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

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

Prostate Cancer - Dilemmas, and Recent Advances

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

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

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

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

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

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

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?

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

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

Age Specific Reference Ranges

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

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

Free versus Total PSA 0-10 56 For men with PSA 4-10ng / ml and % free PSA Probability of cancer % 0-10 56 10-15 28 15-20 20 20-25 16 >25 8

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

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…)

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.

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

Advances in the management of Prostate Cancer

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

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

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

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

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

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

Bladder Cancer

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

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

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

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

Management - depends on type The Good The Bad The Ugly

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

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

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

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 ??

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

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

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

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

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%

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

CT Scan of Renal tumour

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

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 p1079-1084

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

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

End of part 1

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 – 01733 875726 No specific investigations required in advance (except PSA if appropriate)

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

End of Part 2

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

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

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?

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?

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?

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?

End of Part 3

Questions and Answers