Prostate Cancer-14

The same is also true of the bone scan in newly diagnosed patients with a baseline PSA of 10 ng/mL or less--assuming that the Gleason score is less than 7.304 A study by Chybowski et al. concluded that the negative predictive value for a positive bone scan given a serum PSA of less than or equal to 20 ng/mL was 99.7%. Only 1 patient out of 306 with a PSA of less than or equal to 20 (PSA = 18.2) had a positive bone scan. Of the 207 patients with PSAs of less than or equal to 10 ng/mL, none had a positive bone scan and only 1 of the 99 patients with a PSA of greater than 10 and less than or equal to 20 had a positive bone scan. It therefore appears reasonable to forego bone scanning in newly diagnosed, untreated prostate cancer patients who have PSAs of less than or equal to 10 ng/mL.305 In another study, Oesterling et al. reported that only one abnormal bone scan out of a total of 200 bone scans (0.5%) would be missed if the requirement for performing a bone scan was a PSA greater than 10 ng/mL.306

In light of the fact that more and more men are being diagnosed with PSA levels of < 10, the impact on the healthcare economy when physicians order these tests in a reflex fashion is disastrous. Assuming that 180,000 men are newly diagnosed with PC each year in the United States and that at least 70% of them will have PSA levels at diagnosis below 10 ng/ml, and a negligible number will have PSA levels greater than 20 ng/mL, the healthcare financial waste is staggering (see Table 18).

Given that the average cost of a bone scan, CT scan of the pelvis, and CT scan of the abdomen is $600 per test, the waste in healthcare dollars is approximately $300 million dollars each year! If we add to this a pelvic MRI study (not to be confused with an endorectal MRI), the cost could total $400 million a year. These sums represent flagrantly wasted economic resources, misused technician time, unnecessary radiation exposure to patients, and inconvenience to patients. Most importantly, think of what some of this money could do in areas truly needing economic support, be it from private insurance carriers or in the United States to the taxpayer.

The major exception to the above is in the case of a patient with a Gleason score of (4,3) or higher at diagnosis. In such a setting of a high Gleason score, characterized by significant amounts of Grade 4 and/or Grade 5 disease, for example, (4,3), (4,4), (4,5), (5,4), and (5,5), the PSA leak phenomenon must be taken into account.127 Such patients may have low PSA levels, not uncommonly less than 5, yet have metastatic disease to bone. However, it must be emphasized that such patients have Gleason scores of 8-10 at the time of diagnosis or on the occasion that they are rebiopsied due to findings suggesting active PC.


Treatment
(6) Testosterone Deprivation Therapy and Its Far-Reaching Implications: If there is any area of PC management that necessitates a comprehensive understanding by the physician, it is in knowing the spectrum of effects of ADT on male physiology. A lack of such understanding deprives the patient of available supportive care that can mean the difference between success and failure in the patient's life. This not only relates to preventing or minimizing side effects due to treatment, but also to the patient's compliance with therapy--whether he will remain on the medications used in ADT or stop them due to adverse effects.

In the early 1980s, I began treating PC patients using anti-androgen therapy in combination with an LHRH agonist as one of the first American collaborators working with Fernand Labrie. My observation of patients taught me a great deal about the effects of an accelerated and intensified male menopause. The lowering of serum testosterone to castrate levels, defined as less than 20 ng/dL (less than 0.68 nM/L), resulted in a spectrum of possible signs and symptoms that varied from man to man.

Some of these symptoms occurred acutely, while others developed over time. However, all were potentially troublesome, if not aggravating, for the patient. If not treated in a preventive manner, such signs and symptoms can have a negative impact upon the patient's overall health.

Except for hot flashes and impotency, many symptoms resulting from androgen deprivation have been discounted by physicians as being due to old age or due to medical problems such as arthritis or heart disease. However, this constellation of clinical and laboratory abnormalities quickly develops in younger men or older men in otherwise good health after the initiation of ADT. This clearly suggests that these symptoms are not due to "old age" but are characteristics of the androgen deprivation syndrome (ADS).

ADS symptoms are directly or indirectly due to the drop in testosterone level that occurs following orchiectomy or use of an LHRH agonist (LHRH-A) such as Lupron, Zoladex, Trelstar LA, or Viadur. In essence, men who are medically or surgically castrated undergo an accelerated and intensified form of male menopause that leads to many of the same symptoms that are seen in women going through female menopause. Patients treated with combined ADT (LHRH agonists or orchiectomy plus an antiandrogen such as Eulexin, Casodex, or Nilandron) may have more severe ADS symptoms than those treated with an LHRH agonist or orchiectomy alone. This is because the additional use of an antiandrogen also helps to block residual testosterone from interacting at androgen receptor sites located throughout the body. LHRH agonists or orchiectomy suppress testicular androgen and not androgen synthesis from the adrenal glands. In fact, orchiectomy will result in increased production of adrenal androgen precursors due to a reflex stimulation of the hypothalamic-pituitary tract. This causes an increased production of LH along with an overflow stimulation of ACTH, which increases production of adrenal androgen precursors (see Figure 9).307

As mentioned in the section on LUTS (on page 1433), the addition of Proscar will result in a further lowering of androgen effect. This is due to Proscar's ability to block the enzyme 5-alpha-reductase (Type II), which converts testosterone to DHT. DHT is therefore a metabolite of testosterone and is five times more potent than testosterone in stimulating cell growth. In addition to this, Proscar also down-regulates the expression of the androgen receptor. Therefore, it should not be surprising that ADT3, as described previously, would have the greatest potential for side effects due to androgen deprivation, but would also have a higher probability to have a greater anti-tumor effect on the PC cell population for the very same reason. If we were to routinely add the use of an alpha-1-blocker such as Hytrin or Cardura, we should have even greater effects against the PC population due to a decrease in microvessel density, down-regulation of bcl-2, and enhanced apoptosis (as discussed in the section on LUTS and shown in Table 17).

In fact, the designation ADT4 could indicate the addition of a piperazinyl quinazoline compound of the alpha-1-blocker class to the standard ADT3 regimen of LHRH-A, antiandrogen, and 5-alpha-reductase inhibitor.

Androgen deprivation with four agents or ADT4 would involve the routine use of an agent of the quinazoline class of alpha-1-blockers such as Hytrin or Cardura. These agents will not only improve urinary flow, but also act to enhance the effects of ADT3. Therefore, the typical ADT4 regimen would include:

a)LHRH-agonist: Lupron, Zoladex, Trelstar LA, or Viadur
b)Antiandrogen: Eulexin, Casodex, or Nilandron
c)5-alpha-reductase inhibitor: Proscar or Avodart
d)Alpha-1-blocker: Hytrin or Cardura

As emphasized earlier, there is a spectrum of side effects that may be seen with the use of ADT. These untoward effects are highly variable from man to man. Some men have no significant clinical symptomatology associated with the use of ADT, while others state they cannot function with a reasonable quality of life. The supportive care of the patient by the physician in using ADT is vital to the acceptability of this very important modality used in the treatment of prostate cancer. We can improve the therapeutic index of ADT by finding solutions to the problems that may occur as part of the androgen deprivation syndrome, or ADS.

Signs and symptoms that are part of the spectrum of ADS are shown in Table 19. These are divided into systems or tissues affected and the nature and onset of the symptoms, that is, acute and chronic. Again, it is of vital importance to understand that there is significant variability from patient to patient regarding frequency of occurrence and timing of all such findings.

Commonly Reported Acute and Chronic ADS Symptoms

These are possible findings that may occur in men receiving ADT. Many of these issues can be prevented, lessened, or resolved as part of the supportive care directed to the PC patient. This improves the therapeutic index of ADT. The PC patient and his partner, as a result, have an improved quality and quantity of life.

Symptom Onset and Details

A)System or Tissue Affected -Sexual
Acute (Symptoms in < 2 Months)-Decrease in libido; decrease in erectile ability
Chronic (Symptoms in > 6 Months)-Penile shrinkage; testicular atrophy


B)System or Tissue Affected-Psycho-social
Acute (Symptoms in < 2 Months)-Mood "swings;" easy crying
Chronic (Symptoms in > 6 Months)-Depression; hostility

c)System or Tissue Affected-Endocrine
Acute (Symptoms in < 2 Months)-Hot flashes; poor blood sugar control in patients with diabetes
Chronic (Symptoms in > 6 Months)-Gynecomastia (breast enlargement)

D)System or Tissue Affected-Musculo-skeletal
Acute (Symptoms in < 2 Months)-Loss of energy, feeling weak; aches and pains in joints and muscles
Chronic (Symptoms in > 6 Months)-Decrease in strength and endurance; muscle atrophy; chronic fatigue-like symptoms; osteoporosis

E)System or Tissue Affected -Skin and nails
Acute (Symptoms in < 2 Months) -Increased dryness
Chronic (Symptoms in > 6 Months)-Thinning of skin; nails brittle and break easily

F)System or Tissue Affected -Body mass
Chronic (Symptoms in > 6 Months)-Weight increase due to increased body fat; blood pressure control more difficult

G)System or Tissue Affected-Central nervous system
Acute (Symptoms in < 2 Months) -Decrease in short-term memory
Chronic (Symptoms in > 6 Months)-Alzheimer's-like symptoms (severe short-term memory difficulties, inability to concentrate, etc.)

H)System or Tissue Affected -Hematologic
Acute (Symptoms in < 2 Months)-Anemia unrelated to blood loss, iron deficiency or bone marrow involvement
Chronic (Symptoms in > 6 Months)-Chronic anemia

I)System or Tissue Affected -Urinary
Acute (Symptoms in < 2 Months) -Decrease or increase in urinary symptoms

J)System or Tissue Affected -Lipids
Chronic (Symptoms in > 6 Months)-Increase in LDL cholesterol and/or triglyceride levels

To assess the significance of common ADS symptoms, we evaluated 177 hormone-naïve PC patients consecutively treated with an LHRH-agonist and an antiandrogen between 1994-1997. We asked patients to grade the frequency and severity of ADS as absent (Grade 0), occasional (Grade 1), frequent or bothersome (Grade 2), or requiring drug therapy (Grade 3). Other than loss of libido and impotence, Figures 10 and 11 depict the most commonly reported acute and chronic symptoms. Only Grade 1, 2, or 3 findings are shown.

Finally, the incidence and the intensity of bone loss are affected by the duration of ADT. This assumes that the patient on ADT is not receiving concomitant therapies to prevent bone resorption, e.g., a bisphosphonate plus a bone supplement in conjunction with an exercise program. The mechanism of progressive bone loss during ADT relates to the fact that androgens are known inhibitors of osteoclast function. During ADT, this inhibition is lost and osteoclasts are activated, allowing for promotion of bone loss (resorption). Testosterone, therefore, is an anabolic steroid for bone, muscle and other tissues. The deprivation of androgens pushes the balance towards catabolism or breakdown.

Clearly, a comprehensive care plan that takes the overall health of the PC patient into account must look at the impact of each and every ADS-related finding. Prevention of the undesirable consequences of ADT equates with a higher therapeutic index, which in turn means a higher quality of life for the PC survivor. Therefore, the intelligent use of ADT, as with any therapy, should take into account the

1)Therapeutic purpose of ADT
2)Nature of ADT (neoadjuvant, intermittent, or continuous treatment)
3)Age and overall general health of the patient
4)Degree of tolerance by the patient of the various ADT side effects
5)Prevention or resolution of any signs and symptoms of ADS
6)Net picture of pros versus cons

For example, the duration of neoadjuvant ADT rarely exceeds 1 year in patients who are candidates for potentially curative local therapies with RT or cryosurgery. Therefore, such patients have the potential risk for the typical acute ADS symptoms, but they will not experience chronic ADS symptoms to any significant extent. Patients who may be involved in this scenario include those with large-volume PC within the prostate with extracapsular extension (ECE). Such patients fare better when ADT is used up-front (neoadjuvant therapy), prior to the RT or cryosurgery, to decrease both the cancer volume as well as the gland volume. In the Primer, Physician's Note #5 relays such a story in the case of patient GB. The patient completed IMRT over 3 years ago and his PSA remains flat at 0.4 ng/mL.

Even with a highly responsive physician who is knowledgeable about ADS, acute ADS-related symptoms invariably compromise the lifestyles of healthy and active prostate cancer patients. This mandates that certain changes be made in the patient's diet, exercise, and work habits during ADT.

Chronic ADS symptoms are much more prevalent in PC patients treated with ADT than are currently recognized, and some are nearly inevitable in patients treated for longer than 1 year. For such patients, specific treatment strategies must be implemented to minimize or prevent the development of chronic ADS. Left untreated, chronic ADS is progressive with ongoing ADT and often leads to other medical complications. Useful preventive or active strategies against acute ADS-related symptoms are shown in Table 20, and chronic ADS-related symptoms in Table 21.

Preventive and Active Treatments for Acute ADS-Related Symptoms

Acute ADS-Related Symptom -Hot flashes

Treatment Strategy-Soy, genistein, Megace, Depo-Provera,1 DES,2 or venlafaxine (Effexor)1


Acute ADS-Related Symptom -Aches and pains in joints and muscles

Treatment Strategy-Acetaminophen, ibuprofen, Fosamax,1 Actonel,1 Aredia,1 or Zometa,1 plus bone supplement, resistive exercise (weights, Bowflex), walking

Acute ADS-Related Symptom -Fatigue and feeling weak

Treatment Strategy-Walking, muscle stretching

Acute ADS-Related Symptom -Memory difficulties

Treatment Strategy-Ginkgo biloba,3 Eldepryl, memory exercises, DMAE,3 Cognitex3

Acute ADS-Related Symptom -Mood and emotional swings
Treatment Strategy-Patience (may improve), Depo-Provera1

Acute ADS-Related Symptom -Symptomatic anemia (shortness of breath, chest pain, dizziness, severe weakness)

Treatment Strategy-Injections of recombinant human erythropoietin (Procrit1, Aranesp1); iron supplementation only if documented iron deficiency via low ferritin or elevated serum transferrin receptor (> 28.3)

Acute ADS-Related Symptom -Increased urinary frequency

Treatment Strategy-Hytrin,1 Cardura,1 Flomax,1 patience

Acute ADS-Related Symptom -Impotence and loss of libido

Treatment Strategy-Viagra,1 Muse,1 (alprostadil intraurethral pellet) or Caverject,1 or combinations of these.

1 Physician's prescription is required to obtain medication.
2 Not recommended in this setting due to toxicity.
3 Available from health food suppliers, such as Life Extension Foundation.

Preventive and Active Treatments for Chronic ADS-Related Symptoms

a)Chronic ADS-Related Symptom(s)-Loss of muscle bulk and strength; worse in pectoral, biceps, and quadriceps
Treatment Strategy-Exercise with light weights; Bowflex

b)Chronic ADS-Related Symptom(s)-Weight gain and fat redistribution
Treatment Strategy-Sears's Omega Rx Zone approach; regular exercise

c)Chronic ADS-Related Symptom(s)-Chronic fatigue syndrome
Treatment Strategy-Walking, regular exercise, avoid inactivity

d)Chronic ADS-Related Symptom(s)-Penile atrophy
Treatment Strategy-Viagra1 and other similar agents

e)Chronic ADS-Related Symptom(s)-Gynecomastia
Treatment Strategy-Breast radiation to prevent; liposuction or surgery to treat severe established cases

f)Chronic ADS-Related Symptom(s)-Osteoporosis
Treatment Strategy-Fosamax,1 Actonel,1 Aredia,1 or Zometa1 plus bone supplement; synthetic vitamin D (Rocaltrol1); aerobics, walking, resistive exercises

g)Chronic ADS-Related Symptom(s)-Alzheimer's-like symptoms
Treatment Strategy-Ginkgo biloba,3 DMAE;3 see Life Extension Foundation protocols in this book for Alzheimer's disease; reading and other mind-stimulating activities

h)Chronic ADS-Related Symptom(s)-Increased serum cholesterol and triglyceride levels
Treatment Strategy-Sears's Omega Rx Zone approach; if no help, Lipitor,1 Pravacol,1 Zocor,1 Mevacor1 (may require supplemental CoQ103)

1 Physician's prescription is required to obtain medication.
2 Not recommended in this setting due to toxicity.
3 Available from health food suppliers, e.g., Life Extension Foundation.

In the past, patients who were not candidates for local therapy were typically treated with continuous androgen blockade. Armed with our current knowledge about the signs and symptoms of acute and chronic ADS, we prevent or correct these findings with one or more of the therapies listed in Tables 20 and 21.

Another approach that avoids symptomatology attributable to chronic ADT is through the use of intermittent androgen deprivation (IAD). Depending on the required duration of ADT, individually determined for patients, IAD may be a reasonable alternative approach. This is an example of how therapy should be individualized to the patient's biological constitution. (A discussion of IAD with graphs indicating outcomes using ADT2 versus ADT3 can be found in the Primer.)

Supporting the patient through measures such as some of those discussed relates to the fine-tuning that is characteristic of outstanding medical care. This is the essence of holistic medicine. There are other issues of supportive care that relate to the settings of pre- and postoperative care for a patient undergoing RP, cryosurgery, RT, and even watchful waiting. Some of these issues and possible resolution therapies worthy of your review and subsequent discussion with your physician are outlined in Table 22.