Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

CD40 expression in prostate cancer: a potential diagnostic and therapeutic molecule.

CD40, a member of the TNF receptor superfamily, is widely expressed on human immune cells. It is also frequently expressed on epithelial malignancies, suggesting that CD40 may contribute to the pathogenesis of some cancers. Activation of CD40 in cancer cells induces growth inhibition and sensitization to apoptotic stimuli. This study investigates CD40 expression in archival tissue from patients with prostate cancer. In all cases, normal prostatic acini expressed CD40, however, in 56 of 57 cases of prostate cancer no CD40 expression was detected. In the one other case, patchy CD40 expression was associated with prostatic in situ neoplasia. In conclusion, invasive prostate cancer is a CD40-negative tumour. These data may be relevant as a diagnostic tool; in providing insight into progression of cancer from normal epithelium; and in identifying novel therapeutic strategies for prostate cancer.

BCL2 expression predicts survival in patients receiving synchronous chemoradiotherapy in advanced transitional cell carcinoma of the bladder.

It has been reported previously that BCL2 expression predicted a poor response to neo adjuvant chemotherapy but had no prognostic significance in patients receiving radiotherapy alone. We therefore investigated its role in patients receiving synchronous chemoradiotherapy as treatment for advanced bladder cancer. We examined expression of BCL2 and P53 by immunohistochemical analysis using archival tissue samples taken from patients included in the phase I/II trial of synchronous chemoradiotherapy for advanced transitional cell carcinoma (TCC) of the bladder. Data were collected on 24 patients who presented with invasive bladder cancer to the Queen Elizabeth Hospital between March 1998 and January 2001. Eleven patients had died at the time of analysis, with median follow-up of 34 months for the 13 surviving patients. Median survival for patients with strongly BCL2 positive tumours was 12.8 months while, for BCL2 weak or negative patients, the median is yet to be reached (p=0.03). The hazard ratio was 3.37 in favour of BCL2 negative tumours having longer survival. This study shows that over-expression of BCL2 in patients receiving synchronous chemoradiotherapy is an independent indicator of poor survival in muscle invasive TCC of the bladder.

Long-term risk of salvage cystectomy after radiotherapy for muscle-invasive bladder cancer.

OBJECTIVES: To establish the long-term outcome for muscle-invasive transitional cell carcinoma of the bladder treated by radiotherapy with or without neoadjuvant cisplatin. METHODS: 159 patients with T2-T4a NX M0 bladder cancer were entered into a prospective randomized trial between June 1984 and June 1988. Follow-up was by 3-monthly cystoscopy in the first year, 6-monthly the next 2 years and yearly thereafter. Salvage surgery was performed at the discretion of the participating clinician. RESULTS: Minimum follow-up was 9 (median 11) years, at which time 29 patients (18%) remain alive. Median survival was 24 months with no difference between the treatment groups (chi(2) = 0.08, p = 0.77). Overall cystectomy rate was 24% (radiotherapy alone 20%, combined therapy 28%; p = 0.24). Median time to cystectomy from primary treatment was 12 months; range 56 days to 10 years. The risk of cystectomy was 11, 10 and 7% for the first, second and third years after radiotherapy respectively, and 8% in total after the third year. The proportion of patients alive in each successive year who had required a cystectomy was between 20 and 30% for 5 of the first 8 years after treatment. CONCLUSIONS: Salvage cystectomy is necessary in a quarter of patients after radiotherapy and this can be needed up to 10 years after treatment. During this time, multiple invasive procedures are likely to be performed, resulting in significant patient morbidity and cost. Patients should be fully counselled about the need for prolonged surveillance and the persisting risk of salvage surgery when deciding between primary cystectomy and radiotherapy.

Bcl-2 expression identifies patients with advanced bladder cancer treated by radiotherapy who benefit from neoadjuvant chemotherapy.

OBJECTIVE: To assess the prognostic significance of Bcl-2 expression on the clinical outcome after radiotherapy for muscle-invasive bladder cancer, and to determine if it is possible to identify a subgroup of patients to whom neoadjuvant chemotherapy can be targeted to improve survival. PATIENTS AND METHODS: Immunohistochemical staining for Bcl-2 and p53 was performed on the tumours of 51 patients with stage T2-T4a NXM0 transitional cell carcinoma of the bladder who had been included in a randomized clinical trial of radiotherapy with or without neoadjuvant cisplatin. The association between positive staining and salvage cystectomy rate and overall survival was examined, with a median follow-up of 12 years. RESULTS: Bcl-2 and p53 expression was positive in 31 (61%) and 39 (76%) of the tumours, with no association between either, or with tumour stage or grade. There was no difference according to Bcl-2 positivity in the salvage cystectomy rate (P = 0.83) or survival (P = 0.68) for the 51 patients as a whole, but Bcl-2-negative patients receiving neoadjuvant cisplatin had a significantly better prognosis, with a median survival of 72 months compared to 17 months in Bcl-2-positive patients, and a 5-year survival rate of 55% (P = 0.03). CONCLUSIONS: Quantifying Bcl-2 in patients undergoing radiotherapy for advanced bladder cancer identifies those who may benefit from neoadjuvant chemotherapy. Further studies of other members of the Bcl-2 family and other proteins controlling both cell proliferation and apoptosis are warranted, to define the roles and the interactions between them that may contribute to oncogenesis and resistance to standard treatments. This may allow the targeting of specific treatments to patients known to be sensitive to them, and aid the future development of novel therapies for bladder cancer.

CD40 expression in bladder cancer.

The CD40 receptor is expressed in many immune cell types and is known to play a central role in both humoral and T-cell-mediated immunity, being a subject of intense research interest in recent years. It is also expressed on a variety of carcinomas and may therefore be of biological significance in the development and treatment of cancer. The expression of CD40 was examined immunohistochemically in a series of 131 bladder transitional cell carcinomas and the correlation with known prognostic markers and clinical outcome assessed. Seventy-eight per cent of the tumours were CD40-positive, with a highly significant association with both lower stage and lower grade (p<0.001). Ta and T1 tumours expressed CD40 in 89 per cent of specimens compared with 62 per cent seen in T2-T4 tumours and in contrast to normal urothelium, which was mainly CD40-negative. CD40 expression was not related to any other clinicopathological variable including Bcl-2 and p53 expression, nor was it an independent prognostic marker. The lack of the relationship with Bcl-2 staining which is normally seen in basal epidermal cells may indicate alternative or abnormal CD40-mediated cell differentiation mechanisms. The diffuse expression seen in Ta bladder tumours may account for its clinically less aggressive behaviour and is likely to be an important factor in the excellent clinical response seen to BCG immunotherapy. It also raises the possibility of the future development of CD40/CD40 ligand-based immunotherapy for bladder cancer.

Patients' tolerance of transrectal ultrasound-guided prostatic biopsy: an audit of 104 cases.

OBJECTIVE: To determine the frequency and severity of complications following transrectal ultrasonography (TRUS) guided prostatic biopsy, and of pain during the procedure. PATIENTS AND METHODS: The study included 129 men undergoing TRUS-guided prostatic biopsy who were asked to complete a questionnaire about pain and complications one week after biopsy. RESULTS: Of the 104 men who completed the questionnaire, 24% found the procedure moderately to extremely painful and 19% felt that they had had significant complications afterward, the commonest of these being painful or difficult voiding (13%) and haematuria (11%). Systemic symptoms of fever or 'sweats' occurred in 6%, with a diagnosis of septicaemia in three men, despite antibiotic prophylaxis. However, acute urinary retention occurred in only one man. Of all patients, 20% saw their general practitioner within a week, all of whom were prescribed antibiotics in addition to those given prophylactically in hospital. CONCLUSION: TRUS-guided biopsy is often a painful experience for patients and is commonly associated with complications, particularly voiding difficulties. Of particular concern were the three patients with septicaemia, and that one in five men felt sufficiently unwell to visit their doctor within a week of the procedure.

Thigmomorphogenesis: on the mechanical properties of mechanically perturbed bean plants.

The mechanical properties of control and mechanically perturbed (MP) bean stems (Phaseolus vulgaris L., cv. Cherokee wax) were compared. The rubbed plants were greatly hardened against mechanical rupture by previous MP. This hardening was due to a dramatic increase in the flexibility of the stems, but not in their stiffness. The MP-plants were able to bend more than 90 degree without breaking, whereas the control plants broke after just slight bending. A comparison with other work reveals that different species utilize different tactics for achieving similar resistance to rupture due to mechanical stress.