Interesting Paper found on Internet -(long)

PROSTATE CANCER:
FINDING A CURE, FINDING A HEALER
ALAN L. LASNOVER, M.D.
19951 ELFIN FOREST LANE
ELFIN FOREST, CA 92029
January 5, 2005
I am a 67 year-old retired physician who, after noting two PSA values >
4.0, underwent prostate needle biopsy in May 2004, revealing a single
focus of high-grade PIN. Repeat biopsy was performed in November 2004,
interpreted by Jonathan Epstein, MD as showing a small focus of Gleason
3+3 adenocarcinoma in one of four cores on the right and two of five
cores, showing 10% and 25%, respectively, on the left, surrounded by
high-grade PIN. While three examiners have described "possible
increased firmness of the left side of the prostate," no nodules are
described. PSA varied from 4.55 in February 2002 to 3.91 in August
2004. A TRUS study revealed a 25 gm prostate gland.
I present with mild-moderate obesity, and although 17 years post-CABG,
annual echo-treadmill tests have been normal through December 2004.
Adult-onset diabetes, mild hypertension and dyslipidemia are well
controlled on medications.
I have approached this unfortunate occurrence, initially by seeking
guidance from the urologist who performed my biopsy and others of
personal acquaintance. In doing so, I have been guided to speaking with
radiation oncologists to gather their particular perspective on my
illness. Then, I have searched the internet, making personal contact
with a variety of men who, consequent to having the illness, have made
significant added contributions to my knowledge base. I have received
the names of physicians to contact from the people at Theragenics and
Cytogen. Finally, I have searched PubMed for abstracts that I believe
will help answer my many questions.
The studies noted in this presentation are those of concern to my
particular situation. As a physician, I embarked upon a literature
review with the belief that much of what is published in the medical
literature is not worth the paper upon which it is printed. Each study
must be carefully evaluated to insure that the data supports the
conclusions of the author, a task made particularly difficult by
confinement to reading, for the most part, only abstracts. Nonetheless,
careful review of large amounts of information ultimately begins to
distinguish truth from fiction--advice from the experts in the field
helps as well.
After deciding upon brachytherapy as the treatment of
choice for me,. my final investigative approach will be to find a
caregiver, based to a large extent on the criteria noted by Spencer et
al [vide infra].
Since I am interested in knowing the outcome of care to patients with my
particular findings, I have, in most instances, drawn conclusions that
apply to me personally. Furthermore, I lean toward reviewing authors
whom are under consideration for my own treatment The data presented
may therefore be of limited utility to other patients seeking advice.
Spencer et al [1], at the Rand Health Science Program in Santa Monica,
have defined quality-of-care indicators, which provide the patient with
a likely better treatment outcome. They are divided into: (1)
Structure of care, including equipment, resources and provider
experience, such as volume of cases or board certification of providers.
The availability of conformal radiation therapy and knowledge of
treating institution outcomes were considered essential;(2) Process of
care (the best measure), including technical and interpersonal elements
of care that transpire between doctor and patient, such as the extent
and documentation of the workup and the ordering of diagnostic and
laboratory tests. Adherence to CAP guidelines for managing pathology
specimens, use of the TNM staging system, use of dose recommendations
specific to radiation treatment and use of CT scans in treatment
planning were noted, but assessment of target motion was not; and (3)
outcomes including survival rates, complications and patient-centered
outcomes, including biochemical failure documented by PSA and
post-treatment local recurrence as documented by biopsy; post-treatment
urinary, sexual and bowel functioning after treatment reported by
patients; additional medical treatment for radiation complications; 5,
10 and 15-year disease-free survival and 10 and 15-year overall
survival, and patient-reported satisfaction with treatment choice,
continence and potency.
Before delving into studies that deal with available treatment options,
I want to note the editorial by Neugut et al [2], at Columbia, which
reviews many studies relating the onset and progression of prostate
cancer to diabetes. The evidence is mixed but further studies are
underway to see if weight loss impacts the progression of this
condition. Also, it is noted that D'Amico et al [3], at Harvard, have
recently shown that men whose PSA level increases by more than 2.0ng/cc
during the year prior to diagnosis of prostate cancer may have a
relatively high risk of death from prostate cancer despite undergoing
RP; clinical tumor stage and Gleason score at the time of diagnosis were
also influential factors. Finally, Caroll [4], also at Harvard, has
shown an inverse association between baseline plasma selenium levels and
risk of advanced prostate cancer, suggesting that higher levels of
selenium may slow prostate cancer tumor progression.
Radical Prostatectomy. I recognize that multiple treatment modalities
are available for consideration, and have found that the risk of
morbidity associated with RP, in a variety of studies, fails to warrant
a cure rate not dissimilar to that of IMRT or brachytherapy. For
example, Karakiewicz et al [5], at McGill, surveyed 2415 men treated
for localized prostate cancer by radical prostatectomy and found a 75%
rate of erectile dysfunction and a 6.6% rate of severe urinary
dysfunction in patients under 60, noting age and socioeconomic status as
important predictor variables.
Definition of Low Risk. Partin's widely-available 2001 tables show that
my likelihood of having organ-confined disease is 62-83%; Similarly,
Alamen et al [5a], at the Cleveland Clinic, found organ-confined disease
in 71% of 3198 patients treated surgically for clinically localized
disease, noting a linear relationship between patient age and PSA level.
In contrast, Bastian et al [5b], at Johns Hopkins, studied the surgical
specimens of 237 men classified as Stage T1c, based on Gleason Score <7,
fewer than 3 biopsy cores showing carcinoma, less than 50% involvement
of any core with cancer and a PSA density <0.15 ng/cc and found
organ-confined disease in 91.6% of all patients. The authors concluded
that "the majority of patients with T1c prostate carcinoma have
insignificant disease." Similarly, Kattan et al [6], at New York's
Memorial Sloan-Kettering Cancer Center, showed that 20% of 409 patients
with stage T1c or T2a disease were found on post-prostatectomy tissue
inspection to have "indolent" cancer.
I consider myself as a low-risk patient based on the editorial of
D'Amico, [7] who notes that "the risk of PSA failure after RP or any
form of RT depended on the pretreatment PSA level and Gleason score for
patients with clinically localized disease and, to a lesser extent, the
clinical stage based on the DRE....In addition, the percentage of
positive biopsy specimens also seemed to add predictive information..."
(D'Amico also notes studies, which support a post-treatment PSA doubling
time of less than one year as a "powerful predictor" of prostate-cancer
specific death following conventional dose RT.)
Small Prostate Volume. One other recent study by Lehrer et al [8], from
Mt. Sinai Hospital in New York, is noteworthy in that it followed 613
men who had undergone brachytherapy and correlated freedom from failure
with the prostatic volume noted at treatment. They found a
statistically significant inverse relationship, independent of Gleason
score, PSA, stage of disease, D(90), and hormone treatment. They
speculate that circulating cytokines present in BPH might be responsible
for the improved outcome and advise that patients with a small prostate
treated with brachytherapy might benefit from hormone treatment and
larger radiation doses. McNeely et al [8a] in Boulder analyzed dosimetry
results from 501 patients treated in 33 community hospitals and found
that the D(90) was at least 140 Gy in 90% of cases. Patients with
prostate volume of <25cm3 demonstrated a 20% frequency of underdosing
and only a 7% incidence of D(90) >180 Gy. The authors advised that "one
might consider increasing the activity implanted in small prostates."
Urinary Tract Morbidity. I have reviewed studies, which demonstrate a
lower incidence of urinary symptoms following brachytherapy than that
following RP. Arterberry et al [9], at Wayne State, reported on 51
patients whose morbidity was limited in the first six months
post-treatment to mild dyusuria in 17% and urinary frequency in 40%. No
hematuria or urinary incontinence was reported and the majority of this
admittedly small number of patients claimed no impact on "sexual quality
and function." Stock et al [10], also from Mt. Sinai, found in a study
of 276 low-risk patients that D(90) doses of I-125 between 140-180 Gy
were associated with tolerable urinary tract morbidity. Others quote
similar results.
Genital Tract Morbidity. Nori and Moni [11], at Cornell, preserved
potency in greater than 80% of patients with Stage T2a disease. Stock
et al [12] also reported on 416 patients.--Of 313 who reported adequate
erectile function pre-treatment, potency was maintained in 64% at 3
years and 30% at six years. A D(90) of >160 Gy was associated with
higher rates of post-implant impotence. Fisch et al {13], at UCSF,
reported on a small number of sexually active and normal patients who
underwent 3D conformal radiotherapy of the prostate gland. They showed
that patients receiving a dose of <40 Gy to 70% of the penile bulb
noted "a much greater likelihood of maintaining potency," whereas those
receiving 70 Gy or more to 70% of the penile bulb were "at very high
risk of ...radiation-induced impotence."] Whereas destruction of
supraprostatic neurovascular bundles has customarily been associated
with impotence, this study focuses attention on another potential cause.
Similarly, Butler and Merrick [14], in Wheeling, note that "most of the
urinary morbidity and a significant part of the decrease in sexual
function observed may be avoided by controlling the dosimetry along the
prostatic and membranous urethra and at the penile bulb. Potters et al
[15], at Sloan-Kettering, demonstrated a 5-year actuarial potency rate
for 482 patients treated with monobrachytherapy of 52%. Merrick et al
[16], from Wheeling, followed 181 patients who underwent brachytherapy
for its impact on potency. After 6 years, 52% of those not receiving
adjuvant EBRT retained their potency. Only the pre-treatment IIEF
score, use of supplemental EBRT and diabetes maintained statistical
significance.. Those noting impotence often responded well to
sildenafil.
Rectal Morbidity. Merrick and Butler [17] also reviewed the literature
and found that the incidence of rectal ulceration and/or fistula
formation is about 1%, that constipation increased rectal radiation
dosage and may therefore contribute to rectal morbidity, and that rectal
bleeding is correlated with radiation dose. Merrick et al [18] have
also advised against routine post-brachytherapy biopsies of the anterior
rectal wall and advised pre-seeding rectal cleansing and avoidance of
post-seeding constipation to minimize rectal wall complications.
Cure Rates and Predictors. The good news comes from a study by Derweesh
et al [19], at the Cleveland Clinic, who show that PSA screening has
resulted in a "downward pathological stage migration," i.e., more
recently treated patients have improved biochemical failure rates.
Jhaveri et al [20], also in Cleveland, examined 731 RP specimens
removed between 1987 and 1997 and found the incidence of extracapsular
extension (ECE) had decreased from 81% to 36%. Multivariate analysis
revealed that year of treatment was an independent predictor of ECE, as
well as clinical tumor stage, preoperative PSA level and Gleason score.
They attribute the change to increased popularity of PSA screening.
Brenner and Arndt [21], from Heidelberg, Germany, analyzed long-term
survival of prostate cancer patients treated between 1973 and 2000,
finding that excess mortality compared with the general population was
as low as 1% at five years and 5% at ten years following diagnosis.
Two-thirds of the patients were diagnosed with "well- or
moderately-differentiated localized/regional prostate cancer," and among
these patients, five and ten-year relative survival rates were above
100% at all ages.
The bad news is that various studies utilize biochemical disease-free
states as measures of therapeutic efficacy, and these differ widely.
For example, bDFS following RP includes end-points such as "detectable"
PSA (Potters) or PSA of NMT 0.2ng/cc (Walsh), making sense since RP
theoretically involves removal of all prostate tissue. bDFS following
radiotherapy, in contrast, frequently employs consecutive rises in PSA,
the so-called ASTRO definition of biochemical cure or modifications
thereof, although some investigators also employ end points such as PSA
NMT 0.5 or 1.0ng/cc as indicators. These definitions assume that
radiotherapy may not destroy all prostate tissue; the question of
whether posttreatment PSA values reflect residual normal or malignant
tissue is problematic. The ASTRO definition also allows for the "PSA
bounce,' a phenomenon seen in many patients following radiation therapy
of prostate cancer. Stock et al [22] studied 373 patients treated with
brachytherapy alone for Stage T1-2 cancer. Using three definitions of
"bounce," they found that the actuarial incidence of the phenomenon
occurring within five years was 17-31%, that the median time for
development was 20 months, that it was more likely to occur in younger
patients, those receiving higher implant doses, and those with larger
glands and that it had no predictive value for future PSA failure.
Critz employs the "surgical" end-point of 0.2ng/cc following his dual
radiotherapeutic treatment of early and intermediate state prostate
cancers, providing dosages of radiation intended to destroy all
prostatic tissue. Cooley [23], a prostate-cancer survivor, states that
"the ASTRO definition has no place in the calculating of disease freedom
for prostate cancer patients," takes to task those investigators who use
data of less than five years' duration and has created adjustment tables
which tend to lower the survival rates noted in most papers on radiation
therapy of prostate cancer.
One study by Roehl et al [24} studied 3478 consecutive men who underwent
RP over a 10-yer period at Northwestern, followed thereafter by PSA
levels every 6 months and annual DREs. At a mean follow-up of 65
months, actuarial 10-year biochemical-free survival was 68%, while
cancer-specific survival was 97% and overall survival was 83%. Survivals
could be predicted by association with preoperative PSA, clinical tumor
stage, Gleason sum, pathological stage and treatment era. This paper
portends well for patients treated surgically, but fails to clarify the
survival issue for those undergoing radiation therapy. Until further
long-term disease-free survival figures are available, the
biochemical-free survival rates will continue to serve as surrogates.
Despite the admonitions of Cooley, cure rates from brachytherapy studies
are uniformly "good" for the low-risk patient, although cure is defined
differently by many studies. For example, Blasko's seminal 1995 study
[25] of 138 patients with T1-T2 disease showed 93% freedom from
clinical or chemical recurrence five years after monobrachytherapy.
Ragde et al [26], working with Blasko in Seattle, reported in 1997 on
320 consecutive low-risk patients treated with brachytherapy, in whom
actuarial "freedom from biochemical failure," as defined by a PSA of <
1.1 ng/cc, was 80% after seven years. A third study by Blasko et al
[27] showed 94% "biochemical control" nine years after brachytherapy of
230 T1-T2 patients, those of which were at low risk. The authors also
concluded that there was no apparent benefit to the use of adjunctive
external radiation in these patients.
Ragde et al [28] reported a 12-year survival of 147 low-risk patients
of 66% and concluded that ASTRO failure criteria were not significantly
different from a PSA failure end point of 0.5ng/cc. Of interest is his
statement that those 82 patients "at increased risk for extracapsular
disease received supplemental EBR and demonstrated a 10-year survival of
79%. The authors explain this discrepancy on the basis that many of the
so-called "low risk" patients treated with monotherapy were actually
under diagnosed, since more than 80% had palpable disease, PSA levels
were >10 in substantial numbers and many biopsies were undergraded.
Stock and Stone [29], reporting on 258 Stage T1 and T2 patients
undergoing brachytherapy, stated cure in terms of "freedom from
biochemical failure" after four years and negative prostate biopsy after
two years--in both cases, there was clear correlation between
pre-treatment PSA value, Gleason score and clinical stage. 88% of
patients with PSA <10, Gleason score of <7 and stage of T2a or less were
FFBF at four years, in contrast to those with higher risk factors.
Roach [30] advocates "disease-specific survival" rather than a rising
PSA as the "gold standard" in defining survival. A number of studies
demonstrate comparable survival rates between radical prostatectomy,
IMRT and mono-brachytherapy in patients defined by Gleason Score <7,
pre-treatment PSA <4.1 and Clinical Stage <T2b. Nori and Moni [vide
supra] noted 79% "actuarial clinical freedom from relapse" and 64%
"biochemical freedom from relapse" at five years. Grado et al [31], in
Scottsdale, AZ, reported on patients treated either with
mono-brachytherapy or combined brachytherapy and EBT, demonstrating
"actuarial disease-free survival of 79% and "actuarial rate of local
control" of 98% at five years. They noted that a PSA nadir of>< 0.5ng/cc
was predictive of 93% disease-free survival at five years--these
patients were, unfortunately, not classified as to treatment. Ianuzzi
et al [32], at Mt. Sinai, followed PSA levels frequently following
brachytherapy of 207 patients with T1-T2 disease. They noted continuing
decline for the first 12 months, a gradual decline for another 12 months
and little thereafter. The PSA at one year correlated well with PSA
failure, in that patients with PSA <1 ng/cc had a 4-year
freedom-from-failure of 90%.
A subsequent study by Ragde et al [33] reported on 619 patients Stage
T1-T3 and low to high Gleason scores. ASTRO survival rates for 441
"lower risk" patients treated with I125. were 84% at 3 years, 79% at 5
years and 76% at 10 and 13 years. Rates for "higher risk" patients
treated with Pa131 were 87%, 82%, and 80%, respectively! Stone and
Stock, [34] reviewing over 44,000 procedures performed in 2002, found
that "87-93% of patients with PSA <10, Gleason score under 7, and staged
T2a or less can be expected to have an 8-10 year disease-free state,
when treated with at least 140 Gy from I125. Post-implant incontinence
and proctitis can be minimized by controlling high radiation doses to
the urethra and rectum. Potency is preserved in 70% of men with good
preimplantation erectile function."
Kupelian et al [35], from the Cleveland Clinic, reviewed the outcome of
1682 patients treated either with RP or EBR. Analysis of biochemical
survival at a mean of 51 months was performed with standard surgical and
radiological methodologies, yielding similar 71% rates for each group.
Re-analysis using an end point of PSA <0.6ng/cc for both groups yielded
no change. As in other studies, pretreatment PSA, Gleason score and
year of therapy were independent predictive factors. 51% of the RP
patients and 34% of the radiotherapy patients were of low-risk for
failure.
Sharkey et al [36], in Florida, conducted a nine-year retrospective
review of 1305 patients treated for Stage T1-2 disease, either with
seeding or radical prostatectomy. Following post-treatment PSA values
with ASTRO criteria following seeding, they found freedom from
recurrence at seven years in 90% of patients treated with seeds and 97%
of those treated surgically, when pre-treatment PSA was equal to or less
than 4.0ng/cc. The corresponding values for patients with low Gleason
scores were 83% and 82%, respectively. They noted that "a different
serum PSA endpoint is necessary for brachytherapy and prostatectomy
groups because no prostate tissue is left in the latter group.
Therefore, a PSA level greater than 0.2 in the post-surgical patient
indicates recurrence. In the brachytherapy group, where prostate tissue
remains in situ, their statistics show that when the PSA level is less
than 1.5ng/cc and not rising there is a statistical correlation with a
negative biopsy at 2 years. As we go to 3-5 years, most patients' PSA
levels are less than 0.5 to 1.0 ng/cc, indicating the slowly persistent
kill effect of the radioactive seeds on the remaining prostate tissue."
Adequate Brachytherapy Radiation Dose. Stock et al [37] study of 276
patients treated with I125 brachytherapy yielded (only) 68% freedom
from biochemical failure (ASTRO) at five years when D(90) was <140, in
contrast to 97-98% FRBF following D(90) of 140-180 Gy. Potters et al
[38] concluded that "the quality of...brachytherapy as measured by the
D(90) was the most significant predictor for biochemical-free survival
ASTRO) ..at ten years in 883 consecutively treated patients with
"clinically localized" disease. Their rate of 79% was not influenced
by addition of EBT, hormonal therapy or choice of seed. Kollmeier et al
[38a], at Mount Sinai, grouped 243 patients treated by brachytherapy for
clinically localized prostate cancer into those who had received at
least 140 Gy for D(90)--optimal-- and those who had not.--sub optimal.
Using ASTRO definition, the freedom from biochemical failure at 8 years
was in low-risk patients was 94% for the former patients vs. 75% for the
latter. The other usual clinical predictor factors applied, as well.
Monotherapy vs. Combined Radiotherapy. Critz et al [39] in Georgia
published data on 536 patients with Stage T1-T2 prostate cancer treated
with brachytherapy followed by EBR. After a mean follow-up of 40
months, actuarial analysis revealed a 95% five-year and 84% ten year
disease-free survival in those patients whose post-treatment PSA nadir
was at least 0.5ng/cc, in contrast to a 29% DFS in patients whose nadir
was 0.6-1.0ng/cc. The nadir was reached within 48 months by 90% of
patients. Critz et al [40] reported again in 2000 on 689 patients
receiving identical combined radiation therapy and defined his
post-treatment disease-free state as a PSA nadir of NMT 0.2ng%. An
overall 88% five-year survival was noted, 93-94% for those with a PSA of
<0.4-10.0ng/cc and 75% for those whose PSA nadir was 10.1-20ng/cc.
Critz' most recent published data [41] reveals a 10-year survival rate
of 93% for those low-risk patients undergoing combined treatment and
then sustaining a PSA of no more than 0.2ng/cc. Data on morbidity is not
included. Critz is seemingly isolated in the radiation oncology
community by his belief that cure should be defined as a PSA nadir of
0.2ng/cc, and by insisting that all low-risk patients are best cured by
brachytherapy followed by ERT.
Potters et al [42], on the other hand, performed match pair analysis on
628 patients, matched for a variety of pre-treatment factors. Actuarial
chemical relapse-free survival (Modified ASTRO) at 5 years for those
treated with monobrachytherapy was 77%, and 81% for those treated with
combined radiotherapy. They concluded that there was no significant
advantage in the addition of adjuvant radiotherapy and no significant
difference between treatment approaches. The 6-year actuarial survival
for all patients was 81.9%. Merrick et al [43], in their literature
review, also conclude that "for low risk patients there is no advantage
to combining supplemental external beam radiation therapy with
brachytherapy (and) there is no role for adjuvant hormonal
manipulation."
Of interest, however, is a recent study by Stock et al [44] that reports
on treatment of 132 high-risk patients with nine months of androgen
suppression, followed by brachytherapy and EBRT. They note that freedom
from PSA failure at 5 years for those patients with a Gleason score of 6
or less was 97%! Incidence of morbidity is not mentioned.
-o0o-
More recent study by Potters et al [45] reviewed the outcome of
treatment of 1819 consecutively treated patients with clinically
localized Stage T1-T2 disease. Standard end points of cure were
employed, demonstrating 4-5 year cure rates of 74% for brachytherapy,
77% for external beam radiotherapy and 79% for radical prostatectomy.
Pre-treatment PSA and Gleason score were once again defined as
independent predictors of biochemical failure.
Merrick et al [46] showed, in their study of 413 patients undergoing
brachytherapy for clinical T1c-T2b disease, that those with a <34%
percentage of positive biopsy results had a 7-year ASTRO-defined cure
rate of 99.4%, The median post-treatment PSA value for all those
considered disease-free was 0.1ng/cc.
Extracapsular Extension.. The best outcomes are reported by Ellis et al
[47] in Canton, Ohio. Although cohorts are small, they reported an
ASTRO-defined cure rate of 100% after four years in 60 patients with low
risk disease, while cure rates in the same patients, defined by nadirs
of PSA <1.0ng/cc and <0.5ng/cc were 84.4% and 70.6%, respectively.
Seven-year outcomes for these same patients [personal communication] are
ASTRO 95.7%, PSA <1.0 83.5%, PSA <0.5 82.6%. Twenty intermediate-risk
patients showed survival of 89.2% at four years. 85.2% of all patients
showed a post-treatment PSA nadir of NMT 1.0ng/cc at a median follow-up
of 36 months. In a companion study [48], Ellis et al reported on 66
patients with intermediate to high-risk disease, treated with
brachytherapy and EBRT. Patients with one risk factor (Stage T2b or
greater, PSA >10 OR Gleason score >6) demonstrated 5-year ASTRO-defined
cures of 100%; those with two factors showed 81.9% survival. Ellis
utilizes Prostascint radioimmunoguided targeting of biological tumor
volumes and attributes his improved results to this modality.
Similarly, Hricak et al [49], at Memorial Sloan-Kettering, concluded
that preoperative endorectal MRI was found to significantly improve the
surgeon's decision to preserve or resect the neurovascular bundle(s)
during radical prostatectomy. If this is true, the same might apply to
pre-planning for brachytherapy. The same investigators [50] have shown
that pre-treatment endorectal phased coil MRI has been shown to be 81%
accurate in detecting extracapsular extension of prostate cancer.,
admitting that localization of cancer is "subject to error because of
factors such as post-biopsy hemorrhage, chronic prostatitis, BPH,
intraglandular dysplasia, trauma and therapy, each leading to an
overestimation of the spatial extent of cancer and extracapsular
extension." The recent development of MSRI (MR spectroscopic imaging),
when added to MRI, "can improve both staging and localization of
prostate cancer within the gland because of low specificity, according
to Scheidler et al [50], but neither eMRI or MRSI are currently
approved by the FDA for detection of possible tumor extension in
patients at low risk for such disease--similar to proscriptions for
Prostascint.
Roach et al [50a] state that "combined MRI/MSRI has already demonstrated
a potential for improved diagnosis, staging and treatment planning for
patients with prostate cancer." Wang et al [50b] studied 344
consecutive patients with treated surgically for biopsy-proved prostate
cancer. All underwent eMR imaging prior to surgery; many also underwent
MRSI. Multivariate analysis demonstrated correlation of the presence of
extracapsular extension of cancer with PSA level, Gleason score,
clinical tumor stage, greatest percentage of cancer in all core biopsy
specimens, percentage of cancer-positive core specimens in all core
biopsy specimens, presence of perineural invasion and the findings of
eMRI. Serum PSA level, percentage of cancer in all biopsy specimens and
eMRI findings seemed to have the highest predictive correlation.
Haseman et al [51], at UC Davis, advises that Prostascint should be
"reserved for patients with negative bone scans who are at high risk for
metastatic disease" based on other factors, and "used with caution in
patients at low risk for metastatic disease." He states further that
this imaging technique "has not been shown to be reliable in determining
the local extent of the primary tumor." Kipper [52; and personal
communication] has also advised against the employment of Prostascint
scanning to assess the presence of ECE, unless it is part of the
pre-planning process.
The concomitant presence of undiagnosed higher-grade-tumor and
undiagnosable presence of early metastatic spread have both been
suggested as explanations for the demise of patients initially defined
as "low risk." Butler and Merrick [vide supra] state, "Failures as
measured by biochemical no evidence of disease survival may be
attributed to extracapsular disease extension, often expressing itself
as a high percentage of positive biopsies, perineural invasion or the
dominant pattern in Gleason score histology. Failures due to such
factors may be prevented by implanting with consistent extracapsular
dosimetric margins." Sohayda et al [53], at the Cleveland Clinic,
examined 265 radical prostatectomy specimens and found evidence of
extracapsular extension (ECE) in 92 cases. In those measured, the site
was posterolateral in 53%, lateral in 24%, posterior in 13% and basal in
10%.. 90% of specimens from low-risk patients measured less than 3.3mm.
ECE was observed in 30-60% of all patients with clinical Stage T1-2
disease. Roach et al [54], at UCSF, developed an empiric equation, which
showed a direct correlation between pre-treatment PSA and Gleason score
and the presence of ECE, as well as a direct correlation between the
depth of ECE and subsequent risk of biochemical failure following
radiation. They found that men with an estimated risk of having ECE of
<33% had a 4-year risk of biochemical failure of 29% following
radiotherapy.
Ohori et al [55], at Memorial Sloan-Kettering, have also dealt with the
issue of extracapsular extension by development of a nomogram. Studying
763 patients with Stage T1c-T3 prostate cancer, all diagnosed by biopsy
and treated with RP, they identified the same clinical variables noted
by others in predicting ECE, but added the presence of palpable
induration as a predictive variable.
Techniques. Begg et al [56] have shown that outcome following radical
prostatectomy is related directly to the skill and experience of the
urologic surgeon. Although no similar studies are available for
brachytherapy, it makes sense to believe that the same is true, inasmuch
as the techniques of brachytherapy are difficult to learn and apply.
For example, several modalities are utilized for pre-planning of needle
placement. While most brachytherapists use biplanar ultrasound, others
advocate the employment of Doppler ultrasound, magnetic resonance
imaging, stereoscopic MRI or Prostascint scanning, each believing that
his/her own technique provides advantage over others.
Butler et al [56a} engages at length on the details of dosimetry in
prostate cancer brachythrapy.
Some brachytherapists utilize pre-planning, while others make
adjustments immediately prior to and during needle placement. Nag et al
[57], at Ohio State, reporting for the American Brachytherapy Society,
state that "both intraoperative preplanning and interactive planning are
currently feasible...and may help to overcome ...the limitations of the
preplanning technique. The dynamic changes in prostate size and shape
and in seed position that occur.... are not yet quantifiable....The
major current limitation of intraoperative treatment planning is the
inability to localize the seeds in relation to the prostate."
Stone et al [58], in comparing intra-operative and postoperative
CT-dosimetry, conclude that "Although small differences exist between
the OR and CT dosimetry results, these data suggest that this
intraoperative implant dosimetric representation system provides a close
match to the actual delivered doses...and...support the use of this
system to modify the implant during surgery to achieve more consistent
dosimetry results. Fuller [personal communication] performs
post-implantation dosimetry in the operating room, allowing the
placement of added seeds if warranted, whereas Stock and Stone [59]
claim that "the most accurate time to perform post-implant dosimetry is
1 month after implant." Yue et al [60] state: "Because of edema caused
by the surgical procedure in the implantation, if the dose evaluation is
based on the images obtained too early after implantation, dose coverage
will usually be underestimated. Conversely, if the images are obtained
too late, the dose coverage will be overestimated" in their study of 29
patients. They identified the optimum timing for conventional
post-implant dose evaluation as the time at which a minimum difference
between the conventional DVH and the dynamic model DVH was achieved and
concluded that the optimum timing of image scans for post-implant dose
evaluation of prostate seed implantation is 7 weeks for I125 implants.
Other techniques vary as well. While Blasko and his disciples employ
stranded seeds, others in the Midwest and East Coast treatment centers
utilize single seeds and Mick applicators. Minimal needle insertion is
associated with less prostatic inflammation and intraoperative
adjustments. Fuller [61} in San Diego has shown that stranded seeds are
associated with decreased seed migration as well as higher prostate and
urethra dosimetry values. Dattoli and Waller [62], in Tampa, describe a
technique wherein the gland is stabilized by the early insertion of
obliquely-placed needles. Stone et al [63] contend that placement of
needles in the prostate periphery results in minimal gland change, but
is associated with up to 5mm of gland displacement. Grimm et al [64],
inn Seattle, describe a two-stage implantation technique which involves
placement of all needles into all target coordinates and then replacing
stylets with pre-loaded stranded seeds. They noted significantly less
organ movement and improved dosimetry and concluded that the technique
"may offer some advantages...including improved needle loading
verification, better visualization of needle placement, improved gland
stabilization and more consistent postoperative dosimetry."
Although most studies indicate no significant difference between using
I125 or Pa131 seeds, Butler et al [65], in Wheeling, noted that the
"more rapid attenuation of Pa131 photons with distance creates cool
spots in an edematous prostate, and the shorter half life of Pa131
causes a greater fraction of the isotope decay to consist of the
prostate in an edematous state."
Conclusions. Having completed the above review, I have personally
communicated with those brachytherapists whom I believe would provide
best care, mainly to assess "bedside manner," or the caring aspect of
the professional. I have found a caregiver that I believe is kind,
caring, aware of my particular fears and needs and capable of providing
my brachytherapy in a skillful manner. My quest is, at least for the
present, at an end.
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