~Prostate Cancer, part 7 - The Pros and Cons of Treatment Options

Knowing Pros and Cons of Weaponry:
Understanding Pros and Cons of Treatment Options

  • Age
  • Overall Medical Status
  • Patient Priorities
  • Access to Artists in the Selected Modality of Therapy
  • Financial and Insurance Issues
  • Lower Urinary Tract Symptoms at the Time of Diagnosis
  • Prostate Gland Volume
  • History of Scar Formation (Keloids) after Any Prior Surgery
  • Baseline PAP
  • Baseline Plasma TGF-b1, IL-6, and IL-6 Soluble Receptor Levels
  • PSA Response to ADT after 3 Months of Therapy

In winning a military battle, an understanding of the appropriate strategy for the situation at hand is critical for success. Military tactics, including the weapons used, must be matched intelligently to the circumstances that are present. The same is true for the management of PC and other illnesses. The most important aspect of this match is the realization that a local treatment will have its greatest chance of being curative if the biological expressions of disease suggest that it is likely that only local disease is present. Therefore, obtaining as many insights as possible into what constitutes a high probability of OCD is warranted.

The preceding sections have laid the groundwork, the reconnaissance so to speak, for the gathering of that information. The medical strategist takes these variables into account and builds a case for or against local therapy. The major algorithms such as the Partin 2001 Tables 157 and the nomograms from Kattan et al., 162-164 D'Amico et al., 76,158 Narayan et al., 73 Bluestein et al.,165 Gilliland et al., 166 Lerner et al., 167 Pisansky et al.,168 and others 72, 109, 154, 159, 160, 169-180 should be used. These only take minutes to do and there is little to lose in seeing if a consensus is present for organ-confined disease.

If an assumption is made that a patient has a high probability of organ-confined disease and that there are no medical issues or financial issues that preclude any particular choice of local procedure to cure PC, the $64,000 question is this: "What procedure has the best track record?" Certainly, given the many publications on this subject over the last few years, one would have to state that overall there is no striking difference in success rates between any of the local therapies for PC--RP, RT of any type, or cryosurgery.181-183 The longest follow-up period after definitive local therapy relates to RP. However, it appears unlikely that the 10- and 11-year data following RT are going to suddenly deteriorate or that the 15-year data after RP are going to change. The follow-up data after cryosurgery are at most 10 years old with most of the modern-day approaches to this technique beginning in 1992 with the work of Onik and Cohen et al.184,185 The cryosurgery literature is more difficult to evaluate because in the last 10 years there have been major technological advances. These include the following:

  • The use of temperature monitoring using thermo-couples143,186,187
  • The use of double and triple freezing techniques143,186
  • The use of Argon gas188-190 instead of liquid nitrogen to induce the freezing necessary for creation of the iceball
  • The recent use of templates to guide the placement of the cryosurgery probes, similar to those used in brachytherapy191

The issue then is which of these local therapies, if any, does the patient choose. Assuming that the patient at risk is not a candidate for watchful waiting (objectified ongoing observation), any of these therapies might be a perfectly reasonable strategy to eradicate organ-confined or regionally confined PC. My recommendations to patients on this matter are based on the following differential factors:

  • Age
  • Overall medical status after a detailed examination
  • Patient priorities
  • Patient access to artists in the selected modality of therapy
  • Financial and insurance issues
  • Lower urinary tract symptoms (LUTS) at the time of diagnosis
  • Prostate gland volume
  • History of scar formation (keloids) after any prior surgery
  • Baseline PAP
  • Baseline plasma TGF-b1, IL-6, and IL-6 soluble receptor levels
  • PSA response to ADT (androgen deprivation therapy) after 3 months of therapy

In essence, a combined modality analysis of sorts is being employed. This involves variables that have not been interactively evaluated as part of an effort to define the best local therapy for an individual patient. Hopefully, a true nomogram or artificial neural net (ANN) looking at such additional variables can validate their significance for such an analysis.

A short review of each of these topics is justifiable for this section.

Age. Traditionally, patients beyond age 70 are excluded as being candidates for RP. I believe that this decision should be individualized based on the patient's health, youthfulness for his age, and the other listed factors rather than using age as an arbitrary reason for excluding a patient. I have evaluated some men in their 50s who are much older in appearance and in biological status than their stated age. I have seen others in their late 70s who appear to be in their early 60s and who are healthier on examination than men in their 60s.

Overall Medical Status after Detailed Examination. This has been alluded to in the section on medical record-keeping and the use of summary and/or surveillance forms. Patients being considered for any invasive procedure should have a thorough physical examination. Factors that place them at much higher risk for morbidity after RP, RT, or cryosurgery should be candidly discussed with the patient and his partner.192 Cardiovascular disease, Type II diabetes, kidney disease, hypertension, and neurodegenerative diseases should be red flags that an invasive procedure may be associated with greater adverse effects.192,193 The evaluation of the patient's cardiac status with triglyceride/HDL ratios194,195 as well as the conventional LDL and total cholesterol levels, the use of hypersensitive C-reactive protein,196-198 and homocysteine levels are reasonable to do in this setting (discussions of these topics can be found in several other protocols in this volume).

The use of fasting insulin levels and the ratio of AA to EPA may be an excellent screening tool to evaluate the overall health of a patient considering any of these procedures.199-202 In addition to a very thorough internal medicine history and physical examination, the studies that I have found particularly revealing include a stress echocardiogram with calculation of the ejection fraction and electron beam tomography with coronary artery calcium scoring.196

A significant factor in patients having problems with RP, RT, or cryosurgery is small vessel disease due to diabetes or hypertension. Diabetic patients represent a great challenge because of the prolonged delay in return of urinary function after any local therapy. Tissue healing is not optimal in such a setting.

Patient Priorities. The patient's inclinations toward a particular therapy are often a product of decades of programming that will not be undone in a course of weeks or even months. Some men are adamant about having surgery, while others are exactly the opposite. Some feel that RT is the choice for them, while others are more comfortable with freezing. The poet Robert Frost may have encountered this same problem and reflected upon it in "Fire and Ice:"203

There are those patients who cannot decide between fire (RT), ice (cryosurgery), or surgery and who instead pursue objectified ongoing observation.

Patient Access to Artists in the Selected Modality of Therapy. I have no issues with any decision that a patient and his partner make if it has reasonable backing with biological data and the ability to involve physicians with gifted technical skills, that is, artists. I do not necessarily equate artists with members of an academic institution. Instead, this is a very individualized gift that involves technical skills combined with insightful preoperative and postoperative manifestations of caring. Patients should interact with their fellow patients at support groups, asking about the details of experiences with local physicians in these fields. Patients and their partners should explore the Internet, looking for any listings of physicians considered to be outstanding in their skills.

Moreover, patients and their partners should have a formal consultation with the physician(s) that they are considering to see if there is rapport between all three parties and to witness the interaction of the physician with other patients in his or her medical office. The physician should be asked for names of patients who are willing to be telephoned by you and/or your partner. These should be patients who have undergone the procedure within the last year or two. Obtaining three such names would be appropriate--perhaps one that had the procedure 6 months ago, another who had the procedure 12 months ago, and a third who had it 1 1/2-2 years ago. You should not be embarrassed to ask the physician about his success rate or about the incidence rates of complications his patients have experienced. These should be his figures and not those cited in someone else's series of patients.

Financial and Insurance Issues. The choices being made are quality-of-life decisions that also can affect quantity of life. Some patients may elect to stay within their medical insurance plans and feel that this is adequate for them. I believe that as long as the patient and his partner are aware of the issues in this entire process, they have the right to do as they wish. As one physician I know says, "Everyone has the right to make their own wrong decisions."

Lower Urinary Tract Symptoms (LUTS) at the Time of Diagnosis. LUTS will often adversely affect the quality of life of a patient undergoing RT of any kind or cryosurgery. The physiological interaction is likely related to radiation urethritis due to RT or thermal (cold) injury to the urethra from cryosurgery.

LUTS can be quantified with the AUA symptom index score.84,204 Patients should consider scores of 10 and higher as a relative negative risk factor in choosing RT or cryosurgery as a local therapy. A more powerful argument can be made for baseline AUA scores of 15 to 20 and higher. A relatively recent study used a combined modality assessment to determine what findings are most significant for predicting bladder outflow obstruction. A combination of an AUA symptom index of greater than 20, a prostate gland volume of 40 grams or more, and a urine flow of 10 mL or less per second, when present, predicted for obstruction 100% of the time.86 Urine flow rate was determined using uroflowmetry.

The prophylactic and long-term use of alpha blockers (Flomax, Cardura, or Hytrin) to reduce LUTS prior to, during, and after brachytherapy has been reported to reduce the time to return to baseline urinary function.84

Prostate Gland Volume. Often, but not invariably, men with LUTS will have prostate gland enlargement due to BPH. The large gland volume is another confounding factor affecting potential radiation or cryotherapy-related injury to the urethra, rectum, and bladder. Options for the patient in such a situation include the use of ADT to reduce the gland size prior to local therapy. Usually, within 3 months of starting ADT, the gland volume will be reduced by as much as 40%. After 6 months of ADT, the gland volume may be reduced 60% or more from baseline. The proper use of ADT with monitoring of the serum testosterone using the goal of less than 20 ng/dL may be a factor in why some men have dramatic reductions in gland size with ADT and others do not. The use of three-drug ADT involving an anti-androgen plus Proscar or possibly another 5-alpha reductase inhibitor Avodart (dutasteride) in conjunction with an LHRH-agonist like Lupron, Zoladex, or Trelstar LA has provided me with excellent results in both prostate cancer reduction and prostate gland volume reduction.

In men who are reluctant to receive ADT and/or do not have a dramatic response to alpha-1-blockers, choosing an RP is an excellent way to eliminate LUTS and restore urinary function to a high level. The urologist is essentially providing the patient with a new urethra, without the adverse effect of compression of the urethra by an enlarged prostate. Urinary flow in such patients is restored to that of a young man. This presumes that the operating urologist is skilled in the RP procedure and has an impeccable track record with a complication rate for gross incontinence at less than 2%, but total continence rates in the order of 92-95% with no need for protective pads of any kind, and anastomotic stricture rates that are less than 5%.

History of Scar Formation (Keloids) after Any Prior Surgery. If we could identify patients most likely to develop complications, we could direct them to other therapeutic strategies. An investigation that comes close to this was done by Park et al.205 This study correlates the probability of developing a narrowing or stricture after RP to a patient history of excessive scar formation from the actual RP or evidence of such scarring in prior surgical procedures. This study spanned a 5-year period and involved 753 radical retropubic prostatectomies performed by a single surgeon. The overall incidence of stricture at the anastomosis or connection of the bladder neck and distal urethra (anastomotic stricture) was 4.8%. The only significant finding that predicted the development of such a stricture was the maximal width of the abdominal scar resulting from the skin incision made at the time of RP.

In other words, the patient's reaction to surgery at a skin level was reflected in the tissue healing at the site of union (anastomosis) between the bladder neck and membranous urethra joined together after the excision of the prostate and prostatic urethra. Men with a maximal scar of greater than 10 millimeters (mm) were 8 times more likely to develop strictures than men with smaller scars. The percentage of men who required protective pads 1 year following radical retropubic prostatectomy in the stricture group was 46.2%, while the figure for those without a stricture was 12.5%.

The authors of this study speculated that prior history of excessive scar formation may have implications in the adverse outcomes of other surgical procedures such as coronary bypass grafts, angioplasties, bile duct operations, etc. This is highly provocative, and the potential implication is that a history of excessive scar formation after any of the latter procedures may be a warning for those men considering a RP as a possible choice of local therapy.

Baseline PAP

The importance of the baseline PAP blood level has been published in three major papers.74,75,206 The routine use of the PAP as part of our understanding of the biology of PC, its relation to the tumor cell population, and the probability of disease progression after RP or RT (with or without seed implantation) appears to be justified.

Baseline Plasma TGF-b1, IL-6, and IL-6 Soluble Receptor Levels

Molecular biomarkers relate the mechanisms of biologic behavior, function, and cell-to-cell interaction that add to the profile of the PC cell population. This has been known for PAP and PSA as well as CGA (chromogranin A) and NSE (neuron-specific enolase). Many physicians, however, are not aware of the functionality of biomarkers. For example, PSA has major activity as an enzyme--a kallikrein-like serine protease to be exact. PSA is a normal component of the seminal fluid component of the ejaculate and helps to keep the ejaculate liquid. However, as stated earlier, everything in life is a two-edged sword.

PSA produced from malignant prostate cells functions to break down specific proteins. These glycoproteins are found within the basement membrane of the microscopic glandular architecture. Simply, they are the ground substance to which the basal cells of the prostate glands are anchored. PSA degrades these proteins (fibronectin and laminin) and facilitates invasion by the PC cells. Thus, PSA made by the PC cell population is not only a biomarker of disease activity, but also a functional protein that is important to the survival of the cancer cell. Reducing PSA is therefore not only a good sign that a therapy is working, but also that one is reducing a substance that facilitates spread of the disease.207 In another publication, PSA was shown to suppress T-cell mediated immunity.208 This functional activity of PSA may be mediated by TGF-b1 production from the prostate cell.209

That cell products that we simply identify as biomarkers may have function appears to be the case for virtually every cell product identified. These products are not there just for some laboratory scientist to discover and turn into a laboratory test. They have function as well as form. Another enzyme produced by both benign and malignant prostate cells is uPA. uPA was discussed earlier in this review (see the section on General Preventive Measures). uPA is stimulated by IGF-1 and inhibited by GLA and EPA. uPA is believed to play a key mechanistic role in PC invasion and metastasis.210

TGF-b1 is a growth factor produced by the prostate cell as well as by cells of the bone matrix. Interleukin-6 (IL-6) is a cell product, or cytokine, that is made essentially by the primary tumor as well as by osteoblasts. IL-6 facilitates bone resorption by acting on IL-6 receptors located on the osteoclast and osteoclast precursor cells. Studies recently published by Shariat et al. show a very strong positive correlation between higher plasma levels of pre-RP TGF-b1 and findings at RP of ECE (extracapsular extension), seminal vesicle involvement, and lymph node involvement.211 In this study, preoperative plasma TGF-b1 median levels of approximately 15 ng/mL was significantly associated with lymph node and bone metastases. Healthy noncancer controls and men with RP findings not indicating extra-prostatic involvement had median levels of TGF-b1 of 4.7-4.8 ng/mL.

In a subsequent study involving 302 men with clinically localized PC, the same investigators evaluated preoperative and postoperative plasma TGF-b1 levels, and also IL-6 and its soluble receptor (IL-6sR), to determine correlations with disease progression. Of the study participants, 88.8% of the men had PSA progression-free survival at 3 years and 85.1% remained progression-free at 5 years post-RP. Cancer progression occurred in 43 of the 302 men (14%), with average postoperative follow-up of 50.7 months. Of the 43 men with PC progression, 19 were categorized as having nonaggressive progression postoperatively because they had complete responses to salvage RT or because their PSA doubling times postoperatively were equal to or greater than 10 months.

The remaining 24 men had aggressive progression because of positive lymph nodes found at RP (n = 6), because of positive metastatic workup on bone or ProstaScint scan (n = 6), because their PSA doubling times were less than 10 months (n = 23), or because they failed to respond to salvage RT (n = 14). What Shariat and colleagues found were significantly higher pre- and postoperative TGF-b1 levels and higher preoperative IL-6 and IL-6sR levels in men with "aggressive progression" versus those with "nonaggressive progression." These findings are summarized below.

Plasma TGF-b1, IL-6, and IL-6 Soluble Receptor Pre-RP and Post-RP

This battery of laboratory tests done on plasma can predict the findings at RP and also the patient's post-operative course. Modified from Shariat, S.F., Shalev, M., Menesses-Diaz, A. et al. J. Clin. Oncol.; 19: 2856-64, 2001.

Preoperative Test Findings   Positive (+) or Negative (-) Correlations at RP
TGF-b1   IL-6   IL-6sR   ECE   SV   GS   LTvol   LN
      -   -   +   +   -
      +   +   -   -   -
      +   +   +   +   +
Postoperative Test Findings   Correlations with Clinical Course Postoperatively
      Nonprogression of PC post-RP
      Progression of PC post-RP

Key: → not significantly elevated; ⇑ significantly elevated; ⇓ significantly decreased; ↔ no significant change; ECE = extracapsular extension; SV = seminal vesicle involvement; LN = lymph node involvement; GS = Gleason score at RP (+ = higher; - = lower); LTvol = local tumor volume (cancer within prostate gland).

This laboratory testing is allowing us to use the biology of the patient's tumor cell and host interaction to declare the probabilities of organ-confined disease versus nonorgan-confined disease. These findings are nicely in keeping with the Lerner algorithm from the Mayo Clinic in Rochester, MN. In that large-scale study, 904 men with apparently pathologically organ-confined PC were found to have PSA recurrences within 5 years based on the RP Gleason score, baseline PSA, and whether or not the PC at surgery had a normal DNA amount (diploidy) or abnormal amount (aneuploidy). Even in the best of circumstances, with baseline PSA values of less than 10 ng/mL, a Gleason score at RP of 6, and diploidy, the data still show a biochemical failure rate of 15% within the first 5 years. If the RP specimen was aneuploid, this increases the failure probability to 30%. It would be of interest to see whether the TGF-b1 status of the patient is independent of the ploidy status. Evolving algorithms using these kinds of inputs will clarify our recommendations to patients and their partners.

Continued . . .

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