Although IMRT is the standard external beam modality for clinically localized prostate cancer, hypofractionated SBRT monotherapy has recently emerged as a potential alternative
. The studies that have the longest follow-up use the CyberKnife machine for SBRT delivery, but prostate SBRT can also be delivered using other systems that account for intrafraction motion, such as the electromagnetic Calypso system or a transperineal ultrasound system. Multiple single institution experiences with SBRT monotherapy in favorable risk patients use a regimen of 35–40 Gy is delivered to the prostate in 4–5 fractions. Their results suggest that this approach may provide similar clinical outcomes to IMRT, and report high biochemical control rates with acceptable toxicity
[5, 16–24]. Recent updates have confirmed a 5-year biochemical disease-free survival in low-risk patients is in excess of 90%
These SBRT monotherapy studies include mostly low-risk patients, and there is limited data on the use of hypofractionated radiotherapy in intermediate-risk patients, where ECE is more common and the treatment margins may not adequately cover this extraprostatic disease.
Pathologic reviews of post-prostatectomy specimens show that the extent of microscopic ECE in intermediate-risk patients is generally small (2–3 mm) and a 4 to 5 mm margin around the prostatic capsule should cover this spread of disease in an estimated 90-99% of intermediate-risk patients
[25, 33, 38–41]. We consider 33 Gy (94% of the prescription dose for 35 Gy plans or 91% of the 36.25 Gy plans) to be an adequate dose for treating microscopic disease. In our study, the mean distance of the 33 Gy isodose line on the treatment plans extends >5 mm beyond the prostate capsule in all directions except directly posteriorly into the rectum, with generous coverage in the posterolateral directions where ECE more commonly occurs.
The actual dose delivered to the surrounding margin of the prostate can be less than the planned dose due to intrafraction motion of the prostate. Xie et al. calculated that orthogonal imaging every 30–60 seconds would allow 95.6% and 92.5% of the beams to be delivered within 2 mm of the target during CyberKnife treatments of the prostate
. After taking this 1–2 mm of uncertainty into account, the ECE coverage with CyberKnife SBRT is comparable to the coverage achieved in low-dose rate prostate brachytherapy. The average distance from the prostatic capsule of the 33 Gy isodose line in our study in the posteriolateral direction was 11.23 mm at the base, 7.74 mm at the mid-prostate, and 7.26 mm at the apex. This is comparable to the Merrick et al. study, where the distances from the prostate to the 90% isodose line in their series of Pd-103 implants as 8.4 mm at the base, 5.9 mm at the mid-prostate, and 6.8 mm at the apex
. The coverage directly posteriorly towards the rectum is less than in other directions, but the extent of ECE is smallest in this direction, where the rectoprostatic fascia limits the extent of invasion
The mean pre-treatment PSA was 7.67 ng/mL and it decreased to a mean of 1.35 ng/mL by one year post-treatment. PSA data from patients treated with conventional external beam radiation therapy suggest that patients with PSA nadirs < 2 ng/ml at one year following treatment have a high rate of long-term disease control,
[42, 43] and we could predict a similarly high rate of long-term control in the patients treated in our series. Given that the majority of biochemical failures for intermediate-risk patients occur several years after treatment, the median follow-up of 21.5 months in the current study is inadequate to establish the long-term efficacy of CK monotherapy in intermediate-risk patients. However, our 97.6% 2-year biochemical failure-free survival rate is consistent with the limited literature on hypofractionated radiotherapy for intermediate-risk disease. For HDR monotherapy, which the dose distribution of SBRT monotherapy is based on, the two studies that report the biochemical control rate specifically for intermediate-risk patients show excellent 5-year PSA failure-free rates of 93% in Yoshioka et al. and 94% for Rogers et al.
[14, 15] In the fractionated SBRT monotherapy literature, only Lee et al., Bolzicco et al., Katz et al. included a large percentage of intermediate-risk patients. Lee et al. report their series of 29 patients treated with SBRT to a dose of 35 to 37.5 Gy in 5 fractions. Nineteen of these patients had intermediate-risk disease, the others had low or high risk disease. The 4-year biochemical relapse-free survival was 86%. There were no Grade 3–4 acute toxicities, and one patient experienced a late Grade 3 urinary toxicity. These results are encouraging, but the results of the intermediate-risk cohort are not reported independently. Katz et al. reported a separate biochemical failure rate for their 81 intermediate-risk patients of 0%, but the follow-up period of their study was short, with a range of 8 to 37 months for all the patients in the study. Longer follow-up is needed to validate the observations made in our study and prospective studies are necessary for comparison to the reported 70-80% 10-year biochemical failure-free survivals obtained using conventionally fractionated external beam radiotherapy and low dose-rate brachytherapy
Our study suggests that clinically significant late Grade 3 toxicities are infrequent following CK monotherapy, and our low rate is comparable to the rates observed following external beam radiotherapy,
 HDR brachytherapy,
[10, 11, 13, 15] or in other reported CK monotherapy series
[8, 16, 17, 21–23]. Our practice allows for prescribing selective alpha blockers for relatively minor urinary complaints, which may contribute to the higher rate of recorded Grade 2 late urinary toxicity seen in our series compared to the rates reported in these other series. However, this increased higher rate of recorded low grade urinary toxicity is not reflected in our QOL results.
The QOL data indicate that CK monotherapy is well tolerated, with declines in patient reported urinary, bowel and sexual function that are similar to those seen in low-risk patients treated with CK SBRT monotherapy,
 and comparable to the trends seen with conventionally fractionated external beam radiotherapy and brachytherapy
[45–47]. Urinary symptoms peaked in the 1–2 weeks after SBRT, and were generally followed by improvement to pre-treatment levels within 2–3 months. Bowel function declined after treatment and slowly recovered to near baseline at one year. As reported by others, sexual QOL declined slowly over time without recovery
. Longer follow up is needed to fully assess the late impact of CyberKnife monotherapy on QOL.