Cancers of the genitourinary system

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12 Cancers of the genitourinary system

M. Beresford

Cancer of the kidney

Introduction

Renal cell carcinoma (RCC) accounts for 2–3% of all cancers, with 6600 new diagnoses and 3600 deaths per year in the UK. There has been an increasing incidence over the past 10–15 years, at least in part due to more incidental tumours being found with the increased use of cross-sectional imaging. Peak age at presentation is between 65–75 years, with very few cases in the under 40 age-group. The male to female ratio is 3 : 2.

Aetiology

Risk factors for renal carcinoma are as follows:

• Smoking – smokers are more likely to develop RCC than non-smokers and the effect seems to be dose-dependent, with heavy smokers having a relative risk of 2.0.
• Occupational exposure – risk ratios of 1.3 to 1.6 have been observed in individuals exposed to petroleum, hydrocarbon, steel, asbestos, cadmium or dry cleaning products.
• Analgesic nephropathy – there is an increased risk of RCC in patients who develop nephropathy associated with the use of phenacetin-containing analgesics.
• Obesity – obesity increases the risk of developing RCC, with a linear relationship between body weight and risk (odds ratios of up to 4.8). Excessive consumption of red meat and dairy products might increase risk, but there appears to be no relationship with alcohol or caffeine intake.
• Acquired cystic kidney disease – in dialysis patients.
• Genetic factors – Von Hippel–Lindau disease is a familial disorder characterized by the development of multiple tumours including bilateral renal cell carcinomas, retinal/central nervous system haemangioblastomas and phaeochromocytomas. Hereditary papillary renal cell carcinoma (HPRC) is a condition in which patients are at risk of developing multiple, bilateral type 1 papillary renal carcinomas and involves mutation in the c-met oncogene.

Pathology

In adults, 85% of malignant lesions arising from the kidney are renal cell carcinoma, with most of the remainder being metastases from other primary tumours. Other rarer cancers include clear cell sarcoma, lymphoma, oncocytoma and adult form of Wilms’ tumour.

• Renal cell carcinomas (RCCs) – most RCCs are well-differentiated and usually arise within the upper pole. The majority are of clear cell origin although they often contain several different cell types, including granular cells and spindle cells (the poor prognosis sarcomatoid variant).
• Transitional cell carcinomas – are relatively uncommon, accounting for 5% of malignancies in the kidney, and are sometimes a result of analgesic nephropathy. They arise in the renal pelvis and often affect multiple sites of the urothelial mucosa with 50% having a history of bladder tumours. Transitional cell carcinomas of the renal pelvis are usually discovered late, although occasionally present earlier with obstructive symptoms. Due to the proximity to the renal vein, they tend to spread early, typically with metastases to lung and bone. 5-year survival varies from 10–70% depending on tumour grade.
• Squamous cell carcinomas – these are rare and usually associated with chronically infected staghorn renal calculi. Presentation tends to be late, with locally extensive disease.

Presentation

Renal tumours often remain asymptomatic and unnoticed until large. The classical triad (also known as ‘too late’ triad) of presenting symptoms (loin pain, haematuria and flank mass) occurs in less than 10% of patients. Up to 20% of patients have a history of fever at presentation, and a third report weight loss and cachexia. 30% have metastatic disease at presentation and a further 25% have locally advanced disease. Typical sites of metastases include lungs (75%), lymph nodes/soft tissue (36%), bone (20%) and liver (18%). Patients may also demonstrate a number of paraneoplastic manifestations such as polycythaemia, hypercalcaemia etc.

Investigations and staging

Initial investigations include urinalysis for protein, blood and cytology. Blood tests should include full blood count, urea and electrolytes, liver function, clotting and calcium levels.

Imaging

CT scan: CT scan appearance (Figure 12.1) is important in determining the appropriate surgical procedure – laparoscopic, partial or radical nephrectomy. Size is important in diagnosis – benign cortical adenomas can look like malignancies but tend to be less than 3 cm in diameter.

image

Figure 12.1 CT scan showing an irregular mass lesion arising from the left kidney.

Other investigations: for small tumours, a chest X-ray is sufficient for staging if the CT scan does not include the chest. Ultrasound and colour flow Doppler are useful in assessing renal vein and inferior vena caval invasion. A bone scan should be considered if there are symptoms or a raised alkaline phosphatase.

If there are concerns about renal reserve from imaging or renal function blood tests, then more formal assessment of renal function is appropriate.

Staging

Stage (Table 12.1) determines the prognosis and treatment of renal tumours.

Table 12.1 Staging of tumours of the renal parenchyma

Stage    
I T1 N0 M0
7 cm or less in size, confined to kidney
T1a ≤4 cm
T1b >4 cm ≤7 cm

II T2 N0 M0 >7 cm in size, confined to kidney III T1/2 N1 M0 Confined to kidney, metastases in a single regional node T3 N0/1 M0 T3a Invades adrenal gland or perinephric tissues but not beyond Gerota fascia T3b Extends into renal vein(s) or vena cava below diaphragm T3c Extends into vena cava above diaphragm IV T4 N0–2 M0 T4 Invades beyond Gerota fascia T1–4 N2 M0 N2 Metastases in >1 regional node T1–4 N0–2 M1 M1 Distant metastases

Management

Surgery of the primary tumour

Curative

The definitive treatment for renal cancer is surgical resection. Radical nephrectomy is performed by an anterior approach and en bloc removal of the kidney, adrenal and perirenal fat. The adrenal gland is rarely involved in T1 or T2 tumours and can be left behind. If tumour invades the renal vein, this can be ligated distal to the tumour thrombus and even partial vena caval resection may be undertaken if necessary.

Regional lymphadenectomy is sometimes performed during the radical procedure, but its role in prolonging survival is debatable.

Recent improvements in surgical techniques have enabled laparoscopic partial or total nephrectomies as a less invasive technique for removing kidneys with small volume tumours. Nephron-sparing surgery should be considered particularly for patients with poor renal reserve or non-functioning contralateral kidneys.

Palliative

Nephrectomy should also be considered as a palliative procedure in patients with metastatic disease. Although very rarely (<1%) this may result in regression of metastases (‘abscopal effect’), it is not the main reason for considering surgery. It is aimed mainly at reducing symptoms such as pain, haematuria and hypercalcaemia. Removal of the tumour bulk may also improve the efficacy of any subsequent systemic treatment – trials have shown that patients with metastatic disease who are treated with interferon have improved survival if they undergo palliative nephrectomy prior to the immunotherapy.

Adjuvant therapy

Adjuvant therapy with interferon-α following nephrectomy has been investigated and does not appear to confer any survival advantage. More complicated and toxic regimes using combinations of interferon, interleukin-2 and 5-fluorouracil (known as the Atzpodien regimen) have not proved any better and in fact may be detrimental.

Metastatic disease

Interferon-alpha

Interferon alpha is a cytokine with anticancer and antiviral activity. Response rates in metastatic RCC are reported as 10–15% with a 2% complete response rate (although there are also occasional reports of spontaneous remissions off treatment) and a stable disease rate of approximately 25%. A Cochrane review showed a 3-month survival benefit with interferon compared with no interferon. Interferon may be better in ‘good’ prognosis metastatic disease, based on the number of disease sites, performance status and diagnosis to metastases interval.

The optimal regimen of interferon is not yet known. Typical dose schedules are of 9–12 mega-units subcutaneously three times per week, often starting at a lower dose to assess tolerability. Treatment is discontinued at disease progression or after 6–9 months, whichever comes first. Blood counts and liver function should be monitored during treatment.

Interferon has significant side effects (Box 12.1) that impact on quality of life. These effects are dose dependent, but the majority tend to stop quickly on discontinuation of treatment. Common side effects include fatigue, flu-like symptoms, diarrhoea, nausea and vomiting, anorexia, bone marrow suppression and rash at injection site.

Box 12.1
Indication for radical cystectomy

• Severe/persistent carcinoma-in-situ
• Muscle invasion
• Multiple recurrences of T1 disease despite intravesical treatment
• T1 G3
• Squamous cell carcinoma and adenocarcinoma
• Unreliable patient (surveillance is not realistic)

Interleukin 2

Interleukin works by stimulating cytotoxic T-cells. It can be given subcutaneously, by high-dose bolus intravenous injection or by continuous infusion (all give similar results). It has been used instead of or in combination with interferon, and seems to result in improved response rates (of 15–20%), but with no improvement in overall survival and significantly worse toxicity than interferon.

Medroxyprogesterone-acetate

The response rate is only 5–7%. Trials comparing progestins and interferon therapy show a survival benefit of approximately 2.5 months in favour of the interferon.

Chemotherapy

Response rates with chemotherapy are less than 10%. A few cases of sarcomatoid variants of RCC have responded to sarcoma chemotherapy regimes such as doxorubicin and ifosfamide.

Novel agents

Various new targeted therapies have shown positive results in the treatment of metastatic renal cell carcinoma and are generally better tolerated than interferon-α and interleukin-2. Studies are now concentrated on the use of these agents in the adjuvant setting and their sequencing in metastatic disease.

Sorafenib and sunitinib are oral multiple kinase inhibitors affecting VEGF, PDGF and c-KIT tyrosine kinases among others (p. 370). They have both antiproliferative and antiangiogenic activity. A phase III trial of sorafenib versus placebo in metastatic RCC patients on second-line systemic therapy showed an improvement of progression-free survival (5.5 months versus 2.8 months respectively).

In the first line setting sunitinib has shown a median progression-free survival of 11 months in comparison with 5.1 months with interferon-α (p < 0.000001) and the median overall survival was 26.4 months with sunitinib and 21.8 months with interferon (p = 0.51). Sunitinib is the recommended treatment in the UK for patients with performance status 0–1. The dosage is 50 mg once daily for 4 weeks with a 2-week rest period (6-week cycle). Dose may be decreased in steps of 12.5 mg according to tolerance, but there is evidence that efficacy is related to dose-intensity. Adverse events include rash, diarrhoea, hand–foot skin reaction, fatigue, thrombocytopaenia and hypertension. These are usually easily managed and rarely result in permanent discontinuation of therapy.

Temsirolimus inhibits activity of mTOR, which features downstream in the cell signalling pathway and is thought to be a point into which other critical pathways feed. It is an intravenous agent which appears to improve progression-free survival when compared with interferon in metastatic RCC and has shown particular benefit in poor prognosis patients. Everolimus, an oral mTOR inhibitor, has proven benefit in the second-line setting on progression after previous tyrosine kinase inhibitor treatment.

Bevacizumab is a monoclonal antibody which inhibits VEGF. In conjunction with interferon it has been shown to double progression-free survival in previously untreated metastatic RCC when compared with interferon alone.

Radiotherapy

Radiotherapy can be used to control bleeding and pain from primary tumour sites and to treat symptoms associated with bone and central nervous system metastases.

Surgical management of metastases

Resection of metastases from RCC should be considered, particularly for pulmonary lesions, where excellent results can be achieved. Consideration of surgical management should not be confined to solitary metastases, although the best survival figures are seen after complete resection of solitary lesions, with 5-year survival rates of up to 50% compared with 20% following complete resection of multiple lesions. A longer interval between primary tumour and development of metastases correlates with a longer disease-specific survival. Resection of cerebral metastases has also shown favourable results, particularly when there is a long interval from resection of the primary.

Prognostic factors and survival

Survival remains limited for patients with RCC, however in selected patients with metastatic disease, long-term survival is recognized. Characteristics associated with a better prognosis include stage I disease, absence of invasion into the collecting system and predominance of clear cell pattern.

The Memorial Sloan–Kettering prognostic stratification is often used for metastatic disease. Five major prognostic factors are identified: poor performance status (KPS <70), raised lactate dehydrogenase (>1.5× normal), raised serum calcium, low haemoglobin and no nephrectomy. Patients are categorized into three risk groups based on the number of these prognostic factors present: 0 = favourable risk, 1–2 = intermediate risk, 3–5 = poor risk. 3-year survival rates for these risk groups are reported as 31%, 7% and 0% respectively.

Stage-wise 5-year survival for renal cell carcinoma is 66% for stage I, 64% for stage II, 42% for stage III and 11% for stage IV.

Cancers of the urinary bladder and renal pelvis

Introduction

Bladder cancer accounts for 4% of all malignancies, with over 10,000 new diagnoses and almost 5000 deaths each year in the UK. Worldwide it is the 9th most common cancer, but is more common in North America and Western Europe, where it is the 4th most common cancer in males and 8th most common in females. The worldwide male to female ratio is 10 : 3. Bladder cancer is rare in the under 50 age group, and most common in over 70-year-olds.

Aetiology

Risk factors for bladder tumours include the following:

• Smoking (2–5 fold increased risk).
• Infections – especially schistosomiasis which increases the risk of squamous cell carcinoma.
• Occupational/chemical (aniline dyes, aromatic amines, printing industry, rubber industry, firelighter manufacturers, tar manufacturing, sewage workers, pest control, benzidine, cyclophosphamide, 2-naphthyline, xenylamine, phenacetin).
• Bladder calculi (chronic cystitis).
• Chronic indwelling catheters.
• Previous radiotherapy (risk of sarcoma).

Pathology

In Western countries, over 90% of bladder tumours are predominantly transitional cell carcinoma (TCC), often with elements of squamous, adenocarcinoma or sarcomatous differentiation. 80% are papillary and 20% flat in appearance and the most likely areas affected are the posterior and lateral bladder walls. Flat tumours tend to be of higher grade and more aggressive. Less common histological types are squamous cell carcinoma, adenocarcinoma and very rarely small cell carcinoma.

Tumours often present initially as low grade and superficial, but tend to be multiple and recurrent. With each recurrence there is a tendency to progression in cytologic atypia. The whole of the uroepithelial tract is at risk of transitional cell carcinoma with tumours occurring in the ureters and renal pelvis as well as the urinary bladder.

Carcinoma-in-situ manifests as severely dysplastic cells through all layers of the epithelium. It carries a poor prognosis and often has an invasive component. At least 30% of grade III carcinoma-in-situ will become invasive.

Presentation

The most common presentation is with painless haematuria. A patient presenting with macroscopic haematuria has a 25% chance of having a bladder tumour (5% if microscopic haematuria). Other symptoms include frequency, urgency, dysuria and loin pain due to ureteric obstruction. Occasionally patients present with symptoms caused by metastases such as bone pain, fractures or shortness of breath.

Lymph node involvement is strongly related to tumour grade. Less than 10% of grade 1 tumours have nodal involvement, compared with 80% of grade 3. Metastatic spread is predominantly to the lungs and bones.

Investigations and staging

Investigations

Initial investigations include urine cytology, intravenous urogram (IVU) and cystoscopy. Cystoscopy should include bimanual examination, complete inspection of the urethra and bladder, biopsies of all suspicious areas, transurethral resection of visible tumour and a detailed diagram of the findings to assist in comparison at follow-up procedures.

Once a bladder tumour is confirmed further investigations should be considered, including blood tests (renal function, full blood count, liver function and calcium level), chest X-ray, histology review and for muscle-invasive tumours, CT or MRI scan of the abdomen and pelvis (Figure 12.2). MRI is better for showing early invasion of adjacent organs and extravesical spread. A bone scan is only necessary if indicated by symptoms or a raised alkaline phosphatase. Chest X-ray or CT chest is useful to rule out metastatic disease (Figure 12.3).

image

Figure 12.2 CT scan of bladder tumour: tumour shown as filling defect in the right side of base of bladder (short arrow) with contrast filled ureter (long arrow) entering the bladder through the tumour (A). Scan shows an irregular mass arising from base of the bladder (B).

image

Figure 12.3 Chest X-ray of a patient with cannonball lung metastases from metastatic transitional cell carcinoma of the bladder.

Staging

The staging of bladder tumours is shown in Table 12.2.

Table 12.2 Staging of tumours of the bladder

Stage    
I T1 N0
Invades sub-epithelial connective tissue
T1a – deep lamina propria
T1b – muscularis propria

II T2 N0
Invades muscle
T2a – inner half of muscle (superficial)
T2b – outer half of muscle (deep)

III T3 N0
Perivesical tissue invasion
T3a – microscopic
T3b – macroscopic

T4a N0 T4a – invades prostate, uterus, vagina IV T4b N0 T4b – invades pelvic or abdominal wall   T1–4 N1–3
N1 – single regional node ≤2 cm
N2 – 2–5 cm single node
or multiple nodes ≤5 cm
N3 – >5 cm node
  M1 Distant metastases

Management

The management of bladder tumours is dependent upon the degree of invasion into the bladder wall and the histological grade of the cancer. Superficial, non-muscle invasive tumours are generally treated by transurethral resection, with intravesical chemotherapy or immunotherapy for multiple or recurrent tumours. Localized muscle invasive disease is treated by primary cystectomy or radiotherapy to the bladder and perivesical tissues. Figure 12.4 shows the management of bladder tumours by tumour stage. Indications for radical cystectomy are shown in Box 12.1.

image

Figure 12.4 Management of transitional all bladder carcinoma by T stage.

Intravesical therapy

Intravesical therapy reduces short-term recurrence rates following transurethral resection. The options are chemotherapy with agents such as mitomycin, or immunotherapy with BCG. The incidence of chemical cystitis is approximately 40% with chemotherapy but 90% with BCG, so the latter is often reserved for resistant disease.

Intravesical chemotherapy

Mitomycin reduces recurrence rate following first cystoscopy from 25% to 12%. It is administered as a single dose within 6 hours of transurethral resection or weekly for 6–8 weeks. It should be left in contact with the bladder for 1–2 hours. Response rates are reported as 65%, with a 35% complete response. Side effects include cystitis, reduced bladder capacity, palmer desquamation and a rash.

Intravesical immunotherapy

Intravesical BCG results in a response rate of 75%, with a mean time to recurrence of 2 years. It has been shown to reduce cystectomy rate in CIS patients. Side effects include cystitis, fever, haematuria and prostatitis.

Following resection, BCG treatment should be withheld for a month to allow the mucosa to heal. A 6-week induction course (81 mg of BCG in 50 ml of normal saline) of weekly treatments is followed by cystoscopy. If there is a response a second 6-week course is initiated. If there is progression, cystectomy should be considered.

Trials of maintenance therapy have shown variable benefits using a schedule following the initial 6-week course with three consecutive weekly treatments every 6 months for 3 years (but less than a fifth of patients can tolerate this schedule).

Muscle invasive disease

If disease is localized, the aim is for cure with bladder preservation if possible. In disease confined to the bladder, radical cystectomy is curative in 60–70%. Radical external beam radiotherapy might allow preservation of bladder function, but reported cure rates are lower at 50% (although no direct comparisons between surgery and radiotherapy exist). If there is spread beyond bladder (T3 disease), radical treatment is curative in <30% of patients and half of patients will develop distant metastases within 1–2 years.

Radical cystectomy

Radical cystectomy involves excision of the bladder, perivesical fat and the attached peritoneum. In men the prostate and seminal vesicles are removed. In women the uterus, urethra, adnexa, ovaries and a cuff of vagina are resected. Reconstructions tend to be more difficult in women. The role of lymphadenectomy has been controversial, but is now generally accepted as standard. If the urethra is left in-situ, there is a 5–10% risk of urethral recurrence.

Techniques for urinary diversion:

1 Ileal conduit (stoma)
2 Continent diversions

• Mainz II (if no urethra, insert ureters into rectum – increased risk of bowel cancer and lifelong diarrhoea).
• Mitrofanoff diversion (ureters implanted into a small bowel reservoir and use a native tube (e.g. fallopian or appendix) to link reservoir to skin; self-catheterization is required).
• If the urethra is preserved (i.e. no CIS, high tumour) the ureters can be diverted into a reservoir of small bowel which empties via the urethra – no voiding sensation so need bladder training.

Side effects of radical cystectomy include up to 3% mortality, impotence in men (70–100%), dyspareunia in women, uterocutaneous fistulas, infection and small bowel fistulas (30%).

Radical radiotherapy

The aim of radical radiotherapy is cure with bladder preservation. The decision between radical cystectomy and radiotherapy should be made at a multidisciplinary meeting and with involvement of the patient. Randomized studies have shown radiotherapy to have higher rates of local recurrence, but similar overall survival with close follow-up and salvage cystectomy on relapse. Approximately a third of patients treated with radiotherapy will remain cystectomy-free.

There is no survival advantage from nodal irradiation and no evidence of any benefit of adjuvant pelvic radiotherapy following cystectomy.

Poor prognostic factors for radiotherapy include ureteric obstruction, incomplete transurethral resection, sessile (worse than papillary) tumour and persistence/recurrence at first cystoscopy.

Radical radiotherapy is contraindicated in those who had previous pelvic radiotherapy, history of inflammatory bowel disease or small bowel adhesions, extensive CIS, poor bladder function and multiple transurethral resections or multiple intravesical chemotherapy installations (due to reduced bladder function which may worsen with radiotherapy).

Radical radiotherapy is typically CT-planned with a target volume including a 1.5–2 cm margin around the empty bladder, prostatic urethra and tumour extension. This margin is to allow for considerable bladder movement. The rectum and femoral heads should be identified as organs at risk. Treatment is usually delivered via a 3-field plan (anterior and two laterals) to a dose of 55 Gy in 20 fractions over 4 weeks or 64 Gy in 32 fractions over 6.5 weeks using 6–10 MV photons.

Complications of radiotherapy include radiation cystitis (<5%), radiation proctitis (<5%), bowel obstruction (<3%) and erectile dysfunction (60%).

There is interest in partial bladder irradiation (or whole bladder with a second phase tumour boost to a smaller volume) with the intention of reducing toxicity whilst maintaining an effective dose to the tumour.

Palliative radiotherapy

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