Stereotactic Body Radiation Therapy (SBRT) for Clinically Localized Prostate Cancer: A Systematic Review

Early experience with localized prostate cancer treatment using Stereotactic Body Radiation Therapy (SBRT) is detailed in this review report. Examined patients treated with SBRT encompassing cases of localized prostate carcinoma with or without Androgen Deprivation Therapy (ADT). This retrospective analysis utilized data prospectively collected in an institutional database. SBRT was administered using the CyberKnife^®, delivering doses of 35 Gy or 36.25 Gy in 5 fractions. Biochemical control was evaluated based on the Phoenix definition. Recorded and scored toxicities employed the CTCAE v.3, and quality of life assessments utilized the Short Form-12 Health Survey (SF-12), the American Urological Association Symptom Score (AUA), and Sexual Health Inventory for Men (SHIM) questionnaires conducted both before and after treatment. Late urinary symptom flare was defined as an AUA score ≥ 15 with an increase of ≥ 5 points above baseline six months after completing SBRT.

Introduction

Men with localized prostate cancer typically undergo dose-escalated external beam radiation therapy (EBRT) involving daily doses of 1.8-2.0 Gy over eight to nine weeks. However, the extended treatment duration poses challenges for many patients due to logistical reasons and life responsibilities. Hypo fractionated radiation therapy, with larger daily fractions, is considered biologically advantageous for prostate cancer radiotherapy. Limited hypofractionation trials (2.5 to 3.5 Gy) have shown effectiveness without excessive toxicity. Stereotactic body radiation therapy (SBRT) utilizes even larger daily fractions to capitalize on this radiobiological advantage.

Early SBRT investigations lacked continuous tracking of prostate location and intrafraction adjustments, impacting precision. The CyberKnife^® system addresses this limitation, delivering precise treatment with targeting errors under 1 mm. Unlike standard image-guided radiation therapy (IGRT), CyberKnife^® features real-time tracking for updated prostate position information, allowing adjustments during treatment. This reduces the planning target volume (PTV) and limits the dose to critical organs. Institutions have successfully employed CyberKnife^{® for} SBRT on the prostate (35–36.25 Gy doses) with excellent disease-free survival and toxicity comparable to conventional treatments.

Methodology

Patient Selection:

• Eligible patients had histologically confirmed prostate adenocarcinoma and were treated according to our institutional protocol.
• Exclusion criteria: Clinical stage T3, involved lymph nodes, distant metastases on imaging, or prior pelvic radiotherapy.
• Institutional IRB approval was obtained for a retrospective review of prospectively collected data in our database.

SBRT Treatment Planning and Delivery:

• Four gold fiducials were placed in the prostate; MR imaging and a thin-cut CT scan were performed seven days later.
• Fused CT and MR images are used for treatment planning.
• Clinical target volume (CTV) included the prostate and proximal seminal vesicles.
• Planning target volume (PTV): CTV expanded 3 mm posteriorly and 5 mm in all other dimensions.
• Prescription dose: 35–36.25 Gy to PTV in five fractions of 7–7.25 Gy, resulting in a tumor equivalent dose in 2 Gy fractions (EQD2) of approximately 85–90 Gy (assuming an α/β ratio of 1.5).
• Treatment adjustment for older patients with poor baseline urinary function: 35 Gy.

Treatment Planning:

• Plans comprised hundreds of pencil beams, utilizing one to two circular collimators for high conformity (mean new conformity index of 1.28 [range, 1.12-1.59]).
• Inhomogeneous design (mean homogeneity index of 1.29 [range, 1.23-1.42]) aimed to minimize dose to adjacent critical structures (Figure 1a).
• The prescription isodose line is restricted to ≥ 75% to limit the maximum prostatic urethra dose to 133% of the prescription dose.
• The rectum, bladder, testes, penile bulb, and membranous urethra were contoured and assessed with dose-volume histogram analysis using Multiplan inverse treatment planning.
• The dose-volume histogram is illustrated in Figure 1b; critical structure dose constraints are detailed in Table 1.
• No attempt was made to limit the dose to the prostatic urethra or neurovascular bundles to minimize the risk of local recurrence.

Radiation Delivery:

Table 1: Dose targets and constraints for treatment planning

• The treatment was administered every other day with a mean prescription isodose line of 77% (75-81%) in approximately 1-hour-long sessions.
• Mean treatment duration: 10.6 days (5–16 days).
• On average, 247 beams were used (range, 199–289 beams) to treat the mean prescription volume of 135 cc (range, 61–258 cc) with a mean percent target coverage of 95.20% (range, 93.65-96.95%).
• The target position was verified every 30–60 seconds during treatment using paired, orthogonal kV images (total imaging effective dose equals 17.5 mSv).

Follow-up and Statistical Analysis:

• Prostate-specific antigen (PSA) and total testosterone levels were assessed before treatment, one-month post-SBRT, and during routine follow-ups.
• Follow-up visits are scheduled every three months for the first year and every six months for the second year.
• At each visit, alpha-antagonist, antidiarrheal, and phosphodiesterase type 5 (PDE5) inhibitor utilization were documented.
• Toxicity was prospectively documented using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 3.0.
• Acute toxicity is defined during or within six months of radiation therapy; late toxicity is defined as at least six months post-radiation.
• Genitourinary toxicities analyzed: hematuria, dysuria, incontinence, urinary urgency/frequency, and retention.
• Gastrointestinal toxicities analyzed: bowel frequency/urgency, proctitis, and rectal bleeding.
• Toxicity severity is graded from 1 to 3, considering pre-treatment symptoms and medication requirements.
• Quality of life (QOL) was assessed with the SF-12 Health Survey, AUA Symptom Score, and Sexual Health Inventory for Men (SHIM) questionnaires.
• Students’ t-tests and chi-square analyses were used for ongoing PSA, testosterone, and QOL score comparisons to baseline.
• PSA bounce is a rise of 0.2 ng/mL or more above the previous nadir with subsequent decline.
• Actuarial likelihood estimates for late toxicities are determined using the Kaplan-Meier method.
• Analysis of SF-12 scores with norm-based scores, considering minimally important differences (MID).
• Late urinary symptom flare is defined as a ≥ 5-point increase above baseline with severity (AUA score ≥ 15) and resolution criteria.
• Erectile dysfunction is categorized based on SHIM score severity; patients are considered potent if the SHIM score is≥ 10.
• Statistical analysis is limited to time points with ≥ 80% patient data availability to mitigate attrition bias.

Results

Patient Demographics:

• Treatment period: June 2008 to May 2010.
• One hundred prostate cancer patients were treated following the institutional SBRT monotherapy protocol (see Table 2).
• Ethnically diverse cohort: 57% Caucasian, with a median age of 69 years (range, 48–90 years).
• D’Amico classification distribution: 37 low-risk, 55 intermediate-risk, and eight high-risk patients.
• Androgen deprivation therapy (ADT) was administered to 11 patients, predominantly short-term (three to six months).
• Two high-risk patients received long-term ADT (two to three years).
• Treatment specifics: 85% of patients received 36.25 Gy in five fractions of 7.25 Gy each.

Table 2:  Patient characteristics and treatment

Follow-up and PSA Levels:

• Median follow-up duration: 2.3 years (1.4-3.5 years).
• At two years post-treatment, median pretreatment PSA decreased from 6.2 ng/ml (range, 1.9-31.6 ng/ml) to 0.49 ng/ml (range, 0.1-1.9 ng/ml) (Figure 2a).
• Benign PSA bounces were observed in 31% of patients, with a median bounce of 0.5 ng/ml (range, 0.2-2.2 ng/ml).
• Median time to PSA bounce: 15 months (3–21 months).
• One biochemical failure in a high-risk patient confirmed local recurrence, initiating ADT.
• Overall two-year actuarial biochemical relapse-free survival: 99%.

^{Figure 2: Pre- and post-treatment PSA and testosterone levels: (a). PSA levels for all patients (error bars indicate interquartile intervals) and (b). Box-and-Whisker plot of total testosterone
Levels (Only patients who did not receive androgen deprivation therapy (ADT) were included in the testosterone diagram. The p values were from χ2-analysis with baseline testosterone levels.)}

Testosterone Levels:

• Pretreatment total serum testosterone ranged from 4.75 nmol/L to 39.84 nmol/L, with a median of 12.29 nmol/L.
• Twenty-nine percent of patients were hypogonadal (total serum testosterone below eight nmol/L) before SBRT.
• At two years, median serum testosterone reduced significantly to 9.78 nmol/L (range, 2.46-27.60 nmol/L) compared to pretreatment (p < 0.02, Figure 2b).
• Median absolute reduction: 2.5 nmol/L; median percent reduction: 20.5%.
• Pretreatment and 2-year biochemical hypogonadism rates were not statistically significantly different (data not shown).

Table 3 Overview:

• Illustrates the prevalence of GU and GI toxicities post-treatment.
• Single symptoms and maximum GU/GI toxicity per patient are detailed for each follow-up visit.

Table 3: Prevalence of CTC graded gastrointestinal (GI) and genitourinary (GU) toxicities at each follow-up

Acute Urinary Toxicities (Table 3):

• 35% experienced grade 2 toxicities necessitating alpha-antagonists.
• Bowel issues requiring anti-diarrheals were rare (5%).

2-Year Incidence Rates (Late Toxicity):

• Late GI toxicity ≥ grade 2: 1%
• Late GU toxicity ≥ grade 2: 31%

Late Grade 2 and 3 GU Toxicities (Figure 3):

• Actuarial incidence rates showcased.
• Low grade 3 toxicities; one case required TURP due to hematuria.

^{Figure 3 Cumulative late urinary toxicity (grades 2 and 3).}

^{Figure 4: Short Form-12 (SF-12) Health Survey quality of life: (a) SF-12 physical component score (PCS) and (b) SF-12 mental component score (MCS). (The graphs show unadjusted changes in average scores over time. The scores range from 0–100, with higher values representing improved health status. Numbers above each time point indicate the number of observations contributing to the average.)}

Patient Health Perception Post-Treatment:

• Physical and mental health perceptions at two years were statistically similar to baseline (p = 0.76 and 0.90, respectively).

Baseline Lower Urinary Tract Symptoms (Table 4):

• The majority had mild to moderate symptoms (mean AUA: 8).
• Post-treatment, AUA score increased at one month, returning to baseline at three months (p = 0.60).

Table 4 Pre-treatment Quality of Life (QOL) scores

^{* Norm-based scoring for SF-12 with population mean = 50 and SD = 10.
Abbreviations: SF-12, Short-form-12; PCS, physical component score; MCS, mental component score; SD, standard deviation; AUA, American Urological Association; SHIM, sexual health inventory for men; ED, erectile dysfunction.}

Alpha-Antagonist Utilization (Figure 5b):

• Peaked at one month (65% utilization), gradually decreasing.
• 40% reported usage at two years.

Transient Late Urinary Symptom Flare (Figure 5c):

• Occurred in 21% post-treatment.
• Median flare magnitude: 9; median time: 9 months; median duration: 3 months.
• 28% of flares lasted > six months.

^{Figure 5: Urinary quality of life: (a) AUA score, (b) alpha antagonist utilization, and (c) urinary symptom flare. The graphs show unadjusted changes in average scores over time for each domain. AUA scores range from 0–35, with higher values representing worsening urinary symptoms.
Numbers above each time point indicate the number of observations contributing to the average. The thresholds for clinically significant score changes (½ standard deviation above and below the baseline) are marked with dashed lines. Error bars indicate 95% confidence intervals.}

Erectile Dysfunction Analysis (Table 4):

• Significantly prevalent before treatment based on SHIM.
• Sexual function analysis focused on 57 patients with pretreatment SHIM ≥ 10 and no ADT.

^{* Norm-based scoring for SF-12 with population mean = 50 and SD = 10. Abbreviations: SF-12, Short-form-12; PCS, physical component score; MCS,
mental component score; SD, standard deviation; AUA, American Urological Association; SHIM, sexual health inventory for men; ED, erectile dysfunction.}

Post-Treatment SHIM Scores (Figure 6a):

• Median SHIM decreased from baseline 19 to 18 at two years (p = 0.003).

PDE5 Inhibitor Utilization (Figure 6b):

• No statistically significant change over time.
• At two years post-treatment, 51% of patients had used PDE5 inhibitors during follow-up.

^{Figure 6 Sexual quality of life: (a) SHIM and (b) PDE5 utilization.
The graphs show unadjusted changes in average scores over time for each domain among men potent at baseline (N = 57). SHIM scores range from 0–25, with lower values representing worsening sexual symptoms. Numbers above each time point indicate the number of observations contributing to the average.}

Potency Maintenance (Table 5):

• 79% of PDE5 inhibitor users-maintained potency (SHIM ≥ 10) for two years.

Table 5 SHIM scores at baseline and following treatment

^{Abbreviations: Pre-Tx, pre-treatment; SHIM, sexual health inventory for men; ED, erectile dysfunction.}

Age-Related Potency Decline:

• The decline in potency at two years is unlikely due to aging.
• The average age of potent and non-potent patients was not statistically different (p = 0.41).

Discussion

The use of Stereotactic Body Radiation Therapy (SBRT) for clinically localized prostate cancer is gaining traction, particularly due to its accuracy facilitated by intra-fraction image guidance. It allows for smaller treatment margins, making it feasible for four or five large radiation fractions. Data from institutional series and a Phase I study indicate that SBRT yields comparable outcomes to other radiation modalities, ensuring high biochemical control rates with low grade 3 or higher toxicities. Notably, a recent update confirmed a 93% 5-year biochemical disease-free survival for patients with a favorable prognosis, reinforcing the appeal of SBRT, especially given patient preferences for shorter treatment durations.

Institutional experience aligns with the growing evidence supporting SBRT’s effectiveness and safety. Favorable early Prostate-Specific Antigen (PSA) outcomes, with a two-year post-treatment nadir of 0.49 ng/mL, suggest a high likelihood of long-term disease control. Benign PSA bounces, common and transient, were observed, contributing to a reassuring 99% actuarial 2-year biochemical failure-free survival rate, even among a higher percentage of intermediate- and high-risk patients.

Recent dosimetric studies have addressed concerns about SBRT’s coverage for unfavorable patients, indicating adequacy in delivering doses to potential extracapsular extension areas. Toxicity profiles, including late Grade 2 and Grade 3 genitourinary (GU) toxicities, were similar to external beam radiation therapy or brachytherapy, with conservative management effectively resolving issues.

Late urinary symptom flares, a novel observation in SBRT patients, prompted protocol modifications aimed at reducing their incidence and severity without compromising local control. Erectile function maintenance, comparable to conventionally fractionated treatments observed in 79% of patients, underlines the positive outcomes. However, the study acknowledges limitations such as its retrospective nature and suggests future comprehensive studies to assess the impact on overall urinary and sexual function in this elderly patient population.

Conclusion

Stereotactic Body Radiation Therapy (SBRT) emerged as a well-tolerated and effective treatment for clinically localized prostate cancer. The early biochemical response mirrored traditional radiation therapies, marked by common benign PSA bounces. Importantly, late gastrointestinal (GI) and genitourinary (GU) toxicity rates were on par with conventionally fractionated radiation therapy and brachytherapy. While late urinary symptom flares were noted, the majority resolved through conservative management. Noteworthy is the sustained potency observed in a significant percentage of men who were potent before undergoing SBRT, persisting two years post-treatment. This collective evidence underscores the favorable outcomes and tolerability of SBRT in the context of localized prostate cancer.

---

Reference

Chen, L.N., Suy, S., Uhm, S. et al. Stereotactic Body Radiation Therapy (SBRT) for clinically localized prostate cancer: the Georgetown University experience. Radiation Oncology 8, 58 (2013). https://doi.org/10.1186/1748-717X-8-58.