PCRI Insights August 2003 vol. 6, no. 3
By Mark Scholz, M.D., Prostate Oncology Specialists
Newly diagnosed prostate cancer is not a single disease but a spectrum of diseases ranging from very low-risk, prostate-confined variants up to high-grade disease that has already spread outside the prostate. In Part One of this series, Risk Category staging was explained in careful detail. This article (Part Two) will define treatment options for patients with the earliest stage of disease, patients with Risk Category IA; these are the patients who have less than a 10% chance of microscopic spread of cancer to a location outside the prostate. Part Three will define treatment options for patients in higher risk categories, i.e. those who have a greater than 10% chance of microscopic spread of cancer to a location outside the prostate.
Reprinted from Part one
Side-Effects, Not Survival
Risk Category-IA (RC-IA) patients have such a long prostate-cancer-related survival expectation that it is virtually impossible to claim that one form of treatment will make a patient live longer than any other. A good example of this is the experience of Drs Blasko and Grimm from a seed implant series in which 125 patients were implanted with radioactive seeds between 1988 and 1990.1 The majority of men in this study had RC-IA disease, but there was also a significant minority with RC-IB disease. (RC-IB means that the risk of micro-metastasis ranges between 10% and 25%). In this study, ten years after the implantations, 15% of the men had suffered PSA relapse. None of these 19 men who relapsed had died of prostate cancer ten years later; men with low-grade disease tend to have few relapses; the rare individuals who do relapse have low grade, slow growing relapses.2 Even in the rare cases when there is concern about more rapidly progressive disease, hormone blockade can be initiated with very prolonged (>10 year) responses.3
As yet, there is no proven survival difference for RC-IA patients regardless of the treatment selected.4 This is not to say that all treatment options are equally well suited for all patients. Issues such as the side-effects of treatment, age, sexual functioning, preexisting prostate problems, and personal preference are all relevant in the decision-making process. Since personal preferences carry a great deal of weight in this process, patients themselves have to be well informed about all the treatment alternatives; after all, only the patient himself can factor in his own personal life-style preferences and his own quality of life related goals and then render a final decision about the treatment best suited to him.
Presently all the prostate cancer treatment options have drawbacks. Using a shopper’s analogy: nothing is free; you can only aim to get the best deal available. Good shoppers comparison-shop trying to get the best quality item for the lowest available price. Treatment quality relates to cancer control rates. Treatment “cost” relates to side-effects, especially permanent ones.
Therefore, the aim of this article is to be informative and descriptive so that men contemplating therapy for Risk Category IA disease can be introduced to the advantages and disadvantages of seven of the possible treatment choices. Treatment options for men who fall into higher Risk Categories will be the subject of Part Three of this article.
The seven treatments options that will be discussed are:
1. Deferred therapy (previously known as watchful waiting)
2. Androgen deprivation therapy (ADT)
3. Brachytherapy (Seeds)
4. Surgery (radical prostatectomy)
5. Intensity modulated radiation therapy (IMRT)
6. Cryotherapy (Cryo)
7. High Dose Radiation (HDR) Monotherapy
Watching cancer without treatment has long been a standard approach in the very elderly. One advantage of watchful waiting is that delaying treatment affords the possibility that improvements in future technology may lead to more effective, less toxic alternatives. Hence, it would seem that waiting for better, less-toxic treatment makes sense if it is not too risky to wait. There are logical reasons to consider that deferred therapy in younger, good-risk (RC-IA) patients might be safe; small amounts of lowgrade prostate cancer are known to be present in 30% of the general population over age 50.30,31 In the great majority, the disease remains dormant for life. Modern ultrasound-directed biopsy techniques are detecting more and more of these low-grade variants; too often, this leads to unnecessary treatment that places men at risk for the toxic effects of such treatments.
Studies of men with low grade disease show that they rarely develop detectable metastasis within 10 years of diagnosis even though these were studies of men with higher than risk category IA disease.5,6 More recent studies of the deferred therapy approach indicate that careful surveillance with intervention at the first sign of progression may be a safe approach.7,8 Presently the only way to find these non-progressing patients is by selecting men with low-grade disease and closely monitoring them to see which individuals will evidence tumor growth. If there is no evidence of growth, presumably there is no need for invasive treatment.
However, because of the risks associated with delaying treatment in more aggressive forms of prostate cancer, selection criteria for deferring therapy should be stringent; it is a fundamental error to mistakenly assume that a high-grade tumor is low grade. Men with RC-IA disease who have any of the following conditions are not the best candidates for deferred therapy:
- Gleason score > 6 disease
- More than one core biopsy positive
- More than 50% involvement of a biopsy core with cancer9
- PAP elevated above the normal range
Potential watchful-waiting candidates should be screened for more advanced disease missed on initial biopsy. Imaging techniques such as spectrographic endorectal MRI10 or high-resolution color doppler ultrasound11 can help confirm that the cancer is indeed small. Not everyone with good biopsy results has small-volume disease.12 Imaging techniques may also be helpful when used along with PSA and digital rectal exam to monitor for any evidence of tumor progression. When there is ambiguity regarding tumor status, a repeat biopsy can be considered.
A new nomogram has been developed at Memorial Sloan Kettering that appears able to predict the presence of a small, insignificant cancer with 82-90% accuracy.37 This may offer RC-IA patients an additional tool to help decide when deferred therapy is a reasonable option.
Deferred therapy is usually implemented along with substantial dietary changes. Low-fat and low sugar diets help impede prostate cancer progression. An excellent book on the topic of diet and cancer is Verne Varona’s work, Nature’s Cancer Fighting Foods. (Prentice Hall 6/2001, ISBN 0130170879)
Traditionally, androgen deprivation therapy (ADT) has been reserved for the advanced stages of prostate cancer, after it has metastasized to bone. The benefits of ADT have also been documented in localized prostate cancer.13,14 ADT induces prostate cancer cell death via a mechanism called apoptosis, which is automated cell death (cell suicide). All the cells of the body contain suicide genes that can be activated under different circumstances. For example, white blood cells that fight infection only live about 8 to 10 days before initiating apoptosis, dying, and making way for new more vibrant cells to carry on the fight. Apoptosis occurs in prostate gland cells and prostate cancer cells when the quantity of androgen (testosterone) drops below certain levels in the blood stream.
When used in the context of prostate cancer, the term “Androgen deprivation therapy” describes treatment to reduce the activity of the male hormone, testosterone. Testosterone is a hormone secreted into the blood by the testicles (and to some degree the adrenal glands). Testosterone causes secondary male characteristics such as muscle and hair growth, increased libido, and the enlargement of sexual glands and organs. The prostate exists in a vestigial state before puberty and will not develop without the large increase in testosterone blood levels occurring at puberty. Therefore, the cells of the prostate gland are inordinately sensitive to the presence or absence of testosterone in the blood. This sensitivity can be exploited advantageously as a therapy for prostate cancer because prostate cancer cells are derived from the prostate gland and retain the need for testosterone to remain viable. This need for testosterone is unique to prostate cancer, and it is almost universally present when prostate cancer is still in its early stages.
The amount of cancer cell death from ADT in early-stage prostate cancer is usually dramatic. On rare occasions, no cancer at all can be found in the surgically removed prostate glands of men who underwent surgery after ADT. More typically, there is a drastic reduction in the number of cancer cells, but not total elimination. Androgen deprivation therapy also appears to have the ability to put some prostate cancer cells to “sleep.” What all this means is that the effect of ADT on different cells in a prostate cancer tumor can be variable; many of the cancer cells are killed, but others are simply inhibited from growing.
Modern testosterone-blocking medications work by three primary mechanisms. LHRH agonists such as Lupron or Zoladex are injectable hormonal analogs that reduce luteinizing hormone (LH) causing the testicles to stop testosterone production. Anti-androgen blocking agents such as Casodex, Eulexin and Nilutamide are medications in pill form that work by blocking access of testosterone to androgen receptors located inside the cancer cell. Five-alpha reductase inhibitors such as Proscar and Avodart block the conversion of testosterone into dihydrotestosterone, which is a much more potent form of testosterone. These three classes of therapeutic agents can be used either by themselves or in combination. The advantages and disadvantages of using agents singly or in combination in early stage disease are too extensive to expound in detail in this short article. Suffice it to say that one typical protocol we use for newly diagnosed patients is administering one drug from each class for about one year.
In our practice, we stop ADT treatment after a year of therapy, except for ongoing suppressive therapy with Proscar or Avodart. Proscar and Avodart have minimal side effects, and we have found that they can be very effective at inhibiting the rise in PSA after the ADT has been stopped. We recently evaluated the results of using Proscar in our practice and found that men treated with Proscar remained off Lupron an average of three times longer then men who did not use Proscar.
One concern that is repeatedly raised about the use of ADT for early stage patients is the potential for developing hormone resistance. Studies show that even when ADT is administered to patients with higher risk categories than IA, hormone resistance within five years of starting treatment appears to be a very rare event.15,16,17
Side-effects of ADT are common but can be controlled. Once treatment is stopped, testosterone levels recover and side-effects are reversed. While a patient is on treatment, however, a number of potential side-effects have to be addressed and counteracted with medications or exercise, as shown in Table 2.
Table 2. Treatments for ADT Side-Effects
|Osteoporosis (the loss of calcium from the bones)||Can be prevented with once a week administration of Actonel or Fosamax|
|Hot flashes||Can be treated with Effexor, Neurontin, or Megace|
|Joint pains||Joint pains Respond to Celebrex and glucosamine|
|Muscle atrophy and tiredness||Can be prevented with strength training|
|Emotional swings||Reversible with low doses of Paxil or Zoloft|
|Impotence and penile atrophy||Can be reversed with Viagra18|
|Anemia||Reversible with synthetic erythopoetin (if it occurs)|
* There is no effective treatment as yet for loss of libido (loss of sexual desire). The potential for weight gain can only be handled by a low calorie diet.
Androgen deprivation therapy can be a first step for some patients who are undecided about what form of local therapy to choose. Early in the treatment, a patient’s PSA response and his experience of its side-effects can allow a first-hand evaluation of the effectiveness and tolerability of the treatment. If side-effects prove unacceptable, therapy can be stopped.
Androgen Deprivation Therapy (ADT)
There are five commonly used local therapies for prostate cancer: Brachytherapy, Surgery, Intensity Modulated Radiation Therapy (IMRT), High Dose Rate temporary seeds (HDR), and Cryosurgery. The term local therapy describes treatment that has an effect only in the prostate gland. Such treatments make sense in patients with Risk Category IA disease because there is less than a 10% risk of the cancer being outside the gland. The only reason for hesitation with these alternatives relates to their potential for permanent side-effects.
There is one other concern with local therapy that needs emphasis. Good local therapy to the prostate, i.e. therapy that minimizes the chance for side-effects as much as is humanly possible, can only be confidently obtained at select centers of excellence. None of the statistics quoted going forward from this point are in any way relevant outside of this imperative. There is even a large difference in quality between academic physicians from world famous institutions. This means that it is not enough to go to the best institutions; one must seek out the best physicians at the best institutions if one plans to replicate the statistics we are quoting.19 The quality of the physician determines the outcome.
In Brachytherapy treatment, radioactive seeds are implanted in the prostate gland. These seeds, which emit radiation over a short, measurable distance can, if properly localized, be used to increase the total dose of radiation to “cancer fatal levels” without affecting the surrounding tissue. Fortunately, the prostate gland itself is a non-essential organ and can be sacrificed (although this results in dry orgasms). Massive doses of radiation carefully applied throughout the gland will destroy it (and any cancer contained within it) but will spare the bladder and rectum that are in close proximity.
The advances in localizing technique that have developed over the last 15 years are the real reason brachytherapy has come to the forefront as a leading option for control of localized prostate cancer. Figure 2 illustrates how the modern technique of implanted radioactive seeds accomplishes consistent spacing and a high dose of radiation spread evenly throughout the prostate gland.
Figure 2. Seed Implantation into the Prostate. With the patient lying on his back, tiny catheters are guided into the prostate via a template, in which the pattern of holes has been specifically chosen for the patient. Radioactive Iodine or Palladium seeds are then pushed through these catheters into target sites of the prostate. Above photo shows the seed used for implantation in comparison to the tip of an index finger.
The dose of radiation delivered is so intense that over a period of time the prostate gland is “vaporized.” The amount of radiation administered in external beam equivalents is thought to be about 10,000 rads! The destructive force of this high dose radiation is well demonstrated by digital prostate exam a year or two after treatment. No prostate can be felt!
The main side-effect of concern from brachytherapy is radiation effect on the urethra, the small passageway that carries urine out of bladder, through the prostate, and out the penis. The urethra gets a maximum dose of radiation because it is in the center of the prostate. The side-effects of radiation on the urethra, termed urithritis, can include any of the following symptoms: urgency to urinate, painful urination, urinary frequency, slow urination, and occasionally complete blockage of urination requiring the temporary placement of a catheter to drain the urine. About two-thirds of men35,36 treated with brachytherapy have short-term symptoms of urithritis that last a couple of months after the implant.
Short-term symptoms can usually be endured. Of greater concern are the 5-10% of men who have symptoms lasting up to a year, and occasionally longer. Certain medications such as Flomax and Celebrex can reduce but not eliminate these symptoms. Men with larger prostates and men with preexisting urinary symptoms are at much greater risk. However, there is no way to accurately predict who will develop long-term effects.
Another potential side-effect of brachytherapy, indeed all forms of radiation, is called the PSA “bump” phenomenon. The PSA “bump” is a delayed PSA rise occurring after the radiation finishes. Although the exact cause of PSA “bump” is not known with certainty, it is believed to result from irritation of the residual prostate gland by radiation. The “bump” follows a benign clinical course and usually resolves itself within a year. The main danger of the PSA “bump” comes when physicians mistakenly conclude that the rising PSA represents recurrent cancer and decide to start ADT when no cancer is present.
Brachytherapy (Implanted Seeds)
1. High cure rates are comparable to those of Surgery and IMRT
The advantage that surgery has over the other treatment options is its ability to accurately determine the extent and grade of the cancer. Needle biopsies only provide a sampling of the cancer while surgical removal of the gland allows the whole cancer to be thoroughly evaluated. Surgery provides information about tumor size and aggressiveness by looking for the presence or absence of invasion into or through the capsule of the prostate. Also, by examining the whole tumor, pathologists may discover areas of high-grade disease that may have been missed by a random needle biopsy.
The improved staging information obtained via surgery can engender new questions in the process of treatment selection. A small minority of properly staged RC-IA patients will be found to have higher-grade disease after surgery. Findings such as positive surgical margins or seminal vesicle invasion are indications of a substantially increased risk of future relapse. This surgically obtained information can be valuable for making timely decisions about further anticancer treatment while the cancer is still at an early stage.14
Judging the value of this higher quality staging information is difficult. Recent studies have shown that biopsy inaccuracies can be minimized by using more thorough biopsy techniques.20 Better imaging studies with color Doppler ultrasound or spectrographic MRI also improve preoperative staging. Even so, it is clear that none of these techniques can match the ability of a trained pathologist who does a careful microscope review of the surgically removed gland.
Surgery has some side-effects distinctive from the other treatment options. Incontinence (urine leakage) is more frequent with surgery than with other treatments and occurs in 5-8% of men treated by top-flight surgeons. The severity of incontinence is variable and many men can handle the problem with a pad. Severe cases of incontinence may need surgical correction with the placement of an artificial sphincter, a surgical procedure that is usually successful when performed by qualified experts.
Scarring and blockage of the urethra (urinary passage) also seems to occur about 5% of the time. This problem usually responds to periodic stretching of the urethra with dilators inserted though the end of the penis but on occasion the scarring progresses into an intractable problem that can result in incontinence. A detailed review of radical prostatectomy was recently published in Insights.21
Intensity modulated radiation therapy (IMRT) is the latest and most developed form of external beam radiation available.22 IMRT is a third generation form of external beam radiation that is the culmination of an evolutionary process starting with the old four-field beam radiation techniques that later evolved to second generation three-dimensional conformal radiation. IMRT represents an advance over these previous techniques because it does the best job of delivering high uniform doses of radiation to the prostate while sparing the bladder and rectum.
IMRT accomplishes this feat by modulating the intensity of the radiation beam over the width of the beam (see Figure 3). Such modulation is necessary because the prostate is a spherical target. When a beam of radiation is used, the thicker, middle portion of the prostate needs relatively higher doses of radiation to penetrate the gland fully, whereas the thinner, peripheral part of the gland can be covered with smaller amounts of radiation. Only IMRT can modulate the intensity of the beam to make allowance for these anatomical realities.
Figure 3. Intensity Modulated Radiation Treatment (IMRT). Thousand of tiny “beamlets” from multiple directions; highest doses to target with greatest sparing of normal tissue.
Unfortunately, because the anterior rectal wall is so close to the prostate, a small portion of the rectum has to be included in the radiation field. This means that a small minority of patients will develop proctitis, a non-healing radiation burn of the rectum. However, IMRT has the lowest incidence of proctitis of all the forms of beam radiation.23 Symptoms of proctitis vary but can include rectal urgency, pain, bleeding, and incontinence. There are some medications that can reduce the symptoms of proctitis, but nothing cures the problem. Severe bleeding problems, should they occur, can usually be controlled with laser therapy. Men who develop proctitis often adhere to strict diets attempting to minimize irritation to the rectum.
Urithritis is also starting to be reported more frequently as the doses of radiation are escalated above 8000 rads. At doses around 7800 rads, as is typically being administered in the community in 2003, the incidence of long-term urithritis is very low. Impotence occurs with IMRT at a rate similar to well-performed surgery or seeds. The onset of impotence may be delayed for several years. Short-term effects of IMRT also occur, but are milder than the other treatments. There is some risk of urinary and rectal irritation for a month or two. Energy levels may also be reduced for a similar period.
Intensity Modulated Radiation Therapy (IMRT)
Cryotherapy has developed into a favored method of treating men with local relapse after radiation, but it is also be used in men with newly diagnosed disease. Cryotherapy has the advantage of a short hospital stay as well as being a treatment that can be repeated if necessary. Performed under either general or spinal anesthesia, the Cryosurgery procedure itself involves the controlled freezing of the gland in order to destroy both the prostate gland and the cancer it contains. Four to eight Cryo probes are introduced through the perineum (skin surface between the rectum and scrotum) and advanced to pre-selected locations in the prostate gland using ultrasound guidance. After a warming device is placed to protect the urethra, the freezing process begins by circulating liquid Argon through the probes resulting in the formation of an ice ball that encompasses the whole gland. Two cycles of freezing and thawing constitute the treatment. After the probes are removed, the patient is discharged the next morning with a Foley catheter that remains in place for two to three weeks.
The complications of cryotherapy are dependent on the skill of the cryotherapist. A conservative estimate of the most common side effects was reported by six prominent cryotherapists in 2001.24 In that study, 93% of men became impotent, 7.5% became incontinent, 13% needed a transurethral resection to clear out dead tissue, and one half of one percent had the dreaded complication of a fistula connection between the bladder and rectum. However, this study probably overestimates modern complication rates because the article included statistics from patients who were treated in the early years of cryotherapy development.
High dose radiation, otherwise known as temporary seeds, has been used since 1980 but has been traditionally offered only in conjunction with external beam radiation.25 HDR monotherapy is a newer approach that involves two separate implants, thereby forgoing the external beam radiation portion. This newer approach, termed a tandem implant, or HDR monotherapy, is an attractive option for Risk Category IA patients as it avoids the low-dose radiation exposure to the pelvic organs caused by the beam radiation.
Theoretically, the advantage of HDR over brachytherapy is that the doctor performing HDR has the capacity to alter the radiation dose during the course of treatment. Thus, the argument in favor of HDR is its flexibility in controlling the dose and location of the radiation. In theory, then, an attempt can be made to steer the radiation dose away from the urethra, the structure most at risk from high-dose temporary seed radiation.
The procedure itself involves the placement of small hollow plastic tubes through the perineum into the prostate. Ultra high intensity radioactive seeds (iridium 192) are pushed into the tubes. The seeds are only left in place for only a matter of minutes. This process is repeated on three separate occasions over a 24-36 hour period. Historically, the implant has been routinely followed by five weeks of external beam radiation, and there is convincing literature documenting the effectiveness of this older approach to control cancer.
The tandem, or monotherapy approach substitutes a second implant applied a week to a month later in place of the external beam radiation. However, there are not as yet any studies definitely proving that HDR monotherapy reduces urithritis. Clearly, the procedure is attractive on paper and is quite likely to be effective in RC-IA patients. Even so, there are still no published studies proving the effectiveness of this newer approach.
High Dose Radiation (HDR) Monotherapy
Age is a major factor in determining treatment; very old men can easily be managed with watchful waiting since there is no early mortality for RC-IA patients. On the other hand, IMRT may not be the best option for very young men since there are other treatment options that avoid exposure of the pelvic organs to radiation.
The characteristics of the prostate gland itself can make certain local treatment options less attractive; men with very large prostates, excessive urinary problems, or a previous history of prostate surgery for a benignly enlarged prostate risk greater side-effects with brachytherapy. An enlarged prostate can be reduced with 3-6 months of ADT if brachytherapy is strongly preferred, and ADT side-effects are less when it is only administered for 3-6 months. Even so, long-term effects on libido can occasionally occur.
Quality cancer staging is fundamental to prostate cancer treatment. Biopsy techniques,26 Gleason scoring, and prostate scanning can be misleading when improperly performed. Suboptimal staging risks under-treatment of high grade disease. As was previously stated, the quality of the physician determines outcome.
After they review the pros and cons of all different treatment options, many men logically conclude that they personally have several plausible options. Relatively small issues such as ease of administration may surface as the most important factor in the treatment selection process. There would be little controversy about treatment if a completely non-toxic option existed. Unfortunately, all the effective treatments have some negative aspects and no single treatment stands out as being clearly better or worse than all the others;27 since there is no single, medically preferred option, the onus for treatment selection inescapably remains with the patient.28,29
Part 1 deals with diagnosis and risk category staging.
Part 3 deals with higher risk of disease at diagnosis.
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