Trial Design
This is a prospective clinical trial, conducted at an academic center ("UC-Christus Cancer Center"), that explored hypofractionated radiation therapy in the context of SRT or ART. The protocol and design were approved by the local ethics committee (March 5, 2020 (Study number 191016002) and its implementation was under the guidelines of Good Clinical Practice and the Declaration of Helsinki.
Patients
Patients older than 18 years with a diagnosis of prostate cancer, with histopathological confirmation of adenocarcinoma, who underwent radical prostatectomy and indication for adjuvant or salvage radiotherapy were recruited; the need for ART was defined by the presence of risk factors (pT3a-b and / or positive surgical borders or nodal involvement in lymph node dissection) or the need for SRT due to biochemical recurrence (two prostate-specific antigen (PSA) elevations above 0.2 ug/ml). the exclusion criteria were: pT4, macroscopic nodule concordant with persistent disease in the prostate bed or pelvic positive adenopathy concordant with regional or distant metastasis by imaging; history of previous pelvic radiotherapy; severe urinary incontinence, inflammatory bowel disease and / or genetic disease with greater predisposition to radiation therapy toxicity.
Intervention
After defining the need for radiotherapy, the patient was simulated with a pelvic computed tomography for radiotherapy planning, with rectum and bladder preparation according to the local protocol of the cancer center with an empty rectum and a full bladder.
The prostate bed was defined as “clinical target volume” (CTV) according to the RTOG contouring guide (14). The treatment of the nodal areas of the pelvis was according to the preference of treating radiation oncologist, the contouring of the volumen was according to the NRG guide (15). A “planning target volume” (PTV) was created with a 5 mm expansion of the CTV in all directions.
The prescribed dose to the prostate bed / seminal vesicles was 51 Gy in 17 daily fractions (3 Gy per fraction) for a total of 3.5 weeks. Intensity modulated radiotherapy (IMRT) technique with “volumetric arc therapy” (VMAT) Technique was used for planning. When treatment to the pelvis was planned, the pelvis was prescribed to 36 Gy in 12 daily fractions and then a sequential boost to the prostate bed to complete to 51 Gy in 3 Gy fractions was used. The decision of elective treatment to the pelvis was left to the discretion of the treating physician.
The planning objectives were as follows: 99% coverage of the PTV was > 48.45 Gy, allowing a maximum dose in the PTV of < 54.57 Gy. The dose to the tumor bed (51 Gy) is biologically equivalent to 66 Gy (assuming α/β 1.3–1.5 Gy). 36 Gy in 12 fractions to the pelvis was decided based on a calculation of a biologically effective dose (BED) 108, which is similar to the BED of 106 from a standard fractionation scheme of 2 Gy per fraction up to 46 Gy total to the pelvis (assuming α/β of 1.5). The dose restrictions for organs at risk were as follows: Rectum V42 < 40% and V18 < 33%; Bladder V48 < 40%; Intestines V40 < 2 cc and V34 < 17 cc (with maximum dose < 50 Gy) and femoral heads V25 < 5%. All dosimetric plans were evaluated and approved by the treating physician, and quality control was also carried out by the team of physicists prior to each treatment. The positioning and adequate preparation of the bladder and rectum were evaluated with CBCT images (“cone beam computed tomography”) in each treatment.
Endpoints and Statistical methods
The primary endpoint was late toxicity grade > 2 and the secondary objectives was gastrointestinal and genitourinary acute toxicity, disease-related quality of life and biochemical failure-free survival, defined of an absolute serum PSA > 0.4 ng/ml, rising compared to the previous value.
A sample size calculation of 30 patients was planned, based on a reported risk of grade 3 or greater late toxicity of 2% with standard treatment in historical series (17, 18), and calculating that the upper limit of the confidence interval is 12%. If G3 toxicity less than 12% is confirmed, a randomized phase II study will continue.
In relation to the analysis of the quality of life and the domains of EPIC 2.0, the results were transformed into a percentage value of 0-100 (according to EORTC manual), and the average, the maximum and minimum baseline value of each of these were reported. For symptom scales a higher score indicates a worse situation, while a higher score for functional and global health status is an indicator for a good condition.
Follow-up and toxicity assessment
Acute toxicity was evaluated weekly by Common Terminology Criteria
for Adverse Events (CTCAE) version 4.03, Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and International Prostate Symptoms Score (IPSS), during radiotherapy and 4,8 and 12 weeks after its completion. Late toxicity was defined as that presented 6 months after radiotherapy was completed. The disease-related quality of life, urinary, gastrointestinal, sexual and hormonal function were evaluated with the Expanded Prostate Cancer Index Composite (EPIC) 2.0, Quality of Life of Cancer Patients (QLQc30) and module of prostate cancer (PR25) questionnaires at baseline before the start of radiotherapy and then every 6 months. A digital rectal examination and PSA measurement were performed every 6 months.