The literature on metastasis-directed therapy for oligometastatic prostate cancer (PCa) recurrence consists of small heterogeneous studies. This study aimed to reduce the heterogeneity by pooling individual patient data from different institutions treating oligometastatic PCa recurrence with stereotactic body radiotherapy (SBRT). We focussed on patients who were treatment naive, with the aim of determining if SBRT could delay disease progression. We included patients with three or fewer metastases. The Kaplan-Meier method was used to estimate distant progression-free survival (DPFS) and local progression-free survival (LPFS). Toxicity was scored using the Common Terminology Criteria for Adverse Events. In total, 163 metastases were treated in 119 patients. The median DPFS was 21 mo (95% confidence interval, 15–26 mo). A lower radiotherapy dose predicted a higher local recurrence rate with a 3-yr LPFS of 79% for patients treated with a biologically effective dose ≤100 Gy versus 99% for patients treated with >100 Gy (p = 0.01). Seventeen patients (14%) developed toxicity classified as grade 1, and three patients (3%) developed grade 2 toxicity. No grade ≥3 toxicity occurred. These results should serve as a benchmark for future prospective trials.
This multi-institutional study pools all of the available data on the use of stereotactic body radiotherapy for limited prostate cancer metastases. We concluded that this approach is safe and associated with a prolonged treatment progression-free survival.
Keywords: Prostatic neoplasms, Neoplasm metastasis, Oligometastasis, Neoplasm recurrence, Radiosurgery, Stereotactic body radiotherapy.
Metastasis-directed therapy is a lesion-targeted approach reserved for a subset of patients with a limited number of metastases (typically three or fewer or five or fewer), so-called oligometastases, and it aims to control an intermediate state of cancer spread while avoiding or delaying the toxicity associated with the use of systemic therapies  . A few small studies using stereotactic body radiotherapy (SBRT) for oligometastatic prostate cancer (PCa) recurrences have been published  and , showing promising progression-free survival rates with low toxicity. SBRT is defined as external beam radiotherapy used to deliver a high dose of radiation very precisely to an extracranial target. Treatment is typically given as a single dose or a small number of fractions  .
The current study pools all of the available data into a sufficiently large data set to provide benchmark conclusions regarding overall effectiveness and toxicity. This is a retrospective multicentre analysis of PCa patients diagnosed with three or fewer metachronous metastases treated with SBRT. The study was approved by the central ethics committee at Ghent University Hospital (EC2014/0199) and had local approvals from each hospital at which this was required. Inclusion criteria were as follows: histologically proven diagnosis of PCa, biochemical relapse of PCa following radical local prostate treatment, and detection of up to three N1 or M1a/b/c lesions. Patients were excluded if they had serum testosterone levels <50 ng/ml at the time of detection of metastases, had received androgen deprivation therapy (ADT) for >12 mo at the time of SBRT, had a biochemical relapse while on active treatment with ADT (including luteinising hormone-releasing hormone [LHRH] agonists, LHRH antagonists, antiandrogens, maximal androgen blockade, or oestrogens), or had received previous treatment with a cytotoxic agent for PCa.
Patients were staged with 18F-fluorodeoxyglucose (n = 24) or choline positron emission tomography (n = 92) with coregistered computed tomography or magnetic resonance imaging (n = 3) for the detection of metastatic disease. Following restaging, patients underwent SBRT to all metastatic sites. SBRT was defined as a radiotherapy dose of at least 5 Gy per fraction to a biologically effective dose (BED) of at least 80 Gy using an α:β ratio of 3. BED is a measure of the true biologic dose delivered by a particular combination of dose and fractionation, taking into account the radiation sensitivity of the tissue (α:β ratio). It is used to indicate and compare quantitatively the biologic effect of radiotherapy treatments of varying dose and fractionation  . The metastatic sites were irradiated with the following BEDs: 80–99 Gy (n = 29), 100–119 Gy (n = 20), 120–139 Gy (n = 66), and >140 Gy (n = 4). Technical details on SBRT schedule, delineation, planning, quality assurance, and follow-up schedules were previously published separately by the authors , , , , , , and .
The primary end point was distant progression-free survival (DPFS), defined as the absence of new metastatic lesions. Local progression was defined as tumour progression within the irradiated planning target volume. The Kaplan-Meier method was used to estimate rates of DPFS, local progression-free survival, and overall survival (OS). Calculations were done from the start of SBRT. Potential prognostic factors , , and  were examined using univariate proportional hazards regression from the start of SBRT to the time of distant and local progression, respectively. All statistical analyses were performed using SPSS v.21 (IBM Corp, Armonk, NY, USA), with p < 0.05 considered significant. Late toxicity was evaluated and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v.4.0  . Late effects were designated as events occurring >3 mo following treatment or as an event lasting >3 mo after treatment.
A total of 119 patients were treated for 163 metastatic lesions: lymph nodes (N1 in 53, M1a in 19), bone (M1b in 43), or viscera (M1c in 4) ( Table 1 ). The median follow-up for the entire cohort was 3 yr (interquartile range: 1.75–4). At last follow-up, 73 patients experienced distant progression. The median DPFS was 21 mo (95% confidence interval [CI], 15–27) with 70% of patients having three or fewer metastases at the time of progression ( Fig. 1 ). The 3- and 5-yr DPFS was 31% and 15%, respectively. None of the variables were significant on univariate analysis (Supplementary Table 1). Although not significant (p = 0.09), the median DPFS of SBRT versus SBRT and adjuvant ADT was 18 mo (95% CI, 17.1–18.8) compared with 25 mo (range: 18.3–31.6). The 3-yr- and 5-yr LPFS was 93% and 92%, respectively. A lower radiotherapy dose predicted for a higher local recurrence rate with a 3-yr LPFS of 79% for patients treated with a BED ≤100 Gy versus 99% for patients treated with >100 Gy (p = 0.01) (Supplementary Figure 1).
|Characteristics||All patients (n = 119)|
|Age at PCa diagnosis, yr|
|Median (IQR)||61 (56–65)|
|Follow-up from PCa diagnosis, yr|
|Median (IQR)||7.2 (5.0–9.3)|
|Primary therapy, n (%)|
|Radical prostatectomy alone||21 (17.6)|
|Radical prostatectomy with postoperative RT||37 (31.1)|
|Radical prostatectomy with postoperative RT and ADT||31 (26.1)|
|Radiotherapy and ADT||22 (18.5)|
|Radiotherapy alone||8 (6.7)|
|PSA at initial diagnosis, ng/ml|
|Mean (range)||18.1 (1.3–180)|
|Median (IQR)||10.7 (6.8–19)|
|EAU prognostic grouping at initial diagnosis, n (%)|
|Very high||30 (25.2)|
|Interval from diagnosis to metastases, yr|
|Mean (range)||5.0 (0.2–16.8)|
|Median (IQR)||4.7 (2.7–6.6)|
|PSA level at first documented metastases, ng/ml|
|Mean (range)||9.6 (0.1–116.7)|
|Median (IQR)||4.0 (1.6–8.8)|
|PSA DT at first documented metastases, mo|
|Mean (range)||5.6 (1.0–30.0)|
|Median (IQR)||3.9 (2.9–6.9)|
|No. of lesions at diagnosis of metastases, n (%)|
|One metastasis||86 (72.3)|
|Two metastases||22 (18.5)|
|Three metastases||11 (9.2)|
|Primary site of metastases, n (%)|
|Lymph nodes||72 (60)|
|Internal iliac||9 (8)|
|External iliac||17 (14)|
|Common iliac||6 (5)|
|Combination of nodal sites||7 (6)|
|Bones, n (%)||43 (36)|
|Viscera, n (%)|
|Node and/or bone and/or viscera, n (%)||2 (2)|
|Imaging modality at recurrence, n (%)|
|Choline PET-CT||92 (77)|
|FDG PET-CT||24 (20)|
|Adjuvant ADT, n (%)|
|Duration of ADT, mo, median (range)||2 mo (1–8 mo)|
ADT = androgen-deprivation therapy; EAU = European Association of Urology; FDG = fluorodeoxyglucose; IQR = interquartile range; MRI = magnetic resonance imaging; PCa = prostate cancer; PET-CT = positron emission tomography; PSA DT = prostate-specific antigen doubling time; RT = radiation therapy.
The treatment at time of first progression was palliative ADT (n = 33), a new course of SBRT (n = 35), salvage pelvic nodal dissection (n = 2), or chemotherapy (n = 3). The median time from first SBRT to the start of palliative ADT was 28 mo (95% CI, 16.2–69.7). Reasons for starting palliative ADT were biochemical progression (n = 2), oligometastatic progression (n = 18), or polymetastatic progression (n = 37).
Seven patients died from PCa, and one patient died from pancreatic cancer. The 3- and 5-yr OS was 95% and 88%, respectively. Late grade 1 and 2 toxicity was observed in 14% (n = 17) and 3% of patients (n = 3), respectively. The reported grade 2 toxicity was due to gastrointestinal complaints in patients treated for nodal metastases. No toxicity of grade ≥3 was observed.
The 3-yr DPFS of 31% is comparable with series reporting on oligometastatic recurrences of other primary tumours and to salvage lymph node dissection series for oligorecurrent PCa , , and . We acknowledge the inherent limitations of a retrospective analysis. Furthermore, the ADT-free survival outcome is exploratory because institutions had differing indications for commencing palliative ADT. However, this study represents the largest and only multi-institutional series to date reporting the safety and efficacy of SBRT for metastatic recurrences from PCa.
In conclusion, SBRT for oligometastatic PCa recurrence is safe and associated with a prolonged progression-free interval. This is likely to result in a clinically meaningful period without ADT in patients with metastatic disease, particularly if they are retreated with SBRT on development of further oligometastatic disease. This provides a strong justification for the evaluation of SBRT in prospective clinical studies.
Author contributions: Piet Ost had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Ost, De Meerleer.
Acquisition of data: Ost, Jereczek-Fossa, Van As, Zilli, Muacevic, Olivier, Henderson, Casamassima, Orecchia, Surgo, Brown, Tree, Miralbell, De Meerleer.
Analysis and interpretation of data: Ost, Jereczek-Fossa, Van As, Zilli.
Drafting of the manuscript: Ost, Jereczek-Fossa, Van As, Zilli.
Critical revision of the manuscript for important intellectual content: Ost, Jereczek-Fossa, Van As, Zilli, Muacevic, Olivier, Henderson, Casamassima, Orecchia, Surgo, Brown, Tree, Miralbell, De Meerleer.
Statistical analysis: Ost, De Meerleer.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Ost, De Meerleer.
Other (specify): None.
Financial disclosures: Piet Ost certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Piet Ost is a member of the Prostate Cancer Working Group of the European Association of Urology Young Academic Urologists. He is a senior clinical investigator of the Research Foundation - Flanders (Belgium) (FWO). Nick van As, Daniel Henderson, and Alison Tree gratefully acknowledge the support of the Royal Marsden/Institute of Cancer NIHR Biomedical Research Centre.
Funding/Support and role of the sponsor: None.
Appendix A. Supplementary data
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a Department of Radiotherapy, Ghent University Hospital, Belgium
b University of Milan and European Institute of Oncology, Milan Italy
c Department of Radiotherapy Royal Marsden NHS Foundation Trust, London, UK
d Department of Radiation Oncology, Geneva University Hospital, Geneva, Switzerland
e Cyberknife Center Munich Grosshadern, Munich, Germany
f Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
g Ecomedica Radioterapia, Empoli, Italy
Corresponding author. Department of Radiotherapy, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. Tel. +32 3322411; Fax: +32 93323040.
© 2015 Published by Elsevier B.V.