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VOL. I Issue 3 2010
This issue focuses on:
Prostate Cancer
Current Statistics and Retrospective
Review of Prostate Cancer
By Julie Hetler, Cancer Registrar
Prostate cancer is the most common cancer diagnosed in men besides skin cancer1.
According to published data from the American Cancer Society (ACS) Cancer Facts
and Figures, in 2010 an estimated 217,730 U.S. males are expected to be diagnosed
with prostate cancer, which includes 4,160 in the state of Indiana. In addition, the ACS
reports an estimated 32,050 prostate cancer deaths in the U.S., including 620 estimated
prostate cancer deaths in Indiana, making prostate cancer the second most common
cause of cancer death (lung cancer death being most common).
The following is a retrospective review of published data, years 2002 – 2006, comparing
national, state and St. Joseph County incidence and mortality statistics2. As illustrated in
Figure 1, St. Joseph County incidence rate is significantly higher compared to Indiana,
but only slightly higher than the reported national rate. As expected with St. Joseph
County having a higher incidence rate, there is a higher mortality rate compared to
Indiana and national statistics as demonstrated in Figure 2.
Figure 1
Prostate Cancer Incidence 2002 – 2006
165
158.7
Rate per 100,000
160
In This Issue
Current Statistics and
Retrospective Review
of Prostate Cancer ....................1
Screening and Implications
of a Positive Biopsy...................2
Early Stage Prostate Cancer:
Surgery vs. Radiation................4
Systemic Therapy of
Prostate Adenocarcinoma........10
145
140.7
140
130
Figure 2
National
Indiana
St. Joseph County
Prostate Cancer Mortality 2002 – 2006
28
27.8
27.5
Rate per 100,000
Radiation Therapy Options in the
Treatment of Prostate Cancer....9
150
135
Surgical Options for Treatment of
Localized Prostate Cancer.........5
Side Effects of Radical
Prostatectomy...........................7
155
155.1
27
26.5
26.2
26
25.5
25.6
25
24.5
National
Indiana
St. Joseph County
The Stage of Disease at Diagnosis is an important prognostic indicator in making
treatment decisions and overall survival of the patient. As Figure 3 displays, St. Joseph
County and Indiana are seeing more local stage at diagnosis than any other stage of
disease. Of interest, St. Joseph County’s Unknown category is significantly higher
than the state. Unknown stages typically occur when there is not enough information
available to the Cancer Registry to stage the patient. Memorial Hospital’s Cancer Registry
data (2002 – 2006) show similar results to St. Joseph County and Indiana (Figure 4).
continued on page 2
Figure 3
100
Prostate Cancer Stage at Diagnosis
Years 2002 - 2006
107.3
105.2
80
60
40
16.1
20
0
Localized
500
Indiana
St. Joseph
Rate per 100,000
Rate per 100,000
120
Figure 4
27.3
14.4
Regional
8
14
7.1
Distant
Unknown
Memorial Hospital Prostate Cancer
Years 2002 - 2006, by SEER Stage
n=518
451
400
300
200
100
46
0
Localized
21
Regional
Distant
0
Unknown
Julie Hetler, CTR is the Manager
of the Memorial Cancer Registry.
Published data suggests prostate cancer is being diagnosed at
earlier stages due to results of Prostate-Specific Antigen (PSA)
test.1
Data Sources:
1 American Cancer Society, Facts and Figures 2010
2 National Program of Cancer Registry and Indiana State
Cancer Registry
Screening and Implications of a Positive Biopsy
By Philip DePauw, M.D.
Cancer of the prostate is disturbingly common – in America,
men have a 17 percent lifetime risk of being diagnosed with this
disease – but the lifetime cancer specific mortality risk is only
3 percent. And there lies the dilemma for patient and physician
alike. Should men be screened for prostate cancer and does
it help them to do so? While it seems intuitively obvious that
early diagnosis leads to better survival for cancer patients, this
has been difficult to prove. Prostate cancer is challenging, in
part because of the advanced age of many of these patients, the
frequently prolonged course of the disease and the presence
of multiple comorbidities. Two recent New England Journal
of Medicine articles looked at prostate cancer screening.
The American study showed no benefit while the European
study showed a 20 percent reduction in mortality. There were
problems in the U.S. study, in part because of the difficulty
finding men who had never had a PSA, and so most experts
support the notion that screening does provide a benefit. There
are a large number of studies that have shown downward stage
migration because of PSA testing leading to earlier diagnosis,
2
but these two are really the only good studies to address the
question of improved survival from screening.
The American Cancer Society and the American Urological
Association recommend that men get an annual digital rectal
exam and PSA test beginning at age 50. African-American
men and those men with a close relative with prostate cancer
are encouraged to have screening beginning at age 40. No
consensus has been reached regarding an upper age limit
when screening is no longer indicated. Several meta-analyses,
however, suggest that screening does not improve survival
in men who have a less than 50 percent, 10-year survival
probability. Government life table data suggest that white
American males over the age of 75 have less than a 50 percent
chance of living 10 years. Factors to be considered regarding
the decision to do a prostate biopsy include PSA level relative to
age-adjusted normals, the presence of an abnormal digital rectal
exam or the combination of these two. The risks of performing
a prostate ultrasound guided biopsy include gross hematuria
(is the patient on any anticoagulant and what is the risk of
stopping it long enough to permit biopsying the prostate, an
organ that is richly vascularized), urinary infection (there is a
0.5 percent risk of urinary sepsis despite quinolone antibiotic
coverage) and sampling error (only 75 percent of cancers are
found at any given biopsy session). PSA can be insensitive –
20 percent of men with prostate cancer have a normal PSA
– and nonspecific – only 1 out of 3 men with a PSA between
4 and 10 will be found to have prostate cancer. For example,
the PSA is usually elevated with acute bacterial prostatitis and
chronic low – grade prostatitis can also cause false elevation.
Since PSA is a protein produced by normal prostatic tissue,
significant benign enlargement can cause false PSA elevation
also. A significant amount of anxiety can be generated by
having an elevated PSA and the attendant worry about
possible cancer.
There is a new test, prostate cancer antigen 3, which is a
genetic biomarker that appears to be more sensitive and more
specific than PSA and has a high negative predictive value.
The test, however, requires collecting a urine sample after
prostatic massage and measuring messenger RNA. It remains
to be seen how PCA 3 will fit in the scheme of prostate cancer
screening if it becomes generally available.
If a prostate biopsy is positive, tests for metastases such as
CT scan of the pelvis and bone scan are indicated if the PSA
is greater than 10 or the cancer is poorly differentiated. PET
scans are not sensitive to prostate cancer and MRI testing
offers no advantage over CT scanning. The ProstaScint scan
measures isotopes tagged to prostate antibodies but is not
generally felt to be a reliable indicator of prostate cancer
metastases or their absence.
Ultimately, an extended conversation needs to be held
between the patient and his urologist regarding treatment
options once the diagnosis has been made. Factors to be
considered are the Gleason score (how well differentiated is
the histology of the cancer), the level of the PSA (the higher
the PSA, the greater the chances of metastases, gross or
microscopic) and the digital rectal findings. There are several
nomograms, most notably the Partin tables, that use these
three items to predict the extent of disease. The severity
and type of co-morbidities, life table estimates of patient life
expectancy, the ability to tolerate surgery or radiation and
the risk of adverse treatment-related side effects need to be
considered. Finally, the patient’s desires as to how aggressive
he wishes the physician to be in treating this cancer need to
be discussed.
Two of the less aggressive options available for consideration
in prostate cancer management are active surveillance and
watchful waiting (observation with delayed hormone therapy).
Active surveillance is a concept that implies careful
monitoring involving frequent PSA levels and periodic, often
yearly, repeat prostate biopsies. The ideal candidate has a
PSA less than 10, normal digital rectal exam, low-volume
disease and a moderate or well differentiated cancer with a
Gleason score of six or less. The concept involves delaying,
not avoiding, definitive therapy such as radiation or surgery
until progressive disease is documented. The benefit relates
to delaying treatment-related side effects such as impotence,
incontinence, radiation-induced cystitis or proctitis. The risk
is that of initial understaging or delaying therapy resulting in
incurable disease.
Observation/watchful waiting involves periodic monitoring
followed by hormone therapy at an appropriate clinical
moment in the course of the disease. The benefit relates to
the avoidance of surgery and radiation and their attendant
side effects. The downside relates to the fact that this is
not a cure for the disease, and eventual hormone therapy
has distinct side effects and will ultimately fail to control
the disease if the patient does not die of other causes. The
ideal patient for observation is older, has a moderate or well
differentiated cancer and multiple co-morbidities with a slow
PSA doubling time. Studies have looked at life expectancies
for these patients and can be used to help guide the clinician.
For instance, in the patient with a Gleason 6 or better
differentiated tumor, the likelihood of dying as a result of
other causes is twice the risk of dying of prostate cancer.
Ultimately the patient and the urologist need to evaluate all
treatment options that are available and reach an agreement
on a plan with which they are both comfortable.
Philip DePauw, M.D. is a Urologist
with Urology Associates of
South Bend.
3
Early Stage Prostate Cancer: Surgery vs. Radiation
By David Hornback, M.D.
One of the most difficult things a patient will have to deal with,
other than hearing he has prostate cancer, is deciding which
therapy he should receive. For patients who have early stage,
low-risk prostate cancer, those options range from no therapy
to prostatectomy, radioactive seed implant or eight weeks of
radiation therapy. Still other, less commonly used treatments
exist, including HDR brachytherapy, Cyberknife, and
cryotherapy. Patients frequently get overwhelmed with trying
to make a decision and may delay treatment for long periods
of time while they sort through all of these options. Most often,
the decision is boiled down to one basic question, “Is surgery
or radiation the best treatment option?”
For many years, surgery was considered the “gold standard”
therapy for prostate cancer. Patients who could not tolerate
surgery or had more advance disease were referred for a
radiation oncology consultation. Thus, the patient population
for surgery tended to consist of more early stage, low-risk
patients compared to patients who were receiving radiation.
While radiation was clearly effective in this group of patients
with intermediate-risk disease, retrospective comparisons of
radiation results with surgical results led us to believe radiation
was inferior to surgery. Additionally, previous techniques
of radiation planning and delivery were quite crude in
comparison to today’s approach. This resulted in higher rates
of bowel and bladder toxicities and deterred many low-risk
patients from considering this treatment.
With the widespread use of PSAs, fewer and fewer patients
presented with advanced-stage disease and many more men
were found to have low-risk disease. The additional advantage
of the PSA was to help categorize patients (along with the
Gleason score and stage) into low-, intermediate- or highrisk disease. As data began accumulating, we could stratify
patients based on disease risk and get better information on
comparisons between radiation and surgery. However, no
randomized trials have been completed to compare these two
modalities. The latest attempt of a prospective randomized
study was a collaboration between Canada and the U.S. called
the SPIRIT trial which was to randomize patients between
prostatectomy or interstitial radiotherapy (brachytherapy/
radioactive implant). This trial closed after only two years for
lack of accrual – fewer than 100 patients had been randomized.
Physician biases as well as patients’ desire to choose one or the
other of these therapies are blamed for the poor accrual.
4
Comparison between external beam radiation therapy (EBRT)
and surgery have been reported in retrospective trials such
as one from the Cleveland Clinic (Kupelian et al.1), which
reported 8-year outcomes for 1,054 prostatectomy patients
and 628 patients who received EBRT. Despite the fact that
there were younger and earlier stage patients with lower
pre-treatment PSAs in the surgery group, the PSA relapse-free
survival was 72 percent for surgical patients and 70 percent for
patients undergoing EBRT (p = .01). For sub-selected patients
who received > 72 Gy EBRT, their outcomes were similar to
prostatectomy patients (p = .08).
Other studies have published similar data supporting the
fact that low-risk patients who receive appropriate doses
of EBRT have equivalent outcomes compared to matched
patients undergoing prostatectomy. Surgical series from John’s
Hopkins, Baylor and MSKCC report that patients with low-risk
disease have 10-year PSA control rates of 80 – 90 percent after
prostatectomy, whereas other institutions (MSKCC, Fox Chase,
MD Anderson, etc.) reporting on results using modern EBRT
techniques and appropriate doses indicate almost identical PSA
control rates.
There is also an abundance of retrospective data supporting the
use of brachytherapy (radioactive implants). Single institution
studies with 10 to 12 year data confirm patients with low
risk prostate cancer who undergo brachytherapy alone or in
combination with external beam RT have PSA control rates in
the range of 85 – 90 percent, which is at least comparable to
the surgical series.
Based on this data, it appears that good quality radiation,
whether delivered as external beam treatments or as interstitial
implant is very likely equivalent to prostatectomy in terms
of recurrence or survival in the low-risk group. Additionally,
with improvements in treatments (IMRT, IGRT), the side effect
profile and long-term risks have been significantly reduced.
While bowel irritation is more prevalent with EBRT, urinary
irritation with brachytherapy and incontinence with surgery,
the rates of erectile dysfunction appear to be similar among
all three modalities. This is much more difficult to accurately
measure since many men undergoing these treatments are
already experiencing some degree of ED due to effects of
medications, age or other medical conditions. The reported
incidence of ED due to prostate cancer treatment is anywhere
from 25 to 80 percent with most studies in the 30 to 50
percent range. These numbers may decrease as more data is
collected on patients treated with modern techniques such as
IMRT and DaVinci Robotic-assisted prostatectomy.
Ultimately the decision between surgery and radiation is one
of personal preference. The factors that go into making that
decision are too long to list here, but at least patients should
be put at ease by understanding that no matter whether they
choose surgery or radiation, there is an excellent chance that
they will be alive, without evidence of PSA failure many years
after their treatment.
References:
1.Kupelian PA, Potters L, Khuntia D, et al. Radical
prostatectomy, external beam radiotherapy <72 Gy,
external beam radiotherapy > or = 72 Gy, permanent seed
implantation, or combined seeds/external beam radiotherapy
for stage T1-T2 prostate cancer. Int J Radiat Oncol Biol Phys
2004;58:25–33.
2.Perez and Brady’s Principles and Practice of Radiation
Oncology, 5th Edition, pp 1465 – 1472
3.JAMA 2009; 301 (20): 2141-2151; “Review of Prostate
Cancer Treatment”
David Hornback, M.D., is board
certified in Radiation Oncology
and is the medical director for the
Memorial Regional Cancer Center
in South Bend.
Surgical Options for Treatment of Localized Prostate Cancer
By William H. Stonehill, M.D., FACS
The treatment of localized prostate cancer is a complex and
controversial subject. This is mainly due to a lack of appropriate
studies, the slow growth of most prostate cancers and the
perception of significant side effects from its treatment, and
controversies over treatment efficacy in an older population.i
The standard treatment options include observation, radiation
therapy and surgical removal. Curative intent treatment is
indicated only for patients with clinically localized prostate
cancer with a minimum 10-year life expectancy.
under 65 years of age, with under 10 percent of those dying
at 10 years after surgery versus over 20 percent of those with
observation followed by hormone therapy.ii
The first prospective randomized multi-institutional study of
treatment effectiveness of prostate cancer was PIVOT (Prostate
cancer Intervention Versus Observation Trial). PIVOT started
in the early 1990s. I personally recruited two patients into the
study during residency. Unfortunately, very slow accrual, lead to
closure of the study prior to reaching its target. American men
are not very eager to allow randomization to surgery, radiation
or observation. The results from this study are still coming
in, but may not reach statistical significance. (A Swedish
prospective randomized multi-institutional study of surgery
versus observation reported in 2005 in the New England Journal
of Medicine showed after a median of 8.2 years of follow up,
8.6 percent death rate after surgery versus 14.4 percent after
observation in men averaging 65 years of age at enrollment.)
The death rate differential was more pronounced for those
The location of the prostate makes potency and urinary
continence significant concerns for men facing treatment.
As men age, their potency declines from a variety of causes.
The delicate erectile nerves touch the prostate. They are easily
damaged in response to radiation (40 percent rate of severe
erectile dysfunction at two years for 60-70 year old men) or
bilateral nerve sparing (30-40 percent rate of erectile dysfunction
unresponsive to Viagra for 60-70 year old men). These men can
still have orgasms, but have very little, or no, ejaculate.
The slow growth of prostate cancer complicates every study.
This increases costs and often makes results of published
studies of historic interest due to changes in therapeutic
techniques. The da Vinci system, for example, has been
available for fewer than ten years.
Urinary continence is affected by radiation, surgery and, over
time, by observation. A Swedish study shows that men have
more moderate to severe continence issues after surgery (27
percent) than observation (18 percent). This 18 percent rate
was noted to be higher than age matched controls. Thus, there
is contribution of continence issues by the tumor.
5
Radiation is historically known to cause radiation cystitis and
proctitis. The short-term incidence has decreased with current
IMRT, but can cause urgency and frequency of urination
which is bad enough to require long-term padding in fewer
than 2 percent. Even those who don’t need padding can have
significant quality of life issues over 10 or 15 years.
Table 1
Comparison of Open Radical Prostatectomies and
Robot-Assisted Laparoscopic Prostatectomiesv
This short discussion of side effects is in no way complete. The
quoted rates of impotence, incontinence and proctitis vary
widely, as do their definitions. The study that urologists prefer
to discuss involves quality of life scores in a non-randomized
group after five, 10, and 15 years. There was no evaluation
immediately after treatment; however, it would likely favored
radiation. At five years, no statistical difference was found. At 10
and 15 years, progressively higher quality of life was found for
the radical prostatectomy patients over the radiation patients.iii
Potency at one-two years with nerve sparing
Conversely, other studies show that quality of life scores are
noted to be slightly higher for T1c, low PSA, Gleason score 7
patients treated with radioactive seed implant monotherapy.iv
Interestingly, although no prospective randomized study results
have been reported, the cure rates for radiation and surgical
removal seem to be very similar.
There are three main methods of surgical removal of the
prostate for localized cancer:
1.Radical perineal prostatectomy (U-shaped incision between
the scrotum and anus).
2.Radical retropubic prostatectomy (6-inch incision in lower
midline abdomen).
3.da Vinci assisted laparoscopic prostatectomy (the newest
version which attempts to minimize side effects while
preserving effectiveness).
Unfortunately there are no prospective randomized studies to
compare these methods. The three most important outcomes
when compared show comparable results. As noted by the
last two lines of Table 1, comparing open with robotic-assisted
prostatectomies, surgeon volumes have been noted to be of
importance to results. The initial robotic-assisted protatectomy
studies show inflection points varying from 12 to 100 cases
in outcome quality.vi Better training techniques may have
decreased the number of cases required to develop proficiency,
but no mature pedagogical studies have been published. These
studies represent the pioneers at various institutions.
In spite of this mixed data, patients have flocked to the “new
and improved” robot assisted laparoscopic prostatectomy.
It is estimated that 60 percent of the 80,000 radical
6
Continence at one year
Open Radical Prostatectomy
91% - 98%
Robot-Assisted Laparoscopic Prostatectomy
86% - 98%
Open Radical Prostatectomy
68% - 90%
Robot-Assisted Laparoscopic Prostatectomy
68% - 84%
Positive surgical margin rate for pT2
Open Radical Prostatectomy
2% - 5%
Robot-Assisted Laparoscopic Prostatectomy
5% - 27%
Robot-Assisted Laparoscopic Prostatectomy
First 50 cases.
27%
Robot Assist Laparoscopic Prostatectomy
first 50 - 140 cases
5%
prostatectomies in 2009 were done with the da Vinci system,
and the United States is on the course for 80 percent of
90,000 in 2010. Marketing, patient perception and patient
results have driven this national trend.vii
What are the potential benefits that have driven this change?
1.Better vision with 5-15X magnification of the surgical field
2.Lower blood loss than traditional retropubic prostatectomies
3.Quicker recovery than traditional retropubic prostatectomies
4.Less pain
5.Less Scarring
Most of these studies have compared robot-assisted
laparoscopic prostatectomy with retropubic approaches. In
many respects, these benefits are similar to the results achieved
with perineal prostatectomies.
Traditional retropubic surgery involves a 6-inch abdominal
incision which is stretched open to allow access to the deep
pelvis. This can cause significant postoperative pain. Large
veins block access to the prostate and can cause bleeding. The
average blood loss has dropped from 1000 cc in traditional
surgery to less than 200 cc per case when the da Vinci is
employed. Foley catheters are used to reestablish continuity of
the urinary system. These stay in place for one or two weeks,
similar to traditional surgery. Patients, however, can usually go
back to work within a few days of surgery, or soon after their
catheter is removed.
Using the da Vinci system, a surgeon places five finger-sized
Trochar holes into the abdomen. One is for a camera. Three are
used to place surgical instruments controlled by the surgeon
who toggles the controls between these four arms. The fifth
Trochar is used by the surgical assistant to keep the operative
field clear, provide exposure and to pass sutures. The surgeon
then sits at a control station several feet away from the patient.
The system actually can be controlled remotely from several
thousand miles away!
iii
Lim, Quality of Life, Radical Prostatectomy vs Radiation
Therapy for Prostate Cancer. Journal of Urology 1995,
154:1420-1425
iv
A Prospective Quality of Life Study: Quality of Life After
Treatment. Journal of Urology, 2001.
v
Eastham, James A. Robotics: Long-Term Follow-up After
Surgery. Grand Rounds in Urology. June 2009, Volume 8.
Suppliment 1. 27-28.
One of my patients reported that he had talked with several
friends who had traditional prostatectomies. They reported
significant pain and long recovery times. He was happy to
report having used only two pain pills and resuming most
activities within two weeks.
vi
Hu, JD, da Vinci vs Open Prostatectomy, Journal of American
Medical Association, 302; 1557-1564.
vii
Weizer, Alon, et.al. Adoption of New Technology and
Heathcare Quality: Surgical Margins after Robotic
Prostatectomy. Journal of Urology 2007.03-004: 96-100.
In choosing the best method to remove a cancerous prostate, a
skilled surgeon performing an operation in which he or she is
skilled and has comfort is probably the best choice.
i
Klein, E.Is Prostate Cancer Over Treated? Grand Rounds
in Urology, Per-Anders, Abrahamsson, M.D., Ph.D., Vol 8
supplement 1, June 2009. Vol 8. Supp 1, 11-13.
ii
Bill-Axelson, et al. Radical prostatectomy versus watchful
waiting in early prostate cancer. New England Journal of
Medicine, 2005; 352: 1977-1984.
William H. Stonehill, M.D., FACS, is
a Urologist with Urology Associates of
South Bend.
Side Effects of Radical Prostatectomy
By Mark Toth, M.D.
Radical prostatectomy is a proven form of therapy for early
stage prostate cancer. The procedure involves removing the
entire prostate gland, including the prostatic portion of the
urethra and the attached seminal vesicles. There are various
surgical techniques used in performing radical prostatectomy.
The retropubic approach uses a lower abdominal incision
extending from the pubic bone to the umbilicus. A second
open surgical option uses a perineal approach with the incision
between the scrotum and anus. Radical prostatectomy can also
be performed laparoscopically and most recently by employing
the operative robot. All of the above procedures accomplish the
same surgical goal of removing the entire prostate gland and
carry similar operative risks and postoperative complications.
Radical prostatectomy is a major operation and is associated
with the usual operative risks of infection, including
UTI, bleeding which at times require transfusions, DVT,
postoperative pain and anesthesia complications. Mortality
rate is less than 0.1 percent. Rectal injury due to the close
anatomic relationship between the rectum and the posterior
prostate occurs in less than 2 percent of cases. Pelvic abscess
is also rare. A bladder neck contracture, caused by scarring
at the anastomosis of the bladder neck to the urethra, can
cause urinary retention and overflow incontinence. Effective
treatment is either dilatation or incision of the scarred area.
The two most common and distressing complications of a
radical prostatectomy are persistent urinary incontinence and
erectile dysfunction, which I will discuss separately.
7
There are various forms of urinary incontinence. I have
mentioned overflow incontinence. Urge incontinence,
the overwhelming urge to void with involuntary loss of
urine, is rare post prostatectomy and can be treated with
anticholinergic medication. By far, the most common type of
incontinence post prostatectomy is urinary stress incontinence
or the involuntary loss of urine with movement, exercise,
coughing, sneezing, etc. This is directly attributable to the
intimate anatomical relation between the male continence
mechanisms and the prostate. The bladder neck (the internal
sphincter) and membranous urethra (the external sphincter)
are the muscles that control male continence. The resection
margins during a radical prostatectomy are at the bladder neck
and membranous urethra, and the anastomosis is between
the bladder neck and membranous urethra. A catheter is
always left in place postoperatively to allow healing at the
anastomotic site. It is typically removed within the first few
postoperative weeks, and incontinence is common at the
time of the catheter removal. Urinary control is gradually
regained over the first few months, and the vast majority
of patients are either dry or have mild stress incontinence
not requiring protection or treatment. Some, however,
have either total urinary incontinence, or more typically,
significant stress incontinence requiring frequent pad changes.
Treatment consists of exercises to strengthen the pelvic floor
musculature, commonly known as Kegel exercises. These can
be helpful in mild forms of stress urinary incontinence (SUI).
A penile clamp can be worn externally but is cumbersome.
Collagen injection, used as a urethral bulking agent, is at times
effective, again in mild cases. Implantation of an artificial
urinary sphincter works well, but involves another surgical
procedure and the risk of prosthetic malfunction over time.
The most recent surgical procedure for treating SUI is the male
urethral sling, not unlike the sling procedures commonly used
for treatment of female SUI.
Erectile dysfunction, the inability to obtain an adequate
erection for sexual activity, is a common postoperative
problem. Again, this is due to the close anatomical relation
between the pelvic nerves controlling erection and the
8
prostate. A nerve sparing radical prostatectomy, when the
surgeon spares the pelvic nerves running along the side of
the prostate, can be done either unilaterally or bilaterally, if
at all, depending on the extent of cancer within the prostate.
The incidence of ED varies depending on the nerve sparing
status, the surgeon’s technical ability to perform a nerve
sparing procedure, the patient’s age and the patient’s erectile
function preoperatively. The incidence with a bilateral nerve
sparing procedure varies between 16-82 percent. The onset is
immediate but may return within the first postoperative year.
Treatment initially consists of oral therapy with either Viagra,
Levitra or Cialis. Response rate with bilateral nerve sparing
is 70 percent, 50 percent with unilateral nerve sparing and
15 percent with a non-nerve sparing procedure. A vacuum
erection device can be employed and is effective but somewhat
cumbersome. Intracavernosal injection therapy, the injection
of vaso-active medications into the side of the penis, works
well in 85 percent of patients. Implantation of either a semirigid or inflatable penile prosthesis is a surgical option that
works well.
In summary, removal of the entire prostate gland for cure of
prostatic carcinoma has inherent risks of postoperative erectile
dysfunction and urinary incontinence. Both conditions are
treatable as discussed above. In my experience, I have found
that most men remain satisfied over the years after radical
prostatectomy, albeit with typically non-bothersome SUI and
effectively treatable erectile dysfunction.
Mark Toth, M.D., is a Urologist
with the Memorial Medical Group.
Radiation Therapy Options in the Treatment of Prostate Cancer
By Samuel McGrath, M.D.
With an incidence of approximately 190,000 cases a year,
prostate cancer now accounts for roughly a quarter of
cancer diagnoses among men. The majority of patients now
presenting with prostate cancer have localized, curable
disease due in large part to the advent of PSA screening.
Definitive radiotherapeutic treatment options in this setting
are myriad and include external beam radiation therapy
(EBRT) as well as high-dose and low-dose rate brachytherapy.
The most common means of prostate radiation delivery in
the United States is external beam treatment employing a
three-dimensional conformal technique. Using CT images of
the patient in the treatment position, the patient’s prostate is
contoured and the radiation beam portal shape is matched
to the projected shape of the prostate. This conforms the
dose to the target while simultaneously minimizing dose to
the surrounding normal tissue structures. As dose escalation
is paramount in eradicating prostate cancer, utilization of a
second generation 3D-CRT technique, intensity modulated
radiation therapy (IMRT), is now the preferred means of
external beam delivery. IMRT facilitates dose escalation by
using sophisticated algorithms to adjust the intensity of
each beam, further minimizing irradiation of the rectum,
bladder, small intestine, penile bulb and femoral heads, and
significantly reducing both acute and chronic treatmentrelated toxicities.
Of utmost concern in an external beam approach is
localization of the prostate prior to treatment delivery. Simply
put, is the dose prescribed encompassing the intended
target? To account for this, a margin is added to compensate
for organ motion induced by bladder and rectal filling and
potential set up uncertainty. Margins are often non-uniform,
with expansions limited posteriorly to decrease rectal dose.
Standard practice is to minimize this variation by employing
image guidance in the form of implanted fiducial markers or
electromagnetic transponders, cone beam CT imaging with
on or offline adaptive strategies, and B-mode acquisition and
targeting ultrasound.
A viable alternative to EBRT is a brachytherapeutic approach.
Candidacy for such treatment is predicated on minimal
obstructive symptomatology at baseline and requires
transrectal ultrasound evaluation in the lithotomy position,
examining such factors as glandular volume, median lobe
prominence, urethral deviations/presence of TURP defects
and pubic arch separation. Indications for brachytherapy
as monotherapy include a Gleason score of 6 or less, PSA
<10 ng/ml and lobar involvement of less than one-half.
In some instances, individuals with unilateral Gleason 7
(3+4) adenocarcinoma may be eligible. Brachytherapy can
be incorporated as a boost treatment for those with more
advanced disease. With this approach, the external beam
phase of treatment is reduced to five weeks.
Prostate brachytherapy can be administered in either a
low-dose or high-dose rate fashion. Low-dose rate (LDR)
brachytherapy planning and delivery is generally a two-step
process. First, a volume study is performed as described
above. The prostate is contoured on the sonographic images
obtained and in turn, transferred to a computer with the
planning software. An optimized seed implantation pattern
is achieved offline, and the appropriate number of seeds
are ordered. The procedure is subsequently performed
several weeks later, with a one time implantation of either
Iodine-125 or Palladium-103 seeds. Patients are discharged
the same day with the necessary radiation precautions.
Post-implant dosimetry, with assessment of doses to critical
structures and the gland itself, is performed within 30 days
by means of CT imaging.
Arguably more labor intensive, but equally as efficacious,
is high-dose rate brachytherapy. With this approach,
afterloading catheters are inserted into the prostate via
a transperineal approach under ultrasound guidance.
Treatment planning is performed intraoperatively with
ultrasound images or following the procedure with CT. A
high dose afterloading unit employing Iridium-192 as the
single radioactive source is utilized to deliver radiation with
the treatment planning software optimizing the dwell time
and position along the length of the catheter. This allows for
a highly conformal dose distribution. Due to the differences
in radionuclide dose rate, treatment is administered in 2-4
fractions over a two-day period. The afterloading catheters
remain in place during this time (epidural is required).
While an overnight stay in the hospital and prolonged
immobilization are perceived limitations of this technique,
HDR brachytherapy results in less radiation exposure to
patient, family members and hospital personnel; eliminates
concern over seed migration; and reduces urinary toxicity.
Regardless of the patient’s risk stratification at presentation,
radiation therapy can be utilized as definitive therapy
for prostate cancer. With an array of advanced treatment
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planning and delivery techniques, patients can select a
treatment that is right for them without fear of compromising
their clinical outcomes. Furthermore, the emergence of
IMRT with image guidance and brachytherapy has resulted
in well tolerated toxicity profiles with minimal long term
symptomatology. Memorial Hospital of South Bend’s
Department of Radiation Oncology is proud to offer all of the
aforementioned treatment techniques and is committed to
continually delivering state of the art prostate care.
Samuel McGrath, M.D.,
is a Radiation Oncologist at
the Memorial Radiation
Oncology Center.
Systemic Therapy of Prostate Adenocarcinoma
By Rafat Ansari, M.D.
There is a reason to believe that metastatic cancer of the
prostate existed in prehistoric times since malignancy in
the bones has been found in ancient fossils. The systemic
treatment options for prostate adenocarcinoma are multiple.
1. Hormonal Management. It was the seminal work of Huggins
& Hodges in the 1940s that elucidated the relationship between
serum testosterone level and the growth of the prostatic tissue.
They were the first to definitely show that palliation could
be achieved with hormonal manipulation either by bilateral
orchiectomy or by oral administration of estrogen. At present,
there are five major methods of androgen deprivation.
A) Orchiectomy to remove the primary androgenic
producing organ.
B) Estrogen therapy to reduce Leutinizing Hormone (LH)
production.
C) Antiandrogen therapy directed primarily at the target
organs, that is prostate and metastatic sites.
D) Maximum androgen deprivation called MAD whereby
testicular androgen production is ablated and at the same
time, DHT (dihydrotestosterone) drive from the adrenal
is blocked at the receptor sites by antiandrogen.
E) Leutinizing Hormone Releasing Hormone (LHRH)
Agonistics are considered the standard of care in
hormone sensitive, locally advanced and metastatic
prostate adenocarcinoma despite barriers related to cost
and the treatment related adverse events.
In addition, there is much interest in the Gonadotropin
Releasing Hormone (GnRH) Antagonistics. This
investigational class of drugs, the newest option for medical
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castration, has the potential to revolutionize the modern
hormonal management of prostate cancer. Unlike LHRH
agonistics, GnRH antagonistics block GnRH receptors in the
pituitary, inducing a fast reduction of testosterone to castrated
levels without triggering testosterone flares.
Hormone therapy is used across the spectrum of prostate
cancer. In locally advanced disease, hormone therapy has
shown to provide a survival advantage as a neoadjuvant or
adjuvant treatment to radiation therapy in high-risk patients.
In stage T1 and T2 disease, hormone therapy is indicated in
symptomatic patients who need palliation of symptoms and
for whom curative treatment is not an option. The high-risk
patients with a T2c disease, higher Gleason score, higher PSA
levels, hormone therapy is also used to provide intermittent
androgenic blockade.
There are some controversies in the hormonal management of
prostate cancer:
1.Early versus delayed hormonal management for metastatic
prostate adenocarcinoma.
2.Intermittent therapy in a patient with metastatic prostate
adenocarcinoma.
These controversies need to be discussed with the treating
physician in a patient who is about to start the hormonal
therapy.
2. Skeletal Events in Prostate Adenocarcinoma. The
spectrum of the skeletal disease in prostate cancer ranges from
treatment related fractures in men with castrated sensitive nonmetastatic disease to skeletal complications in castrate-resistant
metastatic prostate cancer.
A. In 2002, there was a landmark study by Saad & Colleagues
where patients with prostate adenocarcinoma with bony
metastasis, asymptomatic or minimally symptomatic were
randomly assigned to treatment with zoledronic acid
4 mg/placebo. In a follow-up analysis, treatment with
zoledronic acid for up to 24 months resulted in a significant
36-percent reduction in the cumulative risk of skeletalrelated events, including radiation to bone, pathological
fracture, spinal cord compression, surgery to bone or
change in antineoplastic therapy compared to placebo.
The role of bisphosphonate in a castrate-sensitive disease
has not yet been established. A newer agent denosumab
is currently being evaluated for treatment of osteoporosis,
non-metastatic prostate adenocarcinoma and metastatic
bone disease. In a randomized double-blind multicenter
phase III study with approximately 1,900 men, denosumab
appears to be superior to bisphosphonate.
B. Prevention of Bone Metastasis. There are two ongoing
clinical trials which are evaluating the intervention of
preventing bone metastasis in men with prostate cancer.
The first is a randomized double-blind placebo controlled
multicenter phase III study enrolling approximately 1,500
men with castration-resistant prostate adenocarcinoma
with no bone metastasis and PSA levels over 8 ng/ml or a
PSA doubling time of less than 10 months. The patients
have been randomly assigned to monthly subcutaneous
treatments with denosumab 120 mg or placebo. The
primary endpoint of this study is bone metastasis freesurvival. Another European trial called ZEUS is a multicenter
randomized open level trial evaluating zoledronic acid for
prevention of bone metastasis in men with high-risk disease.
There will be 1,433 patients randomized.
3. Immunotherapy with Vaccines. Immunotherapy has the
opportunity to fill an important clinical gap in the treatment of
hormone refractory prostate cancer. The ideal immunotherapy
for prostate cancer would trigger an antigen cascade causing
T cells to target multiple different antigens on malignant
prostate cells. In prostate cancer, immunotherapy has been
used in combination with other anticancer agents including
cytokine, such as interferon as granulocyte macrophage
colonies stimulating factor, hormone therapy such as LHRH
agnostic, and monoclonal antibody such as Bevacizumab
targets vascular endothelial growth factors. Immunotherapy
may be particular effective in combination with chemotherapy.
Current vaccine strategies exploit features of immune system
to enhance the anticancer immune response. Therapeutic
vaccines currently under investigation in prostate cancer
include GVAX, ProstVAC-VF and Sipuleucel-T.
4. Chemotherapy (Antitubulin Therapy).
A.Two randomized phase III trials have shown that there is
a prolonged survival achieved with docetaxel in hormone
refractory prostate cancer. The TAX-327 trial in 1,006
patients with metastatic hormone refractory prostate cancer
showed that 75 mg/m2 of docetaxel every three weeks with
prednisone 10 mg p.o. daily produced superior survival
and improved rates of response in terms of pain, serum PSA
levels and quality of life with a P value of 0.009 and has
become the standard chemotherapy for hormone refractory
prostate adenocarcinoma.
B.There is a newly approved drug for hormone refractory
prostate cancer with previous exposure of Taxotere called
Jevtana (cabazitaxel).
C.Endothelin Receptor Antagonistic. Atrasentan is an
oral, highly potent selective ETA receptor antagonistic
that has half-life of 24 hours which permits once daily
administration. A phase III trial for management of prostate
cancer in a double blind placebo controlled MOO-211 trial
with 809 patients showed a significant reduction in disease
progression by 19 percent compared to placebo. A phase
III Southwest Oncology Group Trial SO421 which is just
completed with docetaxel 75 mg/m2 every three weeks
with Atrasentan/placebo 10 mg p.o. daily for management
of hormone refractory prostate adenocarcinoma. Seven
hundred patients have been entered on that trial. The
results are pending.
There are multiple other agents which are under investigation
for metastatic hormone refractory prostate adenocarcinoma
and those include small molecule tyrosine kinase inhibitor
such as Sutent, second-line chemotherapy agents such as
Epothilones, and XRP6258.
Rafat Ansari, M.D., is a Medical
Oncologist with Michiana
Hematology-Oncology, Medical
Director of Memorial Regional
Cancer Center and chairman
of the Memorial Oncology Care
Committee.
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615 N. Michigan St.
South Bend, Indiana 46601