Dose escalated radiotherapy, using IMRT with daily IGRT, is the preferred treatment for high risk prostate cancer. The addition of ADT to radiotherapy has been shown to improve outcomes compared to radiotherapy alone. However, the most beneficial duration of ADT 18 to 36 months still remains unresolved.
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 alr of 5 RCTs (High Risk patients n=13,538) a data base analysis by Hall et alr (n=20,028) and Ph III trial by Kuban et al.r Viani et alr 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 3DCRT and high dose RT. On subgroup analysis, all subgroups showed a linear correlation between total dose of radiotherapy and biochemical failure. The analysis by Kalbasi et al found that dose escalated EBRT (> 75.6Gy) was associated with improved overall survival for patients with high risk prostate cancer (HR, 0.82; 95% CI, 0.78-0.85; P < .001) and that for every incremental increase of about 2 Gy in dose, there was a 6.3% (95% CI, 3.3%-9.1%; P < .001) reduction in the hazard of death for high-risk patients.
© Int J Radiat Oncol Biol Physics. Viani et al, 2009r
Androgen Deprivation Therapy (ADT)
Bolla et al (2016)/EORTC 22991r 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, 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 use of ADT in combination with EBRT in patients with high risk prostate cancer has been shown to improve prostate cancer specific and overall survival in a number of key trials (RTOG 86.10r, EORTC 22863,r RTOG 85.31,r SPCG7/SFUO3 - Widmark,r Warder and TROG 96.10r trials).
The 10 year outcomes of the EORTC 22863 trialr where 415 high risk patients were randomised to receive RT alone (n=208) or combined treatment (ADT during and 3 years following RT, n= 207) showed significantly improved 10 year clinical DFS, 10 year OS and 10 year prostate cancer mortality with a median follow up of 9.1 years. OS was 39.8% vs 58.1% for RT alone and combined treatment respectively (HR 0.6, 95%CI 0.45 - 0.80 p=0.0004) and 10 year prostate cancer mortality was 30.4% for RT alone vs 10.3% for combined treatment (HR 0.38 95%CI 0.24 - 0.60 p<0.0001). There was no significant difference in cardiovascular mortality between the treatment groups.
Fossa et alr reported on the 10 and 15 year outcomes of The Widmark trial where 875 men with locally advanced disease from Norway, Sweden and Denmark were randomised to ADT alone (n=439) vs ADT + RT (n=436). After a median of 7.6 years follow up the addition of ADT to RT more than halved the 10 and 15 year prostate cancer specific mortality and substantially decreased the overall mortality.
Between 1995 - 2005, Warde et alr randomised 1,205 men with T3 or T4 prostate cancer to receive either ADT alone (n=602) vs ADT+RT (n=603). With a median follow up of 6 years at time of analysis, 320 patients had died, 175 in ADT alone vs 145 in the ADT+RT group. The addition of ADT to RT, significantly improved overall survival at 7 years, 74% (ADT+RT) vs 66% (ADT alone), (HR 0.77. 95% CI 0.61-0.98, p=0.033). The 7 year disease specific deaths were 9% and 19% for ADT+RT and ADT alone respectively, (p=0.001). 346 patients developed progressive disease, 251 (ADT alone vs 95 (ADT+RT).
© Lancet Oncol Warde et al 2011r
Duration of ADT
The optimal duration of ADT in the high risk patient cohort has not been definitively determined. A number of PhIII RCTs have been conducted to address the issue of timing and the key findings are listed below:
- EORTC 22961r – 970 men received EBRT + 6 months of ADT and were then randomised to either observation (n=483) or an additional 30 months of ADT(n=487). At median follow up of 6.4 years, the prolonged course of ADT was associated with a significant decrease in overall mortality when compared with the 6 months ADT. 5 year mortality rate was 15.2% vs 19% respectively (HR 0.70, 95% CI 0.55 - 0.92). 5 year cumulative prostate cancer specific mortality was 4.7% (short term ADT) vs 3.2% (long term ADT)
- RTOG 9202r - The 10 year follow up of 1,554 men with T2c - T4 prostate cancer comparing short term ADT (SADT – 4 months) + RT vs long term ADT (LADT – 2 years) + RT, demonstrated a significant improvement in all endpoints in favour of long term ADT with the exception of overall survival.
- Disease free survival 13.2% vs 22.5%; p<0.0001
- Disease specific survival 83.9% vs 88.7%; p=0.0042
- Local progression 22.2% vs 12.3%; p<0.0001
- Distant metastasis 22.8% vs 14.8%; p<0.0001
- Biochemical failure 68.1% vs 51.9%; p <0.0001
- Overall survival 51.6% vs 53.9%; p=0.36
- On subgroup analysis of the Gleason score 8 - 10 group, LADT showed an overall survival difference of 45.1% vs 31.9% (SADT); p=0.0061) See graphs below.
© JCO Horwitz 2008r
The use of short term neoadjuvant ADT (2 to 6 months) has been shown to provide improved benefit over RT alone in high risk patients unable to tolerate long term ADT. rr
Nabid et alr randomised 630 men with high risk prostate cancer to either 18 or 36 months ADT prior to radiotherapy. At a median follow up of 6.75 years, 10 year overall survival was 63.6% (36 month) vs 63.2% (18 month) p=0.429 and 10 year disease specific survival was the same for both groups at 87.2%.
TROG 96.01 trialr randomised 818 men with T2b, T2c, T3 and T4 N0 M0 prostate cancer to receive radiotherapy alone, 3 months of neoadjuvant ADT (NADT) plus RT or 6 months NADT plus RT.
- At a median follow up of 10.6 years, compared with radiotherapy alone:
- 3 months of NADT decreased the cumulative incidence of PSA progression (adjusted hazard ratio 0·72, 95% CI 0·57 – 0·90; p=0·003) and local progression (0·49, 0·33–0·73; p=0·0005), and improved event-free survival (0·63, 0·52–0·77; p<0·0001).
- 6 months of NADT further reduced PSA progression (0·57, 0·46 – 0·72; p<0·0001) and local progression (0·45, 0·30 – 0·66; p=0·0001), and led to a greater improvement in event-free survival (0·51, 0·42 – 0·61, p<0·0001), compared with radiotherapy alone.
- 6 month NADT decreased distant progression (0·49, 0·31 – 0·76; p=0·001), prostate cancer specific mortality (0·49, 0·32 – 0·74; p=0·0008), and all cause mortality (0·63, 0·48 – 0·83; p=0·0008), compared with radiotherapy alone.
- The TROG 96.01 trial provides evidence that men with non metastatic locally advanced cancers can be treated successfully with as little as 6 months of NADT before and during radiotherapy.