Reports of non-invasive, hypofractionated, stereotactic body radiotherapy (SBRT) for prostate cancer are now available. Madsen et al., used a conventional linear accelerator to treat 40 early-stage prostate cancers with five fractions of 6.7 Gy (33.5 Gy) (12). At a median follow-up of 41 months, they observed a 70% biochemical freedom from relapse, two Grade 3 genitourinary (GU) toxicities, and no long-term gastrointestinal (GI) toxicity. King et al., from Stanford used the CyberKnife system to deliver SBRT to 41 low-risk prostate cancer patients (13). Patients were treated with 5 fractions of 7.25 Gy (36.25Gy) and followed for a median of 33 months. The median PSA nadir was 0.32 ng/ml. No patient had a biochemical failure. There were no acute Grade 3 or 4 rectal toxicities. Two patients experienced late Grade 3 GU morbidity (14). Another recent study demonstrated that radiation dose distributions approximating those obtained with HDR brachytherapy could be delivered using the CyberKnife, with minimal toxicity in 10 patients treated with these HDR-like dose distributions (15).

Based on early reports from the Stanford experience, we initiated an SBRT protocol for treatment of organ-confined prostate cancer using the CyberKnife. Here we report initial PSA and toxicity outcomes for the first cohort of over 100 patients.

Materials and Methods

Patient Characteristics

Between February 2005 and December 2006, 112 patients, age 55 to 87 years, with clinically localized prostate cancer were treated with SBRT as primary therapy in Naples, Florida. All patients had adenocarcinoma of the prostate, clinical stage T1bN0M0 to T2cN0M0, documented by 12-quadrant, transrectal ultrasound-guided biopsies. Patient, disease, and treatment characteristics, as well as baseline symptom scores, are listed in Table I. Staging work-up included a bone scan and CT scan of the abdomen and pelvis to rule out regional or distant metastases. At the discretion of the treating urologist, 21 patients received adjuvant hormonal therapy.



Treatment Technique

Four gold fiducial markers were placed in the prostate by the treating urologist using transrectal ultrasound guidance. Treatment planning scans were performed one week after fiducial implantation, allowing stabilization of the fiducials in the prostate. Using a flat table top with the patient in a ?feet-first? position, axial CT images were acquired at a slice thickness of 1.25mm, 20cm above and below the prostate, using a kVp of 120, mAs of 400 or higher, and no spacing between slices. Preferred MRI sequences were T2* GRE or T1 post Gd, using a slice thickness of 1-2mm, non-variable and continuous. Planning CT and MRI images were fused, referencing both fiducials and soft tissue structures, to accurately differentiate the prostate and the proximal 1 cm of the seminal vesicles (the gross tumor volume, or GTV), from the rectum, urogenital diaphragm, bladder, distal seminal vesicles, and other surrounding structures. The planning treatment volume (PTV) included the GTV expanded by 3mm posteriorly and 5 mm in all other directions. The planning objective was to deliver the prescribed dose (35gy) to at least 95% of the PTV, using a homogeneous dose distribution (Figure 1). Bladder and rectal doses were maintained below the limits specified in RTOG protocol 0126 (ref), adjusted for a 5 fraction regimen. For the rectum, the V36Gy was <1cc; for the bladder, the V37Gy was <10cc.

The CyberKnife is a 6 MV linear accelerator mounted on a robotic arm, with two orthogonal kV X-ray imagers that provide real-time image guidance throughout treatment. Typically, 150-200 non-coplanar beams were delivered in each treatment session. Patient positioning and target tracking were accomplished using the CyberKnife?s image-guidance system, which registers the location of the gold fiducials in the orthogonal X-rays to their location in the planning CT. Based on that information, the robot corrects the accelerator?s aim to account for both translational and rotational movement of the patient or prostate during the treatment. The spatial accuracy of our CyberKnife system (<1mm) was confirmed independently by the MD Anderson Dosimetry Service numerous times during the study.

All but two patients received 35 Gy administered in 5 equal fractions of 7.0 Gy over 5 consecutive days.

Follow-up Schedule and Toxicity Analysis

Patients were seen in follow-up by the radiation oncologist or urologist 10 days post-treatment, 1 month post-treatment, and every 3 months for 2 years. In year 3, follow up was extended to every 6 months if PSA remained stable. PSA levels were assessed prior to treatment and at each follow-up evaluation. Toxicity analyses were performed using the American Urological Association prostate symptom score (AUA), a rectal assessment score (RAS), and the Sexual Health Inventory for Men (SHIM) (16). AUA, RAS and SHIM questionnaires were completed by the patients at the time of their follow-up appointments. Median follow-up for this series of patients is 24 months.



Figure 1:Representative treatment plans (axial and coronal views) from a patient treated with 5 equal fractions of 700 cGy delivered to the 82% isodose. Tumor coverage was 95% and the conformality index was 1.39.

Results

Toxicity

The mean initial AUA score for all patients was 8.9 (SD=7.3), which corresponds to mild-to-moderate symptoms of urinary obstruction. AUA scores increased over the first month of treatment to 12.8 (SD=7.7) but returned to baseline by 4 months. Seven patients experienced urinary retention during the first month post-treatment, none requiring catheterization. One patient required a TURP immediately following treatment. No patient has developed urethral stricture requiring instrumentation.

The mean initial RAS score prior to treatment was 1.8 (SD=1.9), indicating minimal to no rectal urgency or stool frequency. At 7-10 days post-treatment, RAS scores had increased to 4.6 (SD=2.9), but by 4 months post-treatment, had returned to baseline levels. Only one patient has experienced a Grade 3 rectal complication (rectal bleeding).

The mean SHIM score prior to treatment was 14.1 (SD=10.2), consistent with normal to slightly decreased sexual function. SHIM scores decreased during treatment but returned to baseline within one month, and did not differ significantly from baseline thereafter. Erectile function was assessed using question #2 of the SHIM (ability to achieve an erection adequate for intercourse). Of 50 patients reporting erections sufficient to achieve penetration ?at least half the time? prior to treatment, 41 (82%) retained their erectile function at 1 year. At 2 years, 29 of 36 (81%) and at 3 years, 9 of 11 (82%) patients retained erectile function.



Figure 2: Mean PSA levels (ng/ml, + 1 SD) for all patients (top panel), patients who did not receive hormone therapy (middle panel) and patients who received hormone therapy (lower panel). Numbers above symbols indicate the number of observations contributing to the mean.

PSA Response

The mean initial PSA (iPSA) value for all patients was 6.0 ng/ml (SD=2.8 ng/ml; see Figure 5). One month after treatment, the mean PSA level decreased to 3.1 ng/ml (SD=2.2 ng/ml). PSA continued to decline, reaching a nadir of 0.6 ng/ml at 18 months (Figure 2). PSA levels continued to decrease after 2 and 3 years of follow-up, and almost all patients followed for 3 years have reached a PSA nadir below 1.0 ng/ml. Table II presents the percentage of patients reaching selected PSA nadir thresholds at 1, 2, and 3 years post-treatment.

Three patients have experienced rising PSA levels post-treatment. One developed a PSA increase immediately following therapy. Pre-treatment PSA was 4.33 ng/ml, but by 7 months, PSA had increased to 25.4 ng/ml. A repeat bone scan revealed a solitary bone metastasis. He is currently receiving salvage hormonal therapy. The second patient developed an increasing PSA 35 months post-treatment. Repeat biopsies confirmed Gleason 3+4 adenocarcinoma in 1/12 cores. He underwent cryotherapy as salvage therapy, and PSA has decreased to <1.0. The third patient developed a rising PSA 26 months post-treatment. Repeat biopsies returned Gleason (3+3) in 7/12 cores and Gleason (3+4) in 4/12 cores. He recently underwent high-intensity focused ultrasound (HIFU) as salvage therapy, with no repeat PSA levels to date. Four patients in the series have expired, all from co-morbid conditions. No patient in our series has died from prostate cancer.

Discussion

In recent reviews of quality of life outcomes following prostate cancer therapy, incontinence was reported in 14% of patients at 2 years (17) and 15% at 5 years (18) after prostatectomy. Urinary function was impaired (urgency, frequency, wetness) in 2% of patients at 2 years and 10-29% of patients at 5 years post-prostatectomy, and in 4-14% of patients post-EBRT. Erectile dysfunction (ED), also associated with prostate cancer therapy, was reported by Potosky et al., in 75% of patients after either prostatectomy or EBRT at 5 years. (17) Sanda et al., reported erectile dysfunction in 60% of patients following either procedure at 2 years (18).

The goal of hypofractionated therapy for early stage prostate cancer is to achieve similar or improved disease control, compared to ?standard? treatments, while decreasing toxicity. In a report by Schour and Demanes et al., (19), HDR monotherapy resulted in 96% progression-free survival at 8 years; 4% grade 2 or 3 urinary toxicity; and ?negligible? GI toxicity in 117 low and intermediate-risk patients. In the Stanford study of hypofractionated prostate therapy using the CyberKnife, no Grade 3 or 4 rectal toxicity occurred and only two patients experienced Grade 3 GU morbidity (14). In our series, no urinary strictures or urinary incontinence have been observed. No patient has experienced > Grade 2 urinary complications to date. Only one patient experienced Grade 3 rectal toxicity. Our ED rate in previously potent patients is 19% at 2 years post-treatment. Although these studies present somewhat early results, the relative absence of serious GU and GI toxicity to date suggests that hypofractionated treatment to the prostate can be delivered safely, with toxicity no worse than expected from conventionally fractionated radiation or prostatectomy. Similarly, early PSA outcomes using hypofractionated treatment appear promising. King reported a median PSA nadir of 0.32 ng/ml at 33 months. At 24 months, the PSA nadir in our series is 0.5 ng/ml. However, of the 112 patients reported, 21 (19%) did receive hormonal therapy, either prior to or in conjunction with SBRT. Initiation of hormonal therapy was at the discretion of the treating urologist, but was considered for patients with gland size >70cc or with Gleason grade 7 or higher histology. PSA outcomes for this group are reported separately. Ten patients with intermediate or high risk features were also included in our monotherapy series. As treatment planning parameters and dose schedules were not modified for these patients, we included them in the analyses of both toxicity and treatment outcomes.

The potential benefits and risks of SBRT for prostate cancer were recently examined by the Emerging Technologies Committee (ETC) of ASTRO (20). In their report, the committee stated that SBRT should not be attempted without ?some mechanism for optimization of immobilization? and ?precise, daily real time organ localization?. The CyberKnife robotic radiosurgery system monitors the continual intra-fraction motion of the prostate using real-time imaging and provides translational and rotational movement correction, setting it apart technically from other conventional radiation delivery systems. The ETC concluded that ?if proven efficacious and safe?accelerated hypofractionation may provide social and economic benefits to prostate cancer patients.?

Conclusions

SBRT is an emerging treatment approach for early-stage prostate cancer, made possible by technological advancements in radiation treatment delivery systems. Reported toxicity results, erectile function preservation and early PSA response are encouraging. Additional follow-up is required to better evaluate potential late toxicity and long-term PSA outcomes.

Acknowledgements

The authors would like to acknowledge the editorial assistance of Drs. David Schaal and Mikail Gezginci.

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