Prostate Cancer-9

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

1)Fire and Ice
2)Some say the world will end in fire,
3)Some say in ice.
4)From what I've tasted of desire
5)I hold with those who favor fire.
6)But if I had to perish twice,
7)I think I know enough of hate
8)To say that for destruction ice
9)Is also great
10)And would suffice.

There are those patients who cannot decide between fire (RT), ice (cryosurgery), or surgery and who instead pursue objectified ongoing observation. But as my father used to tell me, "That's what makes horse racing."


Patient Access to Expertsin 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. 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.


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 (see Figure 5). 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 These papers are referenced in detail in the Primer. 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 identify as biomarkers may have function appears to be the case for virtually every cell product identified. 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. This incredible cascade was illustrated in Figure 1 of this chapter. 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 in Table 12.

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
TGF-b1 IL-6 IL-6sR
-> (++) (++)

Positive (+) or Negative (-) Correlations at RP

ECE SV GS LTvol LN
- - + + -
+ + - - -
+ + + + +

Postoperative Test Findings
TGF-b1 IL-6 IL-6sR 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.


PSA Response to ADT after 3 Months of Therapy

Michael Zelefsky of Memorial Sloan Kettering (New York City) a radiation oncologist, published a paper about the predictive value of the PSA after 3 months of ADT.212 The purpose of his study was to identify prognostic variables that predict for improved biochemical and local control outcomes in patients with localized PC who had been treated up-front with ADT, which was then followed by three-dimensional conformal radiotherapy (3D-CRT).

Between 1969-1995, 213 patients with apparently localized PC were treated with 3 months of ADT before 3D-CRT. The ADT consisted of leuprolide acetate and flutamide (ADT2). The purpose of ADT was to reduce the preradiotherapy target volume in order to decrease the dose delivered to adjacent normal tissues and minimize the risk of morbidity from high dose RT. The median pretreatment PSA level was 13.3 ng/mL (range of 1-360 ng/mL). The median 3D-CRT dose was 73.6 Gy (range of 64.8-81 Gy), and the median follow-up time was 3 years (range of 1-7 years).

The significant predictors for improved outcome identified by multivariate analysis included a pretreatment PSA level less than or equal to 10.0 ng/mL (p < 0.001), an ADT-induced preradiotherapy PSA nadir of less than or equal to 0.5 ng/mL (p < 0.001), and a clinical stage less than or equal to T2c (p < 0.04). The 5-year PSA relapse-free survival rates were 93%, 60%, and 40% for patients with pretreatment PSA levels less than or equal to 10 ng/mL, 10-20 ng/mL, and greater than 20 ng/mL, respectively (p < 0.001). Patients with preradiotherapy nadir levels after 3 months of ADT2 that were less than or equal to 0.5 ng/mL experienced a 5-year PSA relapse-free survival rate of 74%, as compared with 40% for patients with higher nadir levels (p < 0.001). The incidence of a positive biopsy among 34 patients pretreated with ADT was 12%, as compared with 39% for 117 patients treated with 3D-CRT alone who underwent a biopsy (p < 0.001).

Zelefsky and colleagues concluded that, in settings of PC treated with ADT2 and high dose 3D-CRT, pretreatment PSA, preradiotherapy PSA nadir response, and clinical stage are important predictors of biochemical outcome. Patients with PSA nadir levels greater than 0.5 ng/mL after 3 months of ADT2 are more likely to develop biochemical failure after radiotherapy and may benefit from more aggressive therapies. A summary of these findings is shown in Table 13.

What Zelefsky et al. have done is to use the biological response of the tumor to indirectly gain insight into the tumor biology in order to help assess the probability of successful outcomes with radiation therapy. A low probability of success should prompt the PPP team to discuss different treatment strategies.

The reduction of PSA to a lowest point or nadir is the same principle used in our study on intermittent androgen deprivation (IAD) to identify men with a high probability of PC that most likely reflects a homogeneous tumor cell population of androgen-dependent cancer cells.213 In our study, we used an ultrasensitive PSA and required a threshold of less than 0.05, 10 times more than the threshold of acceptability in the Zelefsky study. It is quite conceivable that the use of the PSA nadir is identifying a number of biological events that would equate with a better prognosis or response to therapy in general.

Relationship of Pretreatment PSA Levels and 5-Year Relapse-Free Survival in PC Patients Treated with ADT2 and High-Dose 3D-CRT According to Zelefsky et al.212

Prognostic Finding Five-year Relapse-Free Survival
PSA = 10 93%
PSA > 10 = 20 60%
PSA > 20 40%
PSA nadir = 0.5 after 3 m* 74%
PSA nadir >0.5 after 3 m* 40%

*After 3 months of neoadjuvant androgen deprivation with Flutamide, 250 mg every 8 hours, plus Lupron, 7.5 mg i.m. monthly. This is the PSA value after a full 3 months of ADT, i.e., the PSA taken just prior to starting the fourth injection of Lupron.