EBRT as monotherapy is appropriate for men with most men with low-risk disease and some men with low-volume intermediate-risk disease. It is not appropriate, however, for men with high-risk or locally advanced cancer unless there is concern for competing comorbidities. In men with low-risk disease EBRT monotherapy is associated with 10-year BRFS of 80–90 % [7–9]. Men with intermediate- and high-risk features experience 10-year BRFS of approximately 65 and 25 % respectively when treated with EBRT alone [10, 11].

The addition of androgen deprivation to radiotherapy improves overall survival for both intermediate and low risk disease [10, 12]. For intermediate disease 6 months ADT appears to be sufficient [13, 14], while survival for high risk is improved by long-term ADT (~3 years) [15]. The details and results of the following RCTs are detailed in Table 42.2.

With the evolution of radiotherapy technology, data has emerged that supports the concept that higher radiation doses will yield better clinical outcomes with acceptable toxicity profiles. A meta-analysis including seven RCT and 2,812 patients showed that all categories of risk benefited in biochemical control from dose escalation, although there was no change in overall survival or disease-specific survival observed to date [19]. Current recommendations are for doses of 75.6 Gy or higher when conventional fractionation (1.8–2 Gy/fraction) is used. External beam radiation therapy and brachytherapy have been combined in the treatment of prostate cancer as a method of dose escalation beyond what external techniques alone can deliver. Institutional series have shown promising biochemical control of high risk disease using combined EBRT and brachytherapy in conjunction with ADT. Institutional series from Duke [20] and Mt Sinai [21] state 5-year biochemical control of 80 %, although 15-year outcome drops to 68 % [22]. The RTOG has conducted two phase II trials of combination external beam and brachytherapy, either permanent interstitial (0019) or high dose rate (0321). RTOG 0019 enrolled 138 intermediate-risk patients and resulted in 4-year biochemical relapse rate of 14 % but a high GU/GI combined grade 3+ morbidity rate of 15 % [23]. Preliminary results for 0321 show low rate of grade 3+ toxicity (3 % at 18 months) but will need to be evaluated at longer followup [24].

The advent of improved prostate localization and high precision radiotherapy made it possible to deliver shorter courses using higher dose per fraction. Two methods of hypofractionation have resulted: moderate hypofractionation (4–5 weeks of daily treatment) and extreme hypofractionation (4–5 treatments over 1–2 weeks). The results of three RCTs examining moderate hypofractionation have been published, although two used doses that are much lower that contemporary standards [25, 26]. The third RCT compared 80 Gy in 40 fractions over 8 weeks versus 62 Gy in 20 fractions over 5 weeks. With short follow-up, 3 year freedom from biochemical failure was 87 % in the hypofractionated arm compared to 79 % in the conventional arm (p = 0.035) with similar late toxicity rates [27]. Other moderate hypofractionation trials have been reported in abstract form [28, 29]. Three very large studies of moderate hypofractionation with non-inferiority hypotheses containing more than 5,000 patients have recently been completed. The results are expected in 2–3 years and will inform subsequent decision-making.

The results of extreme hypofractionation (4–7 fractions over 1–2 weeks) have also been reported. Prospective cohort data has achieved follow-up of 3–5 years, however less than 20 patients have been followed beyond 5 years [30]. Extreme hypofractionation requires accurate positioning and tight margins on the prostate to avoid the rectum and bladder. The studies reported to date have included mostly patients with low risk disease. The follow-up is short (median usually 3–4 years) with reported rates of biochemical progression-free survival of 90–95 % [30, 31].

Approximately 80,000–100,000 RPs are performed in the US per year and ~30,000 will have a PSA failure [32]. The risk factors for local failure after prostatectomy include positive surgical margins, extracapsular extension, seminal vesicle invasion. The risk factors have been used as eligibility criteria for three randomized trials of adjuvant EBRT (Table 42.3).

These trials have all found an improvement in biochemical relapse- and disease-free survival, and one has shown a significant overall survival benefit to adjuvant radiotherapy for men with pathologic high risk features. However, debate still exists as to whether certain subgroups, particularly those with pT3a negative margin or seminal vesicle-positive disease, benefit from adjuvant radiotherapy compared to early salvage [36].

The EORTC performed a RCT of observation versus immediate RT for high risk post-prostatectomy prostate cancer patients [37]. Eligibility included clinical T1-3N0M0, age <75 years old and a good performance status. Pathologic risk factors were: capsule invasion, positive margins or SVI. EBRT (60Gy) had to start within 4 months of surgery. One thousand and five patients accrued between 1992 and 2001 with a median age 65, median pre-tx PSA 12.3, and median post-op PSA 0.2. The 10-year BFS rate was 61 % versus 41 % in favor of RT (p < 0.0001). Clinical progression-free survival and local control were also improved with RT, but overall survival was not significantly different (77 % v 81 %, p > 0.1) [33]. Unplanned sub-analysis found that when pathology was centrally reviewed, extracapsular extension in the setting of negative margins did not have a statistical benefit from adjuvant EBRT [38]. While seminal vesicle invasion is commonly thought to be a harbinger of distant metastatic disease, the same study showed that adjuvant RT does benefit those with seminal vesicle involvement [38].

The Southwest Oncology cooperative group (SWOG) conducted a RCT of 425 men with extracapsular extension (ECE), seminal vesicle invasion (SVI), or positive margins, with arms of immediate 60–64 Gy to the prostate bed or observation. Overall survival, as well as metastasis-free and PSA relapse-free survival, were improved with adjuvant therapy [34, 39]. This benefit was seen in subsets of PSA stratification (both less than and greater than 0.2 ng/ml), high gleason grade, ECE/positive margin, and SVI-positive patients [34]. The authors calculate that the number needed to treat with adjuvant EBRT to prevent one death was 9.1.

Finally, Weigel published a trial from Germany randomizing men with pathologic T3 disease and undetectable post-operative PSA to adjuvant radiotherapy (60 Gy) or observation. With follow-up just under 5 years, the authors confirmed a biochemical progression-free survival benefit to adjuvant EBRT in undetectable PSA population [35].