherapy docetaxel + predinosolone or estramustine
Residual disease or recurrence after surgery	If persistent local disease or high risk of local residual disease à RT +/- HT. If no evidence of persistent local disease or high risk of metastases à HT or observation +/- RT
Residual disease or recurrence after RT	If Bx +ve & no evidence (or low risk) of metastases, surgery or salvage brachytherapy. If metastatic and not a candidate for local therapy, androgen ablation or observation

Expectant Management:

It is based on the fact that prostate cancers are nowadays detected at a an early stage, and the fact that it so slow growing that if patients life expectancy is less, than his chances of dying of prostate cancer are much less than him dying of other co morbid conditions. Hence, the actual benefit of prolongation of overall survival may not be evident in such patients. Also treating such patients can hamper with quality of life as no treatment modality is averse to side effects.

Radiotherapy

Radiotherapy (External or Brachytherapy) play an important role in both early as well as advanced prostate cancers. With the development in the field of 3D CRT, IMRT and IGRT external beam radiation therapy is now increasingly being used.
With conventional technique, pelvic irradiation is usually done with a four-field box technique. Conventional radiotherapy (two or four field) is associated with disadvantages of excessive radiation to bladder, rectum and intestines. Radical dose required to eradicate the disease (70 Gy and above) is associated with significant toxicities. These disadvantages can now be decreased using conformal radiotherapy.
Conformal means the ability to limit our treatments to the areas of interest only; by directly visualizing our target in the position it will be treated. Advantage lies in the fact that radiation toxicities to our normal tissues can be decreased. Secondly, higher doses can be given which are known to be associated with better outcomes.
Conformal radiation is a double edged sword. If the treatment volumes are to tightly conformed then we may miss some of involved sites. Using CT and MRI fusion aids in better soft tissue delineation including both target and normal tissues. So such treatment should be done under a trained radiation oncologist with sufficient experience for best results.
3D CRT and IMRT are the two forms of conformal radiation.

How radiotherapy planning is done?

A CT Scan of the pelvis is done. This is transferred to the contouring stations where radiation oncologist delineates on each and every slice the areas that require radiation (like the prostate, seminal vesicles and lymph nodes depending on the risk categorization), normal tissues which should be avoided(like the rectum, bladder, femoral heads, intestines). MRI and CT fusion can be done where visualization and exact delineation is a problem.
Then multiple plans are generated by radiation physicist using multiple beams placed all around the patient. The radiation oncologist selects the best plan which includes maximum target region and minimal normal tissues.

What is IMRT?

IMRT stands for Intensity Modulated Radiotherapy. It the most refined form of radiotherapy planning. Cancers have irregular shapes. IMRT provides us an ability to exactly localize our treatment to the shape of the target. Even concave shapes can be defined using IMRT which are not possible using even 3D-conformal radiotherapy. All this could be achieved by using advanced computer systems and better imaging facilities like CT and MRI. The planner in IMRT gives constraints the normal tissues, depending on there tolerance levels. Then using sophisticated algorithms plans are generated. Also in 3D conformal radiotherapy a constant dose is given through a field, while in IMRT plans the intensity of the dose given can be modulated by movement of the multileaf collimators. Studies have shown significantly lesser rectal and bladder toxicities using IMRT plans compared to 3D conformal plans.

Image Guided Radiotherapy

The use of image-guided radiotherapy (IGRT) in the treatment of localized prostate cancer has rapidly advanced over the past decade.

What does it mean?

Daily variations in the location of the internal body organs occur constantly. The source of which is our breathing causing movement of structures in thorax and abdomen, bladder and rectal filling causing movement of pelvic organs like prostate. Even if a CT scan is done and exact localization of structures is done, internal organ motion will result in errors while delivering radiation therapy because the target may now be at a different location than what was planned. IGRT can correct for these daily and continuous movements by use of online imaging.
Image guided radiation therapy can be achieved using:
Fudicial maker based prostate localization using daily EPID or MVCBCT.
Ultrasound guided localization (BAT imaging)
CT based image guidance
We at our institution use Fudicial maker based prostate localization using daily EPID. Patients are placed in the lateral decubitus position. First, the urologist measures the prostate volume using a transrectal ultrasound. Then gold fiducial markers are introduced under ultrasound guidance, with a standard 18-gauge prostate biopsy tool. Risks associated with seed insertion are same as for a prostate biopsy procedure. Fine gold markers 1.2mm in diameter and 3 mm in length are used. Two markers are placed on the left and right at the base, and one at the apex of the prostate, thus forming an equilateral triangle. After at least 5-7 days, time for swelling of the gland to resolve, a planning CT scan is obtained. Structures are contoured and an IMRT plan is generated. Daily online positional verification and correction is done using anteroposterior and lateral films. Significant interfractional (between two fractions) motion exists between patients prostate and pelvic bony anatomy during EBRT. However, these structures also move independently and, therefore, the pelvic bony anatomy should not be used as a surrogate for prostate motion. Fiducial markers are stable within the prostate and can allow significant margin reduction when used for online localization of the prostate gland. Localization based on daily imaging with implanted gold seeds has allowed us for reduction of margins when compared with tattoo localization (the standard method used in daily patient set up). Rectal and bladder doses can be decreased, thus limiting the immediate and long term normal tissue toxicity. Thus gold seed based portal verification can act as a surrogate to CT based IGRT especially in developing countries like India.

What is the dose required to treat prostate cancer?

Higher the dose better are the results. However higher the dose, more are normal tissue toxicities. Thus a balance between the two is essential. In past when facilities for 3DCRT and IMRT were not available radiotherapists had to settle for low doses to limit the side effects to tolerable levels, resulting in poorer control rates. With the advent of these two modalities we can go for higher doses without increase in normal tissue toxicities. Doses of >70 Gy are required for better long term disease control.
We at our centre go for a 70Gy in 28 fractions with each fraction of 2.5 Gy. This regimen is well tolerated with acceptable toxicities. Practitioners even go for doses upto 80 Gy but with smaller fraction size.

Is Radiotherapy required if prostate has been removed?

As shown in guidelines for prostate cancer management, radical prostatectomy is an option for low and intermediate risk patients as a sole modality. However presence of any positive surgical margins or extension outside the prostate are associated with poor survival if surgery alone is used. Studies have shown that use of radiotherapy in these patients prolongs the duration of reappearance of the disease. Also early radiotherapy, rather than delaying it till symptoms of progression appear is associated with better results. However in patients with poor general condition and other comorbid conditions especially if the life expectancy is less, a delayed treatment may be a better option, considering the slow growing nature of the disease. Doses of 60-64 Gy for adjuvant radiotherapy (given immediately after prostatectomy) and 66-70 Gy if it given as a salvage treatment (when disease reappears).

What is Brachytherapy?

It is a form of radiation therapy where radioactive source is placed inside the patients body which gives radiation to the cancerous region only. Advantage of brachytherapy over external beam radiotherapy is lesser dose to the surrounding tissues, lesser life style changes, shorter duration of treatment and ability to give higher doses.
However, it is not possible on account of some technical difficulties like for tumors >60cc, is associated with some operative risk. The most important limitation is lack of expertise available.
Brachytherapy can be used for giving total doses or only boost dose with rest of the dose being delivered using external beam radiotherapy.
In prostate cancer brachytherapy can be done in two ways:
Temporary implants: Radioactive source remains in the body for a short duration under ultrasound guidance and then is then removed. Iridium-192 is most commonly used. Permanent implants: In this form of brachytherapy radioactive source of very low energy are inserted inside the prostate tissue under ultrasound guidance. They emit radiation to a small area where placed, over a longer duration of time. Various radioactive sources commonly used in permanent prostate brachytherapy include the Iodine-125, Palladium-103 and Gold-198.

Why treating breast is important?

Suppressing male hormones by whatever means leads to increase in size of male breasts along with pain, a condition known as gynaecomastia. Once it has occurred, the only treatment is surgical resection of the male breast tissue. However radiating the breasts before starting any hormonal treatment can prevent this condition. It is very simple and safe treatment. We at our centre give single fraction of 8 Gy to both breasts by electron beam. Using appropriate electron beam energy the chances of lung receiving any significant dose is minimal.

Hormonal Management

Prostate cancer cells are dependant upon androgens (male sex hormones) for survival and growth. Withdrawal of the androgen stimulation causes a proportion of the cells to undergo apoptosis (self destruction), while in others growth stops. Role of hormonal treatment is seen in intermediate and high risk patients.

Removing Androgens can be achieved through

1. Orchiectomy (castration): surgical removal of the testicles.
2. Oral drug which has the same effect as castration. They blocks testosterone production. They include LHRH agonists and antagonists and oral estrogens.
3. Anti-androgens which block the effects of testosterone.
4. Combination therapies.

Surgical Orchiectomy or Castration

It provides rapid palliation at a low cost with no issues of compliance. Owing the psychological impact of loosing both the testes it remains the least preferred modality by patients.

Gonadotropin-Releasing Hormone Analogues

These are the drugs which block the release of androgens by acting at the level of brain. However, they are associated with an initial tumor flare (aggravation of symptoms in initial period of treatment) as they cause an initial increase in LH and testostrone secretion. Fall in testosterone levels are seen after 3-4 wks. Formulations include Leuprolide 7.5 mg i.m. monthly or 22.5mg i.m. every 3 months, and Goserelin 3.6 mg s.c. monthly or 10.8mg s.c. every 3 months.

Antiandrogens

Antiandrogens block androgen binding to androgen receptors. They are of two types.
Type I, steroidal antiandrogens (cyproterone acetate and megestrol acetate) have progestational properties that suppress LH levels and lower serum testosterone.
Type II, nonsteroidal agents (flutamide - 250mg TDS, bicalutamide- 50mg OD, and nilutamide- 150mg BD) bind to androgen receptors in the prostate as well as those in the pituitary and hypothalamus.
Side effects include impotence, loss of sexual desire (libido), hot flashes, weight gain, fatigue, reduced brain function, loss of muscle and bone mass, and some cardiovascular risks.

Which Androgen Suppressive Therapy ?

Whatever may be the means of lowering testosterone levels, as long as castration levels are reached there is no difference in overall survival.

Monotherapy or combination?

Adrenal androgens can contribute 5% to 45% of the residual androgens present in tumors after surgical castration alone. The addition of an antiandrogen to a GnRH analogue or orchiectomy has the potential to inhibit the effects of adrenal androgens on prostate cancer cell growth, known as combined androgen blockade Monotherapy with a (non-steroidal) antiandrogen is becoming an increasingly attractive alternative therapeutic approach. Androgen blockade can preserve gonadal function and therefore provide potential QOL benefits, particularly in terms of retained potency and libido, no muscle weakness, and less bone demineralization. Also antiandrogens are combined with GnRH analogues to overcome initial tumor flare.
No significant difference in outcome has been seen in patients receiving combined modality versus single modality.

Sequencing – When to start hormonal treatment?

Hormonal treatment can be given both before and after surgery. Use of hormonal treatment for short duration (3-8months) prior to surgery decreases the prostate size and decreases the chances of positive surgical margins. Similarly giving hormonal therapy after surgery decreases the changes of disease recurrence.

Sequencing with radiotherapy

A 6 month adjuvant hormonal treatment in intermediate risk and 2 year in high risk is recommended along with radiation therapy. Treating physician is the best person to judge when the same needs to be started. It can be given before, during or after radiation therapy.

Should the hormones be given Continuous or intermittently?

Some patients even benefit from intermittent hormonal treatment rather than continuous one. Giving continuous treatment can reduce the sensitivity of the receptors, thus reducing its effect. Giving a break in these patients can help. Also intermittent therapy decreases the side effects and toxicity of androgen deprivation. Cycling durations vary widely.
1. Fixed intervals of 3 to 6 months, or
2. Treat for 2 to 3 months beyond the point of maximal response, at which point all hormones are discontinued.
Testosterone levels then rise, along with the PSA. Androgen ablation is restarted at some predetermined PSA level and cycling continues. About an estimated 35% to 55% of time of each cycle is spent off therapy and 90% respond to re-induction.

Surgical Management

Role of surgery is seen in localized carcinoma prostate, locally advanced carcinoma and metastatic carcinoma
Modalities of surgical treatment include
Radical prostatectomy
Salvage radical prostatectomy
Channel TURP
B/L orchidectomy
Who are the patients who fit for surgery?
Patients who are healthy and free of comorbities
Life expectancy of atleast 10 years
Accepted upper age limit is 75 years.
Radical Prostatectomy includes complete removal of prostate gland, seminal vesicle and modified pelvic lymph node dissection
Patients at low risk do not require Pelvic lymph node dissection. Moderate risk patients do need pelvic lymphadenectomy.

Advantages of surgery

The true stage (extent) and grade (aggressiveness) can be determined.
If the cancer is confined to the prostate, surgery should be curative.
If prostate cancer recurs, radiotherapy can be given.
Corrects any bladder outlet obstruction.
Improves cancer specific and overall survival rates compared to watchful waiting.
Disadvantages
Patient may be required to stay in hospital for few days.
Possibility of incomplete resection.
Risk of urinary incontinence and erectile dysfunction.

Outcomes of radical prostatectomy

5 year PSA free survival following radical prostatectomy depend on the extent of tumor spread. For disease limited to the prostate survival is to the tune of 95%, for those with extracapsular extension 76%, for seminal vesicle invasion 37% and only 18% for those with lymph node involvement. However the same can be improved using post operative radiotherapy.

Palliative surgery
Palliation means symptom relief without any attempt to cure the disease.
Palliative transurethral resection of prostate (TURP)
TURP performed to alleviate obstructive voiding symptoms in patients with advanced carcinoma, previously treated carcinoma and metastatic carcinomas.
However there is a certain risk of incontinence particularly in patients with external sphincter involvement.
Bilateral or unilateral PCN (percutaneous nephrostomy)/Stenting : indicated in locally advanced disease with B/L or U/L HUN
If Pathological fracture has occurred surgical fixation is required for pain control and to promote healing.
Spinal cord compression is an emergency requiring surgical decompression along with medical management and radiotherapy.

Management of Relapse

What is relapse?

Relapse is reappearance of disease characterized by either reappearance of symptoms of the disease or rise in PSA levels with or without appearance of symptoms, the latter being referred to as biochemical failure.
Three consecutive rising PSA values from the nadir value (lowest value) is considered as an indicator for relapse. Date of failure should be midpoint between the post radiation nadir and first of the 3 consecutive rises. (ASTRO consensus definition).
Assessing and managing failure
The failure of first-line androgen ablation can be manifest as
rising PSA alone,
rising PSA and spread to the bones,
spread to other body organs with or without bone involvement. Symptoms may or may not be present.
Which pattern develops in a given patient depends on the reason for initiation of the androgen deprivation therapy.
Regardless of the pattern, the first thing a clinician must look in patients who have not undergone surgical orchiectomy, is their testosterone levels.
If it is not in the castrate range, then testosterone-lowering therapy should be administered.
If the testosterone level is already in the castrate range, a variety of options are available, including second-line hormonal therapies, cytotoxic approaches, and investigational agents
But, independent of treatment, it is important to continue medical therapies that maintain castrate status. Allowing testosterone levels to rise in this setting may shorten survival.
Tumors that are progressing despite castrate levels of testosterone have been variably classified as hormone-resistant, hormone-refractory, androgen-insensitive, and androgen-refractory.
Hormone Refractory Prostate Cancer (HRPC)
Current Management Options in HRPC
Further Hormonal Manipulation
Steroids
Estrogens
Established Chemotherapy Regimen
Docetaxel
Mitoxantrone
Investigational Regimen
New chemo regimens
Biologic therapies

Supportive Care

Ketoconazole is an antifungal agent which acts by inhibition of adrenal steroidogenesis. Dose:- 1200 mg/d, produces castrate levels of testosterone in 24 hours. It is useful for the patient who presents with acute spinal cord compression or disseminated intravascular coagulation, when orchiectomy or GnRH analogues are contraindicated. It is used most frequently as second-line treatment, with fatigue and hepatic dysfunction being the most common side effects.
Estrogens Inhibit androgen production and spermatogenesis. Dose- Diethylstilbestrol (DES)-3mg/day (castrate levels of testosterone reached in 1-2 wks), Fosfestrol- 100mg t.i.d. (used as third line therapy in disease progression after orchiectomy ±antiandrogens). Side effects include thromboembolic events (myocardial infarction, stroke), painful gynecomastia and edema.
Progestational agents like megestrol acetate, medroxyprogestrone acetate and cyproterone acetate suppress LHRH and block binding of DHT to AR.

Chemotherapy

Chemotherapy is an option for hormone refractory prostate carcinomas. Mitoxantrone initially and now docetaxel form the first line management for patients with hormone refractory prostate carcinomas
Options for docetaxel faliures are under investigation. These include satraplatin, abiraterone, sipuleucel-T.