Peter Whelan

Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group.

BACKGROUNDnFew randomised studies have compared intermittent hormonal therapy (IHT) with continuous therapy for the treatment of advanced prostate cancer (PCa).nnnOBJECTIVEnTo determine whether intermittent therapy is associated with a shorter time to progression.nnnDESIGN, SETTING, AND PARTICIPANTSn766 patients with locally advanced or metastatic PCa received a 3-mo induction treatment. The 626 patients whose prostate-specific antigen (PSA) level decreased to <4 ng/ml or to 80% below the initial value were randomised.nnnINTERVENTIONnPatients received cyproterone acetate (CPA) 200mg for 2 wk and then monthly depot injections of a luteinising hormone-releasing hormone (LHRH) analogue plus 200mg of CPA daily during induction. Patients randomised to the intermittent arm ceased treatment, while those randomised to the continuous arm received 200mg of CPA daily plus an LHRH analogue.nnnMEASUREMENTSnPrimary outcome measurement was time to subjective or objective progression. Secondary outcomes were survival and quality of life (QoL). Time off therapy in the intermittent arm was also recorded.nnnRESULTS AND LIMITATIONSn127 patients from the intermittent arm and 107 patients from the continuous arm progressed, with a hazard ratio (HR) of 0.81 (95% confidence interval [CI]: 0.63-1.05, p=0.11). There was no difference in survival, with an HR of 0.99 (95% CI: 0.80-1.23) and 170 deaths in the intermittent arm and 169 deaths in the continuous arm. The greater number of cancer deaths in the intermittent treatment arm (106 vs 84) was balanced by a greater number of cardiovascular deaths in the continuous arm (52 vs 41). Side-effects were more pronounced in the continuous arm. Men treated with intermittent therapy reported better sexual function. Median time off therapy for the intermittent patients was 52 wk (95% CI: 39.4-65.7).nnnCONCLUSIONSnIHT should be considered for use in routine practice because it is associated with no reduction in survival, no clinically meaningful impairment in QoL, better sexual activity, and considerable economic benefit to the individual and the community.

A community study of bladder cancer screening by the detection of occult urinary bleeding.

A possible method of improving the prognosis of bladder cancer may be the widespread introduction of screening. We investigated the ability of urine dipsticks to detect early bladder cancer in a group of men in the community. In 2,356 men more than 60 years old the urine was tested with a dipstick for the presence of blood. The subjects then tested their own urine on 10 subsequent occasions. Of the men 474 (20%) had dipstick hematuria and 319 agreed to undergo urological investigation. An asymptomatic bladder tumor was found in 17 men, associated in 10 with abnormal urine cytological findings. Urine dipsticks for the detection of red cells provided an inexpensive, simple and acceptable screening test for bladder cancer. However, introduction of generalized population screening by this method would produce large numbers requiring investigation. Combining urine cytology with dipstick hematuria results may provide a realistic alternative and further evaluation of the effectiveness of screening for bladder cancer in the community is required.

Using PSA to Guide Timing of Androgen Deprivation in Patients with T0–4 N0–2 M0 Prostate Cancer not Suitable for Local Curative Treatment (EORTC 30891)

OBJECTIVEnEORTC trial 30891 compared immediate versus deferred androgen-deprivation therapy (ADT) in T0-4 N0-2 M0 prostate cancer (PCa). Many patients randomly assigned to deferred ADT did not require ADT because they died before becoming symptomatic. The question arises whether serum prostate-specific antigen (PSA) levels may be used to decide when to initiate ADT in PCa not suitable for local curative treatment.nnnMETHODSnPSA data at baseline, PSA doubling time (PSADT) in patients receiving no ADT, and time to PSA relapse (>2 ng/ml) in patients whose PSA declined to <2 ng/ml within the first year after immediate ADT were analyzed in 939 eligible patients randomly assigned to immediate (n=468) or deferred ADT (n=471).nnnRESULTSnIn both arms, patients with a baseline PSA>50 ng/ml were at a>3.5-fold higher risk to die of PCa than patients with a baseline PSA<or=8 ng/ml. If baseline PSA was between 8 and 50 ng/ml, the risk of PCa death was approximately 7.5-fold higher in patients with PSADT<12 mo than in patients with PSADT>12 mo. Time to PSA relapse after response to immediate ADT correlated significantly with baseline PSA, suggesting that baseline PSA may also reflect disease aggressiveness.nnnCONCLUSIONSnPatients with a baseline PSA>50 ng/ml and/or a PSADT<12 mo were at increased risk to die from PCa and might have benefited from immediate ADT, whereas patients with a baseline PSA<50 ng/ml and a slow PSADT (>12 mo) were likely to die of causes unrelated to PCa, and thus could be spared the burden of immediate ADT.

Soluble forms of the adhesion molecule E-cadherin in urine.

The adhesion molecule E-cadherin is essential for maintaining epithelial intercellular adhesion. Loss or reduced expression of E-cadherin has been related to invasive behaviour in a wide range of carcinomas. Using immunoblotting techniques, the existence of multiple soluble forms of E-cadherin was demonstrated in urine from healthy volunteers and patients with benign urinary tract disorders or bladder cancer. The existence of soluble forms of E-cadherin in the urine may reflect shedding from the urinary tract epithelium as part of the normal turnover of this molecule. The possibility that enhanced shedding may contribute to the loss of E-cadherin expression/function in malignancy is discussed.

An evaluation of the immunochemical measurement of prostatic acid phosphatase and prostatic specific antigen in carcinoma of the prostate.

Serum prostatic specific antigen (PSA) and prostatic acid phosphatase (PAP) were evaluated with double monoclonal radioimmunoassays. In 250 patients with prostatic cancer the normal limits were as follows: PSA 0.1-2.7 ng/ml, and PAP 1.09 +/- 0.45 ng/ml (mean +/- SD). In 91 untreated patients with non-metastatic tumours, 42.8% had PSA greater than 10 ng/ml and 18.6% had PAP greater than 2 ng/ml. In 60 untreated patients with metastatic disease PSA was greater than 10 ng/ml in 91.7%; PAP was greater than 2 ng/ml in 65%. In prolonged remission PSA was generally less than 5 ng/ml and PAP less than 2 ng/ml. Longitudinal studies of 2-4 years showed the independence of these markers and a higher correlation of changes in the PSA level and clinical status than given by parallel PAP measurements. In non-metastatic disease, PSA greater than 10 ng/ml at presentation, with or without a coincidentally raised PAP, carried an increased risk of progression within 2 years.

Intermittent Maximal Androgen Blockade in Patients with Metastatic Prostate Cancer: An EORTC Feasibility Study

OBJECTIVESnIn preparation of an intercontinental Phase III trial comparing continuous maximal androgen blockade (MAB) to intermittent androgen suppression (IAS) in untreated metastatic prostate cancer, a feasibility study on IAS was accomplished.nnnMETHODSn107 patients (median follow-up 92 weeks) were treated with MAB until a PSA nadir was reached. Nadir was defined as PSA below 20 ng/ml corresponding to PSA reduction by at least 80% of baseline value. Criteria for restarting treatment was PSA >20 ng/ml and PSA > nadir + 50%. Trials aim was to assess the likelihood that 80% of patients would reach a first nadir and that 80% of these would also reach a second nadir.nnnRESULTSn51.4% of patients had some degree of pain at entry, 27.1% had >15 hot spots, 23.7% demonstrated obstruction. Only 17.8% had normal potency, 56.1% were totally impotent. One to seven cycles of treatment were given. 76.6% of patients reached a 1st nadir after a median of 19 weeks of treatment, 84.1% of these started the 2nd cycle and 71% of them reached a 2nd nadir after a median of 13.6 weeks. Median time off-treatment was 14.3 and 16.0 weeks corresponding to 38.4% and 48.5% of the duration of each cycle. A similar proportion of patients was reported to be potent during follow-up compared to baseline. 32.7% of patients died during follow-up, 82.9% of prostate cancer.nnnCONCLUSIONnAround 75% of the patients achieved a nadir at each cycle. The concept of IAS seems to be feasible and warrants further investigation.

Differences in Time to Disease Progression Do Not Predict for Cancer-specific Survival in Patients Receiving Immediate or Deferred Androgen-deprivation Therapy for Prostate Cancer: Final Results of EORTC Randomized Trial 30891 with 12 Years of Follow-up

BACKGROUNDnTrials assessing the benefit of immediate androgen-deprivation therapy (ADT) for treating prostate cancer (PCa) have often done so based on differences in detectable prostate-specific antigen (PSA) relapse or metastatic disease rates at a specific time after randomization.nnnOBJECTIVEnBased on the long-term results of European Organization for Research and Treatment of Cancer (EORTC) trial 30891, we questioned if differences in time to progression predict for survival differences.nnnDESIGN, SETTING, AND PARTICIPANTSnEORTC trial 30891 compared immediate ADT (n=492) with orchiectomy or luteinizing hormone-releasing hormone analog with deferred ADT (n=493) initiated upon symptomatic disease progression or life-threatening complications in randomly assigned T0-4 N0-2 M0 PCa patients.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnTime to first objective progression (documented metastases, ureteric obstruction, not PSA rise) and time to objective castration-resistant progressive disease were compared as well as PCa mortality and overall survival.nnnRESULTS AND LIMITATIONSnAfter a median of 12.8 yr, 769 of the 985 patients had died (78%), 269 of PCa (27%). For patients receiving deferred ADT, the overall treatment time was 31% of that for patients on immediate ADT. Deferred ADT was significantly worse than immediate ADT for time to first objective disease progression (p<0.0001; 10-yr progression rates 42% vs 30%). However, time to objective castration-resistant disease after deferred ADT did not differ significantly (p=0.42) from that after immediate ADT. In addition, PCa mortality did not differ significantly, except in patients with aggressive PCa resulting in death within 3-5 yr after diagnosis. Deferred ADT was inferior to immediate ADT in terms of overall survival (hazard ratio: 1.21; 95% confidence interval, 1.05-1.39; p [noninferiority]=0.72, p [difference] = 0.0085).nnnCONCLUSIONSnThis study shows that if hormonal manipulation is used at different times during the disease course, differences in time to first disease progression cannot predict differences in disease-specific survival. A deferred ADT policy may substantially reduce the time on treatment, but it is not suitable for patients with rapidly progressing disease.

Radiotherapy for Node Positive Penile Cancer: Experience of The Leeds Teaching Hospitals

PURPOSEnWe studied the outcomes in patients with node positive penile cancer who received radiotherapy to inguinal and pelvic nodes. Although half of node positive cases are cured by lymphadenectomy, little data are available on the potential further benefits and toxicities of postoperative radiotherapy.nnnMATERIALS AND METHODSnWe retrospectively audited the clinical notes and electronic records of 23 patients referred to a specialist center from 2002 to 2008 who received radiotherapy to the inguinal/pelvic nodes as adjuvant treatment after lymphadenectomy (14), or as high grade palliation for extensive/fixed nodes (8) or extensive local tumor (1). The primary outcome measure was overall survival. Secondary end points were locoregional recurrence-free survival and toxicity.nnnRESULTSnAll 13 deaths were due to penile cancer. Patients with adjuvant therapy had better overall survival (66% vs 11%, p<0.001) and locoregional relapse-free survival (56% vs 22%, p=0.03) than those with high grade palliation. Six of 14 adjuvant cases and 7 of 9 with high grade palliation relapsed locoregionally. Of patients with adjuvant therapy and extracapsular spread 1 of 6 with N1, 1 of 4 with N2 and 3 of 4 with N3 disease relapsed (p=0.31). No life threatening toxicity was observed. It was difficult to determine the relative contributions of radiotherapy and surgery to leg/scrotal lymphedema. The study was limited by its small size, which reflects the rarity of this tumor.nnnCONCLUSIONSnAdjuvant radiotherapy appears to have a role after inguinal lymphadenectomy, particularly in patients with extracapsular nodal spread, in whom historically survival rates have been poor. Our findings warrant further investigation in larger series of patients.

Long-term therapy with a depot luteinizing hormone-releasing hormone analogue (Zoladex) in patients with advanced prostatic carcinoma.

We treated 191 patients with histologically proved locally advanced stage (T3 or T4) and/or metastatic prostate cancer with a biodegradable depot formulation of a luteinizing hormone-releasing hormone analogue (Zoladex). After an initial increase in serum testosterone in week 1 of therapy a continuous decrease of testosterone to castrate levels was obtained. With a monthly injection of the luteinizing hormone-releasing hormone analogue 4 patients (2 per cent) experienced a transient increase in bone pain, 1 had ureteral obstruction and 1 suffered paraplegia during the first few weeks of therapy. Over-all objective and subjective responses were similar to those obtained by castration or estrogen therapy. The absence of local and systemic (long-term) side effects proves the validity of this approach for patients with advanced prostatic cancer.

Locally Advanced and Metastatic Prostate Cancer Treated with Intermittent Androgen Monotherapy or Maximal Androgen Blockade: Results from a Randomised Phase 3 Study by the South European Uroncological Group

BACKGROUNDnFew randomised studies have compared antiandrogen intermittent hormonal therapy (IHT) with continuous maximal androgen blockade (MAB) therapy for advanced prostate cancer (PCa).nnnOBJECTIVEnTo determine whether overall survival (OS) on IHT (cyproterone acetate; CPA) is noninferior to OS on continuous MAB.nnnDESIGN, SETTING, AND PARTICIPANTSnThis phase 3 randomised trial compared IHT and continuous MAB in patients with locally advanced or metastatic PCa.nnnINTERVENTIONnDuring induction, patients received CPA 200 mg/d for 2 wk and then monthly depot injections of a luteinising hormone-releasing hormone (LHRH; triptoreline 11.25 mg) analogue plus CPA 200 mg/d. Patients whose prostate-specific antigen (PSA) was <4 ng/ml after 3 mo of induction treatment were randomised to the IHT arm (stopped treatment and restarted on CPA 300 mg/d monotherapy if PSA rose to ≥20 ng/ml or they were symptomatic) or the continuous arm (CPA 200 mg/d plus monthly LHRH analogue).nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnPrimary outcome measurement was OS. Secondary outcomes included cause-specific survival, time to subjective or objective progression, and quality of life. Time off therapy in the intermittent arm was recorded.nnnRESULTS AND LIMITATIONSnWe recruited 1045 patients, of which 918 responded to induction therapy and were randomised (462 to IHT and 456 to continuous MAB). OS was similar between groups (p=0.25), and noninferiority of IHT was demonstrated (hazard ratio [HR]: 0.90; 95% confidence interval [CI], 0.76-1.07). There was a trend for an interaction between PSA and treatment (p=0.05), favouring IHT over continuous therapy in patients with PSA ≤1 ng/ml (HR: 0.79; 95% CI, 0.61-1.02). Men treated with IHT reported better sexual function. Among the 462 patients on IHT, 50% and 28% of patients were off therapy for ≥2.5 yr or >5 yr, respectively, after randomisation. The main limitation is that the length of time for the trial to mature means that other therapies are now available. A second limitation is that T3 patients may now profit from watchful waiting instead of androgen-deprivation therapy.nnnCONCLUSIONSnNoninferiority of IHT in terms of survival and its association with better sexual activity than continuous therapy suggest that IHT should be considered for use in routine clinical practice.