Oligometastases from prostate cancer: local treatment with stereotactic body radiotherapy (SBRT)

Therapy concepts in prostate cancer (PC) exist for local, advanced locoregional and metastatic diseases, but the situation for non-symptomatic oligometastatic disease remains unclear [ 1]. A specific subgroup of patients presents with few lesions, whereas others develop rapid progression in multiple sites. For the first group, the term “oligometastases” is used to define five or less metastatic lesions per population. Therapeutically recommended are either a surveillance strategy in the absence of symptoms and slow rise of PSA level, or palliative androgen suppression in case of rapid PSA level rise with a doubling of PSA in less than 3 months or when symptomatic metastasis occur [ 2]. Because androgen deprivation therapy (ADT) is associated with a marked reduction in quality of life, current NCCN guidelines version 3.2016 suggest a surveillance strategy in case of asymptomatic metastases. Furthermore, randomized trials for metastatic PC have shown a superiority of early docetaxel-based chemotherapy combined with ADT androgen suppression [ 3, 4]. However, a not negligible number of grade 3–4 toxicities developed in patients undergoing this aggressive combined regimen. As various retrospective studies suggest that the occurrence of isolated metastases could potentially identify a subgroup of patients with a better prognosis despite systemic spread, this subgroup of patients might present a population that could benefit from a regional treatment [ 5]. The distinction between manifest polymetastases and oligometastases has been a central part of the oncological treatment strategy for years, for example in breast cancer, melanomas, sarcomas, renal cell and colorectal carcinomas [ 6– 9]. The local treatment of liver metastases in oligometastatic colorectal cancer, for instance, leads to a significant life-prolongation, as does the local treatment of sarcoma metastases deriving from different localizations [ 9].

Retrospective studies discussing the treatment of solitary or few metastases in patients with PC suggest an improvement of biochemical and clinical relapse-free survival, especially in lymph node and bone metastases [ 10].

The boundary between oligometastatic and polymetastatic disease varies from three to five metastases [ 1, 5, 11, 12]. The published data on local metastasis-directed therapy describe a progression-free survival (PFS) between 12 and 24 months [ 1]. The key to successful local treatment of oligometastasized patients is precise imaging. For prostate cancer, almost all published studies thus far used ¹¹C–choline PET for staging [ 1]. Particularly for the detection of very small lymph nodes, this technique has a low sensitivity of <10% [ 13, 14]. Hence, the probability of under-staging is enormous. In addition, a PSA level of at least 1–2 ng/ml is currently recommended in order to have a good chance of detecting tumor affected regions. ⁶⁸Ga-Prostate specific membrane antigen (PSMA)-PET seems to be significantly more sensitive and specific [ 15, 16]. Here, significant findings are possible with a PSA level starting as low as 0.2 ng/ml. Afshar-Oromieh et al. published sensitivity levels of 76.6% and very high specificity levels of up to 100% [ 17]. Only recently, we have shown a highly significant benefit of ⁶⁸Ga-PSMA for staging prior to radiation therapy [ 18]. Currently, there are no prospective data for the treatment of oligometastatic PC using PSMA PET for staging. However, a retrospective case collection of Demirkol et al. describes significant therapy changes due to the high diagnostic value of ⁶⁸Ga-PSMA-PET [ 19].

Since there are currently no evident treatment recommendations for the subgroup of oligometastasized PC patients due to limited knowledge about the importance of aggressive local treatments, different therapeutic strategies are currently in use, including continuous ADT, intermittent ADT, high-dose radiotherapy (RT) with or without ADT, surgery and surveillance strategies. This retrospective study investigates PC patients treated for oligometastatic disease with high-dose RT to the metastatic lesions analyzing biochemical PFS (PSA-PFS), the time to initiation of ADT, the local control rate (LCR) and distant PFS (DPFS).

The aim of this study was to evaluate the impact of SBRT in oligometastasized PC patients. We evaluated 15 patients with 20 bone metastases cases undergoing locally ablative RT with a curative intent. We showed a high LCR with doses of EQD2 (equivalent dose in 2 Gy fractions) of around 100 Gy. We could demonstrate a beneficial risk-benefit profile with very low rates of side effects and high local control of the irradiated lesions.

Since oligometastasized PC patients represent a special subgroup of patients with long-term overall survival, locally ablative treatments seem justified especially to delay ADT and to spare patients from ADT-related side effects. As SBRT of individual metastases has shown a very good local control in several prospective and retrospective studies, Decaestecker et al. initiated a study comparing SBRT of ¹¹C–choline PET-CT positive metastases to an active surveillance strategy [ 12]. The influence of the ablation of macroscopic metastases concerning further disease process will be investigated.

In the present evaluation, we found a median PSA-PFS of 6.9 months. Only in six cases, PSA failure was observed after 12 months, whilst in 14 cases PSA-failure was detected within the first 12 months. A single arm prospective study showed similar results, in which oligometastatic PC patients with up to three metastases were treated by a stereotactic RT [ 11]; after 2 years, only 18 out of 50 patients were tumor-free and seven other patients were treated one to three additional times with a stereotactic RT and then remained tumor-free until the end of the study. The median PFS was reported at 19 months; LCR was 100%. Given that distant metastasis occurred in 31 patients, it could reasonably be assumed that most patients were understaged, and thus that patients already were already at least microscopically polymetastasized at the beginning of RT.

Three of our 15 patients had concomitant ADT. Due to the fact that the start of ADT was not consistent within the patient cohort, the PSA-PFS data should be interpreted with caution. The combination of a locally ablative RT to the visible lesions with concomitant ADT was studied in a prospective single-arm Spanish-Swiss study [ 22]; in 50 patients, a PFS of 54%, a clinical PFS of 58% and an OS of 92% after a median time period of 30 months was achieved. ADT was not standardized and was given for a median time of 12 months (range 3–34 months). The ideal duration of ADT is frequently debated, in primary as well as in an adjuvant RT setting. One cannot directly compare the indication for ADT between the primary and oligometastasized situation. However, if we believe in the concept of an oligometastasized stage, an approach analog the primary treatment situation appears to be justified given the fact that there is a local problem with one known separate accumulation of tumor cells. Jones et al. have demonstrated an absolute survival benefit of 4% at 10 years for the combination of a four-month ADT and RT of the prostate compared with RT alone [ 23]. Importantly, distant metastases occurred significantly less frequently in the ADT group. A short-term ADT is apparently sufficient for the treatment of subclinical metastasis in patients with intermediate-risk PC. In contrast, in the high- and very high-risk situation, long-term ADT of least 24 months seems to be superior to short-term ADT [ 24]. Not only is the effectiveness of RT with or without ADT proven, but also the importance of local ablative therapy with sustained ADT. Widmark et al. and later Warde et al. described a significant OS benefit for the combination of RT and lifelong ADT compared to ADT alone [ 25, 26]. They concluded that local therapy improves the efficacy of androgen suppression significantly. Whether this conclusion applies to the oligometastatic situation has not yet been evaluated prospectively. We found no difference between the groups with and without ADT-related to PSA-PFS and the time to initiation of ADT or intensification of systemic therapy, however, our patient cohort is small.

Biologically, oligometastases are defined as a state in which the patient shows distant relapse in only a limited number of regions. In this case, the patient may benefit from a local tumoricidal treatment of all noticeable lesions. However, many patients with an initial oligometastasized stage develop more metastases and progress to a polymetastasized stage. To improve the patient selection for the local therapy in oligometastasized patients vs. systemic therapy in polymetastasized patients, biological predictors of progression are needed.

The limited effectiveness of treatments of oligometastases may be due to inability to recognize all present metastatic lesions and the situation might be staged as oligometastatic when in reality it is already widespread cancer [ 27]. There is a second group of oligometastasized patients in addition to the aforementioned patient group as ADT or other systemic therapies become more widely applicable. These are patients who had widespread metastases that were mostly eradicated by systemic agents. Systemic therapy can fail to destroy tumor cells, for example, due to the presence of drug-resistant cells or due to the tumor site. Thus, effective chemotherapy may fail to be curative because of only a few metastases. This example highlights the importance of markers specifically related to where the malignant cells are located. Oligometastasized and poly-metastasized tumors require different therapy schemes. New techniques of RT may allow curative treatment of such oligometastases either alone or in combination with systemic therapy. Their effectiveness will be critically dependent on the specificity and sensitivity of tumor imaging.

Conclusions should be drawn with caution because the presented study has some limitations. The analyzed patient group was very small, the follow-up is rather small and the study has a retrospective nature. Therefore, publication of all treatment concepts with an SBRT approach seem appreciated to give treating physicians as much information as possible to treat these patients adequately. Additionally, cases should be encompassed in a multi-institutional pooled analysis to confirm our results based on larger patient numbers.

We could show that SBRT of bone metastases is a highly effective therapy with an excellent risk-benefit profile. However, PFS was limited due to a high distant failure rate, implying the difficulty for patient selection for this oligometastatic concept. Research on biomarkers besides PSA identifying purely oligometastasized patients would be of great benefit. SBRT offers high local cancer control rates in bone oligometastases of PC and should be evaluated with the aim of curation or to delay modification of systemic treatment.