A single-center study of 100 consecutive patients with localized prostate cancer treated with stereotactic body radiotherapy

The use of stereotactic body radiation therapy (SBRT) in the treatment of localized prostate cancer is supported by recent reports[1‐5]. As an alternative to surgery[6], it provides high biochemical control, low risk of complications, minimal duration of treatment, and outpatient treatment opportunity. In the literature, there is evidence that both tumoral and normal tissue response to radiation dose depends on the respective α/β ratios of the said tissues. For prostate cancer, the α/β ratio has been reported to be around 1.5 Gy, lower than the surrounding normal tissues; therefore, the use of a high-dose-per-fraction (hypofractionated) regimen should lead to a more favourable therapeutic ratio[7, 8]. Treatment of prostate cancer with high-dose-rate (HDR) brachytherapy is well established: it allows high doses of radiation to be delivered precisely to the target tissue while sparing the surrounding healthy tissue, thus achieving high biochemical control and low toxicity[9, 10]. New technologies using image-guided radiotherapy (IGRT) provide a more accurate delivery of the high dose used in SBRT. For instance, CyberKnife® (Accuray Incorporated, Sunnyvale, CA) SBRT (CK-SBRT) delivers hypofractionated treatment regimens with a dose distribution similar to that obtained with HDR-brachytherapy, without the accompanying invasive procedure[11, 12].

Here we report our experience with CK-SBRT in which 100 patients with localized prostate cancer were treated. The resulting outcomes and toxicities are disclosed.

The advantages of hypofractionation (decreased fraction number with increased dose per fraction) in prostate cancer treatment are supported by recent literature[20‐22], based on the presumably low α/β value of prostate cancer cells[2, 7]. There is evidence of the superior radiobiological effects of radiotherapy in higher-dose fractions[23, 24]. The use of SBRT is supported by convincing studies[2, 4, 5] on the clinical results of hypofractionation. Fuller et al.[11] have compared HDR brachytherapy plans with CK-SBRT plans in 10 patients for the same dose and fractionation scheme, favouring the use of CK-SBRT as it spared healthy tissues, such as the urethra, while simulating the delivery of an HDR brachytherapy-like dose distribution to the target. Fuller’s was one of the initial studies, after which several clinical reports have supported the use of CK-SBRT in low- to intermediate-risk prostate cancer treatment.

The present study is an update of our preliminary CK-SBRT experience[17] of 45 low- to intermediate-risk prostate cancer patients. Since then, 16 high-risk patients were also treated in our department. In the present study, they were separately analyzed to assess whether SBRT was an appropriate treatment for prostate cancer patients who cannot have surgery. Katz et al.[25] have reported on the treatment of 12 patients with high-risk prostate cancer with a daily dose of 7.25 Gy delivered in five daily fractions, with a 4-year actuarial (FFBF) of 75%. Kang et al.[26] have treated 29 high-risk patients with daily fractions totalling 32–34 Gy in a four-fraction regimen, resulting in an FFBF of 90.8% at last follow-up. Among our 16 high-risk patients, with a medium follow-up of 36 months, one biochemical recurrence occurred. Six of these patients also received ADT, two were still on therapy at last follow-up; the patient with biochemical recurrence did not receive ADT.

The median planning target volume (PTV) was 67 cc. (range, 46–109 cc), including a 5-mm margin in all directions except posterior, where the margin was 3 mm. The median prostate volume was 33 cc (range, 15–69 cc). Usually, patients with a prostate volume > 60 cc are excluded from SBRT studies, following the example of HDR brachytherapy[27]. Two patients with prostate volumes > 60 cc were treated at our institution, without any higher toxicity.

The prescription dose for all patients was 35 Gy to the 80% isodose line in five consecutive fractions, corresponding to a normalized total dose (NTD) of 92 Gy if delivered in 1.80-Gy fractions, assuming an α/β ratio of 1.5 Gy. In the literature, the prescription dose varies from 32 Gy in four fractions to 38 Gy in four fractions[25]. Katz et al.[28] have used doses of 35 Gy in five fractions and 36.6 Gy in five fractions, reporting no FFBF difference between the two groups and a non-statistically-significant higher urinary late toxicity in the higher-dose group. Freeman and King[29] have compared 35 and 36.25 Gy doses in five fractions in 41 patients with similar conclusions.

Although the dose to the testicles was not constrained in our treatment planning, a random check of 20 patients showed a median testicular dose of 4 Gy; Katz et al.[2] have reported a median D50 testicular dose of 5.28 Gy (range 3.2–11.8 Gy) in 12 CK-SBRT patients. Oermann et al.[30] have published a study on 26 patients treated with CK-SBRT, where serum testosterone levels and endocrine changes were observed: a small decline in total testosterone levels without the endocrine changes, typical of hypogonadism, was reported.

In the present study, treatment planning consisted of four gold fiducial markers placed in the prostate to verify organ position in real time and render prostate’s spatial geometry. Use of a urethral catheter was standard practice in our CK-SBRT patient preparation, although some other institutions may not use this procedure: in fact, one might argue that a distended bladder would avoid higher isodose-lines. In our protocol the bladder receives, based on capacity, an average of 100 cc saline, thus preventing over-distension, which may have a negative effect on target position. The aim of this technique is to try to keep the bladder volume constant during therapy, as also stated in Viswanathan et al.[31]. We also use the urethral catheter to discern the outline of the prostatic urethra perfectly. MRI was used in the treatment planning of 30 of the 100 patients, without any other procedural or planning changes. 3T-MRI was used in CT-MRI treatment planning and staging to avoid certain common staging errors[32] that have been made in surgical series of T1 and T2 patients, which have statistically led to over staging about 40% of patients[33].

In the present study, Grade 2 acute toxicity was found in 30% of the patients – 12% genitourinary and 18% gastrointestinal – thus reproducing the results of our previous study[17] in which, in a total number of 45 patients, we had reported 35% acute toxicity, with no grade 3 or 4 acute urinary or gastrointestinal toxicities. On analysis of the patients treated with and without urethral catheter, acute urinary toxicity was 46% and 50% respectively, with only 10 patients having been treated without catheter. As for gastrointestinal toxicity, Grade 2 acute rectal toxicity occurred in 18% of the patients, all toxicities resolving with minimal medication. No Grade 3 or 4 acute rectal toxicity occurred. Our results were comparable with those in the literature: Jabbari et al.[12] have observed acute rectal Grade 2 toxicity in 5% of the 38 SBRT-treated patients, whereas Kang et al.[26] have reported 9.1% Grade 2 acute rectal toxicity in the 44 patients they treated.

As for late toxicity in the present series, our 5% of Grade 2 or 3 late urinary or rectal toxicity rate is comparable to the literature: Katz et al.[28] have encountered 9.7% late genitourinary or rectal toxicity in 41 patients; Freeman et al.[29] had 12% late urinary or rectal toxicity in 41 patients; Mc Bride et al.[3] observed late urinary Grade 2 toxicity in seven patients (17%) and Grade 3 toxicity in one patient (2.2%), while three patients (7%) experiencing late Grade 2 rectal toxicity and two patients (5%) late Grade 3 proctitis.

When comparing other prognostic factors, e.g., ADT, in relation to acute and late genitourinary toxicities, no differences were seen. Genitourinary acute toxicity occurred in 44.8% and 46.4% of the ADT-SBRT group and SBRT-monotherapy group patients, whereas late genitourinary toxicity occurred in 3.4% and 9.8%, respectively, thus confirming the lack of influence of ADT on toxicity in patients treated with SBRT. When evaluating the results of patients treated with the earlier vs. the newer CyberKnife System, i.e. G4, as for late urinary or rectal toxicity, the former had 5.1% (4/78) Grade 2–3 toxicity, while in the latter group there was no case of toxicity; as the late group’s median follow-up is only 12 months, the data need further confirmation. We also analysed the incidence of late genitourinary toxicity in the seven patients previously treated with TURP, which showed three patients with Grade 1–3 toxicities. The patient who had had TURP 4 years before CK-SBRT had late Grade 3 genitourinary toxicity, which completely resolved at 2 years post treatment.

The results of the present report appear to be favourable on CK-SBRT in the treatment of localized prostate cancer, with the encouraging actuarial freedom-from-relapse rate of 96% at 3 years. We had four relapses in 100 patients, three cases with intermediate-risk and one with high-risk disease. Katz et al.[16] had a 1.9% relapse rate in 254 patients: two failures in low-risk and three in high-risk patients. Friedland et al.[4] have reported 2.6% (3/112 patients) of failures. The PSA results in our group of 100 patients decreased with a nadir of 0.54 ng/ml at 36 months, which may be considered a satisfactory outcome. Among the recurrence-free low-risk-patients treated with SBRT-monotherapy (41 patients), the median PSA nadir was of 0.47 ng/ml (range, 0.02–2.05) at 36 months. King et al.[1] have reported a PSA nadir of 0.32 ng/ml (range, 0.03–2.65 ng/ml) at 33 months in a series of 41 low-risk-patients; in Katz et al.[28], reported a PSA nadir was 0.2 ng/ml in 71% of 82 patients with a four years median follow-up. Considering both the ADT-SBRT (29 patients) and SBRT-monotherapy groups (71 patients), we observed a nadir of 0.16 and 0.75 ng/ml at 36 months, respectively. The nadir PSA at 36 months in non-recurrent patients treated with ADT-SBRT according to their risk categories were, respectively, 0.14 ng/ml and 0.17 ng/ml in low- (7 patients) and intermediate-high-risk patients (22 patients). In the SBRT-monotherapy group, the average PSA was, respectively, 0.54 ng/ml and 0.76 ng/ml in low- (34 patients) and intermediate-high-risk patients (33 patients). Nine of the 71 SBRT-monotherapy group of patients (12.6%) experienced a median benign PSA bounce of 1.08 ng/ml. The median time to PSA bounce was 23 months (range, 18–30 months). King et al.[1] have observed a PSA bounce in 12 of their 41 patients (29%), Katz et al.[2] a PSA bounce in 16% of the patients (37/237) at a median of 18 months, with a median value of 0.35 ng/ml (range, 0.2–1.08 ng/ml); McBride et al.[3] have reported a median PSA bounce of 1.07 ng/ml at a median time of 11.6 months in nine of the 45 patients (20%). In our opinion, the bounce, normally occurring during the first 2 years from treatment, is not prognostic of a recurrence.

Although the advent of SBRT is quite recent, and therefore needs further validation with randomized clinical trials, so far it seems to be a safe, easy, and effective therapy for localized prostate cancer, improving patient convenience. The advanced technology incorporated into the CyberKnife System enhances the possibility of achieving a more precise targeting with lower toxicity. Our 5-year progression-free survival rate of 93% seems to compare favourably with the results obtained with surgery, LDR, or HDR brachytherapy.