This study was approved by the Ethics committee of the Shanghai Changhai Hospital (CHEC2019-110) and is registered on ChiCTR (CHiCTR1900025743). This is a phase I, prospective, single-arm study.
The main objective of the phase I trial is to determine whether metastasis-directed radiation and neoadjuvant hormone and radiation therapy followed by radical prostatectomy for the treatment of oligometastatic prostate cancer is safe and well tolerated, by assessing the occurrence of radiotherapy-related complications along with intra operative and postoperative day-30 morbidity.
Primary endpoint The primary endpoints of the study were safety of radiotherapy as assessed by CTCAE 5.0 grading scale along with intraoperative and postoperative day-30 morbidity. The radiotherapy-related complications encompassed the genitourinary (GU) toxicity, gastrointestinal (GI) toxicity and erectile dysfunction (ED), while intraoperative and postoperative day-30 morbidity consisted of the operation time, intraoperative blood loss, rate of conversion to open surgery, fibrosis in the radiotherapy area, etc.
Secondary endpoints The secondary endpoints compromised of the positive rate of post-operation incisal edge, biochemical progression-free survival (bPFS), postoperative continence and recovery of sexual function, quality of life (QoL), overall survival (OS) and adverse reactions of ADT.
–Age 18–75 years at the time of registration
–Histologically confirmed adenocarcinoma of the prostate without small cell features
–Oligometastatic prostate cancer assessed by emission computed tomography (ECT), magnetic resonance imaging (MRI), Ga-68 Prostate-Specific Membrane Antigen(PSMA) PET/CT, Ga-68 PSMA PET/MR
–< 5 oligometastases (including bone, lymph nodes above renal artery level, distant organ metastasis), and/or lymph nodes below renal artery level metastasis, tumor clinical stage cTx, Nx according to AJCC TNM 2017
–Expected survival time > 5 years
–World Health Organization (WHO) performance status 0–1
–Written informed consent according to International Council for Harmonization/ Good Clinical Practice (ICH/GCP) regulations before registration and prior to any trial specific procedures
–Any previous or ongoing treatment of prostate cancer including radiotherapy, ADT, chemotherapy, focal treatment, etc.
–Patients who have previously undergone transurethral prostatectomy or excision
–Patients who underwent other abdominal surgery within last 3 months
–Patients who had undergone transrectal prostatic biopsy within last 2 weeks
–Patients with history of long-term use of anticoagulant and anti-platelet aggregation drugs and stopped anticoagulant less than 1 week before registration
–Patients with other malignancies, acute or chronic infections such as human immunodeficiency virus (HIV) (+), hepatitis C virus (HCV) (+) and / or positive syphilis
–Severe or active co-morbidity that is likely to impact the advisability of radiotherapy
–Any other serious underlying medical, psychiatric, psychological, familial, or geographical condition, which according to the judgement of the investigator may affect the planned staging, treatment and follow-up, patient compliance, or may cause high risk treatment-related complications for the patient
–Patients who have participated in other clinical trials within last three months
–Patients who have refused to undergo RALP
–Unsuitable to participate in this clinical trial as per the judgement of the investigator
In this trial, patients with oligometastatic prostate cancer are registered to receive the following treatment: ADT, radiotherapy and RALP. The trial schedule is illustrated in Fig. 1. Patients with oligometastatic prostate cancer receive 1 month of neoadjuvant ADT (nADT) followed by metastasis- directed radiation and abdominal or pelvic radiotherapy. Then offer RALP at the interval of 4–8 weeks after radiation, and ajuvant ADT for 2 years.
Both neoadjuvant and adjuvant ADT comprised of an oral antiandrogen (bicalutamide 50 mg once daily) plus goserelin given subcutaneously 14 days after the initiation of bicalutamide as either 10.8 mg with a second shot 3 months later or 3.6 mg with a second shot 1 month later.
2. Radiation therapy
2.1 Radiotherapy for oligometastases
For oligometastases, the method and timing of radiotherapy varies depending on the location of metastasis.
For pelvic oligometastatic lesions, IMRT is administered simultaneously with prostate radiotherapy. The gross tumor volume (GTV1) of oligometastases is based on imaging examination: 68-Ga PSMA PET/CT, CT, MRI, ECT, etc. Planning target volumes (PTVs) for GTV1 are delineated with an additional 5 mm margin. Dose segmentation varies depending on the surrounding organs at risk (OARs) and tumor size. Firstly 49.5 Gy with 22 fractions or 50 Gy with 25 fractions is the recommended dose segmentation.
For non-pelvic oligometastatic lesions, SBRT will be administered. The gross tumor volume (GTV1) of oligometastases relied on imaging examination. PTV-GTV1: GTV1 relied on 3–5 mm uniform expansion. 6-8Gy per fraction with 5 fractions is the recommended dose segmentation which depends on the surrounding OARs and tumor size. If the oligometastases cause obvious symptoms, then SBRT is considered before prostate radiotherapy. If the oligometastases do not cause obvious symptoms, then prostate radiotherapy comes before SBRT. Dose guidelines to OARs in SBRT treatment is based upon AAPM Task Group 101 .
2.2 Radiotherapy for prostate gland and pelvic or retroperitoneal metastatic lymph node (GTVnd)
After the IMRT is administered, all patients have to undergo a contrasted CT simulation of the pelvis or abdomen of 5-mm-slice thickness in a supine position. Then, CT images will be transferred to the treatment planning system for contouring the target volume and OARs. Critical normal structures encompass the small bowel, bladder, femoral head, rectum, spinal cord, prostatic urethra (if visualised), bulb of urethra, kidney, etc. OARs should be contoured according to the pelvic normal tissue contouring guidelines of Radiation Therapy Oncology Group (RTOG) . This protocol offers dose guidelines to OARs based on previous published RTOG trials .
The gross tumor volume (GTV2) is contoured based on the MRI. GTV2 consist of the prostate and seminal vesicle glands. GTVnd is further confirmed by medical imaging, whether CT, MRI, 68-Ga PSMA PET/CT, etc. The clinical tumor volume (CTV) compromises of a 5 mm margin to the GTV2, GTVnd, pelvic/retroperitoneal lymphatic drainage area.
The superior border of the whole pelvis field extends to the L5-S1 interspace for N1 subgroup. The pelvic lymphatic drainage area includes bilateral iliac lymph nodes, external iliac lymph nodes, internal iliac lymph nodes, S1-S3 levels presacral lymph nodes and obturator lymph nodes. The superior border of the retroperitoneal area is 2–3 cm above the positive lymph nodes though not crossing the renal artery level. PTV-GTV2: GTV2 is based on a 5–10 mm uniform expansion, but only 5 mm for the posterior part to reduce any rectal irradiation. PTV-GTVnd for GTVnd should be delineated with an additional 5 mm margin and PTV-CTV for CTV should be also delineated with an additional 5 mm margin separately.
Four radiation dose levels are planned as dose-escalation: 39.6 Gy, 45 Gy, 50.4 Gy, and 54 Gy in 22 fractions, 25 fractions, 28 fractions, 30 fractions, respectively. Radiation therapy is delivered in 5 fractions per week. The initial two dose levels target whole pelvis/retroperitoneum, whereas the latter two dose levels act as a subsequent boost to the prostate, seminal vesicles and pelvic/retroperitoneal metastatic lymph nodes which will be added after reaching 45 Gy.
Dose escalation is conducted in a 3 + 3 design with dose levels of 39.6, 45, 50.4, and 54 Gy in 22, 25, 28 and 30 fractions respectively. A traditional 3 + 3 dose-escalation design is adopted (Fig. 2). Briefly, three participants are initially allocated the starting dose cohort. If no dose-limiting toxicity (DLT) is observed in any of the three participants, the dose can be escalated and the three new patients can be enrolled to receive the next level of radiation dose. Even if one participant develops DLT, then additional three participants will be allocated the same dose cohort. If there are multiple observations of DLT at any given dose level, the dose escalation will be stopped and the previous dose level will be identified as the maximal tolerable dose (MTD). In this trial, DLTs are defined as any Grade III/IV toxicities.
3. Radical prostatectomy
Surgery can be scheduled 4–8 weeks after the completion of radiation therapy, via a robot-assisted laparoscopic approach and extended pelvic/retroperitoneal lymph node dissection should be performed.
68-Ga PSMA PET/CT should be conducted before registration, radiotherapy, surgery, and 1 year after the surgery. The prostate specific antigen (PSA) level of the participants should be check monthly. After the completion of treatment during the study, participants will be given a follow up every 3 months or as needed clinically in the first 2 years, every 6 months in the next 3 years, and annually thereafter. Follow-up examinations include clinical assessment, contrast-enhanced MRI, CT, ECT or 68-Ga PSMA PET/CT. For tumour progression, treatment alternatives can be evaluated inter-disciplinarily considering abiraterone acetate, enzalutamide, reradiation therapy, chemotherapy or others.
Normally distributed continuous data is described by means of ± SD and 95% confidence intervals. Non-normal distributional continuous data is described by the median and range. Qualitative ones is described by percentage. bPFS and OS are estimated using the Kaplan-Meier method. Univariate and multivariable hazard ratios are calculated using the Cox proportion hazard model. For comparisons between the baseline variables, the χ2 test and Fisher’s exact test were performed. P values < 0.05 are considered statistically significant. Statistical analyses can be performed using SPSS software v18.0 or higher.