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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2915_Библиотеки_им_академика_М_И_Перельмана.pdf
Prostate Cancer
161
Study
Description
Bolla et al.
(2003)
After RP, 503 patients were randomized to a wait-and-see policy, and 502 to immediate
postoperative radiotherapy (60 Gy).
After a median follow-up of 5 years, biochemical progression-free survival was
significantly improved in the irradiated group (74.0%, vs 52.6%,; p<0.0001). Clinical
progression-free survival was also significantly improved (p=0.0009). The cumulative
rate of locoregional failure was significantly lower in the irradiated group (p<0.0001).
Severe toxic toxicity (grade 3 or higher) were rare, with a 5-year rate of 2.6% in the wait-
and-see group and 4.2% in the postoperative irradiation group (p=0.0726).
Thompsom et
al. (2009)
431 men with pT3N0M0 prostate cancer were randomized to 60 - 64 Gy adjuvant
radiotherapy or observation.
211 were randomized to observation and 214 to adjuvant radiation. Metastasis-free
survival was significantly greater with radiotherapy (93 of 214 events on the radiotherapy
arm vs 114 of 211 events on observation; p = 0.016).
Survival improved significantly with adjuvant radiation (88 deaths of 214 on the
radiotherapy arm vs 110 deaths of 211 on observation; p = 0.023).
Wiegel et al.
(2009)
After RP, 192 men were randomly assigned to a wait-and-see policy, and 193 men were
assigned to immediate postoperative RT.
Biochemical progression-free survival after 5 years in patients with undetectable PSA
after RP was significantly improved in the RT group (72%; v 54%, P = .0015). On
univariate analysis, Gleason score more than 6 and less than 7, PSA before RP, tumor
stage, and positive surgical margins were predictors of outcome.
The rate of grade 3 to 4 late adverse effects was 0.3%.
9.5. Adjuvant and Salvage Radiotherapy
• Patients with positive margins or with a recurrence following radical prostatectomy
can be treated by EBRT. Adjuvant RT decreases the risk of biochemical failure, but
it requires administering RT to some patients who could never require treatment.
• EBRT has potential to provide long-term disease control if the recurrence is localized
within an area that can be included within the treatment field and a sufficient dose
can be delivered to eradicate the residual/recurrent cancer.
• Factors associated with an improved biochemical control included a positive surgical
margin at prostatectomy, a low PSA level at recurrence, and a long recurrence-free
interval following initial surgery. On the other hand, a short PSA doubling time (PSA
DT < 6 months), Gleason score ≥8, a history of lymph node or seminal vesicle
involvement at original diagnosis, and a persistent elevation of PSA following RT
were all associated with poorer biochemical control.
• Large randomized clinical trials have demonstrated that adjuvant RT significantly
improves biochemical relapse-free survival (RFS) and metastasis RFS.
• A dose of 60 - 64 Gy in the adjuvant setting is recommended according to the results
of both large adjuvant RT trials (table-15).
Table 15. Clinical evidence adjuvant radiotherapy for high rik postoperative
prostate cancer
Gustavo Arruda Viani
162
References
Bolla M, van Poppel H, Collette L et al. Postoperative radiotherapy after radical pros-
tatectomy: a randomised controlled trial (EORTC trial 22911). Lancet. 2005;366
(9485):572
Thompson IM, Tangen CM, Paradelo J et al. Adjuvant radiotherapy for pathological
T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival:
long-term followup of a randomized clinical trial. J Urol. 2009;181(3):956.
Wiegel T, Bottke D, Steiner U et al. Phase III postoperative adjuvant radiotherapy after
radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer
with postoperative undetectable prostate-specific antigen: ARO 96-02/AUO AP 09/95. J
Clin Oncol. 2009;27(18):2924.
10. Radiotherapy Technique
A CT scan is obtained with the patient in the treatment position. Patients are treated
supine position, since this position has been shown to produce less prostate motion, reduce
doses to normal organs at risk, and is more comfortable for the patient. Patients are asked to
empty the bladder and drink 200 mL of water 20 min before the scan and before treatment
each day. A completely full bladder has been shown to displace small bowel away from the
treated volume, but it also leads to greater variation in prostate position and is not
recommended. The rectum should be empty for treatment as a full rectum also leads to greater
variation in prostate position. An immobilization system using a head pad combined with
individually adjustable knee and ankle supports provides a high degree of accuracy without
the need for further pelvic immobilization.
With the patient immobilized in the treatment position radiotherapy planning CT scan is
performed. Skin reference tattoos are placed anteriorly on the midline of the symphysis pubis
and laterally over the hips and aligned with lasers to prevent lateral rotation. Radio-opaque
markers are placed on the skin to locate the tattoos on the CT scans. The CT scan is taken
with 3–5mm slices from the mid sacroiliac joint to 1 cm below the anus/ischium to include
the prostate, seminal vesicles, rectum and bladder, and is extended superiorly to L3 if he
pelvic lymph nodes are to be treated. During the planning CT scan, the size of the rectum and
bladder should be assessed. If the bladder is empty or the rectum is > 4 cm in AP diameter at
the level of the prostate base, the scan should be repeated. CT data are then transferred to a
radiotherapy planning computer for outlining and target volume definition. To improve target
definition, MR scans of the pelvis can be incorporated into radiotherapy planning protocols.
Outlining studies have shown that the size of the prostate is overestimated on CT compared
with MRI, which defines the apex of the prostate better.
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Figure 6. Pelve MRI and CT merged for radiotherapy treatment planning.
10.2. Target Volume Definition
CTV includes the whole prostate and any possible extracapsular extension, with either
the base of, or the entire seminal vesicles. The risk of involvement of the seminal vesicles is
defined using the Roach formulae and target volume chosen accordingly (Low risk of seminal
vesicle involvement < 15% and high risk > 15%).
Prostate outlining starts on the mid gland slice along the fat plane between the prostate
and pelvic floor muscles. The base of the seminal vesicles is included in the CTV for all
patients. This is defined as 1 cm of central seminal vesicles proximal to the base of the
prostate often at the same level as the middle lobe that bulges into the bladder. When the
entire seminal vesicles are included in the CTV, the distal ends may be excluded if the
seminal vesicles wrap around the prostate, to keep the rectal dose within safe limits. Studies
have shown that 90 % of seminal vesicle involvement occurs in the proximal 2 cm. The PTV
is defined with a 3D margin around the CTV to include an internal margin accounting for
physiological variations in the shape, position and size of the prostate, and a set-up margin to
compensate for uncertainties in patient position and set-up during planning and treatment.
The set-up margins can be measured with verification studies and quality assurance programs.
The standard margin is 10 mm around the CTV. To limit the dose to the rectum, the posterior
margin is reduced to 7 mm if verification studies allow, and is reduced further for a phase 2
volume when needed, to keep within rectal dose constraints (figure 7).
Gustavo Arruda Viani
164
Bladder
V75 <25%, V70 <35%, V65 <25–50%, V55 <50%, V40 <50%.
Rectum
V75 <15%, V70 <20–25%, V65 <17%, V60 <40%, V50 <50%,
V40 <35–40%.
Femoral heads: V50 <5%
Small bowel: V52 0%
Penile bulb: Mean dose <52.5 Gy
Figure 7. CT images of prostate cancer patient showing the contour outlines for the GTV, PTV,
bladder, and rectum.
The OARs are the rectum, bladder, nerves of the prostatic plexus lying adjacent to the
penile bulb, small bowel and femoral heads. The rectum is outlined from the inferior level of
the ischial tuberosities and at least 1 cm below the PTV to the recto-sigmoid junction above
the PTV to give a length of approximately 12 cm. Consideration of small bowel in the target
volume is important when pelvic nodes are treated. The dose to OAR is assessed by DVHs.
Plans are reviewed to minimize hot-spots in OAR. The acceptable dose constraints for OAR
are shown in Table-16.
Table 16. Limit doses for organ at risk
10.2.1. Pelvic Contour
The contouring of the pelvic CTV lymph node volumes (CTV LN) is guided by RTOG
GU Consensus. According to this guideline the CTV LN begins at the L5/ S1 interspace (the
level of the distal common iliac and proximal presacral lymph nodes). Place a 7-mm margin
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165
around the iliac vessels connecting the external and internal iliac contours on each slice,
carving out bowel, bladder, and bone. Contour presacral lymph nodes (subaortic only) S1
through S3, posterior border being the anterior sacrum, and anterior border approximately 10
mm anterior to the anterior sacral bone carving out bowel, bladder, and bone. Stop external
iliac CTV LN contours at the top of the femoral heads (bony landmark for the inguinal
ligament). Stop contours of the obturator CTV lymph nodes at the top of the public (figure
8).
Figure 8. Pelvic lymph node according to RTOG GU consensus (a) Common iliac lymph nodes, (b)
Iliac internal and external division, (c) Iliac external and internal lymph nodes and (d) Obturatory
lymph nodes.
As for 3DCRT as IMRT, a five to seven beam iso-centric technique can be used to
minimize radiation to nearby critical organs, such as the rectum, bladder, penile bulb, and
femoral heads. A minimum of 6-MV photon beams should be used.
IMRT can be considered for the treatment of both pelvic lymph nodes and prostate only.
Many centers have migrated to IMRT, though this requires significant knowledge of pelvic
anatomy. The CTV includes the distal common iliac, internal iliac and external iliac nodal
regions, as described in figure –8.
In a comparison between 3DCRT and IMRT showed that IMRT significantly improved
the coverage of the nodes at risk (D95 46.0 vs. 27.4 Gy, p <0.01), while significantly sparing
the rectum (V45 Gy), small bowel (V45 Gy), and bladder (V45 Gy), as showed in figure 9.
Gustavo Arruda Viani
166
Figure 9. IMRT isodose line distributions according to different levels (a) mid prostate, (b) prostatic
base, (c) proximal seminal vesicle and (d) distal seminal vesicle.
Currently the minimum dose to the prostate with conformal radiotherapy is at least 74 Gy
to the PTV, which can be delivered in 1.8 to 2.0 Gy per fraction. The choice of total dose will
vary from center to center and is based on the availability and type of targeting systems,
IMRT, and physician comfort level. With IMRT, the minimum dose should be escalated
further to at least 78 Gy, and with IGRT further than 80 Gy.
For adjuvant radiotherapy, the recommended dose is 64–66 Gy to the prostate bed.
Whole-pelvic radiotherapy (45–50 Gy) and androgen suppression therapy may be considered
for patients with high-risk features, such as Gleason score 8–10, PSA >20 ng/ml, pT3a-b
disease, and pathologic nodal involvement. For salvage radiotherapy, the recommended dose
is 68–70 Gy to the prostate bed. Whole-pelvic radiotherapy (45–50 Gy) and androgen
suppression therapy may be considered for patients with high-risk features, such as Gleason
score 8–10, PSA >20 ng/ml, pT3a-b disease, and pathologic nodal involvement.
Conclusion
• Modern imaging has improved and refined the ability to define radiotherapy target
volumes.
• Treatment margins for radiotherapy treatment have been reduced through the use of
treatment planning and image-guidance technology.
• These technology advances has led to increased total dose resulting in better disease
control and reduced toxicity.
• Image-guided radiation can allow dose escalation to smaller volumes, being more
accurate with improvements in clinical endpoints.
• Further clinical trials should be done testing new treatment schedule, and use of
additional systemic therapy in conjunction with radiation.
Chapter 11
Bladder Cancer
Introduction
Bladder cancer is the second most common urologic cancer. Transitional cell carcinoma
(TCC) constitutes more than 90% of bladder cancers in North America, South America,
Europe, and Asia. The classic presentation of bladder cancer is painless gross hematuria,
which is seen in approximately 80-90% of patients. Any patient with gross or microscopic
hematuria should be urologically evaluated. Cystoscopy with bladder biopsies are needed to
firmly establish a diagnosis. At diagnosis up to 60% of patients have low-grade noninvasive
disease, which is usually treated conservatively with transurethral resection and periodic
cystoscopy. The remainder have high-grade disease, of which 50% is muscle invasive and is
typically treated with radical cystectomy, or less commonly by chemoradiation. In this
chapter we discuss the role of radiotherapy treatment for patients with bladder cancer.
1. Epidemiology
• There were 73,510 cases estimated in the U.S. in 2012, with 14,880 deaths.
• Bladder cancer is the fourth most common cancer in men, following prostate, lung
and colon cancers, and it is the eighth most common cancer in women.
• It constitutes 5–10% of all cancers in men. The risk of developing bladder cancer up
to 75 years of age is 2–5% in males and 0.5–1% in females.
• The incidence of bladder cancer is 9.9/100,000 in men and 2.3/100,000 in women in
the USA.
• The disease is 2.5 times more frequent in men than in women and is most frequent in
industrial northeastern cities.
Reference
American Cancer Society. Cancer Facts and Figures 2012. Accessed January 5, 2012.
Gustavo Arruda Viani
168
Occupational exposure
Aniline dye workers are afflicted 30 times more than the general population.
Aromatic amines and related compounds are the most abundant bladder
carcinogens.
Leather, paint, and rubber industry workers also appear to have an increased
risk for bladder cancer.
Proven chemical carcinogens in these industries are 2-naphthylamine,
benzidine, 4-aminobiphenyl, and 4-nitrobiphenyl.
Schistosomum
haematobium
Infection of the bladder by schistosomum haematobium, endemic regions of
Africa and the Middle East, is associated with bladder cancer, particularly
with squamous cell histology.
Smoking
Increases the risk for bladder cancer fourfold in a dose-dependent fashion.
Pelvic RT
Increases the risk for bladder cancer fourfold.
Drugs
Cyclophosphamide unequivocally increases the risk for bladder cancer.
Other drugs that have been implicated in animal studies but not proved in
humans are phenacetin, sodium saccharin, and sodium cyclamate.
2. Risk Factors
Several risk factors are associated with the risk to develop bladder cancer. Table 1
summarizes the main risk factors.
Table 1. Risk factors fro bladder cancer
References
Heyns CF, van der Merwe A. Bladder cancer in Africa. Can J Urol. Feb 2008;15(1):3899-
908.
Freedman ND, Silverman DT, Hollenbeck AR, Schatzkin A, Abnet CC. Association between
smoking and risk of bladder cancer among men and women. JAMA. Aug 17 2011;306
Silverman DT, Hartge P, Morrison AS, et al: Epidemiology of bladder cancer. Hematol Oncol
Clin North Am 1992; 6:1-30.
3. Anatomy
The bladder consists of the detrusor muscle and the trigone at its base. The bladder is
positioned next to the seminal vesicles and the ampulla of the vas deferens posteriorly, as well
as the lower tips of the ureters and the rectum.
The superior portion of the bladder is covered with peritoneum and is close to the small
intestines by this peritoneum. The inner surface of the bladder mucosa is covered with
transient cells (urothelium).
A smooth muscle layer composed of longitudinal, circular and spiral leaves, as well as
the serosa (adventitia), consisting of fibrous tissue, are found under the subserosa (figure-1).
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169
Figure 1. Bladder anatomy in male and female.
4. Clinical Features
• The most common symptom associated with bladder cancer is hematuria.
• Hematuria occurs as a presenting feature in approximately 90% of patients.
• Bladder irritability can occur in 25% of patients. Other symptoms as hesitancy,
urgency, frequency, dysuria, and postvoiding pelvic discomfort may mimic prostatitis
or cystitis can also occur.
• These symptoms occur in patients with CIS as well as in those with tumors that are
large, extensive, or near the bladder neck.
• Pain in the pelvis or flank can associate with locally advanced disease.
• Edema of the lower extremities and genitalia develops from venous or lymphatic
obstruction.
• During the physical exam the patient must be carefully examined for metastatic sites.
It is mandatory that a bimanual examination is performed by the urologist through
the rectum each time the patient is put under general anesthesia or having a
cystoscopy done. It supplies important information concerning local extension of the
disease not obtainable by current imaging modalities.
References
Mariani AJ, Mariani MC, Macchioni C, Stams UK, Hariharan A, Moriera A. The significance
of adult hematuria: 1,000 hematuria evaluations including a risk-benefit and cost-
effectiveness analysis J Urol. 1989;141(2):350.
Grossfeld GD, Litwin MS, Wolf JS, Hricak H, Shuler CL, Agerter DC, Carroll PR. Evalu-
ation of asymptomatic microscopic hematuria in adults: the American Urological
Association best practice policy--part I: definition, detection, prevalence, and etiology.
Urology. 2001;57(4):599.
Gustavo Arruda Viani
170
Cystoscopy
The cornerstone procedure for diagnosing bladder cancer. Biopsy is
performed on abnormal areas. Biopsies of normal areas at random are
performed to search for CIS.
Urography
An intravenous pyelogram (IVP) is performed in all patients with
unexplained hematuria or cystoscopic or cytologic evidence of tumor
in an attempt to search for primary sites in the ureters or renal pelvis.
CT urography (CTU)
CTU has largely supplanted IVP as the imaging modality of choice for
the upper urinary tract.
It is important to obtain a CTU in any patient with hematuria, a history
of bladder cancer, or positive cytology.
CTU is also useful for staging invasive bladder cancer or upper tract
TCC. Abnormally enlarged lymph nodes and visceral metastasis can be
observed by CTU. Local invasion into pelvic organs or tumor
infiltration into the perivesical fat can also be observed.
Urine cytology
It detects about 70% of bladder cancers that are subsequently
diagnosed by cystoscopy. Cytologic evaluation should not be the
primary diagnostic method for patients suspected of having bladder
cancer.
5. Diagnosis and Evaluation
All patients with macroscopic haematuria should be submitted to an evaluation with urine
cytology, cystoscopy and upper tract imaging to assess for the presence of UC (table-2).
Table 2. Procedures for evaluation of bladder cancer
Imaging studies is used to examine the renal parenchyma and upper tract urothelium.
Three phase computerised tomography (CT) urography is first line to study the renal
collecting system, ureters and bladder. Lymphadenopathy and tumour size can also
be determined.
Magnetic resonance imaging (MRI) is second line, costly and it shows details from
the pelvic soft tissues. Renal impairment limits the use of contrast in both modalities.
Figure –2 demonstrate the appearance of bladder cancers on cross-sectional imaging.
Ultrasonography is sometimes used in low risk patients but provides little detail
about the urothelium.
Asymptomatic patients with large muscle invasive tumours or patients with bone
pain or bony lesions on CT scan should undergo a nuclear whole body bone scan to
assess the skeleton for bony metastases.
References
Herr HW. Routine CT scan in cystectomy patients: does it change management? Urology.
1996;47(3):324.
Tekes A, Kamel I, Imam K, Szarf G, Schoenberg M, Nasir K, Thompson R, Bluemke D.
Dynamic MRI of bladder cancer: evaluation of staging accuracy. AJR Am J Roentgenol.
2005;184(1):121.