Locally Advanced Disease (Stage T3–T4)

Locally advanced disease refers to prostate cancer that is no longer confined to the prostate and has started to invade nearby organs such as the seminal vesicles, but where there is no evidence of spread to distant sites such as the bone (T3–T4). This may also include those patients with biochemical failure following curative treatment, patients with N+ disease and those who are surgical margin positive after radical prostatectomy.

The aim of treatment for locally advanced disease is to reduce the risk of metastatic spread and tissue invasion and thereby prolong survival (Table 3.3). There are several possible treatment alternatives for patients with this early stage of prostate cancer. Some patients may be cured.


Radiotherapy + Hormonal Therapy

Neoadjuvant hormonal treatment prior to radiation therapy

Neoadjuvant hormonal therapy, used in combination with radiotherapy, is generally administered to reduce prostatic size/symptoms. The term neoadjuvant is used to describe a treatment is given before the primary treatment. Examples of neoadjuvant therapy may include hormone therapy commenced prior to radiation therapy.

EBRT (External beam radiotherapy) is often sufficient to suppress PSA levels to within normal ranges and delay disease progression. However, EBRT following neo-adjuvant hormonal therapy has been shown to produce better local control of disease and effect greater reductions in the risk of clinical or PSA relapse than EBRT alone.

The RTOG 86-10 trial investigated the use of MAB (goserelin – ZOLADEX plus flutamide) given for 4 months, starting 2 months before and continuing for 2 months during radiation therapy in T2–T4 disease. Disease free survival at 8 years was significantly improved (33%) in patients receiving neoadjuvant therapy compared to 21% in patients receiving radiation therapy alone.

Overall survival was improved in patients with a Gleason score of 2-6, although survival in all patients was not improved. In addition such neoadjuvant therapy reduces the number of patients requiring salvage therapy (Pilepich MV et al. Int J Radiat Oncol Biol Phys 2001; 50: 1243–52).

Figure 3.10. RTOG – 86-10 - Disease-free survival, all patients

CAB – Combined Androgen Blockade

Since my therapy has entered a new phase, incorporating 'Combined Androgen Blockade' (CAB) and Radiation Therapy, I thought a review of Hormone Therapy (HT) was necessary. In what follows you will see how HT and Anti-Androgen Therapy combine to become CAB. In a further post, we will look at the combination of CAB and IMRT with 'gold seed markers'.

The male sex hormone testosterone feeds the growth of prostate cells and prostate cancer. Male hormones are called androgens. Prostate cancer hormone therapy works by ablating or depriving testosterone in the body. With no hormone to fuel their growth, the cells stop growing. Hormone therapy does not provide a cure; the prostate cancer does not “starve” to death, but for a time the spread of the disease can be slowed or even halted.

Hormone therapy is most versatile of the postate cancer treatments. the ablation and deprivation of testosterone can be used as adjuvant therapy, neoadjuvant therapy, or monotherapy for either primary or salavage treatment. Adjuvant and neoadjuvant hormone therapy is more common for primary treatment. Androgen ablation and deprivation monotherapy is more common during salvage treatment.

During primary therapy, hormone therapy is given to shrink the volume of the prostate gland and tumor. Eventually, the prostate cells become resistant to the androgen deprivation therapy and begin to grow again. When prostate cells become resistant, the next steps are either to stop hormone therapy to see if the reintroduction of testosterone can slow the growth, or chemotherapy.

The testicles produce 90 percent to 95 percent of the body’s testosterone. The adrenal glands produce the remaining 5 percent to 10 percent. The two types of hormone therapies used to combat prostate cancer are castration or anti – androgens. There are two types of castration: surgical castration, also called orchiectomy or orchidectomy, and chemical castration, caused by LHRH agonists and LHRH antagonists.

LHRH agonists and antagonists are usually taken through injections or analogs which continuously release the therapy over a period of time. Castration affects production of testosterone in the testicles, while LHRH antagonists and agonists interrupt the communication in the brain when the brain is ordering the production of more testosterone.

Anti – androgens affect the hormones that are produced in the adrenal glands. They are designed to block receptors in the prostate cells and prevent androgens from feeding cancer cell growth. Anti-androgens are taken orally as a pill or tablet. The female sex hormone, estrogen is also sometimes used for hormone therapy.

When several hormone therapies are used together, it is called Combined Androgen Blockade or CAB, but may also be called total androgen blockade, combined hormonal therapy, or complete hormonal blockade. Combined androgen blockade usually consists of castration and anti – androgens. All men who undergo hormone therapy will experience side effects, however, men who undergo CAB tend to experience more side effects due to the elimination of 100 percent of the body’s testosterone.

Gold Markers Improve Radiation Treatment For Prostate Cancer Patients At Community CancerCare

Marking a prostate cancer tumor with “gold markers” has improved the efficacy of the latest radiation therapy for prostate cancer patients at the Community CancerCare Radiation Therapy centers located in the John DeQuattro Community Cancer Center in Manchester and the Phoenix Community Cancer Center in Enfield.

“By placing three gold markers into the prostate,” says Tim Boyd, a Community CancerCare and Hartford Hospital radiation oncologist, “we can see precisely where the prostate tumor is each day immediately before the patient is treated, which allows us to be as accurate as possible in developing the radiation treatment.”

Accuracy is always important in radiation treatment. Physicians must protect healthy tissue and organs from radiation that kills all cells, not just cancerous ones. An especially high degree of accuracy in radiation therapy has become even more important as radiation technology has improved. IMRT, intensity modulated radiation therapy, for example, is among the most advanced and accurate now used at the Community CancerCare centers.

With standard radiation therapy, according to Community CancerCare’s radiation oncologist Kenneth Leopold, MD, radiation fields of equal intensity converge from all directions on the tumor. With IMRT, the intensity of each field changes to follow more precisely the shape of the tumor. If the contents of a patient’s bladder or rectum moves the tumor between treatments, or if the patient, and so the tumor, moves even slightly during treatment, the dose to the tumor may be compromised and surrounding healthy tissue in the prostate, bladder and rectum may be damaged.

With the addition of gold seed markers to the therapy, computer software can use the radiation beam itself for alignment and hit the tumor, which is a non-uniform, three-dimensional target, precisely each time.

Three gold markers, each about the size of a grain of rice, are placed into the tumor in the prostate during a 10-minute procedure in the urologist’s office.

Radiation treatment’s side effects have been reduced because of IMRT’s high degree of accuracy, Dr. Leopold says, and in some cases IMRT has allowed increases in radiation dose without increasing side effects. The goal of any cancer treatment is to kill the cancer with the least healthy tissue damage and fewest side effects. Using gold markers may allow physicians to strike this balance even better.

“Prostate cancer patients who undergo gold marker implantation may experience fewer treatment side effects, including bladder and bowel problems,” Dr. Boyd says, “Because the gold markers allow us to be more precise and adjust for any change in position of the prostate internally in the pelvis, we’re treating less normal tissue, like the rectum and the bladder, which may result in reduced side effects.”

The American Cancer Society estimates that 2,900 Connecticut men will be diagnosed with prostate cancer in 2007, and 390 of them will die from the disease, but the good news, according to the National Cancer Institute, is that progress in cancer treatment (like the use of gold seed markers), along with progress in prevention and early detection, continues to reduce American’s risk of dying from cancer.

Intensity Modulated Radiation Therapy (IMRT)

More on the latest Radiation technology which I will be undergoing - Intensity Modulated Radiation Therapy (IMRT). But firstly, let's take a look at its most immediate predecessor.


(3D-CRT)

3-dimensional conformal radiotherapy (3D-CRT) combines multiple radiation treatment fields to deliver precise doses of radiation to the affected area. Tailoring each of the radiation beams to accurately focus on the patient's tumor allows coverage of the cancer while at the same time keeping radiation away from nearby healthy tissue.


(IMRT)

Intensity modulated radiation therapy (IMRT) is a form of 3D-CRT that further modifies the radiation by varying the intensity of each radiation beam. This technique allows a precise adjustment of radiation doses to the tissue within the target area. IMRT may allow doctors to direct a higher radiation dose to the affected area and keep more radiation away from nearby healthy tissue.


Important Note

Radiation therapy works by damaging the DNA within cancer cells and destroying the ability of the cancer cells to reproduce. When these damaged cells die, the body naturally eliminates them. Normal cells are also affected by radiation, but they are able to repair themselves in a way that cancer cells cannot.


How it Works

In intensity modulated radiation therapy (IMRT), very small beams, or beamlets, are aimed at a tumor from many angles. During treatment, the radiation intensity of each beamlet is controlled, and the beam shape changes hundreds of times during each treatment. As a result, the radiation dose bends around important healthy tissues in a way that is impossible with other techniques.

Because of the complexity of these motions, physicians use special high-speed computers, treatment-planning software, diagnostic imaging and patient-positioning devices to plan treatments and control the radiation dose during therapy.

For IMRT to be effective, the anatomical position of the tumor and surrounding healthy tissues must be accurately defined. Computed tomography (CT), positron emission tomography (PET) and magnetic resonance (MR) imaging provide the necessary three-dimensional anatomical information. It's also important to accurately position and immobilize the patient during treatment.

This may be done with special head frames (if the head or brain is being treated), or with advanced imaging devices such as electronic portal imaging and scanning ultrasound, which provide daily information about the location of internal organs. Some organs, such as the prostate, move due to normal daily volume changes in the bladder and rectum. Gold seeds may be placed into the prostate to track prostate movement daily and ensure more precise targeting.

A device called a multileaf collimator adjusts the size and shape of the computer-determined radiation beams. The collimator, a computer-controlled mechanical device, consists of up to 120 individually adjusted metal leaves. These leaves move across the irradiated tissue while the beam is on, blocking out some areas and filtering others to vary the beam intensity and precisely distribute the radiation dosage.

Radiation oncologists usually administer a regimen of IMRT treatments over four to eight weeks. The total dose of radiation and the number of treatments given depend on the size, location and type of cancer; the patient's general health; and other medical therapy the patient is receiving.

As can be seen in the following image, IMRT permits the delivery of a high dose of radiation to the cancer while minimizing dose to other sensitive organs. Here multiple beams are all focused on the prostate. Each of these beams has a number of sub-beams or segments, and the intensity of each segment is varied according to the treatment plan.

The image below shows an IMRT plan for treating prostate cancer. The area in red is the prostate gland; the area in blue, the rectum. IMRT focuses high doses of radiation on the prostate while keeping the dose to the rectum at a minimum.

Transrectal Prostate Fiducial Marker Gold Seed Insertion with Ultrasound

For those who are interested in the preparation that leads to the insertion of the gold seeds, I have included the following.


How it Works

Transrectal prostate fiducial marker gold seed insertion with ultrasound guidance is a method of inserting small gold seeds into the prostate gland using a needle inserted via the rectum/back passage. Three seeds are inserted using a 17G needle and the use of an ultrasound to guide the surgeon to the correct region.

The Radiologist performing the procedure specialises in Prostate procedures, assisted by nursing staff and ultrasound technologists.


Time

The procedure will take about 30 minutes to perform but we will want to observe you following the procedure for 1 hour or so if you are an outpatient, so that you may be at the hospital for a least 2 hours - longer after sedation.


How To Prepare

Before the procedure you should have stopped any tablets or injections that may alter your blood clotting - Heparin and Clexane the day before and Warfarin for 3 days. Clopidogrel, Aspirin and most other anti-inflammatory drugs etc will need to be stopped for 10 days or more. If this has not happened or you have any questions about stopping routine medication, please see your referring doctor or ring us.

Your specialist should arrange oral antibiotics (trimethoprim [Triprim or Alprim] 300 mg at night) for the days before and following the procedure. If you have any symptoms or signs of a urinary tract infection (burning sensation when passing urine etc) please ring us.

If you wish to have strong pain relief or sedation (intramuscular or intravenous), you will need to contact us before the day of your biopsy, stay for 1 or 2 hours longer after the biopsy and have someone take you home if you are an outpatient.


What to Expect

On arrival, you will be given a laxative to empty the rectum. You should also empty your bladder at this time. You will also be given an intravenous antibiotic injection (Gentamicin 240 mg). It is necessary for you to sign a consent form to confirm that you know about the risks and benefits associated with the procedure.

After you are taken to the Ultrasound room your Prostate gland will be clinically examined (as has already been performed by your doctor). The ultrasound probe will then be inserted into your rectum and pictures taken of your prostate gland. Immediately following this, the 3 gold seeds will be inserted. This will be uncomfortable, but is not usually unduly painful. It is very important to stay still. Please do not hesitate to ask us to stop at any point if you do not want us to continue.

Following the ultrasound guided seed placement, plain x-rays of your pelvis will also be obtained.


Side Effects

One of the advantages of performing the procedure under ultrasound guidance is to decrease the risk of damage to adjacent organs; however side effects and complications may still occur from this procedure.

For a day or so following the procedure you may notice MINOR pelvic discomfort or pain. MINOR blood staining of your urine/bowel motions may last for up to a week or so.

For a month or so following the procedure, you may notice blood staining in your ejaculate.


Possible Complications

If any of the following main complications develop:

• Severe infection (symptoms include feeling generally unwell, raised temperature, shivers etc most commonly manifested in the first 24-72 hours.)


• Urinary Retention (inability to pass urine for 8 hours or more.


• Profuse bleeding from the rectum or penis.

Contact your referring specialist IMMEDIATELY and proceed to the Emergency Department.

Infection develops in approximately 1 in 100 procedures and urinary retention/profuse bleeding occur in less than 1 in 1000. Spread of infection to the spine and death from infection is rare.


Afterwards

Following the procedure, for your comfort it is recommended that you should rest for the next 24 hours although you may undertake light activity. You may have minor discomfort over the 24 hours for which you may take paracetamol, but NOT aspirin. Depending on what sort of work you do, you may need to arrange a day’s sick leave.

New Plan of Attack

After a lengthy discussion with my Oncologist, concerning the possible treatment options, the following regime was decided upon as representing the best possible outcomes:

1. We will continue the Hormone Therapy, with the LHRH implants (Zoladex 10.8mg) every three months. This appears to be working pretty well but there remains some concern as to whether it is as effective as expected? I am scheduled to have another PSA test tomorrow; only this time, we will also test the Testosterone levels.
   


2. Because the PSA level has not declined at a faster rate, it has been decided to introduce an anti-agonist (Anandron ie Nilutamide) as well. This will continue for some time concurrent with the LHRH Implant.


3. I have been scheduled for an outpatient procedure, in which the Radiologist will insert several 'gold seeds' into the prostate. More on this procedure in my next post.


4. Following this, there will be a recovery period of 24 hours and then a 'planning week' in which the Radiotherapy treatment is discussed and mapped out.


5. I will most likely continue on the Hormone Treatment for at least 2 to 3 years. This then gives rise to the possibility of 'bone thinning' and so I have commenced a daily regime of Calcium and Vitamin D supplements.
   


6. The Radiotherapy will consist of a precisely targetted (thanks to the gold seeds), high dosage of radiation being applied to the prostate. A lower dosage of radiation will also be applied to certain bones and organs within the pelvic region.

The Radiologist also pointed out: "we only get one shot at this and so we will plan to maximise our chances of a successful outcome". While the prognosis remains, 5 years; it is anticipated that I will enjoy many more years, given the (expected good) results.

Finally some Answers

Today, I took myself off to the Radiologist's surgery; armed with a page full of questions - the same questions that the Urologist (Dr J) avoided (for the most part). The questions looked something like this:

• What if anything, can be done about the fatigue?
  


• Should I be concerned about the 'shortness of breath'?
  


• What about the dizziness?
  


• Should we consider addressing the cholesterol level at this time?
  


• What about the ... 'blood in the ejaculate'?
  


• What can I do about the 'hot flushes'?
  


• Um ... ah ... what about ... um ... 'breast tenderness'?
  


• Is the weight gain something to concern myself about at this time?
  


• And the blood in the ejaculate?

Well here are the answers - hot off the press!

• What if anything, can be done about the fatigue? Hopefully I will learn to tolerate this unwanted side effect otherwise medication can be used.
  


• Should I be concerned about the 'shortness of breath'? Worst case, this could point to 'heart related issues' but having 'pretty much' ruled that out, and since this side effect seems to be waning ... we'll press on.
  


• What about the dizziness? This can be caused by any number of things and will be monitored.
  


• Should we consider addressing the cholesterol level at this time? Yes.
  


• What about the ... 'blood in the ejaculate'? This is possibly the result of the 16 core samples taken during the TRUS, 3 and a half months ago, or is related the the tumour itself. Either way it doesn't affect the treatment under consideration.
  


• What can I do about the 'hot flushes'? Again, I should be able to tolerate these, particularly with winter around the corner! However, there are medications that can help with this also.
  


• Um ... ah ... what about ... um ... 'breast tenderness'? If this becomes too bothersome, we can 'zap it' with some radiation and 'VOILA' problem solved (fried?).
  


• Is the weight gain something to concern myself about at this time? It could be ... but we'll see how things go. Diet, exercise and perhaps some weight training offer the best outcomes. [Currently all the above apart from 'weight training' are in play!]
  


• And the blood in the ejaculate? This is to be expected, but again will not affect the proposed treatment.

Prostate 'Gold Seeds' Improve Radiation Treatment

Today I attended my first appointment with the newest member of my healthcare team - 'Dr T' - my Radiation Oncologist. The appointment lasted for over 90 minutes - I finally got to ask, and have answered, ALL of my questions!!

Firstly, I want to talk about the 'new' technique that I will be undergoing in terms of my radiotherapy - sometimes referred to as 'gold seed technology'.

Gold seed technology is a fairly recent innovation in Australia and is only available in a (very) limited number of places. Fortunately for me, my radiologist is one of the few 'experts' who not only possess such technology, but have become very conversant with it's usage.

Now, some history...


November 2005

A new treatment method for prostate cancer patients undergoing radiation therapy that more accurately and effectively targets the cancer while minimizing side effects is now available in Australia.

Fiducial markers, or "gold seeds," are non-radioactive markers that are placed in the prostate. Because it is natural for the prostate to move around in the pelvic cavity, depending on how much liquid a patient has consumed and other factors, it can be challenging to locate the prostate precisely during radiation therapy.

Unlike brachytherapy, which uses radioactive seeds to treat the cancer, gold seeds simply allow the prostate's location to be tracked on a daily basis using X-ray imaging to ensure treatment accuracy. Only a handful of health care organizations offer this treatment in Australia.

Previously, physicians had to leave a margin of error when locating the cancerous tissue because it was difficult to target the exact location of the prostate before the gold seed technology emerged. During this process, healthy tissue may have been exposed to radiation.

Gold seed technology allows the physician to know exactly where the prostate is at any given time. Therefore, a higher dose of radiation can be delivered to a more precise area, while minimizing exposure to nearby healthy tissues.


Gold Seeds Help Pinpoint Prostate Cancer

WCVB-TV 04.07.2006

BOSTON -- Prostate cancer is the most common cancer among American men. One in six men will be diagnosed with the disease in his lifetime.

NewsCenter 5's Heather Unruh reported Friday that treating it can be tricky -- even a slight movement of the prostate can alter the effectiveness of radiation and potentially damage healthy tissue.

Now, doctors at Mount Auburn Hospital are using new technology to pinpoint prostate cancer with the help of some very tiny but very precious metals.

A tiny gold seed is helping doctors treat Joe Crowley's prostate cancer.

"I feel good about the treatment," Crowley said.

The gold seeds are actual gold, but they are not radioactive. Instead, they serve as markers for radiologists attempting to locate and treat the often hard-to-target prostate.

"In the past, our solution was very simple. You simply enlarge the area you're treating to make sure the target is going to be fully covered by the radiation -- but in the process, we were exposing more normal tissue to the radiation and increasing the risk of injury," Mount Auburn Hospital's Dr. Anthony Abner said.

With Gold Seed technology, [a number of] seeds are placed around the prostate. Using X-ray imaging, doctors can then monitor the location of the seeds. If the seeds have moved, the prostate has moved, and they can alter the radiation accordingly.

"The benefit is that we can dramatically reduce the amount of normal tissue that's hit by the radiation. By doing so, we can actually use higher doses of radiation with better cure rates," Abner said.

The treatment is less painful and more accurate than other options, such as balloon dilation and ultrasound. But it does require almost daily monitoring, which means many trips to the radiologist -- a price Crowley said he is willing to pay.

"It's a little lengthy, but I think I have 34 treatments, but hopefully they'll go by fast and I'll pick up where I left off," Crowley said.

While it's too soon to know exactly how much Gold Seed technology is improving prostate cancer outcomes, doctors said that patients report feeling better during treatment, having fewer side effects and fewer long-term complications.


The implications for me are ...

• I can benefit from the higher doses of radiation , without the risk of 'other organ damage'!


• I can also receive a variation of the 'whole-pelvic' treatment described in an earlier post - safely.

We'll look at this in more details in my next post.

Prostate cancer survival improved with whole-pelvic radiation plus hormone therapy

Abstract

Patients with localized prostate cancer who have a 15% estimated risk of lymph node involvement and an elevated prostate-specific antigen level are good candidates for whole-pelvic radiotherapy plus neoadjuvant and concurrent hormonal therapy.


Complete Article - 16 Jun 2003

These are the findings of a phase III study involving 1323 such patients reported by Dr. Mack Roach III of the University of California in San Francisco and colleagues in the May 15th issue of the Journal of Clinical Oncology.

"This trial tested the hypothesis that combined androgen suppression and whole-pelvic radiotherapy followed by a boost to the prostate improves progression-free survival by 10% compared with combined androgen suppression and prostate only prostate-only radiotherapy," they explain. "This trial also tested the hypothesis that neoadjuvant and concurrent hormonal therapy improves progression-free survival compared with adjuvant hormonal therapy adjuvant hormonal therapy by 10%," they further explain.

According to the team, whole-pelvic radiotherapy was associated with a 4-year progression-free survival of 54% compared with 47% for prostate-only radiotherapy (p = 0.022). Patients treated with neoadjuvant and concurrent hormonal therapy had a 4-year progression-free survival of 52% versus 49% for adjuvant hormonal therapy (p = 0.56).

Compared with the other treatment, the combination of whole-pelvic radiotherapy plus neoadjuvant and concurrent hormonal therapy was associated with the longest progression-free survival (60%).

"This study proves that there is a favorable biologic interaction between whole-pelvic radiotherapy and neoadjuvant and concurrent hormonal therapy, but no advantage to short-term neoadjuvant and concurrent hormonal therapy compared with short-term adjuvant hormonal therapy when only the prostate is irradiated," the investigators conclude.

The benefits of whole-pelvic radiotherapy plus neoadjuvant and concurrent hormonal therapy in the lymph nodes "should not be completely surprising," they add. "Occult lymph node involvement despite negative imaging is a well-recognized problem in patients with prostate cancer, and prophylactic nodal radiotherapy has been shown to prolong survival in women with breast cancer," they add.

(Source: J Clin Oncol 2003;21:1904-1911: Reuters Health: June 13, 2003: Oncolink)

Hormone Therapy and Radiotherapy Combined

As mentioned in my last post, further good news, was received concerning my ongoing treatment and came in the form of a 'green light' to commence radiotherapy ASAP. Originally, it was planned that I would have two consecutive implants (duration of 6 months) and then, providing the PSA level was at an appropriate level, we would the consider radiotherapy.

The upshot of the visit was, that we now move into a new phase of treatment - 'Radiotherapy' (RT) as an adjunct to the Hormone Therapy (HT). The latter will most likely continue for approximately 18 to 24 months. However, there is a possiblity that I could be on HT for the remainder of my life; dependent upon the success of the radiation treatment.

[It has also been decided at this stage, to rule out surgery; because of the likely complications; both during and after the operation].

Radiation Therapy will entail daily radiation treatment, 5 days a week for approximately 6 weeks; (with Saturday and Sunday ... 'off for good behaviour').

Unfortunately this will also involve short stays in hospital for each subsequent treatment; thus further complicating my desire to lead as normal a life as possible e.g. juggling work committments, cancer therapies and home and social life etc.


Hormone Therapy

It has long been known that once prostate cancer develops, the male hormone testosterone, produced by the testicles, is closely involved in stimulating the cancer’s growth and spread. Earlier treatments for the disease often involved removing the testicles surgically to reduce testosterone production by the body. Now products are available that can be taken in the form of tablets or injections to suppress testosterone even more effectively. The process is known as hormone therapy.

Hormone therapy is often used to shrink the prostate and the tumour before commencing radiotherapy. It is now quite common for a course of hormone therapy to be administered after primary treatment by radiation or surgery, particularly if there is evidence that the tumour may have spread beyond the capsule (tissue immediately surrounding the prostate). There is emerging evidence that better outcomes are being achieved from these combined techniques.

If the prostate cancer has already spread to other organs or to bone at the time of diagnosis, hormone therapy becomes the primary method of treatment. Monthly or three monthly injections, possibly also accompanied by tablets, are used to try to reduce the PSA reading as close as possible to zero. Most advanced cancers respond well to hormone therapy for several years. Some doctors apply the therapy intermittently - six or twelve months on treatment then some months off - known as "pulsing". This gives the patient some respite from side effects and may extend the period of effective treatment, although this has not been proved.

The advantages of hormone therapy are that it is simple to administer. The disadvantages are the side effects, which can be distressing. They include hot flushes, loss of libido and erections, sweating, mood swings, disturbed sleep, loss of energy and personal motivation, body hair loss, bone loss, weight gain and breast development or tenderness. Unfortunately, most advanced cancers eventually become resistant to hormone therapy, after which the disease resumes its progress.


Radiation

Radiotherapy involves the use of various types of X-rays to treat cancer.

External beam radiotherapy (EBRT) has been the traditional method of delivering the radiation. Short pulses of tightly focused beams of X-rays are delivered from outside the body into the prostate for a few minutes each day. Treatment continues five days a week for seven weeks. Conformal Radiotherapy, allows the X-rays to be directed very accurately to the prostate in three dimensions. EBRT has a track-record of success in "curing" cancers confined to the prostate that is very close to that of surgery.

From a patient’s perspective, the advantages of EBRT are that it is less intrusive and stressful than surgery, with no risk of infection. It particularly suits older men or those with fitness or other health problems that make the risk of surgery greater. The disadvantages are that time for treatment is much longer and may involve travel and accommodation problems, particularly for country patients. Radiation can damage other organs, particularly the bowel and bladder.

Irritation of the bowel is a common side effect that can trouble patients for six months or longer after treatment. Rates of occurrence of incontinence and impotence are similar to surgery, but tend to occur later. With radiotherapy up to 50% of men develop erection problems and many develop mild to moderate inflammation of the bowel, although only approximately 3% of men develop severe, ongoing bowel problems. It is also important to mention that it is not uncommon after radiotherapy to develop a change in bowel habit, with looser and more frequent bowel movements, increased flatus and possible bleeding.

Once again, the skill, experience and result record of the radiotherapist and standard of the treating equipment are paramount to the outcome. Intending patients should enquire carefully into these matters before making a selection.

After treatment you will have further PSA tests to monitor developments. Your PSA should gradually reduce over about 12 months to between 1 and 2. If it fails to reduce to these levels, your doctor may recommend further treatment, probably by hormone therapy. However, regardless of the post-treatment movement of the PSA reading, it is quite common for doctors to recommend hormone therapy immediately after radiation as part of the total treatment.

Latest LHRH Implant

I attended the Urologist's Surgery in Monavale to receive an injection of a luteinising hormone-releasing hormone (LHRH)- specifically a 'Goserelin acetate implant' (the generic name) or Zoladex (the product name).

For a video demonstration of the proper technique for administering Zoladex please click here.


LHRH Agonists

The 'original' 3.6mg formulation of Zoladex has been available since 1989 as a monthly implant. The new formation, 10.8 mg goserelin acetate implant given every three months, offers greater convenience to subjects choosing treatment with a luteinizing-hormone-releasing hormone (LHRH) analogue.

The 'original' 3.6mg formulation of Zoladex was shown to be as effective as orchiectomy (surgical castration) in controlling the spread of prostate cancer, thus offering men a choice between medical treatment and surgery.

This 12-13 week formulation of Zoladex is, a white to cream coloured, cylindrical implant with a 1.5 mm diameter that contains 10.8 mg of goserelin. Given by subcutaneous injection, into the anterior abdominal wall, the biodegradable implant slowly dissolves, delivering therapeutic levels of the drug continuously over a period of 12 weeks. This means an injection will be required every 12 to 13 weeks.

NB: I asked to be able to inject myself on this occasion, not sure why now; but it seemed like a good idea at the time! Well according to witnesses (the doctor and my wife) I was a real 'pro' (professional).

The instructions were simple: "Grab a good fistful of excess skin ... (to the left of the 'belly button') ... and in one swift downward motion plunge the syringe into the abdomen right up to the hilt! Then depress the plunger and this will release the implant."

Well I must admit, in some strange way, I actually enjoyed the experience!

Perhaps it was because I was 'in control'; for the first time since the cancer was discovered. Perhaps it was the release of adrenalin, associated with the whole procedure; I'm not sure.

However, afterwards I do recall the doctor stating: "Very well done ... but ... I'm still charging you for the procedure, even though you administered the implant yourself"!

The success of this treatment (in my case Goserelin 10.8mg every 3 months) will continue to be be monitored by regular blood tests which look specifically at the Prostate Specific Antigen (PSA) readings.


Good News

Further good news, came in the form of a 'green light' to commence radiotherapy ASAP. Originally, it was planned that I would have two consecutive implants (duration of 6 months) and then, providing the PSA level was at an appropriate level, we would the consider radiotherapy.

The Urologist was so pleased with the PSA result and so keen to start the radiotherapy treatment, that he rang one of our largest public hospitals in the country, and spoke to the doctor who would oversee the procedure and monitor my treatment from now on; and asked him (as a personal favour) to 'fast track' the procedure!

The upshot ... I had an appointment made available to me the very next morning to discuss the options available to me, moving forward!!

PSA Level

I attended our local GP's surgery for another blood test last Friday. Specifically, this blood test was to:

• Determine whether my PSA reading [originally 84.8] had continued to drop. Thus showing that the hormonal therapy I have been undergoing for the past 3 months, has in fact had the desire affect; and
  
  
• Determine whether my cholesterol readings had continued to improve as a result of my [now] 'extremely healthy' diet.
  
  
  

I can now report the following:

• My PSA level has continued to decrease! My PSA level in September 2007 was 84.8; in November 2007 it was 12 and in February 2008 it is now 4.8!!
  




• My Cholesterol level has risen sharply? My Cholesterol level in September 2007 was 6.8; in November 2007 it was 6.3 and in February 2008 it is now 7.8??

The PSA result is of course great news, particularly given that I have only been on the Hormonal Therapy for 3 months. However, the cholesterol level is somewhat disappointing. I say somewhat, because somewhere in the back of my mind, I seem to recollect reading that 'hormonal therapy' can cause such an unexpected (and inaccurate) result. I'll have to follow this up with further research.

Tomorrow I see my Urologist for the first time since 20 November last year. I just hope for his sake he is ready for me ... I have a 'mountain of questions' for him. For a report back, read "Silver Lining" tomorrow.

The Treatment of Locally Advanced Disease: An Overview

Introduction

The selection and implementation of appropriate treatments for locally advanced prostate cancer are probably the most difficult challenges which face the physician and his or her patients. If making good decisions is difficult in the treatment of localized prostate cancer and advanced prostate cancer, then making good decisions in the treatment of locally advanced disease can only be described as nerve-racking!

Patients need to understand up front that there are absolutely no "right answers" in the treatment of locally advanced disease. The wise patient, while taking an optimistic approach, may wish to consider the following simple realities:

Once prostate cancer has clearly escaped the confines of the prostate, the chances that it is truly curable become very small given currently available forms of treatment. (It is everyone's goal to change this in the near future.)

Despite the fact that locally advanced disease is not usually curable, current forms of therapy can offer long-term remissions (of 10 or even 20 years) to a very high proportion of patients if they receive suitable and early intervention.

Many patients who are initially advised by their physicians that they have locally advanced disease are found to have micrometastases (and therefore advanced disease) at a later date. In other words, what may initially appear to be locally advanced disease can commonly be seen, in retrospect, to have been advanced disease. This is no one's fault. We simply do not have the diagnostic tools available today to be able to specifically identify patients with micrometastatic advanced disease.

The Prostate Cancer InfoLink recognizes that this information is not, by any manner of thinking, the information which a newly diagnosed patient with locally advanced prostate cancer wants to hear. However, over time such patients will, we hope, discover that the best treatment decisions tend to be made by patients who can work with their physicians because both parties are fully aware of the facts surrounding their situation.

We hope that in time we may be forgiven by those patients who initially react by seeing us as the bringers of news they would have preferred not to hear, and that at least some patients will be able to make better treatment decisions because of their early recognition and acceptance of this situation.


Defining locally advanced disease

There are several types of locally advanced prostate cancer, and we will take the time to itemize them here for clarity. This set of definitions will require the reader to have a good appreciation of the "staging" systems used to discuss prostate cancer. If you have not already read the section on clinical staging of prostate cancer, you are strongly advised to now!


Unilateral and bilateral extracapsular extension

Prostate cancer can grow through the capsule (the wall of the prostate) and into the surrounding tissues. If this has happened from just one lobe of the prostrate, this is called unilateral extracapsular extension, which is classified as clinical stage T3/a/Nx/M0. By contrast, if this has happened from both lobes of the prostate, it is known as bilateral extracapsular extension and is classified as clinical stage T3b/Mx/M0. (Note: The use of Nx means that no determination has been made as to whether the disease has spread to the pelvic lymph nodes.)


Seminal vesicle-positive disease

The seminal vesicles are attached to the prostate (see Where is your prostate and what does it do?). It is common for prostate cancer to spread from the prostate into the seminal vesicles. Spread of prostate cancer from the confines of the prostate into the seminal vesicles is a second form of locally advanced prostate cancer. Regardless of whether the disease has spread into just one of the two seminal vesicles or into both seminal vesicles, it is classified as stage T3c/Nx/M0 disease.


Tumor fixed to or invading adjacent structures

If the tumor has escaped from the prostate capsule and it has become attached to or has infiltrated other nearby parts of the pelvic area other than the seminal vesicles, then it is classified slightly differently.

If the tumor escapes the prostate and invades the bladder neck, or the external sphincter, or the rectum, then it is classified as clinical stage T4a/Nx/M0. Similarly, if the tumor escapes the prostate and invades the levator ani muscles or the pelvic wall itself, then it is classified as clinical stage T4b/Nx/M0.


Lymph-node positive disease

The final category of locally advanced prostate cancer is when the patient is found to have prostate cancer cells in his pelvic lymph nodes. In this case his disease is generally classified as either T3/N+/M0 disease or T4/N+/M0 disease, depending on whether he has T3 or T4 disease. In addition, the degree of lymph node invasion allows for subclassification as follows:


N1 = metastasis in a single lymph node (2 cm or less in greatest dimension)

N2 = either metastasis in a single lymph node (2-5 cm in greatest dimension) or multiple lymph node metastases (none more than 5 cm in greatest dimension)

N3 = metastasis in any lymph node greater than 5 cm in greatest dimension.


Two examples

Pete M. is initially diagnosed with locally advanced prostate cancer on the basis of his DRE, his PSA test, his biopsy results (which included a biopsy of his seminal vesicles) and a bone scan. The PSA was 43 ng/ml; the DRE was negative; the biopsy was positive in four of six cores and in one seminal vesicle; the bone scan was negative. The preliminary clinical stage was given as T3c/Nx/M0. However, before they decided on treatment, Pete and his physician decided to carry out a laparoscopic lymphadenectomy. Pete's physician was just sufficiently concerned about his PSA level in combination with the positive seminal vesicle that he suspected a high risk of positive lymph nodes. He was correct, Pete had small foci of metastasis (both smaller than 1 cm) in two pelvic lymph nodes. He was restaged as T3/N2/M0.

Jerry B. is also initially diagnosed with locally advanced prostate cancer. He has a positive DRE with apparent extracapsular penetration through both lobes of the prostate. His PSA value is 14.7 ng/ml. His seminal vesicles are negative on biopsy and his bone scan is negative. He is tentatively staged as T3-4/Nx/M0. His urologist is uncertain as to the extent of local extracapsular disease and whether Jerry may have positive lymph nodes. However, because the urologist considers radical prostatectomy to be inappropriate for Jerry, no attempt is made to evaluate his lymph node status by the use of a laparoscopic lymphadenectomy.


The treatment options: an introduction

The Prostate Cancer InfoLink will gradually expand to offer detailed commentary on the differing options for the treatment of the various types of locally advanced prostate cancer. At this point in time, patients are advised simply that there are a wide range of options and that the selection of the appropriate option for an individual patient is perhaps as much an art as it is a science.

The general rule of thumb should be that the more advanced the disease, the less likely it is that purely surgical or purely radiotherapeutic interventions will succeed in controlling the disease. Indeed, there are now few surgeons who would consider that surgical intervention without some form of neoadjuvant or adjuvant therapy is appropriate for the management of most forms of locally advanced disease. Equally, the radio-oncology community now seems to accept that radiotherapy is much more likely to succeed in offering long-term progression-free survival if it is combined with hormonal manipulation of some form.


Basically, the list of possible categories of treatment is as follows:

Radical prostatectomy alone, which is probably only even potentially appropriate today in patients who are suspected of seminal vesicle involvement but in whom one or more attempts to biopsy the seminal vesicles were negative

Radiation therapy alone, carried out using external beam radiation or brachytherapy or a combination of the two (and it should be noted that external beam radiotherapy alone is now stated by at least some highly regarded experts on the radiotherapy of prostate cancer to be "inadequate")

Radical prostatectomy followed by adjuvant (post-surgical) hormone therapy

Radiation therapy followed by adjuvant (post-surgical) hormone therapy

Radical prostatectomy followed by adjuvant (post-surgical) external beam radiation therapy

Neoadjuvant hormone therapy followed by radical prostatectomy, with or without adjuvant (post-surgical) hormone therapy

Neoadjuvant hormone therapy followed by radiation therapy, with or without adjuvant (post-surgical) hormone therapy

Neoadjuvant hormone therapy followed by cryotherapy, with or without adjuvant (post-surgical) hormone therapy.

It can be seen from this extensive list just how complex the treatment options for management of locally advanced disease can be. When one starts to consider all of the various categories of adjuvant and neoadjuvant hormonal manipulation that are now either available or in clinical trials, the number of options becomes difficult to assess on a purely scientific basis.


Lymph node positive or lymph node negative?

The question whether the cancer has reached the lymph nodes is one of two questions which are absolutely fundamental to the choice of therapy. Basically, if the cancer has escaped into the pelvic lymph nodes, surgical treatment alone is no longer considered to be effective, although surgical treatment in combination with other forms of therapy may be beneficial.

Patients should be aware, however, that it is common (and very reasonable) for urologists to attempt surgery in the hope that cancer is confined to the prostate, but to discover at the beginning of surgery -- using a rapid pathologic technique known as a "frozen section" -- that in fact the cancer has reached the lymph nodes. In such cases it is not unusual to terminate the surgical procedure without removing the prostate and to inform the patient that other forms of treatment will have to be attempted.

All patients who are scheduled for surgery for prostate cancer will normally be advised of this possibility prior to surgery -- even patients definitively believed to have localized disease. There is always at least some risk that the cancer will have progressed to the lymph nodes, despite every indication to the contrary. This situation is altered by the use of neoadjuvant and adjuvant hormonal therapy or by the prior agreement between physician and patient that the prostate will be removed unless, in the opinion of the surgeon, the degree of lymph node metastasis is so high as to make removal of the prostate pointless.

If a patient has positive lymph nodes, the value of radiotherapy as a primary form of treatment is also open to considerable question. As indicated previously, there are now eminent radio-oncologists who consider that radiotherapy alone is inappropriate for the treatment of any form of T3 or T4 prostate cancer. This is surely even more likely to be the case in patients with node-positive disease.


How did the disease escape the prostate?

Just as this issue of lymph node positivity has significant implications for the management of individual patients, so does the question of whether a patient has T3 or T4 disease. In other words, if a patient is seminal vesicle positive, but otherwise the disease is localized to the prostate capsule, different treatment options may be appropriate than if the patient has clear signs that the cancer has escaped through the wall of the prostate and infiltrated the surrounding pelvic tissues.


Is node-positive disease really locally advanced?

It should be noted that the classification of node-positive disease as "locally advanced" is open to question. Many experts would consider that node-positive disease should be classified as "advanced" or "systemic." In the older Jewett-Whitmore staging system for prostate cancer, node-positive disease was classified as stage D1 disease.

The Prostate Cancer InfoLink takes the position that there is a distinction between definitively node-positive disease, in which the cancer has reached the lymph nodes but has not metastasized beyond these nodes (i.e., true T3-4/N+/M0 disease), and true micrometastatic disease, in which the cancer has really has micrometastasized beyond the lymph nodes but is not clearly identifiable as stage M+. The problem, of course, is that in most cases we are currently unable to distinguish between these two situations.

The Prostate Cancer InfoLink would simply note that just because we cannot yet distinguish between these two clinical situations does not alter the fact that the former situation can be clearly seen as locally advanced (because the disease is still confined to the pelvis, and is therefore theoretically amenable to localized therapy), whereas the latter situation is clearly systemic. We would suggest that it time management decisions will be able to take account of this distinction, and that therefore we should take it into account in our thinking.


Concluding remarks

The information offered here should be seen only as a series of introductory remarks on the options available to physician and patient for the management of locally advanced disease.

Please Note: This article is somewhat dated [1996] new advances may have occured since.

Source: The Prostate Cancer Info Link