Block 5 - Genitourinary Cancers

ONCOL 309 - Clinical Oncology I. University of Alberta

What is the bladder?

A sac-like organ that stores urine produced by the kidneys

• can hold up to 500 mL of fluid: will push up agaisnt the umbilibus when full and will lie behind the pubic symphysis when empty

What do ureters do?

drain the urine from the kidneys into the bladder

what does the urethra do

drains the urine for elimination from the body

does the bladder sit in-front or behind the pelvic bone, and where does the rectum sit

The bladder sits behind the pubic bone, while the rectum is located posterior to the bladder.

what is the lining of the urinary tract called?

the urothelium

• extends from the renal pelvis to the urethra and is lined by transitional epithelium

what are the 4 different layers of the bladder

1. transitional epithellium

• in contact with urine

2. lamina propria

• a layer of connective tissue and blood vessels

3. detrusor muscle

• deep muscle layer made of thick smooth musle to form the wall of the bladder

4. perivascular fat

• outer most layer: fat, fibrous tissue, and blood vessels

is bladder cancer more common in males or females?

males: 3x more likely

• females will get the more aggressive form of the disease though

how does bladder cancer risk increase with age; and what percent of patients are older than 60

risk increases with age

• 80% of case are over the age of 60

What type of bladder cancer is most common in developed countries, what about developing countries?

transitional cell carcinoma (TCC) = developed countries

squamous cell carcinoma (SCC) = developing countries

what is the number one risk factor for bladder cancer

smoking tobacco

• smokers are 2-3 times more likely to develop bladder cancer compared to non-smokers

smokers account for what percent of bladder cancers

approximately 50% of cases

etiological risk factors of bladder cancer

1. arsenic

2. aromatic amines from occupational exposure (diesel engines, paintin, rubber)

3. race (white is twice more likely to get disease, black is twice more likely to die)

4. prior exposure to abdo/pelvic RT

5. cyclophosphamide chemo

6. bladder birth defects

7. irritation and infection

8. lynch syndrome

what is lynch syndrome

a hereditary condition that increases the risk of various cancers, including colorectal and endometrial cancer. It is caused by mutations in DNA mismatch repair genes.

what are the three natural histories of bladder cancer

1. non-muscle invasive

2. muscle invasive

3. metastatic disease

Non-muscle invasive bladder cancer

70-80% of tumors are superfical and non life threatening

• these tumors tend to recur often and is a chronic condition

• can progress to muscle invasion

Muscle Invasive bladder cancer

20-30% of tumors that have grown in to deep muscle layers

• poor prognosis and higher rate of metastatic disease at diagnosis

Metastatic bladder cancer

most patietns who have had prior treatment for localized disease

• median survival is 12-18 months, depending on the disease extent and patient’s health status

Local presentation of bladder cancer

painless hematuria (80-90% of cases)

increased bladder irritability: frequency, incontinence, dysuria, urgency

locally advanced presentaiton of bladder cancer

pelvic pain, lymphedema, and renal poor function

metastatic bladder cancer presentation

bone pain

palpable abdomen or pelvic mass

flank pain from ureter obstruction

edema of lower extremeities

respiratory symptoms: coughing, dyspnea, hemoptysis

What screening is done for bladder cancer

no current screening exits

• no evidence that early treatment of bladder cancer leads to better health outcomes and less mortality

describe the lymphatic trail from the bladder to the thoracic duct

internal iliac —> external iliac —> common iliac —> para-aortic —> cisterna chyli —> thoracic duct

what is the lymphatic spread risk for superficial tumours, detrusor muscle tumors, and deep tumors

superficial tumors: <5%

detrusor muscle: 20%

deep tumors: 20-40%

what three sites does bladder cancer generally spread to

bone

liver

lungs

poor prognostic factors of bladder cancer

• depth of tumor invasion into bladder wall

  • the deeper the dx, the less favourable

• grade

  • high grade tumors tend to grow into muscle walls and metastasize

• carcinoma in-situ

  • associated with poor prognosis and a higher chance of recurrence

• type of tumor

  • SCC is worse than TCC, papillary urothelial have best prognosis

• multiple tumors is no good

• size of tumor

• recurrent tumors

• LN invasion

what are the three types of bladder cancers

1. urothelial (transitional cell) (90%)

2. squamous cell tumors (3-8%)

3. adenocarcinomas

Transitional Cell tumors

tumors in the lining of the bladder wall, these cells can change shape and stretch without breaking apart

• tend to spread in head to toe direction: renal pelvis to ureter

Squamous Cell Tumors

more common in developing countries, worse prognosis

• due to chronic infections, bladder stones, schistosomiasis

what are the two subtypes of Transitional Cell tumors

1. Papilary (Ta)

• finger like projecitons that grow from inner surface towards hollow part of bladder

  • do no grow deep into muscle layers

  • non-invasive, slow growing tumors

  • tend to have good outcomes

2. Flat (Tis)

• do not grow towards the hollow area of bladder, and are only found on the surface of the bladder

  • high recurrence rate

What are the 7 steps to diagnosing bladder cancer

1. history and physical

• including smoking history and occupational exposures

2. urinalysis - rule out UTIs

3. cytology - examine bladder cells under microscope

• identify high grade tumors, cancer recurrences

4. blood work

• CCC, electrolytes, CBC, CEA

5. cytoscopy

• assess size and mobility of palpable masses: location, size, appearance extent of dx

• can do bx at same time

6. intravenous pyelography or ultrasound-

• size of tumor and extension along bladder wall

7. CT/MRI (assess LN and appearance)

what is the gold standard for diagnosing bladder cancer

Cystoscopy with biopsy

• to obtain tissue samples for histological examination. and to assess masses

why are CT and MRI not main choices to diagnose bladder cancer

underestimates extent of the tumor with respect to more deeply invasive tumors

what is a transurethral resection of bladder (TUR)

A surgical procedure used to remove bladder tumors or abnormal tissue through the urethra, often performed to treat bladder cancer.

• removes tumor for early stage dx

• bx and assess muscle invasion

if there is muscle invasion at the time of TUR for bladder cancer, what imaging is then done?

CT abdo/pelvis to see LN involvement

What is an intravenous pyelogram and what is it used for

Opaque medium is injected into a vein and the excretion of the kidneys can be radiographed

• Used to show renal or ureteral disease or for localization

Has been replaced as a means of localization in RT with the use of the CT scanner which is less invasive.

What is the most important stage for bladder cancer

Stage muscle invasion (T2)

• muscle invasion determines what treatment is done

TNM staging for bladder cancer - T

Tx = primary tumor cannot be assess

T0 = no evidence of primary tumor

Ta = non-invasive papillary carcinoma

Tis = carcinoma in situ = flat tumor

T1 = tumor involves subepithelial connective tissue

T2a = tumor invades superficial muscle

T2b = tumr invades deep muscle

T3a = tumor invades perivesical tissue microscopically

T3b - tumor invades perivesical tissue macroscopically

T4a = tumor invades prostate, uterus, or vagina

T4b = tumor invades pelvic or abdominal wall

TNM Staging for bladder cancer - N

Nx = regional LN cannot be assessed

N0 = no regional LN mets

N1 = single regional LN (<2 cm) in true pelvis

N2 = multiple regional LN in true pelvis

N3 = mets. to common iliac nodes

TNM staging for bladder cancer - M

Mx = distant mets cannot be assessed

M0 = no distant mets

M1 = distant mets

Stage groupings

Stage 0a: early cancer, surface of the inner lining of the bladder, No invasion of the muscle or connective tissue of the bladder wall. Noninvasive papillary urothelial carcinoma (Ta, N0, M0).

Stage 0is: A flat tumor or carcinoma in situ (CIS), only on the inner lining of the bladder. No growth toward the hollow part of the bladder, no spread to muscle or connective tissue of the bladder (Tis, N0, M0). High-grade cancer - aggressive disease because it can often lead to muscle-invasive disease.

Stage I: The cancer has grown through the inner lining of the bladder and into the lamina propria. It has not spread to the thick layer of muscle in the bladder wall or to lymph nodes or other organs (T1, N0, M0).

Stage II: The cancer has spread into the thick muscle wall of the bladder - muscle-invasive cancer. The tumor has not reached the fatty tissue surrounding the bladder and has not spread to the lymph nodes or other organs (T2, N0, M0).

Stage III: The cancer has spread throughout the muscle wall to the fatty layer of tissue surrounding the bladder (perivesical tissue) or to the prostate in a man or the uterus and vagina in a woman. Or, the cancer has spread to the regional lymph nodes.

Stage IIIA: The tumor has grown into the perivesical tissue or has spread to the prostate, uterus, or vagina, but has not spread to the lymph nodes or other organs (T3a, T3b, or T4a; N0; M0), or the cancer has spread to a single regional lymph node (T1 to T4a, N1, M0).

Stage IIIB: The cancer has spread to 2 or more regional lymph nodes or to the common iliac lymph nodes (T1 to T4a, N2 or N3, M0).

Stage IV: The tumor has spread into the pelvic wall or abdominal wall, or the cancer has spread to lymph nodes outside of the pelvis or to other parts of the body.

Stage IVA: The tumor has spread to the pelvic wall or the abdominal wall but not to other parts of the body (T4b, any N, M0), or the cancer has spread to lymph nodes located outside of the pelvis (any T, any N, M1a).

Stage IVB: The cancer has spread other parts of the body (any T, any N, M1b).

Bladder Cancer grading (G1,2,3)

G1 = well differentiated

G2 = moderately differentiated

G3 - poorly differentiated

What are the management categories for bladder cancer

• superfical bladder cancer (T1s, Ta, T1)

• muscle-invasive bladder cancer (stage T2a)

  • deep muscle invasion, perivesical fat, prostate involvement (T2b, T3, T4a)

• locally advanced bladder cancer (T4b)

• metastatic 

what is a radical cystectomy

• removal of the entire bladder, nearby LN, part of the urethra and nearby organs containing cancer cells 

• male – prostate, seminal vesicles, and proximal urethra

• female – urethra, uterus, ovaries, fallopian tubes, anterior vaginal wall

• can preserve sexual function/potency

  • 5 year overall survival is 50% after a radical cystectomy

What is a segmental cystectomy

• removal of part of bladder wall

• high recurrence rate of 50-70% (will invade bladder musculature)

• <5% of patients are candidates

  •  if tumour is solitary and localized to the bladder dome and NOT associated with CIS + able to be removed with 3 cm margins

After a cystectomy, what are the three different ways to reconstruct the urinary tract

1. ileal conduit

•  a piece of small intestine is used to create a tube that connect your ureters and kidneys to an opening in your abdominal wall (stoma). 

  • A exterior bag will continuously drain the urine from the stoma

2. neobladder reconstruction

• Using a larger piece of bowel the surgeon creates a new bladder and attaches it to your ureters and urethra to drain urine. Sometimes a catheter is still required to drain the bladder.

3. conduit urinary reservoir

• Using a piece of bowel, the surgeon creates a small reservoir inside your abdominal wall. It is drained with a catheter. No collection bag needed. 

what is Bacilus Calmette-Guerin (BCG) intravesical therapy

an immunotherapy treatment to treat early stage tumors

• drug is given directly into your bladder (germ that is related to TB), this will activate the immune system to attack cancer cells

• leads to a 70-80% 5YS in T1 tumors

Side effects of BCG therapy

flu like symptoms, hematuria, urinary frequency, burning sensation while urinating

what class of chemo drug is considered the standard of care for bladder cancer

Platinum-based chemotherapeutics

• 5% survival benefit and helps patients become eligable for bladder sparing

What is the new combo regiment chemotherapy for bladder cancer

Gemcitabine + cisplatin

• shows good response rate for fewer side effects

Old chemo regime for bladder cancer

MVAC

• methotrexate

• vinblastine

• Doxorubicin/adriamycin

• cisplatin

intravesical chemotherapy for bladder cancer

• mitomycin C

• gemcitabine (less side effects than MC and less blood absorption)

• Valrubin (same side effects as BCG)

why does giving chemo right to the bladder decrease side effects?

Delivering chemotherapy directly to the bladder minimizes systemic exposure, thereby reducing side effects while targeting the tumor more effectively.

Cyclophosphamide for bladder cancer

• Alkylating agent (Nitrogen mustard derivative)

• Can enhance radiation damage to tissues, know as a ‘recall radiation reaction’

  • Acute inflammatory reaction confined to irradiation tissue

is radiation therapy used for superficial bladder tumors?

no

when is RT used for bladder cancer

typically used post-op for bladder preservation

• T3b, T4 or positive surgical margins

is RT indicated for node positive disease?

no, not generally indicated as distant mets are the concern, not local recurrence

What is the treatment protocol for low grade superficial bladder cancers (Ta or T1)

Transurethral resection with bx

• then re-resection within 4 weeks (since tumors are often understaged in bladder)

if the Bx are positive following TUr for low grade superficial bladder cancers, what is the next treatment steps

T1: BCG intravesical injection

Ta: mitomycin C intravesical chemo

Is RT involved in the treatment of low grade superficial bladder cancer?

no

What is the treatment protocol for high grade superfical bladder cancer?

Transurethral resection + mitomycin C chemo

• 4 weeks later: BCG intravesical injection

  • cystectomy if BCG fails 

is there RT involved in the treatment for high grade superficial bladder cancer?

no, does not respond reliably to therapy

What is the treatment protocol for muscle invasive bladder cancer (Stage T2a)

cystectomy

radiation therapy ± chemotherapy (bladder sparing)

what is the treatment protocol for deep muscle, perivesical fat, or prostate involvement (T2b, T3, T4a)?

• radical cystectomy + LN dissection

  • or RT (for bladder preservation)

• we also have multimodality options for concurrent chemo and RT or tri approach

what is the treatment protocol for locally advanced bladder cancer (metastatic T4b)?

initial treatment is with chemo, but then rest of treatment is case by case

• palliative RT or Pt based chemo may then be used

Bladder Cancer Treatment Pathway

good for studying

Bladder Cancer Radical Radiation Therapy - Phase 1:  treatment energy, technique, dose / fractionation and margins,

10 MV or greater

4 Field Box

45  Gy / 25 fraction

treat entire pelvis, including external/internal iliac nodes, bladder, and margin around bladder and prostate. 

we want bladder full if possible but empty is an option

why are the common iliac nodes not targeted in phase 1 bladder cancer treatment

higher risk of disease in internal/external and to limit bowel toxicity

what does bladder filling for bladder cancer treatment depend on

• patient condition - if patient can hold their bladder, if they have a bladder

• doctor preference

• Full bladder is the ideal option for whole pelvis tx to reduce small bowel toxicity

  • May involve clamping/locking a patient’s catheter ahead of treatment to have a consistent bladder volume

  • This must be followed for successive treatment phases or re-sim patient with an empty bladder for boost fields

• Empty bladder - reduces size of bladder and therefore we can have smaller treatment fields

  • consistent way to ensure internal anatomy is localized for treatment

why do we plan patient with bladder cancer for RT with both a full and empty bladder

allows for evaluation of best plan and can use either set-up for boost

Bladder cancer phase 1 treatment volumes - superior

L5/S1

• include internal and external iliacs

Bladder cancer phase 1 treatment volumes - inferior

bottom of obturator foraman or 2 cm below tumor

• men: coverage of prostate

• women: proximal 2 cm or urethra

Bladder cancer phase 1 treatment volumes - laterally

1.5 - 2 cm lateral to pelvic brim

Bladder cancer phase 1 treatment volumes - anterior

extend 2 cm anterior to bladder and pubic symphysis

Bladder cancer phase 1 treatment volumes - posterior

extend 2 cm beyond bladder or any visable tumor/iliac nodes

Radical Bladder Cancer RT Phase 2 - technique and dose fractionation

4 field box with/without oblique combination

20 Gy / 10 fraction (so total treatment with phase 1 = 65 Gy / 35)

• 8 Gy to entire bladder

• 12 Gy to tumor + 2 cm margin

When is palliaitve EBRT used for bladder cancer

for patients who are not eligble for cystectomy or have metastatic disease

Palliative bladder cancer treatment technique and dose fractionation

large pelvic POP

30 Gy / 10 Fractions

5 OARs for bladder cancer treatment

1. bladder

2. rectum

3. small bowel

4. large bowel

5. femoral heads

review TD5/5s and max doses

what is the acute reaciton of the bladder to 30 Gy

cystitis

acute side effects for RT to bladder

fatigue

skin erythema

radiation cystitis (freq, urgency, dysuria)

mild diarrhea and tenusmus (persistent, often painful, sensation of rectal fullness and the urgent need to pass stool, even when the bowel is empty)

hair loss in Tx area

chronic side effects for RT to bladder

cystitis

• decreased bladder capacity = 30 Gy

• increased frequency = 70 Gy

• painless hematuria 

Fibrosis

bleeding

ulcerations

surgical complications from bladder cancer

blood loss, rectal injuries, importence, urinary infection, obstruction

chemo reactions from bladder cancer

chemical cystitis

myelosuppression

why is patient follow up and cytology so important for bladder cancer

This is a very aggressive disease with a poor prognosis.  If disease left untreated: 

• 50 % die within one year

• 75 % die within 2.5 years

do cytology and cyscopy every 3-6 months for 2 years after tx completetion

5 year survival rates for bladder cancer

emerging technology for bladder cancer treatment

hexaminovulinate blue light cytoscopy

• Presence of missed tumour could link to high recurrence rate 

• Photosensitizer injected right into bladder before cystoscopy

• Photosensitizer accumulates in rapidly dividing cells, usually malignant cells, and shows red when under blue light

• Improves visualization of the bladder - more accurate staging and reducing tumour recurrences

Penile Cancer Epidemiology

• rare; occurs <1% of cancer in men

  • occurs in men aged 60 and older

  • peakts at 80

• south america, china, africa have higher incidence

Etiological factors of penile cancer

• poor personal hygiene

• HPV infection

• many sexual partners

• smokers

• phymosis (the inability to retract the skin (foreskin or prepuce) covering the head (glans) of the penis)

Prognostic indicators of penile cancer

• location and size of tumor

• stage (status of nodes)

• tumor differentiation

• incidence of nodal involvement

why is nodal invovement relvant to prognostic factors of penile cancer

tumor free regional nodes = excellent long term survival 

inguinal node involvement = 40-50% 5YS

pelvic node involement = <20% 5YS

what are the two carcinoma in-site premalignant lesions of penile cancer

1. bowen’s disease (SCC in situ)

2. erythroplasia of queyrat (Bowen’s of penis)

what is the name of the precancerous dermatolgic lesion of penile cancer

leukoplakia

what is the histology of penile cancers

mostly well-differentiated SCC

• melanoma, sarcoma, and metastatic dx are possible but rare

where do most penile carcinomas start?

in the preputial area; arising in the glands, coronal sulcus or the prepuce

what is the most common LN penile cancer will go to

the inguinal lymph nodes

what is the most common metastatic site for penile cancer

lungs

what is the clinical presentaiton of penile cancer

• redness, sores on penis

• bloody discharge

• warty growths/ulcers (like SCC of skin)

• dysuria

• hematuria

diagnosis and detection of penile cancers

• Urinalysis 

• CBC 

• CXR 

• Clinical exam 

  • primary lesion  

  • inguinal node (30% are palpable at presentation) 

• Biopsy under local anesthetic 

• CT – to determine LN involvement 

• MRI & US of penis

what are the four pathological types of penile cancer

1. SCC (most common)

2. Verroucous cancer (a slow-growing, rare, low-grade variant of squamous cell carcinoma)

3. Warty and basaloid carcinoma (HPV associated)

4. neuroendocrine (rare)

TNM staging of Penile Cancer - T

T1 - Tumor invades subepithelial connective tissue 

T2  - Tumor invades corpus spongiosum or cavernosum 

T3 - Tumor invades urethra 

T4 - Tumor invades other adjacent structures