Stereotactic body-radiotherapy boost dose of 18 Gy vs 21 Gy in combination with androgen-deprivation therapy and whole-pelvic radiotherapy for intermediate- or high-risk prostate cancer: a study protocol for a randomized controlled, pilot trial

This prospective, randomized, single-center, pilot study on intermediate- and high-risk prostate cancer patients is ongoing at Asan Medical Center. Patients are randomized into two groups with a 1:1 allocation using blocked randomization, and the random block size is 4. The randomization sequence is generated by the clinical research nurse using Excel software. The allocation sequence is concealed from the primary investigator who enrolls the patients using the Excel file locked with a password. Also, the file is saved in a computer located in the place that the primary investigator cannot approach. One group will receive a CyberKnife SBRT boost dose of 18 Gy administered in three fractions (18-Gy group), and the other group will receive a CyberKnife SBRT boost dose of 21 Gy administered in three fractions (21-Gy group).

As shown in Fig. 1, all patients will first receive ADT. Several studies strongly support the use of ADT in addition to EBRT, long-term (i.e., 2–3 years) ADT for high-risk patients [13, 14] and short-term ADT (4–6 months) for the intermediate group [15, 16]. Risk group definition is based on the current National Comprehensive Center Network guidelines (https://​www.​nccn.​org/​professionals/​physician_​gls/​pdf/​prostate.​pdf). Informed consent of patients is mandatory before recruitment and is obtained from the radiation oncologists. Three months after the start of ADT, WPRT (44 Gy in 20 fractions) with intensity-modulated radiotherapy (IMRT) will be initiated. Next, CyberKnife boost will be implemented. Since the primary investigator has to confirm the plan for CyberKnife boost, the blinding is not possible afterward.

The dose schedules are designed to achieve the biological effective dose (BED) as that of the conventional regimen with 78 Gy administered in 38 fractions. BED is widely used in radiation oncology to compare diverse radiation dose regimens using different fraction sizes, fraction numbers, and total doses [17]. For calculation of BED, an α/β ratio constant, i.e., the dose at which cellular death rates with linear and quadratic components are equivalent, is needed. A usual α/β ratio for normal tissue is 3, whereas that for prostate cancer is 1.5. As summarized in Table 1, the normal tissue BED for conventional regimen is 130.0 Gy, which is similar to that for the boost regimen of 18 Gy (130.7 Gy) and lower than that for a boost regimen of 21 Gy (146.7 Gy). The BED values for prostate cancer are 182.0, 197.3, and 226.3 Gy with conventional, 18-Gy boost, and 21-Gy boost therapies, respectively. As result, the 18-Gy group will receive the same BED for adjacent organs, while the tumor will receive 110% BED of conventional EBRT, while the 21-Gy group will be irradiated 110% and 120% BED of conventional EBRT for normal organ and prostate cancer, respectively.

Patients fulfilling the following criteria are eligible for this trial: age, 20 years or older; diagnosis of pathologically confirmed intermediate- or high-risk prostate cancer within 6 months after enrollment; and an Eastern Cooperative Oncology Group performance status of 0–1. Patients should also fulfill the following biochemical and laboratory criteria based on tests performed within 6 months before enrollment: absolute neutrophil count, ≥ 1500 cells/mm³; platelet count, ≥ 50,000 cells/mm³; hemoglobin, ≥ 8.0 g/dl; normal kidney function within 6 months before enrollment as determined by creatinine < 2.0 ng/dl; normal liver function within 6 months before enrollment as determined by total bilirubin < 1.5 times the maximum normal value; alanine aminotransferase or aspartate aminotransferase < 2.5 times the maximum normal value.

Patients who fulfill the following criteria are excluded from this trial: distant metastasis; pelvic lymph node metastasis; history of ADT within 6 months before enrollment; history of definitive treatment for prostate cancer such as radical prostatectomy; history of pelvic irradiation; diagnosis of double primary cancer other than skin or thyroid cancer.

Patients who desire to exit the trial or withdraw consent will be dropped out of the study. Additionally, any medical issues as well as unexpected serious complications occurring during treatment or the follow-up period that hinder completion of the study protocol will result in patient dropout.

ADT will be initiated 3 months before WPRT (Fig. 1). In the intermediate-risk group, ADT will be administered for 6 months, whereas in high-risk group, long-term ADT for 2–3 years will be administered. Administration of antiandrogens and/or luteinizing hormone-releasing hormone agonists is allowed for patients in this study.

Before computed tomography (CT) for treatment planning, an experienced radiologist will insert three gold intra-prostatic fiducial markers via endorectal sonography for CyberKnife tracking. One week later, enhanced CT scans with a slice thickness of 2.5 mm will be obtained in all patients who will have empty bladders and rectal balloons in place. Participants should be in a relaxed supine position facilitated by an ankle pillow. Afterwards, a radiation oncologist will delineate organs-at-risk (OAR) and target volumes. If available, fusion with diagnostic magnetic resonance imaging (MRI) is recommended. Gross target volume (GTV) includes whole prostate glands, involved extraprostatic tissues, and any suspicion of involvement of the seminal vesicles. If seminal vesicle invasion is excluded definitely, they will not be included in the GTV calculation. Clinical target volume (CTV) includes regional nodal areas including obturator, external/internal iliac, and presacral lymphatic areas. Planning target volume (PTV) is expansion of CTV margins by 5 mm, except for the posterior 3-mm margin for rectal sparing. PTV must be irradiated with ≥ 95% of the prescription dose. OAR includes the rectum, bladder, and femoral heads, and all are contoured according to the Radiation Therapy Oncology Group guidelines [18]. IMRT will be used, and the dose regimen will be 44 Gy in 2.2-Gy fractions every weekday. Dose constraints are as follows: (1) bowel (small and large), 30% of the entire bowel volume must not receive more than 40 Gy; (2) rectum, 60% of the volume must receive ≤ 40 Gy; (3) bladder, 35% of the bladder volume must receive ≤ 45 Gy; (4) femoral heads, 15% of the femoral head volume must receive < 35 Gy. WPRT will be initiated within 10 days after the day of CT for treatment planning. For image guidance, daily cone-beam CT will be used. Patients will be asked to empty their bladder before each fraction, while there will be no routine bowel preparation.

For SBRT boost planning, another non-enhanced CT with 1.25-mm slices will be obtained at 1 week before the start of the boost therapy. Patients will be in a supine position with a vacuum cushion and an ankle pillow and with an empty bladder and a Foley catheter inserted for delineation of the urethra. The rectal balloon will not be used for the boost therapy. Boost volume is identical to the GTV of WPRT delineation, whereas the PTV margin is 3 mm in all directions. The urethra as well as the rectum and bladder are also included in the OAR. The CyberKnife robotic radiosurgery system (Accuray Incorporated, Sunnyvale, CA, USA) will be utilized for the SBRT boost, and the PTV must receive ≥ 80% and < 120% of the prescribed dose. OAR dose constraints are as follows: (1) rectum, < 85% of prescription dose; (2) bladder and urethra, < 100% of prescription dose. Prescription doses are 18 Gy and 21 Gy in three fractions, every other day. Tracking for fiducial markers will be used for image-guided radiotherapy. An enema will be performed for bowel preparation before every treatment. The whole radiotherapy period will not exceed 10 weeks.

Patient data will be collected before start of radiotherapy, every week during WPRT, at the end of WPRT, at the end of SBRT boost, and at 1-month and 4-month follow-up visits after radiotherapy (Fig. 2). Patient data will be documented in Case Report Forms on urologic/gastrointestinal toxicities using the Common Toxicity Criteria for Adverse Events (CTCAE v 4.03), patient-reported outcomes (PRO), and PSA levels. After confirmation of the CyberKnife boost plan (at fourth week of radiotherapy), the evaluation of toxicities and efficacy will be no longer be blind. For ADT initiation, patients will be evaluated by the Department of Urology during follow-up visits every 3 months. After radiotherapy sessions, patients will also be evaluated by the Department of Radiation Oncology every 3 months for the first 2 years, every 6 months until 5 years, and annually thereafter. Follow-up evaluations will assess chronic toxicities and PSA levels. If clinical recurrence is suspicious, imaging studies, such as MRI and/or bone scans, will be considered.

For the patient data protection, separate identification code will be given to all patients. Also, data will be protected by password-accessible files, and only investigators can assess the files. All data will be deleted at 3 years after the end of the study.

Primary endpoints of this trial are acute toxicities and short-term biochemical control. Acute toxicities are defined as events occurring within 3 months after treatment and are evaluated according to the CTCAE v 4.03 and PRO, using the Overactive Bladder Symptom Score and the International Prostate Symptom Score. Secondary endpoints are chronic toxicities and long-term biochemical control. Chronic toxicities are evaluated using the Late Effects of Normal Tissues scoring system. Biochemical recurrence (BCR) is defined as the Phoenix consensus definition of a rise in PSA level by 2 ng/ml or more above the nadir value [19].

The trial design and protocol adhere to the Recommendations for Interventional Trials (SPIRIT) criteria. The SPIRIT Checklist and Figure can be found in Additional file 1: Table S1 and Fig. 2.

The present study is being performed as a purely exploratory pilot study; therefore, by calculation for statistical analysis, a total 15 patients in each treatment group is considered as an appropriate sample size. Comparison of the treatment two groups will be conducted using the chi-square test or Fisher’s exact test. Biochemical recurrence-free survival (BCRFS) will be calculated from the ADT start date using the Kaplan-Meier method. Descriptive statistics of all analyzed parameters will be provided, whenever appropriate.