Bladder Cancer

Anatomy

  • Hollow, muscular organ
  • When empty lies within the pelvis
  • Intra-abdominal organ that can project above the umbilicus when full
  • In infants, the true pelvis is shallow and the bladder neck is usually level with the upper border of the pubic symphysis. By puberty, the bladder has migrated to the confines of the deepened true pelvis.
  • Apex
    • . The apex reaches a short distance cephalad above the pubic bone and ends as a fibrous cord, which is a derivative of the urachus—a canal in the fetus connecting the bladder with the allantois. This fibrous cord extends from the apex of the bladder to the umbilicus between the peritoneum and the transversalis fascia.
  • Superior surface
  • Two inferolateral surfaces
  • Base
    • =posterior surface
  • Neck

The superior surface is the only surface of the bladder that is covered by the peritoneum. This surface generally is associated with the uterus and ileum in women and with the ileum and sigmoid colon in men. The base of the bladder is posterior and is separated from the rectum by the vas deferens, seminal vesicles, and ureters in the male, and by the uterus and vagina in the female. The seminal vesicles form a V-shaped structure at the base of the bladder, with the vas deferens entering the middle of the so-called V. The ureters enter into the bladder slightly superior and lateral to the seminal vesicles, with the vas deferens coursing above and in a caudal direction to the ureters. The inferior and lateral surfaces of the bladder are in close relation with the pubic bone, the levator ani, and obturator internus muscles. The bladder is distinctly separate from the pubic bone by the retropubic space containing fat and fibroareolar tissue. The neck of the bladder is its most inferior portion adjacent to the prostate in men and the urethra in women. As the bladder distends with urine, the neck remains fixed in position, and the superior part will rise into the pelvic cavity. Anteroinferiorly and laterally, the bladder is cushioned from the pelvic sidewall by retropubic and perivesical fat and loose connective tissue. This perivesical space is called the space of Retzius.

The bladder mucosa is lined with transitional epithelium and appears smooth when the bladder is full; however, it contracts into numerous folds when it empties. The interureteral fold is a ridge at the bladder neck between the openings of the ureters into the bladder.

Epidemiology

  • 60’000 new case / year
  • 13’000 death / year
  • At presentation
    • Local disease —> 72%
      • >80% present with early disease
      • No invasion of detrusor smooth muscle
    • Regional disease —> 20%
    • Metastatic disease —> 8%
  • Cancer of white old men
    • Male > Female —> 3:1
    • White> Black —> 2:1
    • >65yr
    • Women and black have poorer prognosis.
  • Location
    • Highest rate —> western Europe / north America
    • Low rate —> east Asia and east Europe

Etiology

  • Smoking —> transitional cell ca
    • x2-3 fold
    • responsible for 50% of cases
    • after quitting
      • in first 2-4 years —> reduction of risk; then no further reduction(?)
  • Chronic inflammation like Schistosoma or lifelong indwelling catheter —> Squamous Cell Ca ( less common )
    • Large mass
    • High grade of necrosis
    • Chronic cath —> more mets
    • Chronic UTI
  • Occupational Exposure
    • Chlorinated water
    • Dye and rubber
      • Aromatic amine
    • If start before age of 25
    • Mean time between exposure and Ca —> 25yr
    • Benzidine
    • Formaldehyde
    • Benzene
    • Methylene chloride

Molecular Biology

  • EGFR overexpression
  • HER-2 overexpression
  • Abnormal p53 expression
    • May be related to progression and outcome ( poor prognostic )
  • Bcl-2 +
    • Worse prognosis
  • Loss of heterozygosity in chromosome 9

Family of receptor tyrosine kinase

  • This family has four known member
    • We know erb1 = EGFR and erb2 = Her2 very well
    • Both erb1 and erb2 are expressed in bladder ca
    • Unclear how they respond to Herceptin
    • Unclear about prognostic factor

Screening

  • Cytology of urine
    • Sensitivity —> 35% ( higher for high grade lesions )
    • Specificity —> 80%

Chemoprevention

  • Vit A analogue
    • Retinoic acid
  • Multivitamin
    • alpha tecophorel
    • Vit C
      • Ascorbic Acid
    • Green tea extract
    • Celecoxib

Pathology

  • Transitional Cell Carcinoma > 90% : TCC
  • Adenocarcinoma
  • Squamous cell ca
    • Specified by the presence of keratinization
  • Small cell ca

Papillary growth vs solid tumor

  • Papillary growth more common (80%)
  • Solid Tumor more high grade
    • More invasion to muscularis propria layer
  • Ta is an exophytic tumour arised in the epithelium
    • = Nonivasive papillary tumour
    • Low grade
    • Few pleomorphism
    • Normal nuclear polarity
    • More layers than normal (more than 7 )
  • As soon as invasion to lamina propria —> It become T1
    • Chance of mets exist!

Layers of bladder

  1. Epithelium
  2. Lamina Propria
  3. Muscle
  4. Perivesical Tissusue
  • Ca in situ ( CIS )
    • Noninvasive
    • Flat ca within epithelium
    • High-grade
    • Local vs Diffuse
    • On endoscopy
      • Difficult to differentiate from inflammation
      • Friable red area displacing normal epithelium
      • Loss of cohesive cells
    • Urine Cytology is positive in 90% of cases
  • GRADE
    • I to III ( low – intermediate - high ) —> based on :
      • Number of mitoses
      • Nuclear abnormality ( loss of polarity )
      • Cellular atypia

Symptoms

  • Secondary to primary tumour
    • Painless hematuria —> most common (80%)
    • Dysuria (20%)
    • Severe bleeding and clot formation (17%)
  • Symptoms secondary to mets
    • Bone
    • Liver
    • Lung
    • CNS

Work Up

  • Urine analysis
  • Urine cytology
    • Valuable specially in CIS as is not very well visualized
    • Sensitivity : 50%
    • More sensitive for high grade
    • Specificity : 90%
  • Cystoscopy and Biopsy
    • Number
    • Size
      • <2cm
      • >5cm
    • Location
      • Most invasive ca located in posterior trigone wall
    • Shape
      • Papillary
      • Flat
    • Appearance of surrounding mucosa
    • Urethra
      • Urethral orifices—> any risk for obstruction
  • Pyelography
  • CT-MRI Abdo-Pelvis
  • CXR
  • Bone Scan
  • CBC; Kidney Function Test; Liver Function Test; LDH; lytes

Risk of Nodal involvement based on T stage

  • T1 —> 5%
  • T2 —> 30%
  • T3 & T4 —> >50%

Staging

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Prognostic Factors

  • Prognostic factors:
    • Clinical stage
      • Any extravehicular disease
    • Tumor appearance
      • Papillary
      • Solid
      • Ulcerative
    • Age (<70 years)
    • Hemoglobin level (>12 g/dL)
    • Tumour morphology
    • Completeness of TURB
    • Solitary versus multiple bladder tumors
    • Ureteric obstruction
    • CR after RT
    • RT dose
  • Molecular prognostic factors:
    • Expression of p53, p21, and retinoblastoma tumor suppressor genes, Ki67, and apoptotic index

Predictive Factors

  • Progression from superficial to muscle invasive
    • High grade
    • Penetration of lamina propria
    • Presence of carcinoma in situ
    • Papillary configuration : better
    • Multifocality : worse
  • Once muscle invasion has occurred
    • Predictors of death and mets
      • Bulk of tumour
      • Depth of invasion —> Most important predictive factor

Primary Therapy

Muscle invasion is the key for decision making regarding the treatment.
Bladder cancer is either invading muscle or it is superficial.

Superficial Bladder Ca

  • 70% of all bladder Ca
  • Superficial bladder ca = No muscle invasion
    • Ta, Tis, T1
  • Initial therapy : TURBT( treatment of choice )
    • Transurethral resection of bladder tumour

When should we use adjuvant therapy?

In general 70% recur and 15% are invasive!

-—- 70% reduction in recurrence by applying intravesical treatment

That’s based on risk of progression not risk of recurrence.
See here again!

For example:

  • Ta Grade-1 tumor recurs 100% in 5 yr after TURBT but rarely invades or cause death
  • Ta G2-3 : risk of progression : 20% ( after TURBT alone )
  • T1 : >70% are high grade ( G3 ) : 50% risk of invasion in 5 years
  • Chance for progression to invasive ca
    • Grade
    • Tumor type

Therapy for superficial ca:

  • Intravesical therapy
  • Bacille Calmette-Guerin ( BCG )
      • A vaccine against tuberculosis
      • Prepared from a strain of the attenuated live bovine tuberculosis bacillus (Mycobacterium bovis)
        • Has lost its virulence in humans
      • Decrease rate of progression; decrease cystectomy rate; increase survival and decrease recurrence
  • Ta G2-3; T1 : TURBT + BCG
    • Rate of progression in 5 years : 5-15%
      • Positive impact on progression : survival advantage
        • 10yr OS (TURBT alone) : 62% ; ( + BCG ) : 88%
    • Cystectomy rate (TURBT alone) : 44% ; (+ BCG ) : 20%
    • BCG Also delays recurrence in 50% of patients
  • Other indications for BCG:
    • CIS
      • Complete response for 1 year > 70%
      • Prevents subsequent disease in 40-60% in 5-10yr ( RESPECTIVELY! )
    • Frequent recurrence of low grade ca
    • Urothelial dysplasia
    • Severe atypia
  • Intravesical therapy other than BCG
    • Mitomycin
    • Doxorubicin
    • Thiopeta
      • No effect on OS or rate of progression
      • Decrease chance of recurrence
  • Any role for XRT in superficial bladde ca?
    • If recurrent and high grade
    • There may be a role before cystectomy

Muscle Invasive Bladder Ca

  • 20-25% of total bladder Ca ( T2 and higher )
  • It's a lethal disease —> If not treated 85% will die within 2 years
  • Requires investigation for staging
    • Blood work ( KFT; LFT; CBC ; Alk-P )
    • CXR
    • CT Abdo
    • Bone Scan
    • CT/MRI Pelvis
  • Total cystectomy is mainstay of treatment
    • Even for high grade tumour sometimes cystectomy is the best when it gives the optimal outcome as high grade tumours recur frequently…

Why cystectomy? ( + LND )

  • Best long-term survival rates
  • Lowest local recurrences
  • Morbidity and mortality has improved over the past years
    • Improvements in lower urinary tract reconstruction, particularly orthotopic diversion
      • Orthotopic reconstruction : resembles the bladder in location and function
      • Continency in storing urine
      • Volitional voiding per urethra
  • TCC only moderately sensitive to RT
  • Chemo alone, or with bladder-sparing protocols still not equivalent to surgery
  • Provides accurate pathologic staging
    • better decision making for adjuvant treatment

What is radical cystectomy?

  • En bloc removal of
    • Pelvic and iliac lymph nodes <— Important in outcome in both LN+ and LN-
      • Superior limits of dissection: Inferior mesenteric artery
      • Extending laterally over the inferior vena cava/aorta to the genitofemoral nerve (lateral limits of dissection)
      • Distally to the lymph node of Cloquet medially (on Cooper's ligament) and the circumflex iliac vein laterally
        • Obturator
        • Hypogastric
        • Presciatic
        • Presacral
    • Pelvic organs anterior to the rectum
      • In men:
        • Bladder
        • Urachus
        • Prostate
        • Seminal vesicles
        • Visceral peritoneum
      • In Women
        • Bladder
        • Urachus
        • Ovaries
        • Fallopian tubes
        • Uterus
        • Cervix
        • Vaginal cuff
        • Anterior pelvic peritoneum

Mortality and Morbidity of cystectomy

  • Prior to 1970
    • Morbidity: 35%
    • Mortality: 20%
  • Modern technique
    • 3% mortality

Complications:

  • Dehydration
  • Leakage

What about neoadjuvant Chemo/RT?

  • Does not increase complication
  • Not routine
  • Considered if recurrence ( previous partial cystx)
  • Extravesical tumor
  • Still postop chemotherapy based on accurate path may be better
Pathology LN Status 5yr OS 10yr OS chance of DM Comment
Confined to Bladder Negative 85% 82% 13% No change in OS by depth as long as good resection
Extravesical Negative 58% 55% 32% Chance of LN+: 45%
Any Positive 33% cell-content 52% Consider adj therapy

Points about lymph node positive bladder cancer:

  • Lymph node dissection beneficial
    • >10 better
  • Consider Adj Chemo
  • Prognostic factors:
    • Number of lymph nodes
      • less than 5 better…
    • Extracapsular extension
    • Stage of the primary tumour
      • Organ confined better

Recurrence Following Radical Cystectomy

General Concepts:

  • Overall happens in 30% of patients
  • 86% in the first 3 years
  • Median time to recurrence is 12(DM) to 18(Local) months
  • Can happen anytime—> Lifelong F/U

Types of recurrence:

  • Local (pelvic)
  • Distant
  • Urethral
    • New primary tumor occurring in the retained urethra

Pelvic (Local) Recurrence

  • Almost all of them die after local recurrence.
  • Pre-op RT doesn't help

Metastatic (Distant) Recurrence

  • More common type of recurrence

Urethral Recurrence

  • Involvement of bladder neck
  • Intra-op frozen section to check margins
  • Represents a second manifestation of the multicentric defect of the primary transitional cell mucosa that led to the original bladder tumour.

What about RADIOTHERAPY and bladder cancer?

Definitive Radiotherapy

  • NOT STANDARD ANYMORE.
    • RT was used as radical treatment from 1950-1980
    • Lower tumour control and survival for RT vs Surgery
  • Since 1980s radical RT is less used.
    • Better in outcomes with cystectomy
    • Development of orthotopic lower urinary tract reconstruction
    • Better results with the bladder preservation approach

Outcome of radical RT:

  • Overall OS:
    • 5yr : 30%
    • 10yr: 18%
  • 5yr Cystectomy free survival
    • ~25%
  • Local Control:
    • 5&10yr : 50%
    • CR in 40%
      • Most happen in high grade disease ( grade III )
  • Severe late complication:
T stage 5yr Local Control 5yr OS DM @ 10yr
T1 50%(35-70) 20%
T2 30%(10-60) 30%
T3 20%(10-40) 55%
T4 40% 10%(0-16) 65%

Adding chemo has not added OS but PFS.

  • Salvage Cystectomy
    • Persistent disease radical RT
    • Recurrent disease
    • Median time from RT is 12m

Results and Mortality of salvage cystectomy:

  • 5yr OS —> ~30%

Technique of Radiation

  • 60 Gy in 30 fractions
  • 50 in 20

Pattern of Failure post RT

  • Persistent tumour post RT
  • Local failure
    • 50%
  • Distant Metastasis
    • 65% ( most common failure post RT and surgery )

Treatment Schedules and affect on Local Control

  • Total dose
    • better when >57Gy
    • Try to keep dose > 60-66Gy
    • 1.8-2Gy per fraction
  • Duration of treatment —> not shown to be important

Altered Fractionation Schedules

Hyperfractionation
  • Prospective randomized trial
    • T2 to T4 tumors
    • Duration of treatment both arms —> 8 weeks
    • Arms: Conventional 64/23 vs :
    • Hyperfractionation schedules
        • 1 Gy given three times per day
        • Total dose of 84 Gy
  • Results:
    • 5- and 10-year survival and local-control benefit in hyperfractionation regimen (p = .003)
      • 52% higher mortality in the conventional arm
      • Late toxicity same

Meta-analysis of two randomized trials also

  • Less death
  • More CR
  • Better survival
Accelerated fraction radiotherapy
  • 66 Gy at 2 Gy daily given over a period of
    • 6.5 weeks
    • 5 weeks —> didn't change toxicity
    • 4 weeks —> 64% had grade III and 30% grade IV!

Radiotherapy in Elderly Patients

  • Dose should achieve at least 55Gy
  • Split course might be an option
  • If palliative
    • 35 in 10
    • 21 in 3
    • Single fraction of 10Gy!
      • Usually good response
        • Median duration of response : 5 m
        • ~2 - 8m

Bladder-Preservation Therapy

  • Maintenance of bladder function is the key
  • Optimal TURB followed by 50.4 Gy EBRT given at 1.8 Gy daily with simultaneous cisplatin chemotherapy (25 mg/m2 daily for 5 days during the first and last week of radiotherapy).
  • Response will be assessed at 6 weeks
  • CR about 60-80%
    • OS better in CR
  • In a prospective study : twice daily radiotherapy with concurrent 5-FU and cisplatin
  • Radiation fields generally encompassed the pelvis to include the external and internal iliac lymph nodes in the PTV.
  • A total dose of 40-45Gy in 1.8-2Gy per fraction + boost 20-25Gy to the primary tumour.
  • ChemoRT delivered as initial

Ottawa Experience:

  • 15yr F/U
  • Three courses of intra-arterial cisplatin
  • EBRT: 40 Gy to the pelvis with a 20 Gy boost to the bladder
  • CR —> 83%
  • Bladder preservation rate —> 75%

Role of Systemic Therapy

  • Gemcitabine and Cisplatin
  • Most commonly used platinum-based regimen : M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin)

Neoadjuvant Chemotherapy

  • Conflicting results
  • Overall response : 60-70%
    • CR: 30%
  • Prospective trials failed to show down staging
  • Neoadj Chemo-RT shown to be beneficial in T3 and T4
    • Nordic Trial
    • 26% downstaging
  • M.D. Anderson study
  • 3 cycles M-VAC —> Cystectomy VS Cystectomy alone
  • Median survival: 77m vs 44m (p = .06)
  • 5yr survival: 57% vs 43% (p = .06)
  • 2004 Advanced Bladder Cancer Overview meta-analysis —> tend to better survival for neoadj chemo

Adjuvant Chemotherapy

  • Better patient selection (comparing with neoadj)
  • Disadvantages is delay in systemic therapy and the inability to assess in vivo response

5 prospective trial—> No clear benefit!

Treatment Toxicity and Its Impact on Quality of Life

  • Loss of bladder
  • Loss of sexuality
  • Chemotherap: Malaise and bone marrow suppression in <20%
  • Radiation
    • Bladder irritability, resulting from mucositis with decreased bladder capacity
      • Frequency
      • Urge incontinence
      • Dysuria
    • GI toxicity
      • diarrhea(mild)
      • anal irritaion
    • Late morbidity
      • 3 months after RT
      • Interstitial fibrosis
      • Contracture
      • Obliterative endarteritis of the vessel perfusing the bladder
        • Painless hematuria
        • Chronic frequency
        • Contracted bladder(5% to 11% of the cases)
          • Needs a carafe investigation—> dd is tumour recurrence

Massachusetts General Hospital QOL report after three modality bladder preservation

  • 75% patients had normal bladder function by urodynamic studies
  • 22% reduced bladder compliance
  • 19% continence problems
    • Half found it stressful
  • 11% wearing pads (all women)
  • Majority had sexual function

QOL after cystectomy vs bladder preservation trimodality therapy

  • Urinary function results comparable
  • Bowel symptoms were more common in RT
  • Erectile function was significantly better in RT group

Preoperative Irradiation

Ideal aims of preoperative RT: :)

  • Tumor size reduction
    • In locally advanced, muscle-invasive disease
  • Decrease in the incidence of local recurrence
  • Decrease in the incidence of distant metastasis
  • Improvement of survival
  • No increase in the incidence of surgical complications.

However, results from M.D. Anderson Hospital and Memorial Sloan-Kettering Cancer Center (MSKCC) showed no benefit! :(

Evidence Supporting Preoperative Radiotherapy

Postoperative Radiotherapy

The main advantage of postoperative radiotherapy over the preoperative treatment is the availability of pathologic staging. This allows the administration of adjuvant irradiation only to those patients who have a high probability of tumor recurrence following radical cystectomy. No large clinical trials on the use of postoperative radiotherapy have been reported. It is of interest to review the RTOG phase II trial using a single fraction preoperative radiotherapy (5 Gy) followed by postoperative irradiation (45 Gy in 5 weeks) in pathologically determined high-risk patients (117). Of the study's 65 patients, 29 received preoperative and postoperative radiotherapy. The treatment program was very well tolerated, and there was no pelvic recurrence. The 3-year actuarial survival was 78%, and in the judgment of the study investigators it was better than the available alternative treatments. This therapeutic approach, however, was not followed in subsequent studies.
Treatment of Patients with Uncommon Bladder Tumors
Squamous cell carcinoma is an uncommon tumor in Europe and in North America. A retrospective study in 19 consecutive patients treated in Italy was reported in 2000 (168). None of the study patients had bilharziasis or spinal-cord injury. Involvement of the prostatic urethra was noted in nine (47%) patients, and the upper urinary tract was involved in an additional five (26%) patients. The majority (79%) of these patients were treated with radical cystectomy; one patient was treated with partial cystectomy, and the remaining three patients had TURB followed by EBRT. Neoadjuvant chemotherapy was given to four (21%) patients, and adjuvant chemotherapy was given to three (4%) patients. At a mean follow-up of 52 months, six (32%) patients were alive and free of disease. Pattern of failure was different from that of transitional cell carcinoma, with locoregional recurrence as a primary cause of death and relatively infrequent distant metastasis. A combination of radical surgery with adjuvant radiotherapy is a recommended treatment.
Two contemporary reports on the management of 19 patients with small cell carcinoma of the bladder were identified (6,101). Patients were treated with a combination of polychemotherapy and pelvic irradiation. Radiotherapy to the pelvis was given at 2 Gy per fraction to about 45 Gy to be followed by a 15-Gy dose to smaller fields. In the British Columbia Cancer Agency study of 14 patients, 10 were eligible for a chemoradiotherapy combination. The 2- and 5-year disease-free survival for these 10 patients was 70%. At the last follow-up 36% of patients were alive and free of tumor. However, all four patients treated with a palliative aim died of disease from 2 to 15 months of therapy. It is interesting that in surviving patients there was a 60% incidence of second primary lesions in the bladder within 3 years of therapy. Transitional cell carcinoma was the most common malignancy diagnosed in these patients.
Carcinosarcoma represents a heterogeneous group of very aggressive malignant lesions (102). The basic two variants are carcinosarcoma and sarcomatoid carcinoma. Most patients were treated with radical cystectomy or TURB with or without adjuvant radiotherapy and chemotherapy. Treatment outcomes were generally poor. Pathologic stage was the best predictor of survival, whereas histologic diagnosis was not a good predictor of outcome. Based on the limited published data on treatment results in patients with carcinosarcoma, it is difficult to recommend treatment policy. It appears that an aggressive multimodality treatment approach will produce an optimal outcome in selected patients with disease limited to the pelvis.
Particle Beams
Electron Beam
Electron beams have been used infrequently in the management of patients with bladder cancer, and at this time its application is of historical interest only. The authors do not recommend the use of electron beam for bladder cancer. On the other hand, intraoperative radiation therapy (IORT) is an important application for electron beam. A major problem relates to its cost because it requires a dedicated linear accelerator in the operating room or immediate access to the accelerator, with sterilizable beam-shaping devices. Radiation dose has to be given in a single fraction; therefore, the radiobiologic advantages of the expanded treatment time or the use of a conventional fractionation schedule is lost. In clinical trials IORT frequently was combined with EBRT. The intraoperative dose usually is delivered with a 4- to 9-MeV electron beam. The final choice of energy depends on the thickness of the target volume, and the typical radiation dose is 25 to 30 Gy (154). A recent review of IORT clearly demonstrated a high incidence of tumor control and a low incidence of severe toxicity in patients treated in contemporary clinical trials (173).
Of interest is a study reported in 2000 from France regarding 27 selected bladder cancer patients with muscle-invasive tumors (154). The treatment program consisted of TURB followed by 48-Gy EBRT given at 2 Gy per fraction with the 18-MV photon beam and cisplatin chemotherapy. This was followed with cystostomy and intraoperative 9-MeV EB delivering 15 Gy to the tumor site. The overall and salvage cystectomy 5-year survival was 53% and 48%, respectively. Of the 27 study patients, 10 (37%) developed distant metastasis and five (19%) had local recurrence. Treatment toxicity seems severe, with three patients developing mucosal necrosis and ureteral stenosis. The role of IORT for carcinoma of the bladder needs to be assessed in a prospective trial. Currently its use is not recommended outside of such studies.
Neutron Beam
It is of interest to review a prospective randomized trial comparing 4- to 8-MV photon beams versus a 15-MeV neutron beam in 108 patients with T2 and T3 tumors (138). The 1- and 5-year survival rates for both treatments groups were very similar, with greater toxicity being reported in those treated with neutron beam. Based on a lack of therapeutic gain, the use of a 15-MeV neutron beam with the treatment schedule reported in this study is not recommended in patients with carcinoma of the bladder.
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Treatment Techniques
External Beam Radiotherapy
The use of high-energy photon beams (10 MV or more) is preferred in the treatment of patients with carcinoma of the bladder. The treatment volume initially includes the whole bladder, proximal urethra, and, in male patients, the prostate with the prostatic urethra and the regional lymphatics. The regional lymphatics adjacent to the bladder include hypogastric, external iliac, and obturator lymph nodes. Subsequently, patients receive radiotherapy to a smaller boost volume, which usually includes the bladder with about a 2-cm margin. A common definition of anatomic extent of the radiation portals is as follows:
The anteriorโ€“posterior fields extend laterally about 1.5 cm to the bony pelvis at its widest section with inferior corners excluded to protect the femoral heads.
The lateral fields extend anteriorly to about 1.5 to 2 cm from the most anterior aspect of the bladder as seen on an imaging study (CT). The posterior border lies about 2.5 cm posterior to the most posterior aspect of the bladder and falls within the rectum. Inferiorly, the tissue above the symphysis and the anal canal is blocked.
The inferior border is placed below the middle of the obturator foramen. The superior border is usually at the L5-S1 disc space.
There is, however, an ongoing debate whether the regional pelvic lymph nodes should be included in the radiation portals. The RTOG and some other investigators recommended the inclusion of the regional lymph nodes (177,211), while the recommendations of the Fourth International Consensus Meeting on Bladder Cancer are against this treatment policy (60,136). In the latter policy the bladder with a 2-cm margin is the recommended treatment volume. Digitally reconstructed radiographs of the induction radiation fields are shown in Figure 61.1A,B.
There is an additional controversy regarding the initial pelvic fields with regional lymph node inclusion with a full or empty bladder. The argument for the latter is that the overall irradiated volume is smaller. However, when treated with full bladder the distended organ is expected to push more of the small intestine and some part of the rectum out of the radiation field. The four-field box technique is used most frequently for the treatment of the initial large pelvic volume. It provides a relatively homogeneous dose distribution over the treated volume, while keeping the radiation dose outside this volume to about 50% of the intended tumor dose. Because much of the bladder is anterior to the coronal midplane, preferential weight can be given to the anterior field, relative to the posterior one. The preferential anterior weight and the shape of the external contour of the patient may cause a higher dose in the anterior part of the treatment volume, which easily can be reduced by applying appropriate wedges in the lateral fields. The treatment setup and the resulting dose distribution in the three principal planes are shown in Figure 61.2Aโ€“D.
The boost fields include either the whole bladder or only the involved part of the bladder with at least a 2-cm margin. These fields need to be set up and monitored with great care in view of the well-recognized bladder volume changes occurring during the treatment course (116). Although the most commonly used treatment technique is the four-field box with field sizes adjusted to the smaller boost volume, many other techniques can be employed, such as two lateral fields, three or four oblique fields, or rotational arc techniques. Treatment setup and dose distribution of the four-field box boost is shown in Figure 61.3A,B. As examples for other techniques, treatment setups and dose distributions of three oblique fields and bilateral arcs are shown in Figures 61.4A,B and 61.5A,B. The choice between these techniques depends on a number of factors such as the preference of the radiation oncologist, the tumor location, the target volume, and the dose delivered with the initial large pelvic portals to the dose-limiting structures such as femoral heads, rectum, and small intestines. There is a consensus, however, that when the desired treatment volume is the bladder only, the bladder should be treated empty. To decrease the overall irradiated volume, partial bladder boosts typically are treated with an empty bladder. However, consideration may be given to the treatment delivered with a full bladder if the target volume is relatively small and distending the bladder increases the distance between the target and the dose-limiting structures.
Because of the well-documented mobility of the bladder during the treatment, large enough margins have to be added to the intended target volume to accommodate its possible motion. Treating always with either an empty or full bladder can diminish, but not completely eliminate, the variation of the
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location of the target volume. Neither can this variation be eliminated by using patient immobilization devices such as bean bags, thermoplastic sheets, or the like. The application of these devices still is recommended to increase the reproducibility of the patient setup and to limit the patient's movement during the treatment.
Due to the mobility of the bladder, strictly conformal (no margin) radiotherapy of bladder tumors needs to be given with great care to ensure targeting accuracy for every treatment (95,100). However, advanced localization techniques such as implanted markers and gating technology (the beam turns off if a marker moves out of its permitted range) may make conformal therapy possible in the near future (171). Portal imaging systems are helpful in real-time monitoring of treatment accuracy (56). Since then the rapid development of techniques of conformal therapy inspired intensive research on new methods of external beam bladder irradiation, including conformal, intensity-modulated radiation therapy (IMRT), and adaptive techniques.
The first step is to find reliable methods of observing, predicting, and/or modeling the motion and deformation of the bladder. Easy access to CT (either conventional or onboard cone beam CT) makes repeat imaging feasible, thus the motion and
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deformation of the bladder can be observed. The repeat scans then can be used to:

Build an overall primary tumor volume (PTV), which will be treated during the entire session (113,124),
Modify the PTV as the treatment advances (image-guided radiation therapy [IGRT] and adaptive therapy) (142,147), or
Build mathematical models to predict the location and shape of the GTV and the adjacent organs (237).
At the present time appropriate margin selection and localization of the volume of the irradiated healthy tissues can be reduced, even with the conventional four-field technique. However, more conformal treatment techniques, like IMRT, tomotherapy, and so forth, can also be applied. Some relevant answers may be provided following completion in 2008 of an ongoing clinical trial (NCT00350688) at the Ottawa Hospital Regional Cancer Centre, Ontario, Canada, using helical tomotherapy IMRT in patients treated with a chemoradiation regimen.
The commonly accepted treatment schedule in patients with bladder cancer is 180 to 200 cGy per day to a total of 45 to 50 Gy to the whole pelvis, followed by a boost to a smaller volume to a combined total dose of 60 to 65 Gy.

In case of comorbidities, patient not candidate of surgery and chemo:

Multi-modality Bladder Preservation

Treatment Results

  • Organ preserving modality
    • TUR then : Chemo-RT
  • Total Cystectomy
    • Male : removal of bladder; prostate; proximal vas deferens; proximal urethra; seminal vesicle + margin of adipose tissue
    • Female : removal of bladder; urethra; uterus; fallopian tubes; ovaries; ant vaginal wall +surrounding fascia
  • Before cystectomy gross abNl LN are sampled.
  • If LN+ ==> NO CYSTECTOMY unless for symptoms( urinary diversion )
    • Urinary diversion : through ileal conduit opening into abdo wall through a urostoma