Newly Diagnosed Prostate Cancer: Evaluating the Options
Part 3 of a 3 Part Series

Reprinted from PCRI Insights February 2004 v 7.1
By Mark Scholz, M.D., Prostate Oncology Specialists, Marina del Rey, CA

Background
This is the third article of a three-part series describing treatment alternatives for newly diagnosed prostate cancer patients. In this part, treatment for men who are at higher risk for micro-metastatic spread outside the prostate will be discussed. Combination treatment is the theme of treatment selection for men in this category. Unfortunately, the treatment selection process in men in higher risk categories continues to be challenging since the decisions are the result of measured judgments. These judgments must be made by balancing the benefit of improved cure rates from combination therapy on the one hand and the potential for increased negative side-effects that come from adding multiple treatments together on the other hand.

Familiarity with the different treatments is essential for making sensible choices. The descriptions of treatment options for Risk Category 1A disease covered in Part Two of this three-part series are relevant as we consider combining treatments to improve cure rates for higher risk cancer. However, additional descriptive information about these treatments beyond that covered in Part Two is needed to evaluate treatment options for higher risk disease. The topics requiring further elaboration are 1) androgen deprivation therapy (ADT), 2) radiation, and 3) chemotherapy. The following paragraphs expand our understanding of the treatments available and provide the needed foundation for the subsequent process of determining how to select the appropriate treatment for specific individuals depending on their risk category and their life expectancy.

Reprinted from Part One

Androgen Deprivation Therapy (ADT)
When ADT is combined with some form of local treatment such as surgery or radiation, the duration of the ADT treatment is usually extended for a longer period than the 12-month period recommended for men who are using ADT as a stand-alone treatment. Longer-term androgen deprivation administered with radiation reduces the risk of cancer relapse at five years by as much as 58%. (See Table 2). The longer treatment period is used because the goal is cancer cure, rather than suppression of the cancer.

Table 2. Comparison of the 5-year Relapse Rate Risk after Radiation for ADT Treatment

Study Author	ADT Duration	RR after XRT	RR after ADT/XRT	% decline in RR
Hanks	28 months	56%	28%	50%
Bolla	36 months	60%	26%	58%
Pilepich	Life long	79%	45%	43%

RR = Relapse Rate @ 5 years
XRT = Radiation

The optimum treatment period for ADT used in combination (adjuvantly) with surgery or radiation is not precisely known. However, the shortest duration of ADT that has shown improved survival is 28 months.1,2 Trials using ADT for longer periods than 28 months have also shown improved survival.3,4 Periods of less than nine months are known to be inadequate.5,6 As yet, there have been no trials evaluating treatment periods between nine months and 28 months to determine if a treatment duration in this range would also result in improved survival. At this time, therefore, the safest alternative would appear to be 28 months.

Radiation
Controlling higher risk cancer with radiation requires higher doses of radiation. Only recently have modern Intensity Modulated Radiation Therapy (IMRT) techniques allowed for the safe delivery of doses in the range of 8000 rads; doses at this level appear sufficiently potent to kill all the cancer in the prostate with a high degree of likelihood. Unfortunately, long-term studies detailing if and how often cancer in the prostate can survive these high doses are not yet available. Studies of IMRT that are presently available do show improved cure rates over traditional methods7,8 but do not establish whether further small improvements will be possible with even higher doses. Studies of IMRT at doses above 8000 rads are presently ongoing.

IMRT can be combined with a seed implant (Brachytherapy) boost that can further escalate the dose of radiation inside the prostate. Some experts estimate that radiation doses reaching as high as 10,000 rads (in external beam-comparable rads) can be achieved when a seed boost is applied in combination with partial dose IMRT.9,10,11 These higher doses inside the prostate would logically seem to be advantageous in certain circumstances, but as yet there are no direct studies to prove that these higher doses are really necessary. So until such studies are available, it seems prudent to lean toward doing a seed boost in men who have larger amounts of high-grade disease inside the prostate detected by ultrasound, MRI , biopsy, or DRE.

This bias toward using combination IMRT and seed implant therapy is not applicable in men with documented local extension of cancer outside the capsule, (e.g. into the seminal vesicles). In this situation, full dose radiation to the area immediately surrounding the prostate seems most prudent. IMRT in full doses without any seed boost is better suited to delivering high uniform doses of radiation to the areas closely surrounding the prostate gland.

IMRT in full doses without a seed implant would also be the logical option for men who are contemplating radiation to the pelvic lymph nodes. My formula for determining the percent risk of lymph node involvement is:

Percent risk of spread to the lymph nodes = (2/3)PSA + [(Gleason score – 6) x 10]

Radiating pelvic lymph nodes in men with greater than a 15% chance for cancerous spread to the nodes (as determined by this formula) may be warranted based on a publication authored by Roach et al.12 Prior to this publication, the concept of lymph node radiation had fallen out of favor because older, less well designed studies did not clearly show a benefit. In the Roach study, pelvic radiation reduced relapse rates by 20%. The Roach study also demonstrated that when ADT and radiation are used together, results are better when the ADT is started at least two months before the radiation.

However, pelvic radiation administered with older, non IMRT based techniques (as was done in the Roach study) may increase the risk of intractable bowel problems, especially when used in conjunction with long term ADT.12 More modern and sophisticated radiation methods using IMRT will likely reduce bowel toxicity while retaining improved cure rates.

Chemotherapy
Chemotherapy for newly diagnosed prostate cancer is still investigational. This is in contrast to other common cancers types such as breast cancer and colon cancer where chemotherapy has become standardized. Chemotherapy use in breast and colon cancer has become routine because of well-designed studies documenting improved cure rates.

There is only one small randomized trial of adjuvant chemotherapy in men with prostate cancer.13 This study examined men with an increased risk of micro-metastatic disease who were either treated with ADT or with ADT combined with a type of chemotherapy called Novantrone. The men treated with Novantrone had lower relapse rates and lived longer then the men treated with ADT alone.

More effective drugs than Novantrone now exist. Studies show that a newer agent called Taxotere is three times more effective than Novantrone.14 Studies of Taxotere for newly diagnosed men are already in progress, but the final outcomes of these studies may not be available for several years. Until these studies are completed, we can only estimate the effectiveness of Taxotere by extrapolating from studies performed in breast and colon cancer patients. There is a 50% reduction in relapse rates using chemotherapy in breast cancer patients.15 Studies of chemotherapy in colon cancer indicate a reduction in relapse rates of approximately 33%.16 I believe it is reasonable to expect a similar result in men with prostate cancer treated with Taxotere.

The side-effects of Taxane-based chemotherapy are for the most part manageable.17 The most troublesome effect is fatigue, which usually lasts for about two days after each weekly infusion. In addition, mild to moderate temporary hair loss can occur. There is also a risk of nausea, but this can be prevented with modern anti-nausea pills. Sometimes, low white blood cell counts need to be counteracted with injections of medicine similar to insulin shots.

The primary rationale for adding ADT, chemotherapy, or both to local treatments such as surgery or radiation is to counteract the known propensity for cancer cells to spread through the blood stream to other parts of the body. Both ADT and chemotherapy would be administered routinely in every patient if there were no unpleasant side-effects. The side-effects are the reason that these treatment options are reserved for cancer situations where (1) there is a known high risk of cancer relapse with local therapy alone, and (2) the patient is relatively young and hence has a greater life expectancy.

Determining Treatment Recommendations
With this comprehensive treatment armamentarium at our disposal, the real question is how to determine which of the treatments described in this three-part article should be applied to men with newly diagnosed prostate cancer. This often is not an easy decision, given the great variety in the ages of men with the disease and the different stages and grades of prostate cancer. Treatment selection is based on life expectancy, the degree of cancer risk (risk of micrometastasis), and the patient’s willingness to accept potential side-effects from treatment.

Table 3 outlines suggested treatments, taking into account an individual’s age (life expectancy) and risk of cancer relapse. Table 3 communicates general guidelines and conveys the principle of increasing treatment intensity commensurate with higher risk disease and with younger age. Examining adjacent age and risk categories may also be useful especially if the estimated risk is close to a border between two categories.

Table 3. Suggested Treatments for Different Risk Categories and Conditions

Risk Category IA	Treatment Options
Young (under 65?)	Surgery, Seeds, ADT, WW, HDR
In Between	Seeds, ADT, IMRT, WW, HDR, Cryo
Old (over 75?)	WW, ADT, IMRT, Seeds, HDR, Cryo
Risk Category IB	Treatment Options
Young (under 65?)	Surgery (+/-ADT), Seeds (+/-IMRT) (+/-ADT), ADT, Cryo (+/-ADT)
In Between	IMRT (+/-Seeds) (+/-ADT), Seeds (+/-IMRT) (+/-ADT), HB, Cryo (+/-ADT)
Old (over 75?)	WW, ADT, IMRT, Seeds, HDR, Cryo
Risk Category IC	Treatment Options
Young (under 65?)	IMRT + ADT (+/-Taxotere), Seeds + IMRT + ADT (+/-Taxotere) , Surgery (+/- ADT) (+/- IMRT) (+/-Taxotere), Cryo + ADT (+/-Taxotere)
In Between	IMRT (+/- ADT), Seeds + IMRT (+/- ADT), Cryo (+/- ADT), ADT
Old (over 75?)	ADT, IMRT, Seeds + IMRT, Cryo
Risk Categories II & III	Treatment Options
Young & In Between	IMRT (+/- Seeds) + pelvic radiation + ADT + Taxotere
Old (over 75?)	ADT (+/- IMRT)
Risk Category IV	Treatment Options
Young & In Between	ADT +Taxotere
Old (over 75?)	ADT +/- Taxotere

Treatment recommendations for men at the extremes of age and risk are easier to make. For example, young men with very high-risk disease (Risk Category II and III) have unacceptably high relapse rates with local treatment alone1,2 even when local therapy is combined with ADT. In such circumstances, it is natural to consider adding Taxotere-based chemotherapy and lymph node radiation to local therapy and ADT with the goal of reducing relapse rates as much as possible.

At the other extreme are the elderly men with Risk Category IB and IC disease. We have found that older men in Risk Categories IB and IC usually elect to forgo combination therapy because ADT therapy for relapsed disease is quite effective. A recent study of ADT administered continuously in men with rising PSA after surgery indicated that the average duration of ADT effectiveness was 10.8 years.18 Even if the ADT stops working, other agents such as Nilutamide, DES, ketoconazole, and Taxotere may continue to forestall progression of the disease. There is also reason to hope that newer, less toxic anticancer medications will be developed during the next 10 years. All these factors mitigate against old men (e.g. over 75) opting for combination treatment unless they are in very high-risk categories.

Up to this point, I have been describing the different treatments available. I have also been trying to communicate the concept of less aggressive therapy for men with lower risk disease. Table 3 shows recommendations for men with RC: IA disease broken down by age category. The age categories should not be interpreted precisely but are designed to provide general guidelines. Some older men are in great health and are likely to live longer than life tables predict. The actuarial life expectancy can be determined by examining Figure 1, and this actuarial age estimate should be modified based on the overall general health and strength of the individual.

                Figure 1 Average Life Expectancy

Risk Category IA (less than 10% relapse risk)
Treatment options for men with RC: IA disease were dealt with in detail in Part Two of this series of articles, but the impact of age on treatment selection was not discussed in detail. Clearly young men who have a low risk of dying from this disease are going to have two major priorities:
1. First make sure that the opportunities for cure afforded by discovery of the disease at an early stage are not lost, and
2. Second, try to maintain normal sexual function (no one wants messed up urinary or rectal function either, but these risks are not too great if treatment is handled expertly).

This presents a real contradiction of priorities. The local treatment options have the best chance for outright cure, but are also the options associated with the highest risk of impotence. Younger men, who are most concerned about maintaining potency, also have more years of life at risk and therefore more to lose if there is a cancer recurrence. More and more studies are being published19,20,21 evaluating watchful waiting or primary ADT for early stage disease, but precise information about the risk of cancer progression is still lacking. Young men have to evaluate the options as well as they can and make a decision that reflects their personal life style priorities.

External beam radiation with IMRT is associated with a small risk, that of secondary cancers developing 10 to 20 years in the future.22 Since there are other equally effective treatment options, IMRT seems less desirable for younger men. Surgery, on the other hand, is associated with a higher incidence of side-effects in men over age 70. Once again, because so many other alternatives are available, surgery seems to be an inferior choice in the elderly.

Cryotherapy performed in traditional fashion causes impotence in practically every individual.23,24 The other local alternatives also have a risk of impotence but it is not nearly as great. Focal cryotherapy, where only a portion of the prostate is frozen, is a new experimental approach being evaluated in several centers.25 Freezing a portion of the gland instead of the whole gland should improve the chance for maintaining potency, but this procedure may also be associated with higher relapse rates. So far, there are no statistics indicating what outcomes we can expect with partial cryotherapy, though this approach may be attractive for men who appear to have small unilateral focus of low-grade disease.

High Dose Rate (HDR) radiation is not used as a single modality except in RC: IA individuals. HDR may be the best option for a man with a very large prostate gland (BPH) who either doesn’t want to undergo ADT to shrink the prostate or who has a prostate that remains excessively large even after he has received three to six months of ADT and is not likely to have any additional shrinkage in the gland size.

Older men with RC: IA disease have a wealth of options because their chance of getting sick or dying of the disease (assuming it has been accurately staged) is negligible. Even though most such men do not need to pursue the cancer aggressively, i.e. with Seed implants, Cryo, or IMRT a number of individuals “just sleep better” and prefer to have the cancer eradicated. Such aggressive therapy is probably not necessary but since men in this age group are often no longer sexually active, the downside risks of doing local therapy are not too excessive.

It should be noted that combinations of treatments are rarely recommended for men with RC: 1A disease. The probability of successful treatment with a single local therapy is quite high, and the addition of a second therapy is likely to introduce additional side-effects needlessly.

Risk Category IB (10-25% risk of relapse)
Decisions about treatment for young men in this category are difficult because the administration of long term ADT for 28 months is a profound, life-changing event. In our practice we have noted that some men tolerate ADT treatment quite well and remain sexually active. A minority of younger men (20% or so) even keep their libido while on ADT! Why this occurs is unknown. Unfortunately, for many men, long-term ADT can be very unpleasant. For this reason, some men decide that the side-effects of treatment are too severe to justify a 10 to 12% improvement in cure rates above local therapy alone. Others opt for ADT at least on a trial basis to determine what degree of side-effects they may be able tolerate.

How do I arrive at the figure of a 10 to 12 % improvement in cure rates for men in this category? Men in RC: IB have a 75% or better chance of being cured without ADT. If long term ADT reduces the risk of relapse by 50%, then men who have an 80% projected cure rate, for example, will only have a 10% chance that long-term ADT will change their future. Let me illustrate with the following example. If we take a group of 10 men, each of whom has an 80% projected cure rate, and administer long term ADT to all ten, we would expect the following result: Eight of the men would be cured with local therapy because they were never destined to relapse anyway. All their disease is located in the area of the prostate, and the local therapy alone would have been sufficient for cure. In these cases, the addition of ADT proves to be unnecessary, but we have no way to know in advance that it is unnecessary. Of the two remaining men whose disease does spread outside the prostate, only one will benefit because the treatment is only powerful enough to eradicate micrometastasis half the time. Therefore, the net result for men with a projected cure rate of 80% is that there is only a one out of ten chance that the ADT will help.

Therefore, the essential decision-making process in young men with RC: IB disease is deciding whether enduring the side-effects of long term ADT is justified to reduce the risk of cancer relapse by 10%. The other struggle is determining when one has arrived at an advanced enough age where harboring concerns about cancer relapse is no longer necessary. Even today, 75 year-old men have an actuarial life expectancy of only 10 years. Since ADT will suppress relapsed disease for 10 years on average, it only seems logical to forgo up-front ADT, holding it in reserve only to be used in the 20 or 25% of men with RC: IB disease that will develop a relapse some time in the future.

Handling New Risk Data
Sometimes in the course of administering treatment, new and important risk data surfaces that may warrant rethinking the original treatment plan. Surgical removal of the prostate improves the ability to predict relapse risk because the whole tumor can be examined under the microscope. Information attained about tumor size, Gleason grade, and invasion into or though the capsule is very useful for estimating risk. It should be noted, however, that accurate information from the prostate cannot be obtained from the surgically removed prostate if ADT has been administered prior to the surgery. ADT causes dramatic shrinkage in the tumor. It also makes it impossible to accurately interpret the grade of the cancer. ADT administered before surgery has also been reported to make preserving the nerves that control erections more difficult. All in all, once a man has been exposed to ADT, other local options besides surgery would appear to be more desirable.

Moreover, new information derived from the surgical results has a tendency to indicate increased risk rather than reduced risk. This occurs because needle biopsies only take samples of the gland that may not be representative of the worst areas of disease. The new information gained by examining the surgically removed prostate (not exposed to ADT) may result in a change in treatment plan because the new information may substantially increase or decrease the preoperative estimates of having micrometastasis. Therefore, there is a possibility that the situation could warrant the administration of IMRT to where the prostate used to be or even to the pelvic lymph nodes. Surgical findings can also impact the decision about whether or not to administer adjuvant ADT.

Men who elect to do primary (not adjuvant) ADT for 12 months without local therapy would probably be wise to undergo a repeat high-resolution lesion-directed biopsy with color doppler ultrasound to confirm the absence of residual disease. Cancer that can withstand 12 months of ADT and still be large enough to be detectable on ultrasound directed biopsy is best construed as dangerous cancer. Worrisome cancer variants are also revealed when there is insufficient PSA decline on ADT; i.e. when the PSA fails to drop to less than 0.5 within 9027 days and less than 0.1 within six months28 of starting ADT; in this situation, higher relapse rates can be anticipated. Combination therapy with the addition of some form of local treatment is probably warranted for men with high PSA nadirs.

Risk Category IC (25-50% relapse risk)
Young men in this risk category are facing an escalating risk of future cancer problems. Sixty-year-old men have an average life expectancy of 20 years. Strong consideration has to be given to an aggressive effort to eradiate all the disease before cancer progresses further and the disease gets even more out of hand.

As shown in Table 3, men in the youngest two age categories should consider combination treatments to eradicate the disease. In all of the treatment combinations suggested in Table 3, ADT plays an important part. Men who are approaching a 50% risk of relapse after local therapy are projected to cut that risk by half with long-term ADT leaving them with a 25% risk of relapse (per the analysis summarized in Table 2). If the residual 25% risk of relapse after local therapy plus ADT could be reduced an additional 33% to 50% with adjuvant Taxotere, relapse rates would be further reduced by an additional 8 to 12%.

Once again, as was the case for elderly RC IB men, there comes a point when the effectiveness of ADT to suppress relapsed disease leads to a diminished concern about the dangers of relapse.

Risk Category II (greater than 50% relapse risk)
The majority men in this category have micrometastasis. Recently, radiation to the pelvic lymph nodes for men in this category has been shown to reduce relapse rates by 20% compared to men who did not have pelvic radiation.12 Pelvic radiation is associated with a risk of radiation damage to the intestines but this risk appears to be much less than 10%, suggesting that the treatment is more likely to help than hurt. Recent improvements in radiation techniques with IMRT are likely to further reduce the risk of intestinal damage.

Risk Category II disease is dangerous enough that it may even be prudent for more elderly men to attempt to cure it by adding IMRT to the ADT. Local therapy alone is illogical because of the low probability that disease is contained in the area of the prostate. High-risk cancer of this type can progress rapidly so an attempt to eradicate it up front with combination therapy may be appropriate even for elderly men.

Risk Category III (visible lymph node enlargement)
Men in this category have visible, enlarged lymph nodes in the pelvic region detected by CT scan or MRI. RC: III patients are treated the same as RC: II except that higher doses of focal radiation are administered directly to the area of the enlarged lymph nodes as the scans indicate. Modern radiation technology allows such dose escalation without incurring significant if any additional side-effects because the higher dose radiation is administered to precise areas, thereby minimizing the size of the surrounding area receiving high dose treatment.

Risk Category IV (positive bone scan)
Men with positive bone scans are at very high risk for developing hormone resistance within a very few years. Local therapy is not indicated because most of the cancer is outside the prostate; if ADT and possibly Taxotere are effective in suppressing the disease in the bones, the residual disease in the prostate will also be suppressed in almost all cases. Initiating ADT and Taxotere simultaneously rather than waiting until ADT loses effectiveness is a strong consideration for all except the very elderly because hormone resistance tends to occur fairly rapidly when ADT alone is used. Such a combination approach is still just investigational because studies proving that up front Taxotere in this setting translates into longer survival are still in process. Even so, the down side risk of early Taxotere administered to men who are in generally good health seems small compared to the risk of the early onset of hormone resistance.

Conclusion
The prostate cancer treatment industry tends to rush newly diagnosed men into making a quick decision abut their therapy. However, as emphasized in these three articles, the situation is complex and warrants careful reflection. Men with early-stage disease that is not life threatening need to carefully evaluate the potential toxic side-effects of more than a half dozen treatment alternatives before making their final decision; after all, they, themselves, are the ones who will have to live with any long-term, treatment-related side-effects that occur. Young men with a moderate risk of cancer spread outside the prostate also face difficult decisions. Effective anticancer strategies to reduce relapse rates exist, but the potentially notable side-effects of these strategies may not justify their use in light of the relatively small gains in cure rates.

Treatment-related side-effects are of much less concern for men with unequivocal high-risk disease because these individuals are squarely facing a life threatening disaster. Therefore, treatment selection is fairly straightforward because maximal treatment with combination therapy must be done as a life saving maneuver. New treatment options, treatment improvements, and pharmaceuticals are providing physicians with a growing arsenal for application in a wide range of patient situations and conditions. Coupled with today’s more powerful diagnostic and staging tools, they enable much more precise treatment selection for individual patients.

What You Should Have Learned From This Article
Selecting the best therapy for men with newly diagnosed prostate cancer is a complex and unfolding process that starts by pursuing the most accurate staging methods to best characterize the exact nature of the disease about to be treated. Further understanding of the cancer grade and stage may become available after evaluating the outcome of initial treatment, as is the case after surgery and after ADT. Predicting in advance the degree of side-effects for reversible treatments like ADT and Taxotere is difficult. Some individuals are very tolerant of these therapies others are not.

Contemplating the potential toxicity of long-term ADT can be intimidating for young men but side-effects vary in intensity from one individual to the next. A short-term trial of ADT of a few months may be the best way to estimate its long-term tolerability for specific individuals. ADT should be withheld if surgery is under consideration because ADT makes nerve sparing more difficult and it confuses analysis of the cancer stage and grade. ADT can always be administered adjuvantly after surgery if the surgical findings reveal an elevated risk of cancer relapse.

Finally, men need to make their best effort to understand all their options and fully complete their staging evaluation before embarking on treatments with irreversible consequences.

Part 1 deals with diagnosis and risk category staging.

Part 2 deals with early stage disease (less than 10% chance of microscopic spread).

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