~Prostate Cancer, part 11 - Supportive Patient Care, cont'd

Treatment

• Testosterone Deprivation Therapy
• Chemotherapy

(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.307

As mentioned in the section on LUTS (on page xxx), 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 downregulates 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.

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.

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 the following table. 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.

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:

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

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
System or Tissue Affected		Acute (Symptoms in < 2 Months)		Chronic (Symptoms in > 6 Months)
Sexual		Decrease in libido; decrease in erectile ability		Penile shrinkage; testicular atrophy
Psycho-social		Mood "swings;" easy crying		Depression; hostility
Endocrine		Hot flashes; poor blood sugar control in patients with diabetes		Gynecomastia (breast enlargement)
Musculo-skeletal		Loss of energy, feeling weak; aches and pains in joints and muscles		Decrease in strength and endurance; muscle atrophy; chronic fatigue-like symptoms; osteoporosis
Skin and nails		Increased dryness		Thinning of skin; nails brittle and break easily
Body mass				Weight increase due to increased body fat; blood pressure control more difficult
Central nervous system		Decrease in short-term memory		Alzheimer's-like symptoms (severe short-term memory difficulties, inability to concentrate, etc.)
Hematologic		Anemia unrelated to blood loss, iron deficiency or bone marrow involvement		Chronic anemia
Urinary		Decrease or increase in urinary symptoms
Lipids				Increase in LDL cholesterol and/or triglyceride levels

To assess the significance of common ADS symptoms, we evaluated 177 hormone-na飗e 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).

Several patient-related and treatment-related factors were found to influence the incidence and severity of ADS symptoms: hot flashes with respect to age, intensity of anemia to the specific drugs used in ADT, and the effect of ADT duration on incidence of bone loss.

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:

• Therapeutic purpose of ADT
• Nature of ADT (neoadjuvant, intermittent, or continuous treatment)
• Age and overall general health of the patient
• Degree of tolerance by the patient of the various ADT side effects
• Prevention or resolution of any signs and symptoms of ADS
• 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. 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 and chronic ADS-related symptoms follow.

Preventive and Active Treatments for Acute ADS-Related Symptoms

Acute ADS-Related Symptom		Treatment Strategy
Hot flashes		Soy, genistein, Megace, Depo-Provera,1 DES,2 or venlafaxine (Effexor)1
Aches and pains in joints and muscles		Acetaminophen, ibuprofen, Fosamax,1 Actonel,1 Aredia,1 or Zometa,1 plus bone supplement, resistive exercise (weights, Bowflex), walking
Fatigue and feeling weak		Walking, muscle stretching
Memory difficulties		Ginkgo biloba,3 Eldepryl, memory exercises, DMAE,3 Cognitex3
Mood and emotional swings		Patience (may improve), Depo-Provera1
Symptomatic anemia (shortness of breath, chest pain, dizziness, severe weakness)		Injections of recombinant human erythropoietin (Procrit1, Aranesp1); iron supplementation only if documented iron deficiency via low ferritin or elevated serum transferrin receptor (> 28.3)
Increased urinary frequency		Hytrin,1 Cardura,1 Flomax,1 patience
Impotence and loss of libido		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

Chronic ADS-Related Symptom(s)		Treatment Strategy
Loss of muscle bulk and strength; worse in pectoral, biceps, and quadriceps		Exercise with light weights; Bowflex
Weight gain and fat redistribution		Sears's Omega Rx Zone approach; regular exercise
Chronic fatigue syndrome		Walking, regular exercise, avoid inactivity
Penile atrophy		Viagra1 and other similar agents
Gynecomastia		Breast radiation to prevent; liposuction or surgery to treat severe established cases
Osteoporosis		Fosamax,1 Actonel,1 Aredia,1 or Zometa1 plus bone supplement; synthetic vitamin D (Rocaltrol1); aerobics, walking, resistive exercises
Alzheimer's-like symptoms		Ginkgo biloba,3 DMAE;3 reading and other mind-stimulating activities
Increased serum cholesterol and triglyceride levels		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 above.

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.

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 below.

(7) Supportive Care for PC Patients Undergoing Chemotherapy: A comprehensive review of this topic is a book in itself and such a treatise is being considered. Due to limitations of space and time, this topic is not discussed at this time.

Some Considerations for Supportive Care Involved in Radical Prostatectomy, Radiation Therapy, Cryosurgery, and Watchful Waiting

Suggestions that can be discussed with your physician(s) to prevent adverse effects of any of the major therapies for PC (note that ADT and its supportive care were discussed in earlier sections).

PC-Related Complication		Strategy for Resolution of Adverse Effects
Radical Prostatectomy
Need for blood transfusions		Pre- or perioperative use of Procrit1 or Aranesp1 and iron (only if biochemically indicated)
Incontinence		Kegel exercises (National Association for Continence at www.nafc.org); penile clamp, artificial urinary sphincter, urinary sling procedure
Impotence		Use of Viagra1, Muse1, combination therapy, injections of PGE1, visual aids
Penile atrophy		Viagra1 and other similar new agents; PGE1
Anastomotic stricture		Avoidance of surgery if history of exuberant scar formation (keloids); use of Pentoxifyllene1 and vitamin E3
Radiation Therapy (Any Kind)
Urinary obstructive symptoms		Pre-RT use of ADT to reduce gland volume plus use of Cardura1 or Hytrin1; for post-RT problems, use of Hytrin1 or Cardura1 and, if severe, supra-pubic tube; possibly transurethral laser surgery if scar tissue
Radiation injury to rectum (proctitis)		Rowasa1 suppositories, SOD3 (Orgotein1 or superoxide dismutase3), vitamin E3, Pentoxifyllene1, Sears' Omega Rx Zone approach3
Radiation injury to bladder (cystitis)		Rowasa1 suppositories, SOD 3 (Orgotein1 or superoxide dismutase3), vitamin E3, Pentoxifyllene1, Sears' Omega Rx Zone approach3; avoid spicy foods, alcohol, coffee; use of Prelief 3; trial of Elmiron1
Impotence		Use of Viagra1, Muse1, combination therapy, injections of PGE1, visual aids
Incontinence		Kegel exercises (National Association for Continence at www.nafc.org ); penile clamp
Cryosurgery
Urinary obstructive symptoms		ADT prior to cryosurgery to reduce gland volume; post-cryosurgery use of supra-pubic tube; Cardura1, Hytrin1
Incontinence		Kegel exercises (National Association for Continence at www.nafc.org ); penile clamp, supra-pubic tube
Impotence		Use of Viagra1, Muse1, combination therapy, injections of PGE1, visual aids
Watchful Waiting (Objectified Ongoing Observations)
Progressive disease that is clinically out of control		Interval testing and physical examination (DRE); graphing trends in PSA dynamics (velocity, doubling time); Sears' Omega Rx Zone approach; modified citrus pectin, dietary supplements

1 Doctors prescription is required to obtain medication.

Boosting Morale of the Troops: Fostering a Will to Live, Empowering the Patient

The previous sections have presented strategic issues that need to be addressed in our battle with prostate cancer. And, make no mistake, it is a battle--but one that can be won. There is much to be gained, by many people in viewing this medical confrontation using a military metaphor. Such tactical thinking undoubtedly plays a pivotal role in achieving an optimal outcome for any life-endangering encounters.

However, all the good science and all the outstanding medicine in the world will not achieve its true goal of healing without the presence of spirit. This may not seem relevant to the man feeling the immediate threat of prostate cancer because of its philisophical orientation. But, I assure you, over the course of your journey, at some important crossroad in your life, it will be seen as the take-home lesson for all that has been written here. Your spirit, your will to live fully, is the crust of the wholistic pie of life. Without this esprit, it is unlikely that you would have accepted the challenge of reading this protocol.

The basis for any victory must therefore involve morale--a state of spirit of a person or group as exhibited by confidence, cheerfulness, discipline, and willingness to perform assigned tasks. Morale, as defined in this fashion, and in the context of a war against prostate cancer, is embodied in acts reflecting empowerment of the patient and his partner.

Empowerment in this context becomes a process by which people assert control over factors that affect their health. This comes as a result of sharing resources and collaboration, which in turn lead to a more complete understanding of all aspects of a health issue.308 My perspective developed through thousands of patient encounters each year with prostate cancer is that the empowered patient is better able to decide on treatments, and better able to choose physicians to guide him on his medical journey. The empowered patient is less anxious and more secure about his clinical course.309 Empowerment, by its very nature, links people with resources.310

The empowered patient will explore options, look for new trials, participate in adjunctive or complementary therapies to enhance treatment outcomes, and be interactive in support groups. The empowered patient will take a politically active stance to increase funding, research, and awareness of the disease. The empowered patient is the purveyor of his medical records. The empowered patient views the physician as co-navigator, companion, and friend on his medical journey. An empowered patient expects bidirectional communication with his medical team to be the rule and not the exception.

In the process of opening channels of learning to the patient, we foster his empowerment and that of his partner, and that in turn encourages further learning. This extension of the physician as educator to the patient at a time of need is a manifestation of love. From this love comes wisdom in many walks of life.

Those of you with prostate cancer are focused on your lives--your life is in jeopardy and what you took for granted before is no longer guaranteed to be there in the years to come. But out of crisis comes opportunity.

During this crisis of prostate cancer, you will be provided multiple opportunities to overcome many obstacles. This is part of the lesson of life, of living, and of evolving. Remember that there are many out there without prostate cancer who will live their lives, day after day, without the appreciation to see the beauty of a tree or a sunrise; to say I love you; to smell the flowers; to marvel at the innocence of children; and to appreciate the uniqueness of your humanity. But this journey you are on should not be just an appreciation of life at a time of crisis, which is conveniently forgotten once the crisis is over. There are lessons here, crucial to your well-being and to that of your family, friends, community, and to all life forms.

Louis Armstrong said: "It's a wonderful world." The creation is wonder-full. We are part of that creation. We are also the caretakers of this wonderful world. Prostate cancer should change your life; it should make you aware of this creation--not just the natural wonders, but the wonder of you and your fellow humankind--all are linked together in a system longing for balance and communication. This is the essence of health for all biological systems.

On a biological level we are multicelled organisms that seek to achieve and maintain high levels of communication to remain in balance. It is a restatement of yin and yang. On every level of existence, from that of cellular interactions to the complexity of the individual human being to societies and governments, the call is the same: communication and balance. Without this, our health declines. Without this, our world dies.

Continued . . .