Progression-directed Therapy for Oligoprogression in Castration-refractory Prostate Cancer

Charlien Berghen, Steven Joniau, Piet Ost, Kenneth Poels, Wouter Everaerts, Karel Decaestecker, Karin Haustermans, Gae¨tan Devos, Gert De Meerleer
a Department of Radiation Oncology, University Hospitals Leuven, Leuven, Belgium;
b Department of Urology, University Hospitals Leuven, Leuven, Belgium;
c Department of Radiation Oncology, University Hospitals Ghent, Ghent, Belgium;
d Department of Urology, University Hospitals Ghent, Ghent, Belgium

In metastatic castration-refractory prostate cancer (mCRPC), state-of-the-art treat- ment consists of androgen biosynthesis inhibition (abiraterone), inhibition of the androgen receptor (enzalutamide), chemotherapy, or radium-223 in combination with androgen deprivation therapy (ADT). A subgroup of these patients show oligoprogression, with the progression of only a limited number of metastatic spots, while all other metastases remain controlled by ongoing systemic therapy. In a bi-institutional retrospective study, we tested the hypothesis that progression- directed therapy (PDT) targeting oligoprogressive lesions might defer the initiation of next-line systemic treatment (NEST). A total of 30 patients were diagnosed with mCRPC and experienced oligoprogression, defined as a total of three or fewer progressive lesions either at known metastatic sites and/or the appearance of new metastasis and/or local recurrence. All patients were under active ADT with or without second-line systemic treatment. All patients received PDT targeting the oligoprogressive lesions, while ongoing systemic treatment was maintained. There was median NEST-free survival of 16 mo (95% confidence interval [CI] 10–22) and progression-free survival of 10 mo (95% CI 6–15) with only minor radiotherapy- or surgery-related toxicity. These findings encourage further prospective trials.
Patient summary: In patients with metastatic castration-refractory prostate cancer, surgical treatment or high-dose radiation therapy directed to only the limited number of progressive metastatic spots, while all other metastases remained controlled by ongoing systemic therapy, led to substantial postponement of next-line systemic treatment in our study.

In metastatic hormone-sensitive prostate cancer (mHSPC) the sensitivity to castration will eventually disappear due to selection of castration-resistant clones, so the patient progresses to metastatic castration-refractory prostate cancer (mCRPC). Median survival in mCRPC is approximate- ly 35 mo [1], depending on different prognostic factors and the use of second- and third-line systemic treatment regimens, which come with a non-negligible financial cost and toxicity [2]. Clinical and iconographic progression (and to a lesser extent biochemical progression) traditionally implies a switch to next-line systemic treatment (NEST). A subgroup of mCRPC patients presents with oligoprogres- sion, defined as the appearance or progression of a limited number (typically a maximum of 3) of lesions while the majority of lesions are controlled by the ongoing systemic therapy [3]. This heterogeneous response to treatment reflects the heterogeneity of subclones within the different metastatic spots [4]. When oligoprogression occurs, only a minor fraction of the total disease burden progresses. The majority of the total disease burden is still sensitive to the ongoing systemic treatment. By using progression-directed therapy (PDT) targeting these oligoprogressive lesions, patients can possibly remain on their current systemic therapy, thereby delaying the need for NEST [5,6].
For this retrospective study, we identified patients from two institutional databases fulfilling the following criteria: all patients received PDT on all the oligoprogressive lesions, either metastasis-directed therapy (MDT) of stereotactic
In our study, oligoprogression was defined as the appear- ance or progression of up to three lesions as metastatic spots (N, M1a, M1b, and/or M1c) and/or local relapse/ disease in patients with mCRPC while under treatment with androgen deprivation therapy (ADT) with or without other systemic treatments. CRPC was defined as a rise in prostate-specific antigen (PSA) with testosterone level below 50 ng/dl, with proven documentation of testosterone serum castrate levels in all cases. The study was approved by the ethics committee of University Hospitals Leuven (S61314) and was conducted according to the Declaration of Helsinki. In total, 30 patients fulfilled the inclusion criteria and presented with 45 oligoprogressive lesions. Treatment of metastatic disease consisted of SBRT (n = 18), metasta- sectomy (n = 2), or fractionated radiotherapy (n = 7). Treat- ment of locoregional progression consisted of fractionated radiotherapy (n = 3). We calculated the time to NEST from the last day of radiotherapy or the day of surgery until the start of NEST. Progression-free survival (PFS) was calculated from the date of the multidisciplinary oncological board meeting on which the decision between PDT and NEST was made until clinical or biochemical progression in the case of PFS. At the time of initial diagnosis of prostate cancer, 47% of the patients had upfront bone metastases, and 53% received ADT as part of the initial treatment. Primary treatment consisted of surgery (n = 4), radiotherapy (n = 5), a combi- nation of both (n = 15), or ADT only (n = 6). Table 1 summarizes the patient and disease characteristics.
The imaging used to define the oligometastatic setting was, as expected, heterogeneous. Conventional imaging with computed tomography (CT) scan and bone scans were used in 11 patients, choline positron emission tomography (PET)/CT in three, prostate-specific membrane antigen PET/ CT in 14 (in combination with other imaging for 2 patients), and magnetic resonance imaging in two. The therapeutic strategy was discussed in multidisciplinary board meetings. In the case of SBRT, patients were treated to a normalized isoeffective dose in 2-Gy fractions (NID2) of between 78 and 142.8 Gy, delivered in three to five fractions. Fractionated therapy consisted of 13 × 3 Gy or 5 × 4 Gy for metastatic progression, and 35 × 2.2 Gy, 25 × 2.64 Gy, or 16 × 3.65 Gy for locoregional relapse. The two metastasectomy sites were one perirectal metastatic mass and one solitary lesion in the lower lobe of the lung. An overview of the disease span and treatments is shown in a swimmers plot in Fig. 1. Over median follow-up of 18 mo (interquartile range 8–25) the median NEST-FS was 16 mo (95% confidence interval [CI] 10–22) and PFS was 10 mo (95% CI 6–15). The group receiving SBRT or metastasectomy (n = 20) had NEST-FS of 21 mo (95% CI 14–28). At the time of last follow-up, 87% of the patients were still alive. Kaplan- Meier survival curves for NEST-FS are presented in Fig. 2A,B. Toxicity was scored according to the Common Terminology Criteria for Adverse Events scoring system for radiotherapy and the Clavien-Dindo classification for surgery. Treatment- related toxicity was minor, with three patients experiencing grade 1 toxicity, consisting of acute gastrointestinal (GI) toxicity (n = 2), acute genitourinary (GU) toxicity (n = 1), and fatigue (n = 1). One patient developed grade 2 acute GI toxicity and one patient had late grade 3 GU/GI toxicity (due to local treatment).
Data on PDT in the setting of oligoprogression in mCRPC are scarce but emerging. A case report demonstrated the potential of SBRT as an additional tool in long-term control of oligoprogressive disease in CRPC, while the mainline systemic therapy could be preserved [7]. In a multicenter retrospective analysis [5], a subset of patients experienced oligoprogressive CRPC while on ADT. For these patients, initiation of second-line systemic therapies could be postponed for 22 mo when the oligoprogressive lesions were treated with SBRT, which closely resembles our results, although patients receiving second-line systemic treatment were allowed in our series. Others reported on SBRT for oligometastatic disease in both mHSPC and CRPC [8,9], with only limited information on CRPC patients. Tran et al [10] observed 1-yr NEST-FS of 30% in a group of 17 CRPC patients. Ongoing prospective trials are investi- gating the role of Abiraterone for oligometastatic CRPC (NCT02192788, NCT02759783, NCT02816983, and NCT01859221) and others are addressing the combination of SBRT and second-line hormone therapy (NCT03449719 and NCT02685397).
This trial has several limitations inherent to its retro- spective design. Patient characteristics and the imaging and treatment modalities are heterogeneous. Nevertheless, the NEST-FS of 16 mo (and 21 mo for the SBRT/metastasectomy group) is hypothesis-generating. In terms of health economics, PDT has the potential to significantly reduce costs. Properly designed prospective trials are needed in which the role of the new imaging modalities needs to be addressed in comparison with conventional imaging. End- points such as NEST-FS are subject to the decision made by the multidisciplinary board and clear prespecified criteria for initiation of NEST need to be established; for example, a PSA doubling time of <4 mo could imply a need for subsequent systemic therapy. Our research group has initiated a prospective phase 2 trial on the basis of the encouraging results from this investigation.