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.

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

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.

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.

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.

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).

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).

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
III	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