DOI: https://doi.org/10.21203/rs.3.rs-1337836/v1
Background To analyze outcome and toxicity of 41 consecutive patients with localized low- and intermediate risk prostate cancer treated with CyberKnife-Stereotactic Body Radiotherapy.
Patients and Methods Patient selection and treatment protocol was according to (but not on) the PACE-trial protocol. Staging was in accordance with the German S3-guideline for prostate cancer. Prior to treatment, four gold-fiducials were implanted into the prostate. All patients received MRI-based prostate SBRT with 4 x 9.5 Gy (n=10) or 5 x 7.25 Gy (n=31). Toxicity was scored using the IPSS, ICIQ and IIEF-5 questionnaires. FU was every 3 months for 2 years and every 6 months onwards.
Results With a median follow-up of 40.7 months, overall survival was 100% and progression-free survival 98%. One patient had a biochemical recurrence and was subsequently diagnosed and treated for lymphatic oligo-metastases. There was a non-statistical increase in toxicity after SBRT. Due to a TUR-P for urinary retention, there was one case of grade 3 toxicity. Mean PSA dropped from 9.4 ng/ ml to a mean of 2.4 ng/ml in year two of follow up and 0.1 ng/ml in year five with the greatest decrease within 6 months after SBRT.
Conclusion In a cohort of 41 patients with predominantly intermediate risk localized prostate cancer, we could show that Cyberknife-Stereotactic Body Radiotherapy is feasible with very good tumor control and an only moderate and statistically non-significant increase in toxicity. Our results strengthen the case for Stereotactic Body Radiotherapy as a primary treatment option for patients with low and intermediate risk prostate cancer.
Hypofractionation increases the therapeutic ratio in prostate cancer (PC) irradiation due to the purported low alpha/beta ratio1 compared to that of the surrounding tissue. The use of Stereotactic Body Radiotherapy (SBRT) is increasing2 for it allows dose escalation while at the same time maintaining very small safety margins and hence sparing adjacent normal tissue. While Fuller et al. emulated the heterogeneous dose distribution of high-dose-rate (HDR)-brachytherapy3, King et al. and Katz et al. went for a more homogenous approach comparable to intensity-modulated radiotherapy (IMRT)4. A 2019 meta-analysis of >6000 pts. treated on prospective protocols showed high rates of bPFS (biochemical Progression-free Survival) over all risk groups with very low genito-urinary- (GU) and gastro-intestinal (GI)-toxicity. The five-year bPFS rate was 95.3% (96.7% for low and 92.1% for intermediate risk group) and GU and GI toxicity ≥grade 3 was less than 2.5%5. Similar results could be shown in a study with long-term FU6. With the recent publication of the HYPO-RT-PC trial (ISRCTN45905321)7 and early toxicity reporting from the PACE-B trial8, comparative data has been added to the growing body of evidence supporting the use of ultra-hypofractionation in selected low- and intermediate risk pts. We retrospectively analyze our first 41 consecutive patients (pts.) with localized low- and intermediate-risk prostate cancer treated with CyberKnife-SBRT with regard to feasibility, outcome and toxicity.
Between and 2011 and 2019 41 pts. were treated with CyberKnife (Accuray, Inc., Sunnyvale, CA, USA) SBRT for localized low- and intermediate risk PC. Staging was in accordance with the German S3-guideline for prostate cancer. Three out of 41 pts. received a staging PSMA-PET-CT with either Ga-68 PSMA or F18-PSMA. The pts. were classified into four risk groups as low (PSA ≤10ng/mL, Gleason ≤ 6, T stage ≤2a), favorable intermediate (iPSA >10-20 ng/ mL, Gleason 7a, T stage 2b), unfavorable intermediate (iPSA 11-20 ng/mL, Gleason 7b, T stage 2b) and high (iPSA >20 ng/mL, Gleason >7, T stage 2c) risk. Contouring, margins and treatment planning was according to the international randomized multicenter PACE-protocol (Prostate Advances in Comparative Evidence) (NCT01584258) which allowed for two different fractionation schemas. Six pts. had bridging-ADT, no pt. had ADT following SBRT. Prior to treatment, 4 gold fiducials were implanted under ultrasound-guidance. The implantation was performed by radiation oncologists experienced in prostate cancer brachytherapy (DB and AG). We initially used single fiducials but later switched to two pairs of Fleximark® gold on titanium fiducials with two nodes and 20 mm spacing preloaded in a 18 GA by 20 cm sterile needle (Riverpoint Medical, LLC, 825 NE, 25th Avenue, Portland, OR, 97232, USA). Image registration of an axial MRI and the planning CT (slice thickness 1 mm, supine position, hands on chest, kneefix, feetfix) was performed using the Registration Software within Multiplan® (Accuray Inc., Sunnyvale, California, USA). The prostate and base of seminal vesicles (in intermediate risk) constituted the clinical target volume (CTV), the PTV was 2 mm isometrically for the pts. receiving 4 x 9.5 Gy and 5mm isometrically/3mm towards the rectum for the rest. The first ten pts. (24.4%) were treated using 4 x 9.5 Gy with inhomogeneous (60% Isodose) planning with a bladder catheter for urethra-sparing. We found the catheter placement to be the greatest source of dissatisfaction for our patients and hence switched to the 5-fraction approach (5 x 7.25 Gy, 85% Isodose) with homogenous planning and without catheter placement. Treatment quality-assurance was according to statutory provisions and current clinical standards9. Patients were treated every other day10. Bladder, urethra (if visible on the MRI), rectum, bowel, penile bulb and femoral heads constituted the OARs. We evaluated toxicity and PSA-levels at follow-up (FU) visits every three months during the first year and about every 6 months from the second year on. At the time of this analysis, we invited all patients to a FU visit or to fill out the questionnaires and send them by mail. PFS was defined as PSA relapse, any new manifestation of the disease or the initiation of ADT. Biochemical relapse was defined as PSA-nadir + 2 ng/mL. GU- and gastrointestinal GI-adverse events were scored using the International Prostate Symptom Score (IPSS), the International Consultation on Incontinence Questionnaire (ICIQ) of the International Index of Erectile Function (IIEF-5) and the Common Terminology Criteria of Adverse Events (CTCAE). The analysis is registered at the Charité ethics board under EA4/056/21.
Mean age and BMI at the time of treatment was 69.2 years (47-81 years) and 25.4 kg/m². All patients had ECOG ≤1. Mean initial PSA was 9.4 ng/ ml (median 7.4 ng/ ml) and initial PSA groups were <11 ng/mL, 11-20 ng/mL and >20 ng/mL in 80%, 17.5% and 2.5%. Distribution of T-stage was T1, T2a, T2b and T2c in 80.6%, 11.1%, 0% and 5.6%. 24.4% of the patients had Gleason 6, 7a (56.1%) and 7b (19.5%). Risk group allocation was 9.8% low risk, 63.4% favorable-intermediate, 24.4% unfavorable-intermediate and 2.4% high risk. Six pts. (15%) had ADT prior or during SBRT, no pt. had ADT after completion of SBRT (Table 1). Median volumes for prostate, CTV and PTV were 57.84, 69.74 and 92.74 cc. Fixed vs. iris collimator-use was 31.7% and 68.3%. Average irradiation time was 60 minutes and 10 seconds per fraction. The mean dose to the testes was 1.08 Gy. IPSS initial scores were low, mild, severe in 64.7, 11.8 and 23.5%. ICIQ groups 0, 1-5 and 6-10 initially were 72.4, 24.1, 3.45%. IIEF groups prior to SBRT were 22-25, 17-21, 12-16, 8-11 and <8 in 46.4, 10.7, 28.6, 3.57 and 10.7%. There was a moderate but not significant increase in adverse events (AE) after SBRT (Table 2, Figures 1, 2, 3). One pt. had urinary retention during FU and was subjected to TUR-P. Unfortunately, we were not contacted prior to the procedure; hence, we do not know if medication or a temporary catheter placement would have sufficed, nevertheless it was scored as a grade 3 AE. Ten pts. were treated with 4 x 9.5 Gy, subsequently we switched to 5 x 7.25 Gy (Figure 4). Overall survival was 100%, PFS was 98% (Figure 5). After a median FU of 46.3 months (median 40.7 months; range 8.5 - 102.0 months), we saw a decrease in median PSA from 9.4 ng/ ml to 2.4 ng/ml (median 0.4 ng/ml) in year 2 of FU and o.1 ng/ml (median 0.0m ng/ml) in year five. (Figure 6). There was no statistically significant difference in the survival- and toxicity-outcomes between the pts. receiving 39 Gy or 37.25 Gy. One pt. had a biochemical recurrence 28 months after therapy (the first PSA increase was at 25 months and the second confirmatory one at 28 months) and was subsequently treated for lymphatic oligo-metastases with ADT and SBRT.
In our cohort, at a median FU of 41 months OS was 100% and PFS was 98% although the retrospective nature of this analysis and the rather small pt. cohort are bias-prone. In a pooled analysis of 1100 pts. including all risk groups the 5-years biochemical progression-free survival was 93%, 84% and 81% for low-, intermediate and high-risk patients6. Our median FU-time of 41 months is short with respect to the nature of PCA-recurrences although other studies have not shown a dramatic decline in PFS over longer FU-periods6. One of our pts. had a PSA recurrence. The pt. was diagnosed with lymph-node metastases in a PSMA-PET-CT and was salvaged with ADT and SBRT. Six pts. had bridging-ADT prior to SBRT, no pt. had ADT following SBRT. Katz et al. could show in 304 low- and intermediate-risk patients with a five year actuarial FU that ADT did not affect outcomes11. We saw a PSA decline from 9.4 ng/ ml to 2.4 ng/ml (median 0.4 ng/ml) in year 2 of FU and o.1 ng/ml (median 0.0 ng/ml) in year five. PSA fall-off occurs early and more steeply than in conventional EBRT12. Aluwini et al. saw a 53% decrease at three months and 81% at six months13. Continued decreases in PSA two to three years after treatment can regularly be seen14. Katz et al. could report on a PSA nadir of less than one ng/ml in 97% of 304 treated patients at 17 to 30 months median FU. At a median FU of five years, Freeman and King reported a median PSA nadir of 0.3 ng/ ml15. At ten years median FU, it was 0.1 ng/ ml in strictly low-risk cases16. GU and GI toxicity was mostly grade 1 and 2. Acute GU- or GI-toxicity ≥grade 3 is very rare (≤1%)4 . Overall, there was an increase in mild but a decrease in severe IPSS scores. Arscott et al. witnessed an increase in bother with voiding symptoms of approximately 10%, which declined fast, there was a second less prominent peak at about 1 years post SBRT17. In a cohort of 204 pts. with 12% baseline dysuria of whom 1% felt that to be a moderate to big bother, post SBRT dysuria peaked at 1 month and 6-12 months post treatment. While 43% of patients reported a one-month peak in dysuria, only 9% felt it to be a moderate to big problem. Dysuria subsided to baseline values at 18 months post SBRT18. We saw a slight but continuous increase of ICIQ and decrease if IIEF scores. In a series of 204 pts. 79.3% never leaked and 72.9% said they have total urinary control. There were 16.3% patients with a frequency of ≤1 leak per day and 26.1% describing occasional dribbling. Only 1% of the patients though described that to be a moderate to big problem while most checking at “no problem” [75.9% or “small problem” (23.2%)]. At 36 months there is an increase with 29.9% ≤1 leak per day and 5.7% with >1 leak per day. Occasional dribbling has increased to 29.9% with 4.5% frequent dribbling. The portion of patients describing the issue as not problematic falls from 75% to 58% in the same time. Still most of the patients (87.7%) check no- or small problem19. In the Phase II cohort initially described by King, baseline erectile dysfunction (ED) medication was used by 3% of their patients progressing to 25% at last FU with a median time to initiation of ED medication of 18 months after RT 20. They saw a progressive decrease in all EPIC sexual subdomains by 49%. The sexual bother score on the other hand decreased by only 25% and plateaued at 20 months. Age played an important role as pts. younger or older than 70 years remained a satisfactory erectile function in 60 vs. 12% of cases (p.0008). Freeman et al.21 and Dess et al. corroborated age as an independent factor for erectile dysfunction. The latter could determine baseline health-related quality of life (HRQoL), age and body mass index as independent predictors for ED at 60 months22. In a series of 216 men with a median age of 66.8 years receiving prostate SBRT, 49.5% were found to have baseline erectile dysfunction and 36.1% already using sexual aids (mostly PDE5 inhibitors). Two years post RT 77.8% had erections satisfactory for sexual activity. Sexual aid usage prior to SBRT was associated with increased probability of potency preservation in uni- and multivariate analysis23.
SBRT is a comfortable and cost-effective24 treatment approach. It shows very good tumor control and self-limiting, medically manageable toxicity. Based on meta-analyzed data from prospective comparative trials like HYPO-RT and PACE-B, we propose SBRT as a primary option for selected pts. with localized low- to intermediate-risk prostate cancer25.
SBRT – Stereotactic Body Radiotherapy
PC – Prostate Cancer
HDR – High Dose Rate
IMRT – Intensity Modulated Radiotherapy
bPFS/ PFS – biochemical Progression-Free Survival
GU- genito-urinary
GI- gastro-intestinal
FU- Follow-up
PSMA-PET - Prostate-Specific Membrane Antigen Positron Emission Tomography
PSA- Prostate-Specific Antigen
ADT- Androgen Deprivation Therapy
DB – Dirk Böhmer
AG- Arne Grün
GA - Gauge
MRI – Magnetic Resonance Tomography
CT – Computed Tomography
CTV – Clinical Target Volume
PTV- Planning Target Volume
OARs – Organs At Risk
IPSS – International Prostate Symptom Score
ICIQ – Incontinence Questionnaire
CTCAE – Common Terminology Criteria of Adverse Events
BMI – Body Mass Index
AE – Adverse Events
EBRT – External Beam Radiotherapy
ED – Erectile Dysfunction
EPIC – Expanded Prostate Cancer Index Composite
HRQoL – Health-Related Quality of Life
PDE5 – Phopho-Diesterase
RT - Radiotherapy
All authors declare that they have no conflict of interest
All treatments were conducted according to Good Clinical Practice and the German Radiation Protection Laws. The analysis is registered at the Charité ethics board under EA4/056/21. All patients gave written consent for the use of their data for scientific purposes.
All patients gave written consent for the use of their data for scientific purposes including publication.
This manuscript contains no individual`s personal data in any form. All data supporting the results reported in this article are available on a secured data server owned by the Charité University Medicine, Berlin, Germany. The datasets used and analyses of all data of this manuscript are available from the corresponding author on reasonable request.
Not applicable
There was no funding for data analyses. The manuscript was edited and proof-read by San Francisco Edit, 1755 Jackson Street, Suite 610, San Francisco, CA 94109. Manuscript proof-reading was funded by a scientific grant of Varian Medical Systems, Palo Alto, California, USA.
AG and VHE had full access to all patient related data. AG was responsible for the design of the study, performed database set-up, and data integrity checks. VHE was responsible for data collection and database set-up and statistics. AG and VHE are responsible for interpretation of data. AG and VHE prepared the manuscript. GK, CS, MK and VB substantially revised and edited the manuscript. All authors approved the submitted version of the manuscript and its publication.
We thank all patients for their valuable and much appreciated contribution to this manuscript. Thanks to all technicians, nurses, physicists, and physicians who were responsible for preparation, planning, and daily treatment of all participants. Special thanks go to Prof. Dr. Volker Budach, Head of the Department for Radiation Oncology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.
Tables are only available as a download in the Supplemental Files section.