1. Current Opinion in Urological Cancer
Mr C Dawson MS FRCS
Consultant Urologist
Cromwell Clinic, Huntingdon
Edith Cavell Hospital, Peterborough

2. Urological Cancers Difficulties, and Recent Advances
- Prostate Cancer
- Bladder Cancer
- Renal Cancer
Local Referral Protocols
Case Discussions
Q & A Session

3. Prostate Cancer - Dilemmas, and Recent Advances

4. The scale of the problem
Prostate Cancer is third commonest cause of cancer death in men (after lung and bowel) - mortality rate 34 per 100,000 men
Incidence rises with age, only 12% of clinically apparent cases arise before the age of 65
Men with a family history are at higher risk, but the presence of lower urinary tract symptoms is not a risk factor

5. The scale of the problem
Rate of registration of prostate cancer is rising
Ageing of the population
Increased diagnostic accuracy and recording of cases
Increased incidental detection after surgery for BPH
? widespread use of PSA

6. The scale of the problem
Natural History of Prostate cancer uncertain
30% of men over 50 (50% of men over 80) have histological evidence of prostate cancer at autopsy while showing no sign of disease during life
Most men with prostate cancer die with CAP rather than from it
Many men (up to 40%) present with locally advanced or metastatic disease

7. Difficulty 1 - The Diagnosis of Prostate Cancer
No symptoms specific for prostate cancer
Presenting symptoms therefore those of BPH
Full history and examination essential, particularly digital rectal examination (DRE)
Biopsy of the prostate should be performed in those with abnormal DRE or raised PSA

8. The Role of PSA
Single-chain glycoprotein of 240 amino acid residues and 4 carbohydrate side chains
Physiologic function is lysis of the seminal coagulum
Has a half-life of 2.2 days
Prostate specific, but not-cancer specific
Should not be used indiscriminately

9. Prostate Specific Antigen
In addition to Prostate cancer, an elevated level may be found with
Increasing age
Acute urinary retention and Catheterisation
TURP
Prostatitis
Prostate biopsy
BPH
but NOT rectal examination

10. Difficulty 2 - The Problem with PSA
Men with Prostate cancer may have a normal PSA
Men with BPH or other benign conditions may have a raised PSA
No longer thought to be prostate-specific
What to do with men with PSA in the range 4-10 ng/ml?

11. Refinements in the use of PSA
Refinements theoretically most useful when PSA between 4-10 ng/ml
Below 4ng/ml prevalence of CAP ~ 1.4%, above 10ng/ml prevalence rises to 53.3%
PSA Density
PSA Velocity
Age-Specific PSA
Free vs. total PSA

12. Age Specific PSA Ranges
Determined from evaluation of PSA values and prostate volumes according to age
Age specific ranges make PSA a more sensitive marker for men <60yrs, and more specific in men > 60 yrs

13. Age Specific Reference Ranges

14. Free versus Total PSA
The majority of PSA in serum is bound to alpha-1-antichymotrypsin (ACT)
The proportion of free to total PSA is significantly lower in CAP
Not yet understood why this ratio changes in CAP
May be a way of discriminating patients with BPH and those with CAP

15. Free versus Total PSA
Choice of ratio cut-off remains to be decided - balance between missing some cancers and dramatically reducing the number of biopsies
The Free to Total (F/T) PSA Ratio is perhaps best reserved for difficult diagnostic cases; for example men with a PSA between 4-10ng/ml, or those who have previously had a negative biopsy

16. Free versus Total PSA 0-10 56 For men with PSA 4-10ng / ml and
% free PSA Probability of cancer %
>25 8

17. Difficulty 3 - Screening for Prostate cancer
The Case For:
In order to hope to cure a patient the disease must be diagnosed when it is organ confined
The incidence of prostate cancer is rising by 3% per year
Prostate cancer is now the second commonest cause of death in men in Northern Europe

18. Screening for Prostate cancer
The case against
Transrectal ultrasound and biopsy has a morbidity rate
Negative biopsies lead to significant patient anxiety
Correct protocol has not yet been defined
May detect only incurable disease, or small tumours that are clinically unimportant (but…)

19. Cancers that are PSA detected
have been shown to be clinically significant
are frequently poorly differentiated or spread widely throughout the prostate
when removed by radical surgery will often be upgraded or upstaged.

20. Current opinion? Remains divided
Support for screening for prostate cancer is growing among eminent urologists (admittedly, those with an interest in prostate cancer)

21. Advances in the management of Prostate Cancer

22. Management of Prostate Cancer - Hormonal
The mainstay of treatment of metastatic disease is Anti-androgens, LHRH agonist, or Orchidectomy
Maximal androgen blockade has not proved of benefit for the majority of patients
Intermittent androgen blockade may be of benefit for selected patients, but the long-term durability and advantages are not clear at present

23. Management of Prostate Cancer - Surgery
Radical Prostatectomy is available in Peterborough
Morbidity and mortality rates in published series are low
Long-term data on cure rates is still awaited from clinical trials

24. Management of Prostate Cancer - Radiotherapy
Interstitial radiation therapy (brachytherapy) appears to be making a comeback
Used more widely in USA, results not available to compare with external beam radiotherapy, or surgery
Early evidence that intermediate- or high-risk patients may do worse with brachytherapy

25. Conclusions Incidence of CAP, and mortality from it, is increasing
Screening by currently available modalities does not appear to reduce mortality, and may be the cause of considerable morbidity
PSA remains a useful tool if used judiciously, particularly in the follow up of patients after radiotherapy or radical prostatectomy

26. Conclusions
No new medical treatments available, but better understanding of currently available ones
Radical Prostatectomy offers the possibility of cure, but may also cause significant morbidity
Future markers for biological activity desperately required

27. Points to remember
Always do a DRE in men presenting with lower urinary tract symptoms
Perform a PSA in these men, and refer if PSA above age-specific reference range
Always refer if DRE abnormal
If you have uroflowmetry available it can help decide on the management of the patient’s lower urinary tract symptoms

29. Bladder Cancer

30. Bladder Cancers are...
Predominantly Transitional cell carcinoma (TCC) (>90%)
Squamous (SCC)
75% of bladder cancers in Egypt
only 1% of bladder cancers in England
Adenocarcinoma - <2% of primary bladder cancers
Primary vesical (arise from urachal remnant)
Metastatic

31. Epidemiology - Incidence
54,000 new cases in U.S. in 1997 with 11,700 deaths
4th most common cancer in men (after Prostate, lung, colorectal; 10% of all) - 5% of all cancer deaths
8th most common cancer in women (4% of all), 3% of all cancer deaths

32. Aetiology of Bladder Cancer
Occupational Exposure to chemicals
Cigarette smoking
Analgesics
Bacterial / Parasitic infections
Bladder calculi
Pelvic irradiation
Cytotoxic chemotherapy

33. Presentation of Bladder Cancer
85% of patients present with Painless haematuria
“bladder irritation” (frequency, urgency, dysuria) - often associated with diffuse CIS or invasive cancer
Flank pain (suggests ureteric obstruction)
A pelvic mass

34. Management - depends on type
The Good
The Bad
The Ugly

35. The Good
Surveillance cystoscopy - about spotting change to a worse stage or grade
Small low-grade tumours  TUR followed by surveillance
Multiple / Large / Recurrent tumours, or CIS in random biopsy  consider intravesical chemotherapy (mitomycin c) or immunotherapy (bcg)
pT1 G3 tumours have a high rate of progression  consider early cystectomy

36. The Bad Any TCC invading the muscle wall 25-30% 3 year survival
No real advance in treatment over last 50 years
Stage T2 or T3 - partial or radical cystectomy, radiotherapy, or combination of both
Stage T4 - Chemotherapy, followed by radiation or surgery

37. The Ugly Diffuse CIS is overtly Malignant 78% risk of invasion
Intravesical chemotherapy preferred primary treatment for CIS - treatment effective in 30% and produces complete regression in 50-65% of patients
Radiotherapy and chemotherapy ineffective
Early cystectomy required for recurrent CIS

38. Palliation of Symptoms
Advanced local disease
May lead to persistent bleeding, or pain
bleeding  tranexamic acid or embolisation of internal iliac arteries
may sometimes require cystectomy
Ureteric Obstruction (hydronephrosis)
usually signifies muscle invasive cancer
Cystectomy if disease confined to bladder
consider nephrostomy ??

39. Palliation of Symptoms
Painful bony metastases  radiotherapy
Palliative radiotherapy may also control local symptoms
Blocked Catheter - may be difficult to manage

40. Summary
No new treatments available for the treatment of bladder cancer
Early diagnosis remains important
Surveillance essential to spot the change to more aggressive forms

41. Points to remember Refer ALL cases of visible haematuria
Never assume that visible haematuria is solely due to “infection”
Remember that bladder cancer can present with “malignant cystitis” – symptoms of pain/urgency/frequency

43. Renal cell carcinoma 3% adult cancers, M:F ratio 2:1
Majority of patients diagnosed in 6th to 7th decade
Sporadic and hereditary forms exist
No specific causative agent detected - smoking suggested as a significant risk factor

44. Presentation of renal cell carcinoma
“Classic triad” of pain, haematuria, and flank mass (rare)
More commonly just pain and haematuria
Symptoms of metastatic disease
Paraneoplastic syndromes
INCIDENTAL - discovered while investigating another problem - now accounts for 50%

45. Investigation Ultrasound - to distinguish solid from cystic mass
CT - Staging, prior to surgery
MRI - less sensitive than CT for lesions less than 3cm
Angiography - tumour in solitary kidney, or if partial nephrectomy considered

46. CT Scan of Renal tumour

47. Treatment of Renal Cancer
Radical nephrectomy (remains the only effective method of treating primary renal carcinoma)
Embolisation

48. Treatment of metastatic disease
Generally poor prognosis
Renal cancer remains refractory to treatment with Chemotherapy
Hormonal therapy
Immunotherapy
Palliative nephrectomy
Chemotherapy - Most drugs lack any therapeutic efficacy.
Hormonal therapy - Basis for hormone therapy of advanced renal cancer was the demonstration of its efficacy against and oestrogen-induced clear cell tumour in the adult Syrian hamster.
Progesterone therapy (Medroxyprogesterone acetate [Provera]) ) given twice weekly continues to be a method of management in the absence of more effective agents.
However, no proper study has proved the efficacy of these agents in the management of advanced renal carcinoma.
Immunotherapy - theory is that host immune functions play a role in tumour control and that these immune functions can be stimulated.
Several reports of small numbers of patients treated with BCG have shown some benefit. INTERFERON - Type 1 (alpha) interferon has been used in metastatic renal cancer and responses of 16.5% (complete), and 26% (partial) have been noted. Responses appear independent of preparation used, and correlate with those patients who have undergone previous nephrectomy, and who have a good performance status, a long disease-free interval, and lung-predominant disease. TCGF (IL-2) is a 15k dalton glycoprotein produced by Th cells. In vivo it generates LAK cells, and enhances NK cell function, augments alloantigen responses, and stimulates production of T cells with antitumour function. Variable responses have been produced, but id does seem that in some patients IL-2 can alter the natural history of the disease - probably 5% complete, and further 10-15% partially. NB side effects are awful! - fever, chills, malaise, nausea, vomiting, diarrhoea, Renal and cardiopulmonary
“Adjunctive” nephrectomy - Anecdotal evidence that removal of primary tumour may lead to regression of metastases. However regression occurs in <1% after adjunctive nephrectomy, and such regressions are often short lived. One study of 73% patients followed for 5 years reported a spontaneous regression rate of 6%, so it is difficult to support a routine practice of adjunctive nephrectomy. Nephrectomy prior to trial of interferon therapy has been suggested to improve outcome, but this has not been conclusively shown.
Campbells p

49. Palliation of advanced symptoms
Persistent bleeding / pain - treatable by embolisation
Pain from locally advanced disease - only effective remedy is radical surgery

50. Points to remember
Refer ALL cases of frank (visible) haematuria urgently – do not delay because of assumption of a benign cause
Be aware of the manifold ways that bladder and renal cancer can present

51. End of part 1

52. Local Referral Protocols
Very Urgent Cases – contact duty team at Edith Cavell Hospital who will admit cases if necessary
Urgent “GPM” referrals – Outpatient Slots available with all consultants within 2 weeks
Refer GPM cases by fax –
No specific investigations required in advance (except PSA if appropriate)

53. Microscopic haematuria
Investigate all dipstick proven microscopic haematuria (i.e. anything more than “trace” haematuria)
All patients require renal ultrasound
If patient < 45 years old, AND normal renal ultrasound  refer for Nephrological opinion
Patients > 45 years old, and ALL those with abnormal renal ultrasound  refer to Urology

54. End of Part 2

55. Case Discussion 1 65 year old lady
Previously well apart from mild hypertension
No medications
6/12 history of frequency and urgency
Has had one proven UTI but other 3 MSUs negative

56. Case Discussion 1 What investigations would be appropriate?
What would you do next?
What might be the diagnosis?

57. Case Discussion 2
56 year old man with 9 month history of nocturia and frequency
Otherwise well
PSA 3.7
Rectal examination normal
He is not worried
What would you do?

58. Case Discussion 3 47 year old man comes to surgery
Has read about prostate cancer in newspaper
Is concerned because his father (aged 74) has been diagnosed with prostate cancer recently
What would you do?

59. Case Discussion 4 53 year old woman with right sided abdominal pain
You send her for an USS scan
She has gallstones but the scan shows a lesion in the lower pole of the right kidney
What would you do next?

60. Case Discussion 5 24 year old man with swollen testis
Has been uncomfortable for some time
Referred for USS 3 weeks ago – “signs consistent with infection”
No improvement despite antibiotics
What would you do next?

61. End of Part 3

62. Questions and Answers