Assessing the safety and feasibility of metastasis-directed radiation and neoadjuvant hormone and radiation therapy followed by radical prostatectomy for treating oligometastatic prostate cancer: protocol for an open-label, dose-escalation, single-centre phase I clinical trial


 Background The systemic therapy is currently recommended for patients with oligometastatic prostate cancer, however the prognosis has not been satisfactory. Therefore, it is necessary to explore more effective treatment to improve the prognosis. Oligometastatic prostate cancer is a special subgroup in patients with advanced cancer. The paragrim of treatment is shifting to a more aggressive approach. Stereotactic body radiotherapy (SBRT) is an emerging treatment alternative for patients with oligometastases with minimal toxic effects. What’s more, accumulating studies have proved safety as well as feasibility of radical prostatectomy and local or metastasis-directed radiotherapy for oligometastatic patients. The aim of this phase I prospective trial is to demonstrate the early evidence of safety and feasibility of metastasis-directed radiation and neoadjuvant hormone and radiation therapy followed by radical prostatectomy for treating oligometastatic prostate cancer Methods The patients with oligometastatic prostate cancer received 1 month of neoadjuvant androgen deprivation therapy (ADT) followed by metastasis-directed radition and abdominal or pelvic radiotherapy. Then offer radical prostatectomy at the interval of 4-8 weeks after radiotherapy and adjuvant ADT for 2 years. The primary endpoints of the study are safety as assessed by CTCAE 5.0 grading scale and intraoperative and postoperative day-30 morbidity. Secondary endpoints include the positive rate of post-operative edge, biochemical progression-free survival (bPFS), postoperative continence and sexual function recovery, quality of life (QoL), overall survival (OS) and adverse reactions of ADT. Discussion This is the first, phase I trial assessing the safety and feasibility of metastasis-directed radiation and neoadjuvant hormone and radiation therapy followed by radical prostatectomy treatment for patients with oligometastatic prostate cancer. If positive, the results of this trial may help to design subsequent phase II trials exploring the role of metastasis-directed radiation and neoadjuvant hormone and radiation therapy followed by radical prostatectomy in the randomized controlled study.


Background
The systemic therapy is currently recommended for patients with oligometastatic prostate cancer, however the prognosis has not been satisfactory. Therefore, it is necessary to explore more effective treatment to improve the prognosis. Oligometastatic prostate cancer is a special subgroup in patients with advanced cancer. The paragrim of treatment is shifting to a more aggressive approach.
Stereotactic body radiotherapy (SBRT) is an emerging treatment alternative for patients with oligometastases with minimal toxic effects. What's more, accumulating studies have proved safety as well as feasibility of radical prostatectomy and local or metastasis-directed radiotherapy for oligometastatic patients. The aim of this phase I prospective trial is to demonstrate the early evidence of safety and feasibility of metastasis-directed radiation and neoadjuvant hormone and radiation therapy followed by radical prostatectomy for treating oligometastatic prostate cancer

Discussion
This is the first, phase I trial assessing the safety and feasibility of metastasis-directed radiation and neoadjuvant hormone and radiation therapy followed by radical prostatectomy treatment for patients with oligometastatic prostate cancer. If positive, the results of this trial may help to design subsequent phase II trials exploring the role of metastasis-directed radiation and neoadjuvant hormone and radiation therapy followed by radical prostatectomy in the randomized controlled study. 4 Background Prostate cancer (PCa) is the most common malignancy in men with an incidence rate of 29.3%. It is also the leading cause of death among cancer entities with a mortality rate of 7.6% globally [1].
Traditionally, radical prostatectomy is recommended as the standard therapy for localized prostate cancer. However, if the patients present with evidence of metastasis even if it is a single positive lymph node, aggressive treatments are precluded and systemic therapies such as androgen deprivation therapy (ADT) or chemotherapy are strongly recommended [2,3]. The current paradigm for treatment of advanced PCa is shifting towards more aggressive approach. The last two decades have witnessed a great progress in surgical and radiation techniques, such as robotic-assisted laparoscopic radical prostatectomy (RALP), intensity modulated radiation therapy (IMRT) and stereotactic body radiotherapy (SBRT). The emerging evidence indicate that the various aggressive approaches might provide survival benefits to patients with lymph node-positive and metastatic PCa [4][5][6][7][8].
Oligometastatic prostate cancer has been proposed as an intermediate stage of cancer spread between the localized disease and the widespread metastases. The curative treatment of oligometastatic prostate cancer actually requires a 3-step method: firstly, local consolidate therapy for the primary tumor; secondly, metastasis-directed therapy and; thirdly, systemic ADT or chemotherapy. With the development of DaVinci Robotic System, RALP has become more clinically significant for tumor control, functional outcomes and complication manipulation for locally advanced prostate cancer [9,10]. As an increasingly safe and effective treatment, the value of metastasisdirected radiation therapy remains promising for oligometastatic Pca [10]. In this study, we propose the use of radiation therapy for local as well as distant metastatic lesions thus changing the current status of oligometastasis into advanced prostate cancer for further treatment.
For patients with locally advanced prostate cancer, multimodality approach including radical prostatectomy with lymph node dissection and adjuvant long-term ADT plus radiotherapy is strongly recommended to minimize the recurrence risk [2,3]. In addition, adverse pathological features from radical surgery can identify patients who are likely to benefit from adjuvant radiotherapy. The phase III randomized controlled trials have demonstrated that locally advanced PCa patients can benefit from adjuvant radiotherapy in terms of tumor control and biochemical progression [11][12][13].
Randomized clinical trials of other malignancies such as rectal cancer have demonstrated safety and efficacy of neoadjuvant radiotherapy with tolerable toxicities [14]. Compared to postoperative radiation, preoperative therapy has the following advantages. Firstly, there is improved oxygenation of target tissues in neoadjuvant setting that decreases the radio-resistance without altering the blood supply of prostate [14]. Secondly, the neoadjuvant radiation requires a lower dose to achieve the equivalent level of tumor control which helps in reducing potential side effects [15]. Thirdly, preoperative radiation can decrease viable cancer cells at the time of radical prostatectomy and sterilize extra-prostatic clonogenic stem cells in close proximity to the gland leading to reduction in probability of local recurrence [16]. Furthermore, the metastasis-directed radiation can decrease the total tumor burden of oligometastatic PCa patients. Pre-operative radiation partially increases down-staging, and incorporation with neoadjuvant ADT further decreases the tumor stage and also aims micrometastasis. Furthermore, the duration of treatment becomes shorter when radiation is given preoperatively.
Therefore, randomized controlled trials are required to address the promising effects of metastasisdirected radiation and neoadjuvant hormone and radiation therapy plus radical prostatectomy for oligometastatic prostate cancer. Hereby, we present a phase I study in order to demonstrate early evidence of safety and efficacy of the intervention.

Methods/design
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.

Objectives
Primary endpoint The primary endpoints of the study were safety of radiotherapy as assessed by

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) [18]. This protocol offers dose guidelines to OARs based on previous published RTOG trials [19]. 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 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.

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.
Follow-up 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 interdisciplinarily considering abiraterone acetate, enzalutamide, reradiation therapy, chemotherapy or others.

Statistical analysis
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.
For patients with oligometastatic prostate cancer, multimodality approach including consolidate local treatment, metastasis-directed therapy and systemic hormonal therapy might be the best to minimize the risk of recurrence. Some other metastatic cancers have shown improved clinical outcomes with local aggressive approach for primary tumor and the cytoreductive radical prostatectomy may derive similar benefits in oligometastatic PCa by delaying the aggressive tumor burden [20][21][22][23]. Several retrospective studies have found that the safety and efficacy of radical prostatectomy in limited metastatic PCa with complication rates is comparable to locally advanced Pca [9,[24][25][26][27]. The first multicenter retrospective study include106 patients with M1a-b PCa reported perioperative complication (all Clavien 1-3) rates of 29% [9]. Gandaglia et al. reported 7-year clinical progression-free rates of 45% and cancer-specific mortality-free survival rates of 82% in a cohort of 11 patients with oligometastatic Pca [25]. Studies have shown the advantages of pre-operative radiotherapy over post-operative radiation in other malignancies [28,29]. Neoadjuvant radiotherapy, to some extent, could increase down-staging before radical prostatectomy and decrease the complexity of the surgery.
Furthermore, increasingly large number of data has shown that adoption of SBRT as metastasisdirected therapy for metastatic lesions of oligometastatic PCa provides excellent local control with minimal toxicity [30][31][32][33]. All of these studies reported zero (0%) Grade 3 toxicities using CTCAE 5.0 criteria of adverse effects and > 95.5% local control rates.
Based on these promising results, our trial may represent an optimal treatment modality for oligometastatic prostate cancer. To acknowledge, our study is the first prospective trail to assess the safety and feasibility of metastasis-directed radiation and neoadjuvant hormone and radiation therapy followed by radical prostatectomy for oligometastatic PCa. Our project is expected to maximize the total tumor control outcomes while minimizing perioperative as well as long-term complications.

Conclusion
Metastasis-directed radiation and neoadjuvant hormone and radiation therapy followed by radical prostatectomy for treating oligometastatic prostate cancer is worth exploring.