Prostate Cancer13

Supportive Care Measures Involved in the Diagnosis, Evaluation, and Treatment of Men with Prostate Cancer

a)Diagnosis
b)Evaluation
c)Treatment

Diagnosis

a)3D-conformal RT
B)Neutron beam RT (1) DRE (digital rectal examination): This must be done gently, and with ample lubricant. The patient's rectal sphincter should be given time to adjust to the initial palpation of the gloved finger. This should not be a "ram job" that is too often described by traumatized patients. No patient should be reaching for the chandelier during a DRE. There may be an uncomfortable sense of fullness, an awkward feeling that there may be some leakage of seminal fluid, but if the physician is adept at doing a DRE, the patient should not be fearful of another such examination.273 I have found that if I describe to the patient what I am doing, and feeling, during the entire procedure, the patient is more focused on listening to what I am saying than on any minor discomfort he may be experiencing.

The physician's notes concerning the DRE should be detailed. An estimate of the gland volume, a notation of any areas suspicious for PC, and if present, their extent regarding size, should be clearly entered in the medical record. The use of descriptors such as moderately enlarged or 1+ enlarged is worthless. The physician should commit to an estimate of the gland volume in cubic centimeters. A T-stage designation, essentially equivalent to the clinical stage of the disease, should also be routinely recorded.

After the DRE is complete, the physician should have tissues available for the patient to wipe himself and allow him to use the restroom to clean himself up further and wash his hands. The patient should not spend the rest of the day sliding around on lubricant left over from the DRE. This may seem to be an excessive amount of words to spend on this subject, but this is one of the first physically intimate interactions the physician has with the patient. It should create a sense of trust that the physician is sensitive to this embarrassing and awkward situation.

(2) Venipuncture (blood drawing): This is something that the physician's staff does, but it is also so potentially traumatizing that some discussion is necessary. Assuming a good-sized vein is found and the R.N. or laboratory technician has had no problem in obtaining blood, a gauze pad should be placed over the vein as the needle is withdrawn. The patient should be told to apply firm pressure with his fingers over this gauze pad and to hold it for a few minutes.

What I have seen too often is that the needle is withdrawn and almost immediately a Band-Aidtm is applied to cover the venipuncture site. No mention is made for the patient to apply pressure for at least 3-4 minutes. It is as if the covering of the needle exit site with a Band-Aidtm will eliminate the chance of bleeding after venipuncture. Too often, the patient is left with blood on his clothing, a hematoma at the site of the venipuncture, possible loss of use of that vein, and emotional stress the next time he has blood drawn. These two interactions are very simple, yet often poorly done.

(3) TRUSP (transrectal ultrasound of the prostate) with biopsies: The procedure should be discussed in advance with the patient and his partner. The importance of avoiding drugs such as aspirin and NSAIDs for at least 10 days prior to prostate biopsies should be mentioned. Given the commonality of bleeding into the prostate and blood in the urine or semen after TRUSP with biopsies,274,275 I believe it would be reasonable for physicians to do an in-office template bleeding time (TBT). This is a cheap and easy test to rule out a drug effect on the platelets that would be associated with an increased risk for prolonged bleeding after multiple biopsies.

The Surgicutt TBT normal range is less than 9 minutes. Surgicutt is available through ITC, Inc. at www.itcmed.com. The U.S. customer service number is (800) 631-5945. Secondly, a urologist or other physician planning to do the biopsies should, as a matter of routine, check the patient's CBC (complete blood count), absolute platelet count, PT (prothrombin time), and the APTT (activated partial thromboplastin time). If the platelet count is normal (over 150,000) and the PT, PTT, and TBT are all within normal limits, then any potential risk for significant hemorrhage from TRUSP with biopsies as a result of a blood-related problem(s) would be excluded.

If bleeding is persistent after TRUSP with biopsies, Proscar at a dose of 5 mg a day should be considered. Even in the face of coagulation abnormalities, as mentioned above, a report by Kearney et al. showed a marked decrease in gross bleeding (hematuria) with the use of Proscar. Note that this study involved men with BPH and the bleeding that occurred was unrelated to prostate biopsies.276 Critical to the results of this study are additional reports indicating the key role that androgens such as testosterone and dihydrotestosterone (DHT) play in increasing VEGF.218,240,277 It should come as no surprise that Proscar and/or other inhibitors of DHT formation would have the ability to decrease bleeding due to the hypervascularity of tissue known to occur in BPH and in PC.278

As part of the supportive care of the patient, physicians should employ such pharmacologic strategies in patients with persistent bleeding after TRUSP with biopsies. This intervention would take into account that the use of drugs such as Proscar or other 5-alpha-reductase inhibitors such as Avodart® (dutasteride) are effective at reducing angiogenesis by virtue of decreasing VEGF within prostatic tissue.

Additionally, other studies in breast cancer patients have shown that the COX-2 enzyme is up-regulated in breast cancer tissue and that this is associated with an increase in tumor blood vessels (microvessel density) and VEGF.279 We know that many PC patients will also have over-expression of COX-2 and this should suggest treatment by COX-2 inhibition, be it via dietary manipulation or by drugs. Therefore, in the management of persistent bleeding from prostate tissue or any tissue that may have an increase in blood vessels due to the activation of the COX-2 ? VEGF ? angiogenesis pathway, these measures are reasonable options to discuss with your physicians.

Not only is the bleeding complication of biopsy traumatic for the patient, but it also interferes with the interpretation of other investigational studies due to the effects of hemorrhage within the prostate. For example, if PC is diagnosed and an endorectal MRI is suggested for evaluation, the occurrence of any significant intraprostatic bleeding will complicate the interpretation of the MRI because cancer and hemorrhages both demonstrate the same low signal intensity.280 It will take a minimum of 8 weeks for the postbiopsy hemorrhage to clear sufficiently to allow the endorectal MRI to be done under optimal conditions.

The patient's preparation for the TRUSP with biopsies should include a 1-day course of prophylactic antibiotics (Cipro, Floxin, or Levaquin) and a Fleet's enema to clear the rectal chamber.281-283

The patient should receive some type of pain medication prior to the actual biopsies.284,285 It is amazing that a dentist will routinely give Novocain to fix dental cavities, but men going through 6-13 biopsies of their prostate gland have been offered local analgesia only for the last 5-6 years. Studies showing efficacy in reducing pain from the biopsy procedure have utilized injections of lidocaine (1%) into the tissue surrounding the prostate285-288 or have used lidocaine gel (2%) as a lubricant for the insertion of the transrectal probe in order to provide analgesia during the biopsy procedure.289,290 It is sad testimony that such studies were not done 10-15 years ago and that currently less than 50% of patients undergoing biopsy are offered periprostatic analgesia or some other approach to lessen their pain.281,291,292

Although not as distressing to the patient as a TRUSP with biopsies, the use of an endorectal probe during an endorectal MRI study can cause discomfort and pain. All along the road of diagnosis, evaluation, and management, the caring physician should be sensitive to any emotional or physical misery the man with PC may encounter. The road should be smoothed and the journey thus made easier. Insertion of an endorectal probe and inflation of the balloon surrounding the probe can be an unpleasant surprise. I have heard this from many men caught unaware. It is very simple to inform a patient who is planning this procedure about the possible discomfort and to propose workarounds.

Perhaps a complete liquid diet the day before and a Fleet's enema until clear on the morning of the endorectal MRI will lessen the discomfort because the rectal vault will be empty. The patient's primary physician may also prescribe Valium 5 mg and Vicodin ES, with 1 tablet of each medication to be taken about 30 minutes prior to the procedure. If the patient has not had prior experience with these drugs, his physician could prescribe a few extra tablets of each so that the patient can experience how he feels after taking this combination. Of course, the patient should not consume alcoholic beverages or drive when these drugs are taken. This kind of approach can change the patient's experience from one characterized by anxiety and pain to one of assuredness and acceptable discomfort.

(4) LUTS (lower urinary tract symptoms): In the course of the above evaluations leading to a diagnosis of PC, it is not uncommon for the physician to encounter men having problems with LUTS. Symptoms relating to slowness of urinary stream, difficulty in initiating urination, intermittent flow of the stream, dribbling of urine near the end of urination, getting up at night to urinate (nocturia), and other symptoms are cataloged objectively by the AUA symptom index score. This is described in detail in Appendix F (Forms) of the Primer.

Out of these problems come opportunities for the physician focused on supportive care. He can not only lessen the problems caused by LUTS, but also implement a pharmacological strategy that has an anti-PC effect. The efficacy of multitasking relates to the fact that, more often than not, our therapies, if chosen carefully, can elicit multiple benefits. Clearly, if LUTS is treated with finasteride (Proscar), we also are initiating the following biochemical effects:

Inhibition of 5-alpha-reductase Type II, blocking conversion of testosterone to DHT
Reduction in epidermal growth factor (EGF), especially in the periurethral zone293
Reduction in both glandular and stromal elements within the prostate gland294
Decrease in VEGF
Decrease in microvessel density
Decreased expression of basic fibroblast growth factor (bFGF)295
Down-regulation of androgen receptor (AR) expression296
Decrease in IGF-1 gene expression in BPH patients35
Increased programmed cell death of PC epithelial cells297
To add compliment to benefit, agents (alpha-1-blockers) that improve urine flow by affecting periurethral smooth muscle have been shown to be synergistic with Proscar in causing prostate cell apoptosis.297 These effects are not restricted to the benign prostate cell population of BPH, but are also operative in PC. In the study by Glassman et al., terazosin (Hytrin), an alpha-1-blocker used in treating LUTS, was shown to cause apoptosis of prostate cells and to be synergistic with Proscar. In our supportive care of PC patients, we can choose drugs that have multiple modes of biological action and by doing so improve the outcome for our patients. In other words, we can treat LUTS and improve the quality of life for men with these symptoms, while at the same time having a beneficial effect against PC.

Table 17 lists some of the literature citing activity of alpha-1-adrenoreceptor blocking agents in causing programmed cell death to prostate cells, both benign and malignant. Of the alpha-1-blockers used in the United States today to treat LUTS, two are in the piperazinyl quinazoline class. These are Hytrin (terazosin) and Cardura (doxazosin). These agents cause apoptosis of PC cells. The third agent, Flomax (tamsulosin), an alpha-1-blocker in the sulphonamide class, does not have the apoptotic effects of either Hytrin or Cardura.

Drugs Normally Used to Treat LUTS May Cause Apoptosis and Have Other Effects against Androgen Independent PC (AIPC)

This table highlights how a physician utilizing the multi-tasking effects of drugs currently in use can enhance the supportive care of men with PC. These findings also suggest a possible role for these agents in the prevention of PC.


A)Study Drug(s) -Hytrin
Cell Population -BPH
Biologic Effect(s) -Apoptosis increased
AuthorGlassman
Reference 297

B)Study Drug(s) -Hytrin
Cell Population -BPH with PC
Biologic Effect(s)- Apoptosis increased; microvessel density (MVD) decreased; PSA expression in tissue decreased; VEGF unchanged
Author-Kaledjian
Reference241

C)Study Drug(s) -Cardura
Cell Population -PC (AIPC)
Biologic Effect(s)- Apoptosis increased via bcl-2 down-regulation
Author-Ng
Reference-298

D)Study Drug(s)-Both drugs
Cell Population -BPH
Biologic Effect(s) -Apoptosis in epithelial and stromal cells; smooth muscle alpha-actin expression decreased
Author-Chon
Reference-299

E)Study Drug(s) -Both drugs
Cell Population -PC (AIPC)
Biologic Effect(s) -Apoptosis of PC cells increased independently of alpha-1 blockade
Author-Benning
Reference-300

F)Study Drug(s) -Both drugs
Cell Population -BPH and PC
Biologic Effect(s) -Apoptosis increased in dose-dependent manner
Author-Kyprioanou
Reference-301

G)Study Drug(s) -Both drugs
Cell Population -PC (AIPC)
Biologic Effect(s) -Apoptosis synergistic with radiation therapy (RT) when Hytrin or Cardura given prior to or after RT; BAX or caspase-3 not increased
AuthorCuellar
Reference-302

LUTS also has another potential role in the supportive care interactions between PC patients and their physicians--the choice of the primary PC treatment. The currently accepted choices of primary therapy include:

a)RP
b)RT of any kind, such as

3D-conformal RT,

1)Conventional brachytherapy,
2)High-dose rate brachytherapy,
3)Proton beam RT,

Neutron beam RT;

1)Cryosurgery;
2)ADT;
3)Watchful waiting.

In the setting of significant lower urinary tract symptoms that are not responsive to available therapies, RP, done by a surgeon, will resolve the issue of LUTS. In contrast, RT will usually aggravate LUTS and not occasionally cause problems with urinary retention necessitating TURP (transurethral resection of the prostate). What an RP accomplishes in this respect is the removal of the prostatic urethra--the site of compression by tissue of the transition zone of the prostate. The transition zone is the portion of the zonal anatomy of the prostate gland that is significantly increased in men with BPH, a problem that commonly occurs in association with PC (see Figure 4).

It is reasonable to consider, in this respect, the use of ADT3, which combines an LHRH-agonist agent such as Lupron, Zoladex, Trelstar LA, or Viadur with an antiandrogen such as Eulexin, Casodex, or Nilandron and a 5-alpha reductase inhibitor such as Proscar or Avodart, as well as an alpha-1 blocker in light of the data presented in Table 17. If the ADT3 plus alpha-1-blocker is given with other supportive care measures, the patient has numerous ways to use this therapy with both therapeutic and prognostic strategies. This is especially true in men not physically fit enough to undergo an RP or in those with risk factors that would suggest that RP is not likely to be curative. This will be discussed in a later section.


Evaluation
(5) Choice of Diagnostic Studies to Evaluate Stage in Newly Diagnosed Men with PC: Supportive care of the patient also involves a physician knowledgeable enough about PC to know when not to use healthcare dollars in ordering tests of negligible yield in the workup of a PC patient. This decreases the costs to patients, minimizes exposure to ionizing radiation, and reduces the workload on healthcare personnel when tests inappropriate to the patient's biological status are not needed.

This is especially true for CT scans of the pelvis and abdomen. Such studies done shortly after diagnosis are rarely abnormal. Eliminating such expensive procedures could better direct medical funds to more productive testing or treatment. In newly diagnosed PC patients with Gleason scores of less than (4,3)--validated by an expert laboratory or pathologist--a CT scan is not indicated unless the PSA exceeds 20 ng/mL. In a study of 425 PC patients, the authors concluded that in asymptomatic patients with newly diagnosed, untreated prostate cancer and serum PSA levels of less than 20 ng/mL, the likelihood of positive findings on abdominal/pelvic CT is extremely low (< 1.0%).303

Implications of Misuse of Staging Studies in Newly Diagnosed PC Patients with a PSA of < or = 10 ng/mL or < or = 20 ng/mL.
Most newly diagnosed patients with PC are subjected to a bone scan as well as CT scans of the pelvis and abdomen and some patients are also advised to have a conventional pelvic MRI. The healthcare waste in the setting of a newly diagnosed patient having a validated Gleason score of less than (4,3), and a PSA of < or = 10 ng/mL (bone scanning) or < or = 20 ng/mL (CT pelvis, abdomen, MRI pelvis), misdirects money and effort away from a rational strategy that could offer far more guidance to the PC survivor, his partner, and his physician.

A)Diagnostic Test -Bone scan
Setting -PSA = 10 ng/mL
Yield -0.3-0.5% abnormal (1 in 200-333)
Suggestions/Ramifications-Forego bone scan; savings of $76 million a year in the United States

B)Diagnostic TestCT scan of pelvis
Setting -PSA = 20 ng/mL
Yield -< 1% (< 1 in 100)
Suggestions/Ramifications-Forego CT pelvis exam; savings of $108 million a year in the United States

C)Diagnostic Test-CT scan of abdomen
Setting-PSA = 20 ng/mL
Yield -< 1% (< 1 in 100)
Suggestions/Ramifications-Forego CT abdominal exam; savings of $108 million a year in the United States

D)Diagnostic Test-MRI pelvis
Setting-PSA = 20 ng/ml
Yield-0.6% (1 in 150)
Suggestions/Ramifications-Forego MRI pelvis; savings of $160 million a year in the United States

E) Total Savings of $300-400 million each year!