The efficacy of Stereotactic body radiation therapy and the impact of systemic treatments in oligometastatic patients from prostate cancer

Abstract Background Diagnoses of oligometastatic prostate cancer (PC) increased in the recent years thanks to the advancement in imaging and more effective systemic therapies. Here we evaluate the efficacy of Stereotactic Body Radiation Therapy (SBRT) in oligorecurrent and oligoprogressive PC. Methods We included patients with a maximum of five metastases diagnosed in a maximum of two target organs. Concomitant treatment with hormonal therapies or chemotherapies was allowed. End points of the present study were the outcome in terms of Local control of treated metastases (LC), out‐field progression free survival, overall progression free survival (PFS), and overall survival. Results We included in the analysis 64 patients treated on 90 metastases. Fifty (78.1%) patients were treated on lymph nodes, 2 (3.1%) patients simultaneously on lymph node and bone while 10 (15.7%) patients on bone only. Lung metastases were treated in 2 (3.1%) patients. Thirty‐seven (57.81%) were without androgen deprivation therapy when treated with SBRT. Median follow‐up was 15.2 months. Rates of LC at 6‐, 12‐, and 18‐ months were 94%, 88%, and 84%, respectively. Oligoprogressive patients compared to oligorecurrent (HR 9.10, P = 0.049) and prolongation of time from diagnosis of metastases to SBRT (HR 1.03, P = 0.047) were associated with worse LC. Median PFS was 6.6 months (range 1.1‐42.4). Castration resistant patients experienced worse PFS compared to castration sensitive group (HR 2.12, P = 0.021). Conclusions Stereotactic body radiation therapy seems to be an effective treatment for metastases from PC. Prospective trials are necessary to better define selection of patients and to evaluate combination of SBRT and new systemic drugs in castration resistant patients.


| INTRODUCTION
In 1995, Hellman and Weichselbaum coined the term "oligometastasis" as an intermediate state between localized tumor and widespread diffuse disease. 1 Since that year several studies focused on the attempt to understand the benefit from local therapies on isolated metastases, with the conviction that oligometastatic patients are affected by a disease with a biology different from the classic concept of metastasis. 2 Prostate cancer (PC) can metastasize to different sites. According to Harada et al 3 , in an autoptic series on 136 patients, 36% and 32% were identified with one and two bone lesions, respectively. The number of metastases that defines the oligometastatic state in PC is still unclear. A wide variability exists in the recent literature. Some studies limited the number of metastases to five 4 and the majority of published trials included a maximum of three lesions. 5,6 Singh et al 7 reported that a number of metastases limited to five lesions, developed during follow-up after curative treatment of primary tumor, was significantly associated to better 5-year survival (73% vs 43% of patients with more than five metastases). Diagnoses of oligometastatic PC increased in the recent years; possible causes of this increase include the advancement in imaging with new PET tracers, and the longer survival improved by more effective systemic therapies. [8][9][10] According to the study of Sobol et al, 11 among 2466 men underwent choline-PET for suspected relapse, 134 (67%) were diagnosed with metastatic disease, (25% with axial or appendicular bone, and 75% with recurrences in the soft tissue]. De Bruycker et al analyzed prospectively 208 patients candidate to PET scan and showed that 153 patients (74%) had low-volume recurrence, defined as isolated local recurrence or with ≤3 metastases (with or without local recurrence). Among 153, 119 had only metastatic recurrence. 12 Historically, PC with any number of metastases was treated with systemic therapy, more commonly androgen deprivation therapy (ADT). Optimal management of oligometastatic patients is still to be defined. No real advantage from systemic treatments has been demonstrated in early recurrent PC. According to Duchesne et al, 13 in the TOAD trial there was no improvement of survival from immediate ADT in PSA-recurrent patients (P = 0.10). Gravis et al analyzed patient subgroups from the CHAARTED and GETUG-AFU15 according to metastatic burden. While the analysis showed survival benefit from adding immediate docetaxel to ADT in high volume patients, no benefit was observed for low volume disease with HR of 1.03 (95% CI: 0.77; 1.38). The role of local approaches in oligometastatic PC patients has been investigated recently in few reports. [14][15][16] Decaestaker et al 17 treated 50 patients with 70 metastatic lesions from PC; the authors included hormone sensitive patients with up to three synchronous metastases in bones or lymph nodes. Local control was reached in 100% of sample and median PFS was 19 months with ¾ of patients recurring with a maximum of three metastases. Here we evaluate the efficacy of Stereotactic Body Radiation Therapy (SBRT) in oligorecurrent and oligoprogressive PC and the impact of systemic therapies on the behavior of disease.

| Study population
We included in this single institution analysis patients with histologically confirmed diagnosis of prostate adenocarcinoma, treated with surgery +-adjuvant/salvage radiotherapy (RT) or radical RT, which developed metachronous metastases during follow-up from 2009 to 2016. All cases were presented to and approved by the multidisciplinary uro-oncology team. The local ethics committee approved the analysis. Patients were candidate to SBRT if a maximum of three metastases with a maximum diameter of 5 cm were diagnosed in 1-2 organs (eg bone and lymph node). Concomitant treatment with hormonal therapies or chemotherapies was allowed. All patients were staged with 11c-choline PET or CT scan together with 99mTc-bone scan. The study was conducted in accordance with Good Clinical Practice guidelines, the ethical principles of the Declaration of Helsinki and local regulations. Exclusion criteria were patients with diagnosis of synchronous metastases.

| Techniques of radiotherapy
The clinical target volume (CTV) was equal to gross tumor volume (GTV) and was delineated on simulation CT imaging, coregistered with MRI scan or PET scan when available. In-vein contrast for CT was used in case of treatment of lymph node metastases. In case of disease located into organ subject to internal movement (such as lung), patients were simulated with 4D-CT scan. All patients were positioned supine, with a thermoplastic mask, both for abdomen and pelvis. An isotropic margin of 5-10 mm, depending on disease site and dimensions, was added to CTV to obtain the planning target volume (PTV). In case dose constraints for organs at risk were not met, dose to PTV was deescalated. All patients were treated with Volumetric Modulated Arc Therapy technique. The patient's position was evaluated daily with Cone-beam CT imaging before each treatment session. Patients treated with systemic therapy were submitted to SBRT for comparison on new isolated sites of disease (Oligorecurrence) or for progression of few sites while the remaining were controlled by systemic therapy (Oligoprogression).

| Response assessement
First evaluation was planned 3 months after the end of the SBRT and then every 3 months for the first year and every 6 months from the second to the fifth year. Clinical evaluation and PSA values were obtained for every follow-up visit. Diagnostic imaging (CT, Choline-PET or MRI scan) was planned at physician choice. In general reassessments with imaging were planned in case of three rising PSA values after response or in case of PSA rise above the pre-SBRT value or in case of new potentially disease related symptoms. Tumor response was classified according to European Organization for Research and Treatment of Cancer Response Evaluation Criteria In Solid Tumors (EORTC-RECIST) criteria version 1.16. PET Response Criteria in Solid Tumors (PERCIST) 18 were used to evaluate metabolic response in patients who underwent PET scan for restaging. Globally castration resistant patients' were evaluated after treatment according to Prostate Cancer Clinical Trials Working Group 3 (PCWG3). 19

| Statistical analysis
Data were collected and analyzed retrospectively. End points of the present study included the outcome in terms of local control of treated metastases (LC), out-field progression free survival (OF-PFS), progression free survival (PFS), and overall survival (OS). Local control was analyzed at patient's level and defined as the time from the beginning of SBRT to the infield progression of treated metastases or last follow-up. Outfield progression free survival was defined as the time from the SBRT to the onset of new metastases. Additionally PFS was defined as the time from SBRT to the evidence of in-field or out-field progression or increase of PSA. Overall survival was calculated from the SBRT to either death or last followup. Univariate analysis was performed with the log-rank test, and Cox proportional hazards regression was used to estimate hazard ratios (HR). Multivariable Cox regression analysis was performed to evaluate the association between clinical factors and survival, with a significance level of P < 0.05. Statistical calculations were performed using STATA, version 14 (StataCorp 2015, College station, Texas: StataCorp LP.).

| RESULTS
A total of 64 PC patients with 90 metastases were treated with SBRT. Patients' characteristics are summarized in Table 1. Median age was 71.8 years (range 51.3-82.9) and median PSA at first diagnosis (iPSA) was 9.95 ng/mL (range 3.7-146). Forty-eight (75%) patients were treated on primary tumor with radical surgery while 5 (7.81%) patients underwent radical RT. The remaining patients underwent ADT (7.81%) or high intensity focused ultrasound ( Radiotherapy was delivered with a median dose of 42 Gy (range 18-60) in 2-8 fractions. Median dose per fraction was 7.5 Gy (range 5-12). Thirty-seven (57.81%) were without ADT when treated with SBRT. Twenty-seven patients were treated with ADT when submitted to radiation. Nineteen (29.7%) patients were classified as castration-resistant when treated with SBRT on metastases. Treatment's characteristics are summarized in Table 2.
Median follow-up time was 15.2 months (range 3-101.4). Best radiologic response after SBRT was classified as complete response in 41 (64.1%) patients, partial response in 10 (15.6%) patients, and stable disease in 2 (3.1%) patients. Eight patients didn't performed radiological examination for evaluation of response and were evaluated only with PSA value. Overall median value of nadir PSA (nPSA) reached after SBRT was 1.64 ng/mL (range 0-45.05). Median nPSA in patients without progression after RT was 0.39 ng/mL (range 0.01-5.8). Biochemical response was observed in 25 patients.
Globally 44 (68.7%) patients had in-field or out-field progression of disease after SBRT with a median PFS of 6.6 months (range 1.1-42.4). Rates of PFS at 6-, 12-, and 18-months were 70% (95% CI: 56%-80%), 38% (95% CI: 25%-51%), and 25% (95% CI: 13%-38%) as in Figure 2. Analysis of correlation between risk factors and PFS is summarized in Table 4. Castration resistant patients metastasis-directed therapy for oligometastatic PC. The analysis showed that the median ADT-free survival was 13 months for the surveillance and 21 months for the treatment group (P = 0.11). 21 Control of limited burden of disease could be a relevant point in PC patients, in whom the number of metastases are considered an important prognostic factor. 22,23 Globally we observed control of treated disease for a median time of 14.1 months; the time was prolonged to 15.9 months in patients who didn't experienced in-field progression. Oligoprogressive patients seem to be characterized by a worse LC, however this data could be affected by imbalance in the sample, being only two patients in oligoprogression. Time to SBRT correlated to the response to local treatment, indeed the effect is quite light with an increased risk of 3%. Main question is the identification of patients actually oligometastatic who can benefit from SBRT as local approach. In our study, PFS value at 18 months was 25%, with high percentiles reaching 38%. Data are in line with the one reported for other solid tumor, about 35% of PFS at 2 years. 24 The majority of our patients relapse out-field after 18 months (63%) with about 50% after the first year. The addition of systemic treatment to SBRT seems to not affect the out-field progression in our sample. These results confirm the need to better understand the selection of patients who can benefit from SBRT or the advantage to associate According to our analysis, PFS seems to be worse in castration resistant PC. One year PFS rates were 46% (29%-61%) for ADT sensitive patients vs 16% (2%-40%) for castration resistant patients. For several years the only available treatment for castration resistant PC was chemotherapy, in particular docetaxel. Only in the recent decade the introduction of new generation hormonal therapies improved outcome of this subset of patients. The efficacy of abiraterone and enzalutamide has been proved by several prospective randomized trials, both in pre and postchemotherapy setting. [26][27][28][29][30][31] The AFFIRM trial 30 that investigate the use of Enzalutamide postdocetaxel demonstrated a radiographic PFS (rPFS) of 8.3 months against 5.4 months of placebo. The COU-AA-301 31 explored the efficacy of abiraterone in the same setting and demonstrated a rPFS 5.6 (2.0 in placebo). Higher rates of PFS are reported by trials of prechemotherapy setting (rPFS of 16.5 months of COU-AA-302 trial 27 and median not reached in PREVAIL trial 28 ). The castration resistant patients treated in our study reached a median rPFS of 8.4 months. Patients diagnosed as castration resistant when treated with SBRT are more likely to have subclinical disease that becomes evident during posttreatment follow-up. However the role of local treatment in metastatic castration resistant prostate cancer patients has not been investigated, including the addition of new generation hormonal therapy to SBRT.
The present study is limited by several issues, including its retrospective nature and the short duration of follow-up, due to which we were not able to analyze the impact on overall survival.

| CONCLUSIONS
Our results confirm that SBRT in an effective treatment for oligorecurrent and oligoprogressive metastases from PC. Ablative RT could be beneficial in the oligometastatic setting where the treated metastases can sometimes be the only burden of disease. However studies of association of SBRT with systemic therapies, including new generation hormonal therapy, are necessary. The combination of new hormonal therapy and SBRT could potentially give the best results in selected patients.