Prostate adenocarcinoma definitive EBRT conventional high-risk

• Intact prostate.

• High-risk prostate adenocarcinoma. See prostate adenocarcinoma risk category features table.

• ECOG 0-2.

• Life expectancy >5 years.

Cautions

• Previous high dose radiation to the pelvis.

• Poor urinary and bowel function.

• Radiosensitising medications (e.g. methotrexate).

• Inflammatory bowel disease and/or history of adhesions/bowel obstruction.

• Bilateral hip replacement.

• Non-rheumatoid collagen vascular disorders.

• Cardiac implantable electronic devices (CIEDs).

Indications notes

• An alternative way to dose escalate is high dose rate (HDR) brachytherapy.
  • See ID 415 Prostate adenocarcinoma definitive brachytherapy HDR.

• Hypofractionated radiation therapy may be appropriate for selected patients with high-risk prostate cancer. See ID 3370 - Prostate adenocarcinoma definitive EBRT hypofractionation.

• If the patient has recently undergone a transurethral resection of the prostate (TURP) wait 8-12 weeks until urinary function has stabilised, before commencing radiation therapy.

• If inserting fiducial markers, ensure insertion is more than 5 days prior to planning CT.

• Optional use of a rectal spacer.^r Caution where posterior extracapsular extension is present.

Androgen deprivation therapy (ADT)

• Androgen deprivation therapy is recommended for these patients. Risk factors should be considered in relation to individual co-morbidities.

Prescription notes

• *Elective nodal irradiation is optional in patients with high-risk prostate cancer, based on assessment of risk factors. Although there is limited randomised evidence that treating the pelvic lymph nodes is superior to not treating nodes, a significant proportion of randomised trials included nodal irradiation for patients with intermediate and high-risk prostate cancer. EQD2 ~45-50 Gy is recommended for nodal volumes.

• Dose prescriptions of 78 Gy EQD2, or slightly higher, are favoured if they can be delivered safely using IGRT and/or IMRT techniques and DVH constraints can be met. 

• Lower doses of 73.8-74 Gy EQD2, can be considered for patients where tolerability of treatment is a concern.

• Hypofractionated radiation therapy should be offered to low, intermediate, and select high-risk patients. See ID 3370 - Prostate adenocarcinoma definitive EBRT hypofractionation.

Margin ranges have been agreed by the Radiation Oncology reference committee and reflect safe clinical practice.

Target volume guides

• FROGG consensus guidelines for definitive EBRT in prostate adenocarcinoma.^r

• Radiographic and anatomic basis for prostate contouring errors and methods to improve prostate contouring accuracy.^r

• ESTRO ACROP consensus guidelines of localised prostate cancer.^r

• NRG oncology updated international consensus atlas on pelvic lymph node volumes for intact and post-operative prostate cancer.^r

Target verification recommendations reflect the minimum imaging required for the safe delivery of this protocol.

Efficacy

Evidence suggests high-risk prostate cancer should be treated by multimodal therapy which may take the form of surgery, with or without RT, and with or without ADT, or dose-escalated radiation therapy with long-term ADT RADAR.^rrrRecent results suggest further intensification of adjuvant therapy with the addition of chemotherapy, may further improve outcome for this group, but at the cost of greater toxicity. Further trials and results are awaited to confirm the value of additional chemotherapy and systemic agents.

Dose escalation

Dose­ escalated radiation therapy, using IMRT and daily IGRT, is the preferred radiation therapy treatment for high-risk prostate cancer. 

Dose escalation above 70 Gy has been analysed by Viani et al. in a meta-analysis of 7 RCTs (n = 2,812), by Kalbasi et al. in a comparative effectiveness study of 5 RCTs (high-risk patients, n = 13,538), by Hall et al. in a database analysis (n = 20,028), and by Kuban et al. in a phase III trial.^rrrr Viani et al. 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 radiation therapy versus 34.6% with conventional dose radiation therapy (p <0.0001).^r There was no difference in mortality and prostate cancer-specific mortality rates between high dose and conventional dose radiation therapy. On subgroup analysis, all subgroups showed a linear correlation between total dose of radiation therapy and biochemical failure. The analysis by Kalbasi et al. found dose escalated EBRT (>75.6 Gy) was associated with improved overall survival for patients with high-risk prostate cancer (HR = 0.82, 95% CI:0.78-0.85, p <0.001) and for every incremental increase of approximately 2 Gy, there was a 6.3% reduction (95% CI:3.3-9.1%, p <0.001) in the hazard of death for high-risk patients.^r

© Int J Radiat Oncol Biol Physics 2009^r

Evidence supporting moderate hypofractionation for select high-risk prostate cancer is not discussed within this protocol, but can be found in the evidence and efficacy sections of ID 3370 Prostate adenocarcinoma definitive EBRT hypofractionation.

Androgen Deprivation Therapy (ADT)

The addition of ADT to radiation therapy has been shown to improve outcomes compared to radiation alone. Several recent studies have explored the question of ADT duration in the high-risk setting. There is growing evidence to support a duration of 18 months of ADT in combination with radiation therapy.

Bolla et al (EORTC 22991) randomised 819 patients with prostate cancer, intermediate-risk (75% of patients) and high-risk (25% of patients), to receive radiation therapy alone or radiation therapy plus ADT. Radiation doses were 70, 74 or 78 Gy, with ADT given during and following RT.^r After a median follow-up of 7.2 years, radiation therapy plus ADT improved biochemical progression-free survival compared to radiation therapy alone (HR = 0.53, 95% CI:0.42-0.67, p <0.001) irrespective of radiation doses. Clinical progression-free survival also showed statistically significant improvement, 88.7% for radiation therapy plus ADT, compared to 80.8% for radiation therapy alone (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 86.10, EORTC 22863, RTOG 85.31, SPCG7/SFUO3-Widmark, Warde, and TROG 96.10.^rrrrrr

The 10-year outcomes of the EORTC 22863 trial showed showed significantly improved 10-year clinical disease-free survival, 10-year overall survival and 10-year prostate cancer mortality. High-risk patients (n = 415) were randomised to receive combined treatment (ADT during and 3 years following radiation therapy, n = 207) or radiation therapy alone (n = 208), with a median follow-up of 9.1 years.^r Overall survival was 58.1% for combined treatment, 39.8% for RT alone (HR = 0.6, 95% CI:0.45-0.80, p = 0.0004) and 10-year prostate cancer-specific mortality was 10.3% for combined treatment, versus 30.4% for RT alone  (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 al. reported on 10 and 15-year outcomes of the Widmark trial of 875 men (from Norway, Sweden and Denmark) with locally advanced disease, randomised to ADT alone (n = 439) versus ADT plus radiation therapy (n = 436).^r After a median of 7.6 years follow-up, the addition of ADT to radiation therapy more than halved the 10 and 15-year prostate cancer-specific mortality rates and substantially decreased overall mortality.

Warde et al. randomised 1,205 men with T3 or T4 prostate cancer  to receive either ADT alone (n = 602) or ADT plus radiation therapy (n = 603), between 1995 and 2005​.^r With a median follow up of 6 years at time of analysis, 320 patients had died (175 in the ADT alone group and 145 in the ADT plus radiation group). The addition of ADT to radiation therapy significantly improved overall survival at 7 years, 66% in the ADT alone group versus 74% in the ADT plus radiation therapy group (HR = 0.77, 95% CI:0.61-0.98, p = 0.033). The 7-year disease-specific deaths were 19% for ADT alone and 9% for ADT plus radiation (p = 0.001). A total of 346 patients developed progressive disease, 251 in the ADT alone group and 95 in the ADT plus radiation group.

© Lancet Oncol 2011^r

Duration of ADT

The optimal duration of ADT in the high-risk patient cohort has not been definitively determined. A number of phase III RCTs have been conducted to address the issue of timing. The key findings are listed below:

• EORTC 22961 – 970 men received EBRT plus 6 months of ADT and were randomised to observation (n = 483), or an additional 30 months of ADT(n = 487).^r At median follow-up of 6.4 years, the prolonged course of ADT was associated with a significant decrease in overall mortality compared to 6 months ADT, 5-year mortality 15.2% versus 19%, respectively (HR = 0.70, 95% CI:0.55-0.92). The 5-year cumulative prostate cancer-specific mortality was 3.2% for prolonged ADT versus 4.7% for short-term ADT.
• RTOG 92.02 - 10-year follow-up of 1,554 men with T2c-T4 prostate cancer, comparing radiation plus short-term ADT of 4 months to radiation plus long-term ADT of 24 months.^r Radiation therapy plus long-term ADT, demonstrated a significant improvement in all endpoints, with the exception of overall survival:
  • Disease-free survival 13.2% versus 22.5%, p <0.0001.
  • Disease-specific survival 83.9% versus 88.7%, p = 0.0042.
  • Local progression 22.2% versus 12.3%, p <0.0001.
  • Distant metastasis 22.8% versus 14.8%, p <0.0001.
  • Biochemical failure 68.1% versus 51.9%, p <0.0001.
  • Overall survival 51.6% versus 53.9%, p = 0.36. On subgroup analysis of the Gleason score 8-10 group, long-term ADT showed an overall survival difference of 45.1% compared to 31.9% for short-term ADT, p = 0.0061.

The use of short-term neoadjuvant ADT (2-6 months) has been shown to provide improved benefit over radiation therapy alone in high-risk patients unable to tolerate long-term ADT.^rr

In a non-inferiority trial, Nabid et al. randomised 630 men with high-risk prostate cancer to receive either 18 or 36 months of ADT in combination with radiation therapy.^r At a median follow up of 9.4 years, 10-year overall survival was the same for both groups at 62%, with similar disease-specific survival of 92% and 91%, for 18 months and 36 months ADT, respectively.

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 neoadjuvant ADT before and during radiation therapy.^rThis trial randomised 818 men with T2b, T2c, T3 and T4 N0 M0 prostate cancer to receive radiation therapy alone, or 3 months of neoadjuvant ADT plus radiation therapy, or 6 months neoadjuvant ADT plus radiation therapy.^r At a median follow up of 10.6 years, compared with radiation therapy alone:

• 3 months of neoadjuvant ADT decreased the cumulative incidence of PSA progression (adjusted HR = 0.72, 95% CI:0.57-0.90, p = 0.003) and local progression (HR = 0.49, 95% CI:0.33-0.73, p = 0.0005), and improved event-free survival (HR = 0.63, 95% CI:0.52-0.77, p <0.0001).
• 6 months of neoadjuvant ADT further reduced PSA progression (HR = 0.57, 95% CI:0.46-0.72, p <0.0001) and local progression (HR = 0.45, 95% CI:0.30-0.66, p = 0.0001), and led to a greater improvement in event-free survival (HR = 0.51, 95% CI:0.42-0.61, p <0.0001). 
• 6 month neoadjuvant ADT decreased distant progression HR = (0.49, 95% CI:0.31-0.76, p = 0.001), prostate cancer-specific mortality (HR = 0.49, 95% CI:0.32-0.74, p = 0.0008), and all-cause mortality (HR = 0.63, 95% CI:0.48-0.83, p = 0.0008).

TROG 03.04 RADAR trial randomised 1071 men with T2a (and Gleason score ≥7), or T2b-4 N0 M0 prostate cancer, to receive 6 months neoadjuvant ADT and radiation therapy with or without a further 12 months ADT.^r Two further treatment arms examined the addition of zoledronic acid to the 6 or 18 month ADT arms in a 2 by 2 factorial design. At a median follow-up of 10.4 years, 18 months of ADT was associated with a reduced prostate cancer-specific mortality of 9.7% compared to 13.3% with 6 months neoadjuvant ADT (absolute difference 3.7%, sub-hazard ratio = 0.70, 95% CI:0.3-7.1, adjusted p = 0.035).

© Lancet Oncol 2019^r 

The evidence appears to support a duration of 18 months of ADT, but the optimal duration for any individual patient requires careful consideration of a number of factors including disease related risk features and pre-existing medical co-morbidities. For further information related to ADT agents and toxicities refer to eviQ medical oncology for urogenital cancers.

Toxicity

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