Prostate adenocarcinoma definitive EBRT conventional intermediate risk

Target verification notes

• Consideration should be given to dose delivered from verification imaging and whether this needs to be accounted for in treatment planning, particularly with respect to critical OARs.

Efficacy

Dose Escalation

Dose escalation above 70Gy has been analysed by Viani et al,^r a meta analysis of 7 RCT’s (n=2812), a comparative effectiveness study by Kalbasi et al^r of 5 RCTs (High Risk patients n=13,538) a database analysis by Hall et al^r (n=20,028) and Ph III trial by Kuban et al (2011).^r Viani et al^r found a significant reduction in the incidence of biochemical failure in patients with low, intermediate and high risk localised prostate cancer 24.8% with high dose RT (HDRT) vs 34.6% with conventional dose RT (CDRT) (p < 0.0001) (see graph below). There was no difference in mortality rate and specific prostate cancer mortality rates between CDRT and HDRT. On subgroup analysis, all subgroups showed a linear correlation between total dose of radiotherapy and biochemical failure. The analysis by Kalbasi et al^r found that dose escalated EBRT (> 75.6Gy) was associated with improved overall survival for patients with high risk prostate cancer (HR 0.84, 95% CI, 0.80 - 0.88; p < 0.001) and that for every incremental increase of about 2Gy in dose, there was a 7.8% (95% CI, 5.4 - 10.2%; p < 0.001) reduction in the hazard of death for intermediate risk patients.

© Int J Radiat Biol Phys 2009 Viani^r

Use of Androgen Deprivation Therapy

Bolla et al (2016)/EORTC 22991^r randomised 819 patients with intermediate and high risk prostate cancer to RT alone or RT + ADT. The RT doses were either 70Gy, 74Gy or 78 Gy and ADT was given during and following RT. 75% of patients had intermediate risk disease and and 25% high risk. After a median follow up of 7.2 years, After a median follow-up of 7.2 years RT+ ADT improved Biochemical PFS compared to RT alone (HR=0.53, CI: 0.42-0.67, P<0.001) irrespective of the radiation dose. Clinical PFS was also statistically significantly improved 80.8% for RT alone vs 88.7% for RT+ADT (HR=0.63, 95% CI: 0.48-0.84, P=0.001) .

The addition of short­ term ADT to dose ­escalated (>70 Gy) radiotherapy may be considered. However, the risk of adverse effects versus the potential benefit should be discussed with patients prior to treatment.

Multiple randomised trials have demonstrated an improvement in disease outcomes when short term ADT (3-­8 months) was given in addition to radiotherapy.

• In RTOG 94­08, 1979 patients were randomly assigned to radiotherapy (66.6Gy) with or without ADT (6 months in total, commencing 2 months before radiotherapy). At a median follow ­up of 9.1 years there was a benefit for short ­term ADT and radiotherapy in 10 year overall survival (62% vs. 57%, P =0.03) and disease specific mortality (8% vs. 4%, p =0.001).^r
• Other randomised trials have also shown a benefit in terms of overall survival^r and freedom from failure.^rr
• D'Amico^r published a small study of 100 patients reporting that intermediate risk patients randomised to conformal lower dose RT + 6 months ADT had a significantly better survival and lower prostate cancer specific mortality when compared to RT alone. 8 year survival rates were 74% (95% CI 64-­82%) vs 61% (95 CI, 49­-71%) for RT + ADT and RT alone. Approximately 75% of patients in this study had intermediate risk disease.

Toxicity

A summary of the most clinically significant toxicities associated with this protocol are included in the table below:

Cardiovascular death associated with ADT

The use of ADT and cardiac mortality in men with prostate cancer has been highly controversial for the past 5 years. In 2011, the FDA published a safety warning regarding the increased risk of diabetes, heart attack, sudden cardiac death and stroke. In response to this Nguyen et al (2011) performed a systematic review and meta­-analysis of randomised PHIII trials to determine whether ADT is associated with cardiovascular mortality, prostate cancer specific mortality and all cause mortality in men with unfavourable prostate cancer.

The review consisted of 4,141 patients in 8 randomised trials with a median follow up of 7.6­ - 13.2 years, and reported:

• Cardiovascular death in patients receiving ADT vs control was not significantly different. (255/2,200 vs 252/1,941 events; incidence, 11%; 95%CI, 8.3%­ - 14.5%; vs 11.2%; 95% CI, 8.3% -­ 15%; RR, 0.93; 95% CI, 0.79­ - 1.10, p=0.41).
• ADT was not associated with excess cardiovascular death in trials of at least 3 years ADT duration, 11.5% vs 11.5% for ADT and the control respectively and 10.5% vs 10.3% in trials using ADT for < 6 months (RR, 1.00; p=0.99).
• Of 4,805 patients from 11 trials, overall death data reported, ADT was associated with lower PCSM (443/2,527 vs 552/2,278 events, 13.55 vs 22.1%, RR, 0.69; p<0.001) and lower all cause mortality (1140/2,527 vs 1213/2,278 events, 37.7% vs 44.4%; RR, 0.86; p<0.001).

© JAMA Nguyen 2011^r