Study design
This was a single-arm multi-institutional prospective phase II study with the University Hospital Medical Information Network Clinical Trials Registry (http://www.umin.ac.jp/ctr/index-j.htm), identification number UMIN000007810. Patients with pathologically confirmed localized adenocarcinoma of the prostate with low(T1-T2a and PSA < 10, and Gleason score (GS) ≤ 7)or intermediate risk (cT1-T2c, PSA < 20 and GS < 7, but not low risk) or high risk (having one of the following factors, cT3a, 20 < PSA ≤ 30, or GS = 8 or 9) were eligible for participation. Other eligibility criteria were the age range of 50–80 years and Eastern Cooperative Oncology Group performance status of 0–1. Patients with lymph nodes involvement or metastatic disease, history of pelvic or prostate surgery, prior radiotherapy to the prostate or pelvis, severe medical disorders, a history of inflammatory bowel disease, active collagen vascular disease, and previous malignancy within 5 years of prostate carcinoma diagnosis (except completely treated carcinoma in situ or T1N0M0 glottic cancer) were excluded from this study. The study was conducted under an institutional review board-approved prospective clinical protocol at 20 institutions in Japan, and all the patients enrolled signed an informed consensus.
Treatment
Radiotherapy alone was recommended for patients with low-risk prostate cancer. However, hormonal therapy within 8 months before radiotherapy was permitted. For patients with intermediate- or high-risk prostate cancer, neoadjuvant hormonal therapy consisting of a luteinizing hormone-releasing hormone (LH-RH) analogue alone or a combination of LH-RH analog and antiandrogen for 4–8 months was mandatory. After radiotherapy, the use of hormonal therapy is not allowed until tumor relapse occurs.
Hypofractionated radiotherapy was performed with a total dose of 70 Gy in 28 fractions (2.5 Gy per fraction). Patients were treated 5 days per week for 7 consecutive weeks. In this study, an α/β ratio was assumed as 1.5 Gy for prostate cancer. Under this assumption, the equivalent dose to 70 Gy delivered in 28 fractions for prostate cancer was estimated to be the same biologically equivalent dose of 80 Gy if delivered at 2 Gy per fraction.
Computed tomography (CT) planning was performed with 0.3 cm slice thickness or less. All patients underwent CT scanning with an empty rectum and a moderately full bladder. The gross tumor volume (GTV) was defined as the prostate. However, extracapsular invasion was included in GTV in patient with T3a tumor. The clinical target volume (CTV) was defined as the GTV only in low-risk patients, or the GTV and the base of the seminal vesicle (1 cm) in intermediate- or high-risk patients. The margin of the planning target volume (PTV) from the CTV should be 4–8 mm (at least 5 mm except on the rectal side) for organ motions and set-up errors. The bladder, rectum, small intestine, large intestine, and femoral head were defined as organs at risk. All organs should be contoured as the solid organ. The bladder is enclosed from the neck to the base of the bladder. The rectum is enclosed from the anus (level of the ischial tuberosity) to the rectosigmoid transition. The level is usually below the caudal end of the sacroiliac joint.
The dose was prescribed to the D50 of the PTV (dose that covers 50% of the PTV). However, if it is judged to be medically dangerous to follow the protocol, compliance with dose constraints for organs at risk should be given priority over PTV and/or CTV coverage, and changes should be made as appropriate according to the medical judgment of the physician in charge. A maximum dose of 105% of the prescribed dose was allowed to < 2% of PTV, and D95 (dose that covers 95% of the PTV) was allowed to ≥ 95% of the prescribed dose. The dose constraints for organs at risk were as follows: bladder V70/V65/V60/V55, 15%/25%/35%/50%; rectum V65/V55/V50/V45, 15%/25%/35%/50%; small intestine V55 < 0.5 cc; large intestine V60 < 0.5 cc; femoral heads Vmax < 50 Gy. However, recommended dose constraints were; bladder V70/V65/V60/V55, 10%/20%/25%/40%; rectum V65/V55/V50/V45, 10%/20%/25%/40%.
Radiotherapy was delivered by IMRT using daily IGRT with prostate matching. Ultrasound, CT, and intraprostatic gold fiducial markers was permitted as image guidance. Prophylactic irradiation to the pelvic lymphatic region was not performed. Hydrogel spacers were not inserted in all patients.
After completion of radiotherapy, patients were observed without any treatment until recurrence was observed. Treatment after the event of recurrence is not prescribed. However, it was strongly recommended that hormone therapy in the patients with PSA recurrence should not be considered until the PSA level increased to 4 ng/mL or higher. Acute and late adverse events were prospectively scored by the radiation oncologist using an adapted CTCAE ver.4.0-based criteria. Follow-up appointments were scheduled at least every 3 months in the first 2 years after the completion of treatment, then every 6 months to collect data on acute/late bowel and bladder toxicities and serum PSA values.
The primary endpoint is the cumulative incidence of late toxicities at 5 years, and the secondary endpoints are the cumulative incidence of the acute adverse events, 5-year biochemical failure-free survival rate according to Phoenix definitions (nadir + 2 ng/mL), clinical recurrence-free survival rate, and overall survival rate. Patients without biochemical relapse or clinical recurrence were censored at death or last follow-up.
Statistics
The sample size was calculated to 130 patients, considering as an acceptable and unacceptable grade ≥ 2 late toxicities of ≤ 7% and ≥ 15%, respectively, with 80% power and a one-sided significance level of 5%.