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.

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).

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

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.

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

For node positive or locally advanced disease, palliative radiotherapy can be beneficial, particularly for patients with haematuria or pelvic pain. Palliative fields are planned conventionally, sometimes with use of a cystogram to localize the bladder at simulation. Typical dose schedules include 30 Gy in 10 fractions over 2 weeks, 21 Gy in three fractions over 1 week or, in particularly frail patients, a single fraction of 8–10 Gy. Improved symptoms are observed in approximately half of patients, but a similar proportion suffers acute side effects.

Chemotherapy

Chemotherapy in bladder cancer has been primarily used in the palliative and metastatic settings, but there is good evidence to support the use of neoadjuvant chemotherapy prior to cystectomy. However, the platinum-based regimes are toxic and emetogenic, and many patients with invasive bladder cancer are frail with poor renal function so tolerate the chemotherapy poorly.

Chemotherapy in metastatic disease

Response rates of 40–70% have been observed with combinations such as CMV (cisplatin, methotrexate, vinblastine) and MVAC (methotrexate, vinblastine, adriamycin, cisplatin). Newer combinations such as gemcitabine and cisplatin have similar response rates and survival outcomes, with less toxicity (Box 12.2). Single agent platinum regimes are less effective (response rates of 30%).

Box 12.2
Chemotherapy regimes in bladder cancer

Gem/Cis:	Gemcitabine – 1 g/m² Day 1, 8, 15
	Cisplatin* 70 mg/m² Day 1
	Repeat every 28 days (or 21 days omitting day 15 gemcitabine)
CMV:	Cisplatin* 100 mg/m² Day 2 only (70 mg/m² if palliative)
	Methotrexate 30 mg/m² Day 1 and 8
	Vinblastine 4 mg/m² Day 1 and 8
	Repeat every 21 days
MVAC:	Methotrexate 30 mg/m² Day 2, 15, 22
	Vinblastine 3 mg/m² Day 2, 15, 22
	Adriamycin 30 mg/m² Day 2
	Cisplatin* 70 mg/m² Day 2
	Repeat every 28 days

* For patients with poor renal function (creatinine clearance of 30–60 ml/min), consider replacing cisplatin with carboplatin (AUC 4–5).

Neoadjuvant chemotherapy

A meta-analysis of neoadjuvant trials in muscle invasive bladder cancer has revealed a 5% absolute benefit in overall survival for patients treated with cisplatin-based combination chemotherapy. This benefit was seen irrespective of the type of local treatment (surgery or radiotherapy) and applied across all patient groups. There may also be a role for neoadjuvant chemotherapy in bladder preservation, with responding patients being treated with radiotherapy and non-responding patients going on to cystectomy. This is currently being investigated in randomized trials.

Adjuvant chemotherapy

There is conflicting evidence on benefit and a Cochrane review did not recommend this as routine treatment. Studies of immediate versus delayed chemotherapy in high risk (node positive or T3/4) patients post-cystectomy have failed to recruit sufficient numbers.

Concurrent chemo-radiotherapy

There is no definite evidence that concurrent cisplatin with radiotherapy is better than radiotherapy alone. Concurrent 5-fluorouracil and mitomycin-C is being investigated as a less toxic regime to combine with radiotherapy.

Management of carcinomas of the renal pelvis and ureter

The staging of tumours of the renal pelvis and ureter is given in Table 12.3. Renal pelvic and upper urothelial transitional carcinomas are treated by radical resection of the kidney and ureter. Nephron-sparing procedures can be undertaken in small, localized tumours if there are concerns about function of the remaining kidney. Adjuvant radiotherapy confers no survival advantage following complete resection, but may be considered in patients with positive margins or residual local disease. Doses are limited by surrounding structures, but typically 45–50.4 Gy in 25–28 fractions can be delivered. There is some evidence to suggest that the addition of concurrent cisplatin chemotherapy to radiotherapy improves overall and disease-free survival in T3/4 and/or node-positive disease following surgical resection. The majority of relapses are distant, so systemic adjuvant therapy using platinum-containing chemotherapy regimes should be considered, although there is little published data as to the benefits of this approach. The current evidence for adjuvant chemotherapy is stronger for node positive disease than for locally advanced but node negative disease.

Table 12.3 Staging of tumours of the renal pelvis and ureter

Stage
I	T1 N0 M0	Tumour invades subepithelial connective tissue
II	T2 N0 M0	Tumour invades muscularis
III	T3 N0 M0	Tumour invades peripelvic (or periureteric) fat or renal parenchyma
IV	T4	T4 Invades adjacent organs or perinephric fat
	or N1–3	N1 Metastases in single node ≤2 cm N2 Metastases in single node >2 cm but ≤5 cm or multiple nodes N3 Metastases in single node >5 cm

or M1 M1 Distant mets

Metastatic disease is treated with similar platinum-based chemotherapy regimes to those used in metastatic bladder cancer.

Management of small cell carcinoma of the bladder

Small cell bladder cancer accounts for less than 1% of bladder cancers and commonly presents at an advanced stage. In localized disease patients should be treated with neoadjuvant platinum-based chemotherapy prior to surgery or radiotherapy. Responses to chemotherapy are seen in metastatic disease, but median survival is less than 12 months. Most published data relates to the use of neuroendocrine regimes such as carboplatin/cisplatin with etoposide.

Survival

5-year survival rates for bladder cancer are as follows:

Stage	5-year survival
Ta, T1, CIS	70–95%
T2	50–80%
T3a	40–70%
T3b	20–50%
T4	10%

Survival with metastatic disease is poor despite reasonable response rates to chemotherapy, with <10% 2-year survival.

Cancer of the prostate

Introduction

Prostate cancer accounts for 12% of all cancers (23% of cancer in men), with 32,000 new diagnoses and 10,000 deaths each year in the UK. There has been a large increase in incidence over the past 10–15 years due to increased detection through PSA screening and surgery for benign prostatic disease. The majority of cases occur in the over 70 age-group and the disease is rare in the under 50s. As yet there is no evidence that PSA screening reduces mortality rates from prostate cancer.

Aetiology

The exact aetiology is not known and there are various suggested risk factors such as a high fat diet, anabolic steroids, oestrogen exposure and genetic. A hereditary prostate cancer gene on chromosome 1p has been identified. Mutation of the androgen receptor domain may be associated with high grade disease, extraprostatic extension and distant metastases. Mutation of the vitamin D receptor gene may also play a role. There is a link with BRCA genes as well.

Pathology

The vast majority of prostate tumours are adenocarcinomas. Malignant areas are frequently multifocal and most often involve the posterolateral part of the gland. 70% arise in the peripheral zone of the prostate. Rare variations include mucinous, small cell, squamous cell, adenoid cystic and endometrioid carcinoma (the latter is characterized by a normal PSA and lack of hormone response). Transitional cell carcinoma of the prostatic urethra may occur and there are rare reports of secondary spread from other tumours such as melanoma and lung cancer.

The Gleason grading system, an important prognostic factor, describes the degree of differentiation of the malignant cells (Box 12.3). Each tumour is graded twice, each out of five to give a total score out of 10 – the first grade relates to the most commonly observed pattern (primary pattern) and the second to the next most common pattern.

Box 12.3
Gleason grading

1 Well differentiated; uniform gland pattern

2 Well differentiated; glands variable

3 Moderately differentiated; papillary/cribriform features or well-spaced acini

4 Poorly differentiated; cords, sheets, fused cells

5 Very poorly differentiated; minimal gland formation and necrosis

Presentation

The majority of prostate cancers are initially detected following a raised serum prostate specific antigen (PSA) level and approximately half of patients are completely asymptomatic. The PSA blood test may have been taken as part of investigations into non-specific lower urinary tract symptoms of bladder outflow obstruction such as hesitancy, frequency, nocturia and terminal dribbling, or increasingly as part of a well-man screening programme. In symptomatic patients who require a transurethral resection of the prostate (TURP) for presumed benign prostatic hypertrophy, it is not uncommon to discover cancer cells in the prostatic chippings.

Locally advanced cancers can be detected on rectal examination, and occasionally patients may present with symptoms due to local extension such as pain or bleeding. Metastases to bone are common and bone pain or pathological fracture can be presenting features. Other areas of spread include obturator, perivesical and para-aortic lymph nodes and rarely liver, lung or brain metastases.

The strongest predictors of metastasis are a high PSA, high Gleason score (8–10) and age >70 years. The Roach formulae (based on Partin’s tables) are commonly used in treatment algorithms to predict the risk of local extension and lymph node spread (Box 12.4).

Box 12.4
Roach formulae

Risk of lymph node involvement (%):	2/3 PSA + 10 (Gleason-6)
Risk of seminal vesicle involvement (%):	PSA + 10 (Gleason-6)
Risk of extracapsular extension (%):	3/2 PSA + 10 (Gleason-3)

Investigations and staging

Initial investigations include a PSA blood test and digital rectal examination (DRE). Patients with raised PSA are offered a transrectal biopsy of the prostate to obtain histological diagnosis (usually 8–12 core biopsies of the prostate are obtained, half from each lobe).

If cancer is confirmed, further investigations are determined by the grade, volume of disease and PSA level, but may include a pelvic MRI scan to define extracapsular spread and seminal vesicle or lymph node involvement (generally offered to patients with Gleason 4+3 disease or above, or with PSA >20 ng/ml, in whom radical treatment is being considered) and a bone scan (if PSA >10–15 ng/ml). If there is doubt over lymph node involvement, a laparoscopic retroperitoneal lymph node biopsy might be considered prior to proposed radical treatment.

Table 12.4 shows the staging of prostate cancer.

Table 12.4 Staging of prostate cancer

As well as the absolute PSA level, various other PSA parameters have been developed in an attempt to improve the predictive value of the test for diagnosis and monitoring:

• PSA density (PSA/volume of gland) allows for higher PSA levels in older men with large, hypertrophied glands. A value of 0.1 ng/ml/cc is considered normal (e.g. a PSA of 5 ng/ml with a 50 cc prostate volume).

• Percent-free PSA (fPSA) is the ratio of how much PSA circulates free compared with the total PSA level, including that attached to blood proteins. The percentage of free PSA is lower in men who have prostate cancer than in men who do not and may be useful in determining which patients with intermediate PSA levels should have a prostate biopsy for diagnosis. There is some controversy over where the cut-off should lie, but fPSA levels of <10% are very suspicious.

• PSA kinetics give an indication of the rate of tumour growth, and include the PSA doubling time, expressed in months or years, and the PSA velocity, expressed as ng/ml/year (this is commonly utilized in patients on active surveillance – see below). To get an accurate indication of PSA velocity, at least three measurements should be taken over a period of 18 months.

Note that very poorly differentiated cancers may not secrete PSA and are therefore more difficult to diagnose, predict and monitor.

Management of localized disease

The treatment options for localized disease are:

• Active surveillance (for patients suitable for radical treatment).

• Watchful waiting (for patients not suitable for radical treatment).

• Radical treatment with surgery or radiotherapy or both.

Active surveillance and watchful waiting

Many patients will have slow-growing disease which may have little or no impact on their life-expectancy, and they might therefore be spared the toxicities and inconvenience of radical treatment. Active surveillance implies close monitoring with early curative treatment offered to patients who show signs of progression. There are no absolute criteria for considering active surveillance and the decision should be made with the patient, but typical parameters would be T1–T2b disease, Gleason grade ≤7, PSA ≤15 (with favourable kinetics). A surveillance programme might consist of 3-monthly visits for the first 2 years, followed by 6-monthly visits thereafter, with a DRE and PSA checked at each visit. Repeat transrectal biopsies should be performed at 18 months. Criteria for consideration of radical treatment would be PSA progression (doubling time <2 years), clinical progression or upgrading of the Gleason score on repeat biopsy.

‘Watchful waiting’ is appropriate where patients deemed unsuitable for radical treatment are treated with palliative endocrine therapy when there is symptomatic progression.

Radical treatment

Radical treatment options for prostate cancer include radical prostatectomy, external beam radiotherapy and brachytherapy (low-dose rate or high-dose rate). Each treatment has its own characteristics and may be suitable for certain types of patients, but reported success rates are similar if patients are chosen appropriately.

Radical prostatectomy

Perineal, retropubic or laparoscopic approaches can be considered. There is a 5–15% risk of urinary dysfunction after surgery. Nerve-sparing techniques have improved morbidity, with approximately 50% impotence rates.

External beam radiotherapy

Conformal CT planning is well established in prostate radiotherapy (Box 12.5 and Figure 12.5). The Medical Research Council RT01 study randomized between 64 Gy and 74 Gy and found a hazard ratio for biochemical progression free survival of 0.67 (CI 0.53–0.85; p = 0.0007) in favour of the escalated group. However this was achieved at the expense of increased late bowel and bladder toxicity. It is not yet known whether there will be any improvements in overall survival.

Box 12.5
Radiotherapy for prostate (see Figure 12.5)

Localization

CT planning with empty rectum. Target volume defined on planning CT or co-registered CT/MRI

Tolerance

• Rectum: 55.5 Gy to no more than 50% of the rectum, 70 Gy to no more than 25% and 74 Gy to no more than 3%.

• Bladder: Less than 50% of the bladder should receive 67 Gy.

Figure 12.5 Target volumes for radical prostate radiotherapy. Orange line phase I PTV including prostate and seminal vesicle with a 10 mm margin and purple line phase II PTV including only prostate with a 5 mm margin.

Newer techniques such as intensity modulated radiotherapy (IMRT) might enable even further increases in the dose administered or further sparing of normal tissues.

Radiobiological studies have suggested a surprisingly low alpha-beta ratio for prostate cancer (1.2–1.5 Gy), which implies that hypofractionated courses of radiotherapy with a high dose per fraction might result in improved cancer control for a similar level of side effects. For this reason doses such as 57–60 Gy in 19–20 fractions over 4 weeks are being investigated. These shortened schedules have the additional advantage of sparing resources and being more convenient for patients.

Though the survival benefit of whole pelvic radiotherapy in high risk of pelvic lymph node involvement (≥15% on Roach criteria) remains to be demonstrated, it is commonly practised.

Acute side effects of radiotherapy include dysuria, frequency, diarrhoea, lethargy and erythema. Late effects include proctitis (diarrhoea, rectal bleeding, tenesmus: 30% mild, 5% severe), impotence (30–40%) and urinary incontinence (1–5%).

Brachytherapy

Low-dose rate (LDR) brachytherapy

Permanent radioactive seeds are implanted directly into the prostate via transperineal needles that are inserted with ultrasound guidance under general or spinal anaesthetic. Approximately 50–100 Iodine-125 or Palladium-103 seeds are implanted to achieve a prescribed dose of 145 Gy. Patients eligible for this treatment are those with a prostate volume of <50 cc, Gleason ≤6, PSA ≤15, T2 or less disease, those haven’t had a previous TURP and not at high risk of extracapsular extension or lymph node involvement. Patients should have a transrectal ultrasound volume study to assess suitability for brachytherapy.

Although there is good evidence to confirm the efficacy of brachytherapy in terms of PSA control and biopsy findings, there is as yet no long-term survival data. The procedure has not been directly compared with external beam radiotherapy or radical surgery in randomized studies, but comparative and cohort studies show similar 5-year biochemical recurrence-free and overall survival.

High-dose rate (HDR) brachytherapy

HDR brachytherapy is suitable for intermediate-high risk patients. It is typically given as a boost following a shortened course of external beam radiotherapy but can also be used as monotherapy. Treatment is delivered through catheters implanted with ultrasound guidance into the prostate under general anaesthetic. HDR boost patients are typically treated in two or three fractions, 12 hours apart, necessitating overnight stay with the catheters and template in-situ. Box 12.6 shows some of the HDR boost schedules currently in use.

Box 12.6
High-dose rate brachytherapy boost schedules

External beam dose and fractionation	HDR brachytherapy boost dose and fractionation
35.7 Gy in 13	17 Gy in 2
46 Gy in 23	16.5 Gy in 3
46 Gy in 23	17 Gy in 2
50 Gy in 25	18 Gy in 2
45 Gy in 23	16.5 Gy in 3
46 Gy in 23	23 Gy in 2

Role of hormones in curative treatment

Patients undergoing radical radiotherapy are commonly treated with 3 months of neoadjuvant luteinizing hormone releasing hormone (LHRH) analogues. This approach may enable a reduction in the volume of tissue irradiated due to shrinkage of the prostate gland. An EORTC study compared radiotherapy alone versus radiotherapy with immediate androgen suppression started on the first day of radiotherapy and continued for 3 years. 5-year clinical disease free survival was 40% versus 74% and overall survival was 62% versus 78% in favour of the adjuvant endocrine group.

Prolonged adjuvant treatment for 2–3 years should be offered to all patients with high risk disease (Gleason 8–10, clinical T3/4 tumours or lymph node risk >30%). The role in low and intermediate risk patients is being assessed in randomized studies, but these patients are currently treated with 3–6 months of LHRH analogues before and during radiotherapy.

It should be noted that LHRH analogues are not without side effects (see Box 12.7) and can add considerably to the morbidity of patients undergoing radiotherapy.

There is no established role for neoadjuvant or adjuvant hormonal manipulation in patients undergoing radical prostatectomy.

Management of locally advanced and metastatic disease

Locally advanced disease

For patients with locally advanced disease radical radiotherapy or surgery may add little or no additional benefit over hormone therapy alone, although there is emerging evidence that radiotherapy does improve biochemical control in patients with PSA levels up to 70 ng/ml. The mainstay of treatment is with LHRH analogues or anti-androgens. Prolonged treatment with LHRH analogues results in significant toxicity due to reduction of testosterone levels (see Box 12.7). Androgen receptor inhibitors, such as bicalutamide, or 5-alpha reductase inhibitors effectively reduce the delivery of testosterone to the prostate without reducing serum testosterone levels and therefore tend to have a better side effect profile, although they can cause significant gynaecomastia. Prophylactic radiotherapy to the breast buds or prophylactic tamoxifen 10–20 mg/day can reduce and sometimes prevent the painful gynaecomastia. Typical radiotherapy doses are 8–10 Gy in a single fraction or 15 Gy in three fractions given on alternate days, using electron radiotherapy delivered to an 8–10 cm circle around each nipple.

Metastatic disease, elderly and those with significant comorbidities

Metastatic disease (Figure 12.6) is generally treated with endocrine therapy, usually LHRH analogues in the first instance, with the addition of an anti-androgen to give maximal androgen blockade on biochemical or clinical progression. The typical duration of response to first line endocrine therapy with LHRH analogues is 18–24 months. There is increasing interest in intermittent LHRH analogue therapy as a way of prolonging the useful lifespan of the drug and of allowing patients to have periods of time off treatment and therefore avoid some of the side effects. Typical schedules are to treat until PSA falls below 4 ng/ml (or <80% of initial value) and restart when PSA rises above 10 ng/ml. Studies have shown no difference in survival when compared with continuous therapy, but significant improvements in quality of life, with patients spending a median of 1 year off treatment.

Figure 12.6 Bone scan in metastatic prostate cancer. Note the absence of uptake in the kidneys and bladder (arrows) suggesting that uptake is preferentially by the extensive metastases. This picture is called a ‘superscan’ which is a contraindication for radioisotope treatment (risk of lethal bone marrow suppression)

Third line hormonal therapy with oestrogens can be considered but response duration tends to be short unless response to first and second line treatment has been particularly good.

Elderly patients and those with significant co-morbidities can be treated symptomatically with or without hormones.

Management of relapse after radical treatment

Some authorities advocate postoperative radiotherapy to the prostatic bed in cases with a positive margin at radical prostatectomy, whilst others would wait and offer radiotherapy if the PSA fails to completely suppress or subsequently rises. In these situations, salvage radiotherapy is most effective if given before the PSA reaches a value of 2 ng/ml (Box 12.5).

Salvage surgery for radiotherapy failures is rarely undertaken due to the complicated nature of the procedure and questionable results. Newer invasive techniques such as cryotherapy and high frequency ultrasound (HiFU) have shown some success in terms of PSA control after radiotherapy failures (and perhaps as primary treatments in place of radiotherapy), but long-term outcomes are awaited.

Role of chemotherapy in prostate cancer

Until recently, chemotherapy has been reserved for advanced metastatic prostate that has become refractory to endocrine treatment (known as hormone refractory prostate cancer, HRPC, or more accurately as castration resistant prostate cancer, CRPC). Docetaxel is now well established in this setting, with studies showing quality of life and overall survival benefits (in the order of 10–12 weeks) when compared with the previous standard regimen of mitoxantrone and prednisolone. Doses of 75 mg/m² are administered on a 3-weekly basis for up to 10 cycles. Although low-grade neutropenia is fairly common, the rates of febrile neutropenic sepsis are reassuringly low (<3%) without colony-stimulating factor support.

Chemotherapy agents are now being investigated in earlier stages of prostate cancer, both in metastatic disease prior to the development of CRPC or as an adjuvant to radical prostatectomy for localized disease. There is also interest in second-line chemotherapy after failure of taxanes; there is some evidence for PSA response with satraplatin, an orally active platinum-based drug. Cabazitaxel, a new taxane, has demonstrated a 2.5 month survival benefit in the second-line setting.

Palliative treatment

• Steroids: Low-dose steroids (0.5–2 mg of dexamethasone daily) are effective in some patients in terms of both quality of life improvements and PSA control.

• Bisphosphonates: Zoledronic acid administered intravenously once a month has been shown to reduce the incidence of skeletal events, including fractures or the need for radiotherapy, in men with bone metastases. It is effective at controlling refractory metastatic bone pain.

• Radiotherapy: External beam radiotherapy is very effective in controlling metastatic bone pain and symptoms of primary tumour invasion such as haematuria and pain. Prolonged fractionation regimes have not been shown to be more beneficial than a single fraction of 8 Gy. Radiotherapy is also commonly used in cases of spinal cord or nerve root compression from vertebral metastases (p. 328).

• Radioisotopes: Strontium-89 and Samarium-153 are effective at controlling pain in up to 80% of patients with widespread bone metastases. Radioisotope treatment is particularly useful in patients with diffuse bone pain that cannot easily be targeted with external beam radiotherapy (Figure 12.6). Care must be taken if chemotherapy is to be considered at a later date because of a suppressive effect on the bone marrow.

Prognostic factors and survival

Survival figures from prostate cancer vary widely, depending on histology, stage, PSA level and therapeutic intervention. Patients with localized disease treated with either radiotherapy or radical surgery have 5-year biochemical control rates of 75–85% and 10-year overall survival rates of 60–70%. Patients with metastatic disease can survive for many years, particularly if the tumours are hormone-responsive and if the metastatic spread is confined to the bones.

Cancer of the testes

Introduction

Testicular cancer accounts for 0.7% of all cancers, with fewer than 2000 new diagnoses each year in the UK. There has been an increase in incidence over recent years for reasons unknown. The majority of cases occur in younger men, with around half in men under 35 years of age and 90% in men under 55 years.

Aetiology

Apart from age and race, other risk factors include a previous history of testicular cancer or carcinoma-in-situ. Cryptorchidism (undescended testes at birth) increases the risk by 2–4 fold. There are some reports of increased incidence in men with subfertility and also suggested links with high dietary dairy product intake and a sedentary lifestyle.

Pathology

The majority of testicular malignancies are germ cell tumours (>90%), either seminomas or teratomas. Approximately 20% are of mixed cell type and should be classified as non-seminomatous germ cell tumours (NSGCT). Other types include sex cord tumours, lymphomas and sarcomas.

Intratubular germ cell neoplasia has features similar to carcinoma-in-situ, seen in the contralateral testes in 5% of testicular cancer patients. There is a risk of progression to malignancy of 50% at 5 years. This risk can be prevented with radiotherapy (20 Gy in 10 fractions), which will result in infertility, but avoids the need for a second orchidectomy. It is diagnosed by open or needle biopsies and is more likely in young patients with an atrophic contralateral testis.

Presentation

The majority of testicular tumours (75%) present with a painless, firm swelling of the testis. Occasionally patients present with lower back pain due to intra-abdominal or pelvic lymph node spread, or indeed palpable lymphadenopathy, particularly in the left supraclavicular fossa. Other methods of presentation include infertility, gynaecomastia, secondary hydrocoeles or with symptoms due to secondary spread to other organs such as lung or liver.

Investigations and staging

Preoperative investigations should include testicular ultrasound, chest X-ray and tumour markers including alpha-foetoprotein (AFP), beta-human chorionic gonadotrophin (beta-HCG) and lactate dehydrogenase (LDH). One or more tumour marker is raised in 75% of teratomas and 35% of seminomas. If AFP is raised or beta-hCG is >200, then treat as a non-seminomatous germ cell tumour (NSGCT). Tumour markers should be done preoperatively and repeated a minimum of 7 days after orchiectomy.

Postoperative investigations should include a CT scan of the thorax, abdomen and pelvis for full systemic staging. In case of borderline lymph node size (normal <1 cm), a repeat CT scan after 6 weeks is indicated prior to deciding further management; CT of the brain is indicated if there are multiple lung metastases or beta-HCG levels >10,000 IU/L.

Postoperative tumour markers should be repeated (the half-life of the markers is up to 7 days) and are useful in measuring treatment response and monitoring for recurrence. A bone scan is usually only requested if indicated clinically. Sperm storage should be considered, particularly if chemotherapy is planned.

The staging and risk classification of testicular cancer is shown in Tables 12.5 and 12.6.

Table 12.5 TNM staging of testicular cancer

Stage 0	T1sN0M0 – intracellular germ cell neoplasm
Stage IA	pT1N0M0 – tumour limited to testis and epididymis with no LVI or tunica vaginalis invasion (TVI)
Stage IB	pT2–4N0M0 – pT2 – tumour limited to testis and epididymis with LVI or TVI pT3 – invades spermatic cord pT4 – invades scrotum

Stage IIA Any T, N1 (≤2 cm regional node) M0 Stage IIB Any T, N2 (>2–5 cm) M0 Stage IIC Any T, N3 (>5 cm) M0 node Stage IIIA/B Any T, any N, M1A (non-regional nodes and/or lung metastasis) Stage IIIC

Any T, any N, M1b (other visceral metastasis)

Mediastinal primary, any N and any M

Table 12.6 International Germ Cell Consensus Classification prognostic criteria for non-seminomatous tumours

Good prognosis	Intermediate prognosis	Poor prognosis
AFP <1000 ng/ml β-HCG <5000 iu/l LDH <1.5 times the upper limit of normal (ULN)	AFP 1000–10,000 ng/ml HCG 5000–50,000 iu/l LDH 1.5–10 × ULN	AFP >10,000 ng/ml HCG >50,000 iu/l LDH >10 × ULN
Testis or retroperitoneal primary	Testis or retroperitoneal primary	Mediastinal primary site
No non-pulmonary visceral metastases	No non-pulmonary visceral metastases	Non-pulmonary visceral metastases

Management of testicular cancer

Primary management is a radical inguinal orchidectomy and ligation of the spermatic cord at the internal ring which should be performed within one week after diagnosis. In patients with advanced life-threatening testicular cancer, orchiectomy should not delay chemotherapy. In these situations, if clinical picture and markers are diagnostic, treatment with chemotherapy can be started. Organ sparing surgery may be an option in cases of bilateral testicular cancer.

Postoperative management of seminoma (Figure 12.7)

Stage I disease

Around 80% of patients with seminoma present with stage I disease and survival is >99%. There are two risk factors for recurrence: rete testis invasion and tumour size of >4 cm. 5-year relapse rate is 12% with no risk factors, 16% with one factor and 32% with both factors. Current treatment is active surveillance irrespective of risk factors. If surveillance is not an option the active treatment options are a single dose of carboplatin (AUC7) and para-aortic radiotherapy (20 Gy in 10 fractions) (Box 12.9).

Figure 12.7 Postoperative management of seminoma.

Figure 12.8 Radiotherapy in seminoma. Outline any enlarged lymph nodes on the CT scan and modify the field to ensure that nodes are covered with a 1.5 cm margin.

Stage II–IV disease

Clinical stage IIA disease should be verified beyond imaging (e.g. needle biopsy) before systemic treatment. Standard treatment for stage IA and stage IB with 2–2.5 cm node is radiotherapy to para-aortic and ipsilateral iliac nodes (‘dog leg field’). An alternative option is three cycles of PEB chemotherapy (3 or 5-day schedule). Treatment option of stage IIB with 2.5–5 cm node is three courses of PEB (Box 12.8).

The treatment of stage IIC/III is three cycles of PEB for good prognosis patients (3 or 5-day schedule) and four cycles for intermediate prognosis patients (5-day schedule). Three cycles of PEB may be substituted by four cycles of PE in cases of increased bleomycin toxicity.

Residual disease and relapse

Management of residual disease is shown in Figure 12.7. In general, patients with >3 cm residual mass need PET scan or frequent follow up or resection.

Patients relapsing after radiotherapy are treated with chemotherapy. Patient who relapse >3 months after initial chemotherapy are platinum sensitive and the standard options are VIP, TIP or VelP. There is no benefit of high dose chemotherapy as second or third line chemotherapy.

Patients who are truly platinum-resistant (relapse during or within 3 months post treatment) have a very poor prognosis (approximately 10% survival) and there is no standard treatment. Gemcitabine/paclitaxel, high dose chemotherapy and surgery if localized disease are the options.

Postoperative management of non-seminomatous germ cell tumours (NSCGTs) (Figure 12.9)

Stage I patients are divided into low (20% relapse rate) and high risk (40–50% relapse) based on absence or presence of vascular invasion. The management is outlined in Figure 12.9. Treatment choice is based on toxicity, tumour burden and patient preference. Active surveillance is intense follow up with frequent clinical examination, tumour marker estimation and scans. Frequency of follow-up depends on risk of relapse.

Figure 12.9 Postoperative management of non-seminoma.

Management of stage IIA–III disease is outlined in Figure 12.9. It is important that in patients undergoing chemotherapy, dose intensity is maintained (Box 12.8, see also Box 4.3).

Management of residual masses and recurrence

Residual masses >1 cm in size should be resected. Management after resection is based on the extent of resection and proportion of viable tumour cells (Figure 12.9). Chemotherapy for relapse is similar to seminoma.

Management of testicular intraepithelial neoplasia (TIN)

3–5% of patients with testicular cancer have TIN in the contralateral testis with the highest risk if testicular volume <12 ml and age <40 years (34%) and in patients with extragonadal germ cell tumours (≥33%). If untreated, 70% of TIN progress to testicular cancer in 7 years.

Patients should be offered the choice of testicular biopsy or monitoring only (both strategies have excellent survival outcomes). If chemotherapy is given, biopsy should be delayed at least 2 years after treatment. The treatment options in proven TIN include surveillance and active treatment with radiotherapy (20 Gy in 10 fractions) or orchiectomy (in patients with no gonadal tumour, e.g. incidental finding during biopsy for infertility or extragonadal tumour).

Prognostic factors and survival

Seminoma has >90% long-term survival with that of stage I disease at >99%. Stage I non-seminoma has a long-term prognosis of 98–100%. In advanced non-seminoma, survival is 90% for the good prognostic group, 80% for intermediate group and 60% for poor prognostic group.

Follow-up

Follow-up after active treatment involves frequent clinical examination, estimation of tumour markers, chest X-ray and CT-scan up to 5 years. Follow-up beyond 5 years is useful in detecting late toxicities and second cancers.

Cancer of the penis

• Erythroplasia of Queryat: single/multiple shiny red plaques on glans/prepuce. Approximately a third progress to invasion.

• Bowenoid papulosis: multiple pigmented plaques (very similar to Bowen’s). Rarely becomes malignant.

The vast majority (>90%) of cancers are squamous cell carcinomas (SCC). Verrucous carcinoma is an indolent variant which can present with bulky cauliflower-like lesions. Other rare malignancies of the penis include melanoma, sarcomas (particularly Kaposi’s sarcoma), basal cell carcinomas and metastases from bladder, prostate or bowel primary tumours.

Presentation

Penile cancers present as erythematous patches, exophytic growths, nodules or ulcers. There may be associated discharge from the prepuce and/or phimosis. Advanced cases can present with inguino-femoral lymphadenopathy.

Investigations and staging

Diagnosis is made by biopsy of the lesion. Investigations should include a full blood count, urea and electrolytes and liver function. The inguinal, pelvic and abdominal lymph nodes should be assessed with a CT or MRI scan. Clinically enlarged inguinal nodes can be assessed with fine needle aspiration or biopsy. A MRI of the pelvis with an artificial erection may be useful in assessing cavernal invasion (Figure 12.10). A chest X-ray is usually sufficient for distant staging unless there is suspicion of disease elsewhere. It is sensible to photograph the lesion prior to treatment for future reference. The staging of penile cancers is shown in Table 12.7.

Figure 12.10 Figures show a cancer of the glans penis (A) and an MRI (B) of the pelvis with artificial erection showing a tumour involving the meatus (T3) (red arrow) but without involvement of tunica albuginea (yellow arrow) or corpora cavernosa (green arrow).

(Courtesy of Mr. David Ralph, Institute of Urology, London, UK.)

Table 12.7 Staging of penile cancers

Stage
I	T1 N0	Invasion of sub-epithelial tissue
II	T2 N0	Invasion of corpora or cavernosum
II	T1/2 N1	Single superficial inguinal lymph node involvement
III	T3 N0/1 T1–3 N2

Invasion of urethra/prostate

Multiple or bilateral superficial inguinal nodes

T4 N0–2

T1–4 N3

Invasion of adjacent structures

Deep inguinal or pelvic nodes involved

Distant metastases

Carcinoma-in-situ can be treated with topical 5-fluorouracil applied twice a day. Patients should be warned to avoid contact with their hands and to abstain from sexual intercourse during the treatment. Alternatively, laser excision can be considered.

Invasive disease

Surgery is the treatment of choice and radiotherapy is an alternative. Amputation with good margins has the best long-term outcome with 90% 5-year survival. Radiotherapy has a 30% long-term failure rate. Circumcision should be performed in all patients, even if treated with radiotherapy.

Surgery

For very small foreskin lesions, circumcision and laser surgery can be curative. For other T1/2 lesions of the glans, a glansectomy or partial amputation may suffice. For larger tumours, particularly if the urethra is involved, total amputation is required.

External beam radiotherapy

If disease is limited to the glans, treatment is with electron-beam radiotherapy with a 2 cm margin around the tumour. Perspex or bolus is placed over the cut-out section to ensure that the skin surface dose is 100%. For more extensive disease, photon irradiation is appropriate. Two lateral fields are applied with the penis placed between two halves of a wax block. The testis and groin are shielded with lead. The conventional dose is 60–64 Gy in 30–32 daily fractions using 4–6 MV photons. If there is residual disease following radiotherapy, surgical excision should be considered as a salvage treatment. Box 12.10 lists the side effects of penile radiotherapy.

Box 12.10
Side effects of radiotherapy to the penis

Early	Mucositis
	Oedema of the prepuce
	Local infections
	Dysuria
	Difficulty with micturition
Late	Telangiectasia
	Superficial necrosis
	Urethral meatal stenosis
	Deep fibrosis
	Loss of sexual function