Antony Verbaeys

Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911)

BACKGROUND Local failure after prostatectomy can arise in patients with cancer extending beyond the capsule. We did a randomised controlled trial to compare radical prostatectomy followed by immediate external irradiation with prostatectomy alone for patients with positive surgical margin or pT3 prostate cancer. METHODS After undergoing radical retropubic prostatectomy, 503 patients were randomly assigned to a wait-and-see policy, and 502 to immediate postoperative radiotherapy (60 Gy conventional irradiation delivered over 6 weeks). Eligible patients had pN0M0 tumours and one or more pathological risk factors: capsule perforation, positive surgical margins, invasion of seminal vesicles. Our revised primary endpoint was biochemical progression-free survival. Analysis was by intention to treat. FINDINGS The median age was 65 years (IQR 61-69). After a median follow-up of 5 years, biochemical progression-free survival was significantly improved in the irradiated group (74.0%, 98% CI 68.7-79.3 vs 52.6%, 46.6-58.5; p<0.0001). Clinical progression-free survival was also significantly improved (p=0.0009). The cumulative rate of locoregional failure was significantly lower in the irradiated group (p<0.0001). Grade 2 or 3 late effects were significantly more frequent in the postoperative irradiation group (p=0.0005), but severe toxic toxicity (grade 3 or higher) were rare, with a 5-year rate of 2.6% in the wait-and-see group and 4.2% in the postoperative irradiation group (p=0.0726). INTERPRETATION Immediate external irradiation after radical prostatectomy improves biochemical progression-free survival and local control in patients with positive surgical margins or pT3 prostate cancer who are at high risk of progression. Further follow-up is needed to assess the effect on overall survival.

Postoperative Radiotherapy After Radical Prostatectomy: A Randomised Controlled Trial (EORTC Trial 22911)

Summary Background Local failure after prostatectomy can arise in patients with cancer extending beyond the capsule. We dida randomised controlled trial to compare radical prostatectomy followed by immediate external irradiation withprostatectomy alone for patients with positive surgical margin or pT3 prostate cancer. Methods After undergoing radical retropubic prostatectomy, 503 patients were randomly assigned to a wait-and-seepolicy, and 502 to immediate postoperative radiotherapy (60 Gy conventional irradiation delivered over 6 weeks).Eligible patients had pN0M0 tumours and one or more pathological risk factors: capsule perforation, positivesurgical margins, invasion of seminal vesicles. Our revised primary endpoint was biochemical progression-freesurvival. Analysis was by intention to treat. Findings The median age was 65 years (IQR 61–69). After a median follow-up of 5 years, biochemical progression-free survival was significantly improved in the irradiated group (74·0%, 98% CI 68·7–79·3

Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3?pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial

BACKGROUND Patients with muscle-invasive urothelial carcinoma of the bladder have poor survival after cystectomy. The EORTC 30994 trial aimed to compare immediate versus deferred cisplatin-based combination chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder. METHODS This intergroup, open-label, randomised, phase 3 trial recruited patients from hospitals across Europe and Canada. Eligible patients had histologically proven urothelial carcinoma of the bladder, pT3-pT4 disease or node positive (pN1-3) M0 disease after radical cystectomy and bilateral lymphadenectomy, with no evidence of any microscopic residual disease. Within 90 days of cystectomy, patients were centrally randomly assigned (1:1) by minimisation to either immediate adjuvant chemotherapy (four cycles of gemcitabine plus cisplatin, high-dose methotrexate, vinblastine, doxorubicin, and cisplatin [high-dose MVAC], or MVAC) or six cycles of deferred chemotherapy at relapse, with stratification for institution, pT category, and lymph node status according to the number of nodes dissected. Neither patients nor investigators were masked. Overall survival was the primary endpoint; all analyses were by intention to treat. The trial was closed after recruitment of 284 of the planned 660 patients. This trial is registered with ClinicalTrials.gov, number NCT00028756. FINDINGS From April 29, 2002, to Aug 14, 2008, 284 patients were randomly assigned (141 to immediate treatment and 143 to deferred treatment), and followed up until the data cutoff of Aug 21, 2013. After a median follow-up of 7.0 years (IQR 5.2-8.7), 66 (47%) of 141 patients in the immediate treatment group had died compared with 82 (57%) of 143 in the deferred treatment group. No significant improvement in overall survival was noted with immediate treatment when compared with deferred treatment (adjusted HR 0.78, 95% CI 0.56-1.08; p=0.13). Immediate treatment significantly prolonged progression-free survival compared with deferred treatment (HR 0.54, 95% CI 0.4-0.73, p<0.0001), with 5-year progression-free survival of 47.6% (95% CI 38.8-55.9) in the immediate treatment group and 31.8% (24.2-39.6) in the deferred treatment group. Grade 3-4 myelosuppression was reported in 33 (26%) of 128 patients who received treatment in the immediate chemotherapy group versus 24 (35%) of 68 patients who received treatment in the deferred chemotherapy group, neutropenia occurred in 49 (38%) versus 36 (53%) patients, respectively, and thrombocytopenia in 36 (28%) versus 26 (38%). Two patients died due to toxicity, one in each group. INTERPRETATION Our data did not show a significant improvement in overall survival with immediate versus deferred chemotherapy after radical cystectomy and bilateral lymphadenectomy for patients with muscle-invasive urothelial carcinoma. However, the trial is limited in power, and it is possible that some subgroups of patients might still benefit from immediate chemotherapy. An updated individual patient data meta-analysis and biomarker research are needed to further elucidate the potential for survival benefit in subgroups of patients. FUNDING Lilly, Canadian Cancer Society Research.

Combined magnetic resonance imaging and spectroscopy in the assessment of high grade prostate carcinoma in patients with elevated PSA: A single-institution experience of 356 patients

PURPOSE To assess the ability of combined whole-prostate magnetic resonance imaging and magnetic resonance spectroscopy imaging (MRI+MRSI) to predict the presence or absence of high grade (Gleason 4+3 or higher) prostate carcinoma in men with elevated PSA. MATERIALS AND METHODS Between March 2002 and September 2007, 356 subjects (mean serum PSA 11.5 ng/ml, range 0.4-133.0 ng/ml) were examined with fast-T2-weighted magnetic resonance imaging (MRI) and 3D-magnetic resonance spectroscopy imaging (MRSI) on a 1.5T scanner. Prostate cancer was histopathologically proven in 220 patients (41 with high grade and 179 with lower grade cancer) and non-evidence of cancer was determined after at least 12 months (mean 21 months) clinical follow-up in 136 subjects. The sensitivity, false positive rate, and negative predictive value of MRI+MRSI were calculated using histopathology and follow-up results as reference standard. RESULTS MRI+MRSI had a significantly higher sensitivity for high grade tumors (92.7%) than for lower grade tumors (67.6%), and was false positive in only 7.4% of patients with non-evidence of prostate cancer. For exclusion of a high grade tumor, MRI+MRSI had a negative predictive value of 98.4%. CONCLUSIONS MRI+MRSI holds great potential for predicting presence or absence of high grade tumors in men with elevated PSA. This can be important in the selection of patients for active surveillance, or in the decision to rebiopsy patients with prior negative biopsies.

Solubility of Calcium Oxalate Monohydrate and Hydroxyapatite in Edta Solutions

The effect of the addition of a buffer to an ethylenediaminetetracetic acid (EDTA) litholytic solution on the solubility of calcium oxalate monohydrate and hydroxyapatite is investigated. The experiments show that the addition of triethanolamine as a buffer to EDTA solutions at pH 8 and 8.5 enhances the solubility of these salts, confirming theoretical predictions. The solubility of calcium oxalate monohydrate at 25C in solutions with varying ratios of buffer to EDTA concentrations and an osmolality of 0.9 was determined. The solutions resulting in the highest solubility were finally tested for their litholytic ability at 37C. At pH 8 solubilities of 22.5 g X l-1 for calcium oxalate monohydrate and 20.2 g X l-1 for hydroxyapatite were obtained. The corresponding solubilities at pH 8.5 were respectively 24.5 g X l-1 and 19.2 g X l-1.

European Experience with 1-stage Urethroplasty with Free Full Thickness Skin Graft

A series of 57, 1-stage urethroplasties with a free full thickness skin graft is reported. Results were good in 90 per cent of the cases, fair in 2 per cent and bad in 8 per cent. The bad results were noted in elderly men, suggesting that decreased viability of the surrounding tissues is a contraindication to this type of operation.

Low-dose fortnightly methotrexate in advanced prostate cancer

THE Genito-Urinary Tract Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer (EORTC) has performed a series of phase II studies with strict criteria for the assessment of response in patients with bidimensionally measurable soft tissue or visceral metastases [ 1, 21. Reviewing chemotherapy in urological tumours, Stoter and Williams [3] concluded that methotrexate was not useful in the treatment of prostate cancer. Response to methotrexate in the American National Prostatic Cancer Project (NPCP) protocol 1100 was only 5% [4]. However, the scheduling of methotrexate doses was under investigation in the mid-1980s and in view of activity in other adenocarcinomas (e.g. breast cancer), together with anecdotal reports of activity in prostate cancer, a phase II study of ‘low-dose’ methotrexate (40 mg/m’) given every 2 weeks was started to investigate the effectiveness and toxicity of this schedule in prostate cancer patients. Entry criteria included: positive histology, bidimensionally measurable (clinical, ultrasound, computed tomography) soft tissue or visceral lesions to assess response, age 75 or less, additive hormone therapy to be stopped at least 1 day before the start of therapy, no previous chemotherapy or radiotherapy to the indicator lesion(s), WHO performance status 2 or better, life expectancy greater than 60 days, initial white blood count 3 X 109/1 or greater, initial platelet count 100 X 109/1 or greater, adequate renal function (serum creatinine 120 u,moYl or less, creatinine clearance greater than 75 ml/mm), adequate liver function (bilirubin less than 20 mmol/l), no second tumour, no significant cardiac disease, and no uncontrolled infections. Resnonse was assessed after every two cvcles. WHO criteria for evaluation of response and toxicity were-used [5]. 28 patients with documented progressive hormone-resistant disease entered the study between January 1986 and April 1989. 4 patients were ineligible; 1 had no measurable lesion and 3 had not received previous hormone therapy as required by the protocol. Of the 24 eligible patients (age 46-75 years, median 63.5 years), all had received previous androgen suppressive therapy; in addition 2 had received estramustine phosphate and eight had received radiotherapy to various sites. WHO performance scores were: 0 in 4 patients, 1 in 14, and 2 in 6. 1 natient died before the first assessment after two cvcles (early death from malignant disease). 1 patient died of toxicity after one cycle (early death from toxicity) with nausea and vomiting WHO grade 3, diarrhoea grade 4, oral toxicity grade 4, liver toxicity grade 1, renal toxicity grade 1 and minor haemorrhage. A toxic death was also reported in 1 patient who had a further cycle of therapy after withdrawing because of progression. No complete responses were observed. One patient (5%) had a partial response in inguinal lymph nodes, 10 patients (46%) showed no change and 11 patients (50%) had progressive disease. Full doses of drug were given with all cycles of treatment. Leucovorin rescue was only given if toxicity was encountered. The median number of courses was two (mean 3.5, range l-10). The dose was delayed (3-7 days) on three occasions. Haematological toxicity was tolerable. The lowest white cell count was 3.2 x 109/1 (range 3.2-9.7 x 109/1, median 4.5 x 109). The lowest platelet count was 17 x 109/1 (range 17-530 X 109/1, median 174 X 109). Methotrexate at a dose of 40 mg/m2 given every 2 weeks (with

Influence of feeding, blood sampling method and type of anaesthesia on renal function parameters in the normal laboratory rat

With sophisticated experiments it is necessary to handle laboratory animals many times. To determine the effect of minor handling a series of experiments was performed to measure the impact of fasting, anaesthesia, blood collection method and serum creatinine analysis on renal function. Simple clinical methods to measure renal function parameters such as diuresis, urinary osmolality, urinary creatinine excretion and serum creatinine were used. During fasting a significant increase (P<0.01) in diuresis and a significant decrease (P<0.01) in urinary osmolality were noted. Fasting and anaesthesia have the additional effect of significantly decreasing (P<0.05) urinary creatinine excretion. Blood sampling method also has a significant impact on serum creatinine: venous sampling causes false-positive differences compared with simultaneous arterial sampling.

Results of urometabolic evaluation in 127 patients with renal calculous disease

One hundred twenty-seven selected stone formers were evaluated. With the simple ambulatory tests proposed by Pak for metabolic screening and a complete urologic evaluation an anomaly was found in more than 90 per cent of the cases. The patients were divided into three groups: (1) patients operated on for staghorn stones; (2) patients with episodes of spontaneous stone eliminations or young people with only one stone episode; and (3) patients operated on for stone disease. No significant differences were noted except for the occurrence of urinary tract infection and for struvite and calcium oxalate occurrence in the different groups. Urinary tract infection combined with a metabolic disorder appear to make the evolution from small kidney stone to staghorn stone a reality.

Toxicity of litholytic ethylenediaminetetraacetic acid solutions to the urothelium of the rat and dog

SummaryThe toxicity to the urothelium of bipotassium ethylene-diaminetetraacetic acid (K2-EDTA) buffered with 0.2 M triethanolamine (TEA) at pH 8 and 8.5 was tested in rats and dogs. Even at a low concentration of 3.125 mM, K2-EDTA is very noxious to the bladder mucosa. This toxicity is not due to the buffer TEA, which is well tolerated. Although buffered K2-EDTA, at pH 8.5 is an excellent chemolytic agent for calcium-containing stones, its clinical use is limited by this toxicity.