Introduction

The importance of local control in prostate cancer is clear; local failures from radiotherapy can lead to higher distant failure rates (1) and morbidity resulting from uncontrolled local disease can be significant including urinary obstruction, bleeding and pain. Achieving improved local control within the prostate therefore carries promise of reducing the sequelae attributable to uncontrolled local disease as well as improving survival.

Radiation Oncologists’ efforts to improve local control, by optimizing the therapeutic ratio, have been directed toward limiting the high dose volume to the prostate while escalating the dose within that volume. Along these lines, three-dimensional conformal radiation treatment (3DCRT) has increased local control rates with lower complication rates when compared to standard external beam techniques (2, 3). Similarly, intensity modulated radiation therapy (IMRT) has allowed dose-escalation to 81 Gy with acceptable levels of complications (4). Yet, with 8-year biochemical relapse-free rates of 78% and 67% for intermediate- and high-risk patients, it is clear that even higher doses may be required to eradicate prostate cancer (5-7).

Recent data suggest that large radiation fraction sizes are radio-biologically favorable over smaller fraction sizes in prostate cancer radiotherapy (8). High dose rate (HDR) brachytherapy as a boost to external beam radiation therapy (EBRT) has shown promise in this regard. Several studies have reported 5-year biochemical control rates of 93-98% (9-11), 89-93% (9-11) and 69-83% (7, 9-11) for low-, intermediate-, and high-risk prostate cancer with 5-year cause-specific survival rates of 96-98% independent of risk (7, 9-12).

In an effort to further improve patient tolerance in comparison to HDR brachytherapy, we have examined the use of CyberKnife stereotactic radiosurgery as a boost to IMRT for the treatment of patients with intermediate- and high-risk clinically localized prostate cancer. The CyberKnife uses hundreds of non-isocentric beams to deliver a highly conformal radiation dose with steep dose gradients (13) which can be used to limit dose and toxicity to surrounding structures. Unlike HDR brachytherapy treatment, the CyberKnife does not require anesthesia or hospitalization. When compared to intensity modulated radiation therapy, dosimetric studies have shown that CyberKnife plans show rapid dose fall-off rates from the prostate with significantly better conformity than IMRT plans at a relatively greater dose inhomogeneity (14). This relative inhomogeneity can be taken advantage of to allow for HDR-like dose escalation within the prostatic peripheral zone (15). The CyberKnife incorporates a dynamic tracking system consisting of an orthogonal pair of diagnostic-quality x-ray imaging devices and software that can locate fiducials implanted in or near the target. This provides updated position information in six-dimensions (3 translations combined with roll, pitch and yaw rotations) for targeting of the therapeutic beam during treatment and allows for correction of intrafraction motion (16). We report on the use of CyberKnife SBRT as a homogeneous hypofractionated boost to IMRT for the treatment of 24 prostate cancer patients.



Figure 1: SBRT treatment planning axial (A) and sagittal (B) computed tomography images demonstrating the CTV (red), PTV1 expansion (dark blue), bladder (orange), rectum (yellow), and membranous urethra (pink). The prescription isodose lines are shown at 84% (light blue), 70% (yellow) and 50% (green). (C) Summary of SBRT dose volume constraints for the critical structures where Vx Gy denotes the volume of the structure receiving a dose of x Gy.


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Enlarge Figure 2

Figure 2: Summary of acute toxicity scoring using the Common Toxicity Criteria version 3.0 guidelines.

Methods

Patient Selection

Patients eligible for inclusion in this study had histologically confirmed adenocarcinoma of the prostate, clinical stage T1c-T3b, and a baseline AUA score of less than 20. Exclusion criteria included clinically involved lymph nodes on imaging; distant metastases on bone scan; prior pelvic radiotherapy or prior radical prostate surgery. Androgen deprivation therapy was administered at the discretion of the treating Urologist. Institutional IRB approval was obtained for the treatment protocol. All patients signed a consent form.

SBRT Treatment Planning and Delivery

All patients had at least four gold fiducials placed in the prostate prior to treatment planning: two at the apex and two at the base. To allow for fiducial stabilization, planning imaging was performed at least 7 days after fiducial placement. Patients underwent 1.5 T MR imaging followed shortly thereafter by a thin cut (1.25 mm) CT scan. Both scans were performed with an empty bladder. Patients were advised to adhere to a low-gas, low-motility diet, starting at least five days prior to all treatment planning imaging and treatment delivery. They were nothing by mouth (NPO) the night before and an enema was administered 1-2 hours prior to imaging and treatment.


Fused CT and MR images were used for treatment planning. The clinical target volume (CTV) included the prostate, areas of radiographic extracapsular extension and the proximal seminal vesicles to the point where the left and right seminal vesicle separate (Figure 1A & B). The SBRT planning target volume (PTV1) equaled the CTV expanded 3 mm posteriorly and 5 mm in all other dimensions. The prescription dose was 19.5 Gy to the PTV1 delivered in three fractions of 6.5 Gy over 3-5 days with some patients receiving treatments on 3 consecutive days and some patients receiving treatment on alternating days. The volume of the PTV1 receiving 19.5 Gy, termed the V19.5 Gy, was to be at least 95%. Variations of the V19.5 Gy that were less than 95%, but greater than or equal to 90%, were considered minor variations; whereas major variations occurred when the V19.5 Gy was less than 90%. The prescription isodose line was limited to > 75% which limited the maximum prostatic urethra dose to 133% of the prescription dose. For the CTV, at least 95% of the volume was to receive 21 Gy (V21 Gy). Variations were considered minor if the V21 Gy was less than 95%, but greater than or equal to 90%; whereas variations less than 90% were considered major. The rectum, bladder, penile bulb and membranous urethra were contoured structures and evaluated with dose-volume histogram analysis during treatment planning using Multiplan (Accuray Inc., Sunnyvale, CA) inverse treatment planning. The neurovascular bundles and prostatic urethra were not contoured as planned due to poor visualization on the 1.5 T treatment planning MRI. The rectal contour included the lumen and rectal wall from the anal canal to the rectosigmoid flexure. The bladder and bowel contours were the larger composites of the MRI and CT volumes. Sigmoid colon and other bowel adjacent to the PTV1 were contoured if present. Our rectal dose–volume histogram (DVH) goals were <50% rectal volume receiving 50% of the prescribed dose, <20% receiving 80% of the dose, <10% receiving 90% of the dose, and <5% receiving 100% of the dose (17). Dose and volume constraints to the critical structures are summarized in Figure 1C.
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Figure 3: Summary of patient quality of life: (A) SF-12 physical component (PC) score, (B) SF-12 mental component (MC) score, (C) AUA score and (D) SHIM score. The graphs show unadjusted changes in mean toxicity and QOL scores over time. SF-12 scores range from 0-100 with higher values representing improved health status. AUA scores range from 0-35 with higher values representing worsening urinary symptoms. SHIM scores range from 0-25 with lower values representing worsening sexual function. Numbers above each time point indicate the number of observations contributing to the mean.

The protocol was designed to deliver a total radiation dose to the PTV1 biologically equivalent to 92.1 Gy in 2 Gy fractions assuming an α/β ratio of 1.5 Gy. To achieve this, all patients were treated with IMRT immediately following SBRT. For all IMRT treatments fiducial guidance was used for set-up. The more generous PTV2 included a margin of 1.0 cm around the CTV except at the rectal interface where a margin of 0.5 cm was added. Daily doses of 1.8 Gy were delivered to the PTV2 5 days a week to a total dose of 50.4 Gy in 28 fractions. The minimum target dose constraint to the PTV2 was 49.5 Gy and the maximum target dose constraint was 53 Gy. In addition, 100% of the PTV2 was to receive at least 95% of the prescription dose and 5% of the volume was to receive no more than 105% of the prescription dose. For the bladder and rectum, the maximum dose constraint limit was 50 Gy, the full- volume dose constraint limit was 30 Gy and no part of either volume received more than 55.5 Gy. Dose to the femoral heads was limited to 45 Gy.

Follow-up

Acute toxicity was defined as those events that presented and resolved within the first 6 months following completion of treatment. Toxicity was assessed pre-treatment, during treatment and at 1, 3 and 6 months using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 3.0 (Figure 2) and the American Urological Association (AUA) symptom score (also known as International Prostate Symptom Score) (18). Quality of life (QoL) was assessed pre-treatment and at follow-up visits using the Short Form-12 Health Survey (SF-12), the Expanded Prostate Cancer Index Composite (EPIC) questionnaire (19) and the Sexual Health Inventory for Men (SHIM) questionnaire (20).

Statistical Methods

A pilot protocol was written to test whether patients could have Cyberknife plans developed and delivered with no major treatment planning variations, with early stopping if there was 1 major variation in the first 10 patients. Toxicity and treatment planning variations have been tabulated. Differences in ongoing quality of life scores were compared to baseline using paired t-tests. Mean scores at baseline, 1, 3, and 6 months were presented graphically.

Results

From April 2008 to April 2009, 24 prostate cancer patients were accrued for the IRB approved protocol. The median patient age was 68.5 years (range, 47-80 years). Similar numbers of Caucasians (C) and African Americans (AA) were enrolled reflecting the distribution of our normal patient population. Thirteen patients were intermediate-risk and eleven were high-risk using the D’Amico Risk Classification (21). Baseline median PSA was 9.1 ng/ml (range, 2.5-27.3 ng/ml). Forty-two percent of patients received androgen deprivation therapy (ADT). For patients who did not receive ADT, the median pre-treatment PSA was 10.6 ng/ml. Table I provides detailed patient characteristics.

Table IIA provides a summary of the treatment characteristics. Minor protocol variations occurred in 50% of the patients, but these were small deviations from the planned treatment and likely of little clinical significance (Table IIB). One major variation from the treatment protocol occurred. In this case, the dose to the CTV was limited to maintain the rectal dose within protocol limits. Our rectal DVH goals were obtained in most patients.

At an average follow-up of 9.3 months (range: 6.6-16.9 months), the initial PSA response has been favorable. The median 6 month post-treatment PSA was 1.5 ng/ml for patients who did not receive ADT. Toxicity has been minimal with no Grade 3 or higher gastrointestinal (GI) or gastrourinary (GU) toxicities (Table III). Grade 2 toxicities included urinary symptoms requiring alpha blockers and bowel frequency/spasms requiring antidiarrheals.

Figures III and IV present a summary of the changes in quality of life indicators over time. By six months post-treatment, the patients’ perceptions of their physical health (Figure 3A) and mental health (Figure 3B) had improved. In the case of mental health, this improvement was significant (p = 0.03; Table IV). At one month post-treatment the mean AUA toxicity scores had increased to a value of 10.7 from a baseline of 7.4 (p = 0.01; Figure 3C, Table IV). By 6-months post-treatment the mean AUA toxicity score had returned to baseline. Similarly, at one month post-treatment the mean SHIM scores had decreased to a value of 8.6 from a baseline of 10.9 (Figure 3D). Mean SHIM quality of life returned to baseline by 6 months (Table IV). As with the AUA and SHIM scores, the EPIC urinary and EPIC sexual scores decreased at one month and returned to baseline by 6 months (Figures IVA and IVC, Table IV). The mean EPIC bowel score decreased slightly at one month and six months (Figure IVB). However, the decrease at six months was not significant (Table IV).

Discussion

This study aimed at assessing the feasibility and safety of performing IMRT with CyberKnife SBRT boost for intermediate- to high-risk clinically localized prostate cancer. Hypofractionated SBRT boost was chosen for this study due to the potential benefits of hypofractionation (8) including radiobiologic dose escalation. In addition, SBRT does not require anesthesia and/or hospitalization expanding its potential utilization in the elderly prostate cancer patient population. Acute Grade 2 GU toxicities and GI toxicities were observed in 13% and 4% of patients, respectively. There were no toxicities greater than Grade 2. In comparison, published brachytherapy boost publications have reported acute Grade 2 and 3 GU toxi­city rates ranging from 5.5-22.5% and 1.8-3.9%, respectively; reported Grade 2 GI toxicities for HDR boost have ranged from 3.9-7% (16-19). Table V provides an overview of observed acute toxicities for prostate boost publications reporting with the CTC criteria. Our results appear comparable to others.


Enlarge Table IV

Preliminary quality of life also appears favorable with AUA, SHIM and EPIC scores returning to baseline by six months after treatment. A study of prostate cancer patient quality of life using EPIC examined patients treated with external beam radiation therapy (EBRT) alone, EBRT plus low dose rate (LDR) brachytherapy and LDR brachytherapy alone (22). At six months, EPIC scores had not returned to baseline.

Summary

Hypofractionated SBRT combined with IMRT is a promising new treatment option for men with intermediate- and high-risk prostate cancer. Acute toxicity in this pilot study was minimal and the treatment appears well tolerated with little impact on quality of life. Early results suggest encouraging biochemical response with low toxicity. These data provide a basis for the design of a phase II clinical trial.



Enlarge Table V

Conflicts of Interest: None.

Acknowledgements

We acknowledge Robert Meier, M.D, Solomon B. Makgoeng, Kathryn Taylor, Ph.D. and Arnold L. Potosky, Ph.D. for helpful discussions. We gratefully acknowledge the editorial assistance of Pam Commike, Ph.D., Accuray Incorporated. The views expressed here are entirely the authors’; Accuray did not provide assistance with data collection, compilation, or interpretation.

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