Clinical Oncology 27 (2015) 290e297 Contents lists available at ScienceDirect

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Overview

Stereotactic Body Radiotherapy for Oligometastatic Disease G.G. Hanna *, D. Landau y * Centre y

for Cancer Research and Cell Biology, Queen’s University of Belfast, Belfast, UK Department of Oncology, Guys and St Thomas’ Hospital, Division of Imaging Sciences, King’s College London, London, UK

Received 2 January 2015; received in revised form 14 January 2015; accepted 5 February 2015

Abstract Stereotactic body radiotherapy (SBRT) is now an established therapy in stage I lung cancer with comparable local control rates to surgical resection. Owing to the conformity of treatment dose delivery and with appropriate fractionation considerations, minimal side-effects to surrounding normal tissues are observed in most patients. SBRT is now being used in the treatment of oligometastatic disease, alone or alongside systemic therapy. At present there is a paucity of evidence available showing a clinical benefit, but several international studies are being set-up or have started recruitment. This overview considers the clinical entity of an oligometastatic state, discusses the role of SBRT in the management of oligometastatic disease and discusses potential novel therapy combinations with SBRT. Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Key words: Oligometastases; SABR; SBRT; stereotactic

Statement of Search Strategies Used and Sources of Information The terms ‘stereotactic body radiotherapy’, ‘stereotactic ablative radiotherapy’ and ‘oligometastases’, together with their derivatives, were used to search PubMed. All studies relating to stereotactic body radiotherapy in the treatment of oligometastatic disease and of relevance to this overview were included in the preparation of the review. No limitations were placed on language or year of publication.

Introduction Stereotactic body radiotherapy (SBRT), or stereotactic ablative radiotherapy, has become more practical over the last decade owing to seismic technical advances in both imaged-guided radiotherapy and with advances in the precision of radiotherapy delivery with the various forms of intensity-modulated radiotherapy currently available [1]. However, the term stereotactic is perhaps misleading in so far that stereotaxis, as used in the neurosurgical sense, is Author for correspondence: D. Landau, Guys & St. Thomas’s Hospital, Westminster Bridge Road, London SE1 7EH, UK. E-mail address: [email protected] (D. Landau).

not used. SBRT is used to denote the precise and accurate delivery of high-dose, hypofractionated radiotherapy to targets generally less than 5 cm in maximum diameter, with relative sparing of surrounding normal tissues [2]. SBRT is now an established therapy in stage I lung cancer, with comparable local control rates to surgical resection and the role of SBRT is under investigation in a number of primary tumour sites, such as prostate carcinoma [3e5]. There is increasing use of SBRT for the treatment of oligometastatic disease, but the evidence of clinical benefit is not as strong as the evidence supporting its use in stage I lung cancer [6]. Owing to the conformity of treatment dose delivery and with appropriate fractionation considerations, side-effects to surrounding normal tissues are frequently minimal [7]. Also, for most primary tumour sites and treatment locations, local control after SBRT treatment is high. Thus, it follows that SBRT may have a role in the treatment of oligometastatic disease to provide long-term control or even cure if the metastatic sites treated represent the only sites of residual disease. In the oligometastatic setting, SBRT has been delivered alone or in conjunction with systemic therapy. At present there is a paucity of evidence available showing a clinical benefit, but several international studies are being set-up or have started recruitment. However, the trials under development now

http://dx.doi.org/10.1016/j.clon.2015.02.003 0936-6555/Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

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need to be put in context for the reader so that the results that will soon start coming through thick and fast can be reviewed. This overview seeks to do this and does not seek to be a systematic review of the area. Using non-small cell lung cancer (NSCLC) as an exemplar, this overview considers the clinical entity of an oligometastatic state, discusses the role of SBRT in the management of oligometastatic disease and discusses potential novel therapy combinations with SBRT.

The Concept of Oligometastatic Disease The term oligometastatic, posited by Hellman and Weichselman [8], describes the presence of a limited number of metastatic sites of disease, usually less than six in number and in some descriptions less than four. The potential existence of this clinical entity implies that cure may be possible because there are no viable micrometatases and that all the metastases that are present have declared themselves [9]. Hence, the oligometastases present are simply an extension of locally advanced disease and, as Hellman and Weichselman [8] suggest, are an intermediate state between locoregional and widespread metastatic disease. At the time this theory was proposed, all that was missing were potentially curative or ablative techniques to deal with most metastases not amenable to low-morbidity surgery. Where surgery is possible the results are encouraging and in patients with complete resection of lung metastases overall survival at 5 years of 46% has been reported [10]. With the availability of SBRT, at least as a research tool in this context, testing of the oligometastasis hypothesis may occur. According to this theory, the addition of local ablative treatment to the metastases may increase cure rates. Logically, therefore, the correct trial design to test the theory is to concentrate on these local therapies in addition to the local therapies for the primary tumours and the end point should be cure rate and not overall survival: tail on the overall survival curve rather than the median. Using the number of long-term survivors as the end point for any oligometastatic study might be logically correct, but does not address some important patient and disease variables. First, the advocates of the oligometastatic state agree that patient cure can only be reliably identified retrospectively [11]. It is hoped that the current round of randomised trials will generate translational research, one outcome being to be able to identify upfront patients with very low further metastatic potential. This will probably be a function of both tumour genetics and host environmental factors. For now, though, the oligometastatic patient group contains a mixture of patients with and without potential for further metastases. These patients cannot be forgotten in a trial design that includes or replaces the standard treatment of this patient group. For these patients, in whom there seems to be general agreement that with current systemic therapies there is no chance of cure for most primary tumour types, a median overall survival end point is surely more relevant than cure rate.

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Second is the assumption that patients who do have further metastatic potential will not benefit from ablative treatment of the metastases. If a drug was shown to act with such high complete remission rates as SBRT, even though it was only to act on visible disease, trials would undoubtedly be undertaken to investigate its role alongside standard systemic therapy. We do not as a rule in clinical oncology blindly follow the drug development pathway with all of its quirks. Nevertheless, there is a logic that says that a highly effective boost treatment to well over 90% of malignant disease (i.e. all that is visible in oligometastatic patients) might give additional value to standard systemic therapy. This value, if present, is likely to be measured in metastatic disease-free and overall survival. A number of prospective randomised trials designed to show a survival advantage with ablative treatment of oligometastatic disease are either recruiting or in planning. One of the first is the recently completed UK PulMicc trial, testing surgical metastasectomy for colorectal cancer patients with oligometastases to the lung [12]. In the planned UK NSCLC SARON trial, the control arm will be four cycles of platinum-based doublet chemotherapy followed by maintenance systemic therapy according to local guidelines. Finally the issue of the definition of oligometastases requires consideration. What is ‘a few metastases’? At present no standard definition is agreed and it remains for those researchers designing clinical trials to define the maximum number of sites of metastatic disease that may be considered as oligometastatic. Therefore, only by conducting welldesigned prospective trials that compare the outcomes in the oligometastatic state to the general metastatic population of each tumour type will we ever get close to an answer as to the true definition of oligometastases, if indeed an over-arching definition exists. Patients with molecular alterations that significantly alter their outcome with systemic therapy only, such as sensitising EGFR mutations and Alk-fusion or ROS-1 rearrangements, have a different natural history and outcome to those without [13e15]. Although the general cancer biology principles of oligometastatic disease might apply equally to this group in order to maintain as homogeneous a population, it is imperative that any trial of ablative interventions has clearly defined inclusion criteria based on molecular disease classifications in addition to the standard disease and patient criterion. A number of other points in the 1995 editorial are directly relevant to clinical trial design. Hellman and Weichselbaum [8] argued that tumours that have only single organ metastases might be less likely to be harbouring further metastases in other organs. Furthermore, patients with more sites of disease and overall greater tumour burden were hypothesised to have a higher rate of microscopic metastases. To address these points, trials in this area should stratify patients by the number of organs involved and should collect data on the overall volume of disease present to correlate with clinical outcomes. These factors may form the basis of future selection criteria for the use of SBRT in oligometastatic disease.

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Metachronous versus Synchronous Metastases A number of studies have established that the length of disease-free progression time between the primary or last active tumour and the presentation of the oligometastases is of prognostic importance [16]. Similarly, patients with oligometastases at the time of initial presentation (synchronous) will not fare as well as those who develop metastatic disease some time later (metachronous). Another key issue to remember is that standard treatment for synchronous metastases does not usually include local radical therapy of the primary tumour (and nodes). Therefore, in assessing the effect of radical or ablative strategies in clinical trials, the intervention for metachronous oligometastatic disease is the SBRT to the metastases. For trials including patients with synchronous disease, however, the trial intervention also includes radical treatment of the primary. This difference is exemplified in two of the currently CRUK-funded UK trials, CORE and SARON. The former is in the metachronous setting and the latter is in the synchronous setting. The former only mandates SBRT to the metastases and the latter also mandates radical radiotherapy to the primary tumour and nodes.

The Effect of the Volume of Disease Burden on Survival Focusing on NSCLC, unselected European patients with metastatic NSCLC have a median survival of 8.5e10.5 months [17,18]. This includes patients with any number of metastases. In patients with fewer sites of metastases, the overall survival seems to be better than in those with more sites of disease. Oh et al. [19] from MD Anderson reported a retrospective review of outcomes in 1284 patients with metastatic NSCLC. Patients with one organ site of disease had an overall survival of 9 months compared with 8 months in patients with two sites of disease and 7 months in patients with three organ sites involved. For patients with no brain metastases, the equivalent figures were 10, 8 and 6 months, respectively. In a subgroup 137 patients with lung metastases only, the risk of death was correlated with the number of metastases, in addition to other variables, such as tumour size. In the prospective FLEX trial, 1125 patients with metastatic NSCLC were randomly allocated to either cisplatin and vinorelbine chemotherapy or the same plus cetuximab. In a review of the prognostic influence of baseline characteristics, overall survival was better on multivariate analysis in patients with metastases to one site compared with two sites compared with three or more sites (12.4 months versus 9.8 months versus 6.4 months, P < 0.001, see Figure 1) [20]. In 1991, the Southwest Oncology Group (SWOG) group published an analysis of prognostic factors in 2531 patients enrolled in 14 phase II and phase III trials before that date [21]. The variables analysed were gender, performance

Fig 1. Overall survival curves from the FLEX trial comparing patients with one, two or more organs involved by metastatic disease (Reproduced with permission from Pirker et al. [20]).

status, age, race, year of registration, weight loss, smoking status, single lesion versus multiple metastases, haemoglobin and platelet, lactate dehydrogenase (LDH), alkaline phosphatase, total bilirubin, SGOT and calcium. The results confirmed the prognostic significance of single versus multiple metastases on multivariate analysis. None of these studies reported survival figures for patients based on overall number of metastases. All, however, support the hypothesis that a lower tumour burden is associated with improved outcome. Patients with a lower tumour burden could therefore be candidates for a more radical approach to their management.

Local Control and Safety of Stereotactic Body Radiotherapy for Oligometastatic Disease A number of non-randomised studies have now been reported detailing the safety of and clinical outcomes after SBRT in the oligometastatic setting. Local control rates after SBRT have been reported after treatment to individual metastases in a range of organ locations (lung [22], spine [23], liver [24e26], lymph nodes [27e29], adrenal glands [30,31]), as well as multiple metastases in individual organs (liver [24e26], lung [32,33]) or multiple organs [34e36]. Primary disease sites in these studies include NSCLC [30], prostate cancer [29], melanoma [37] and colorectal cancer [32], with most series reporting metastases from a mixture of primaries. The rates of grade 3 or 4 toxicities are very low, as long as strict protocols are adhered to, and local control is high. As a caveat it is worth noting that the number of lesions and the specific combinations of anatomical sites that might present in the clinic have not all been subjected to rigorous toxicity testing. This is another reason why welldesigned studies are required before SBRT can be declared a safe and appropriate therapy in this context.

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The Role of Radiotherapy in Patients with Metastatic Non-small Cell Lung Cancer In the treatment of patients with metastatic NSCLC, radiotherapy has only been used for the prevention or palliation of symptoms. Two recent papers in NSCLC suggest that, when used in this setting, radiotherapy may have an effect on overall survival. Rusthoven et al. [24] reviewed the records of 387 consecutive patients with NSCLC seen at the University of Colorado, Denver in the period from January 2005 to June 2008. After the maximum response to firstline therapy before progression, disease was categorised as eligible or not eligible for SBRT to all sites of measurable disease, based on institutional SBRT trial criteria. Sixty-four of these patients met the strict criteria for inclusion in this analysis. Metastatic disease was present in 89%, including brain metastases in 31%, before the initiation of systemic therapy. Thirty-four of these patients (53%) were also considered eligible, in theory, for treatment with SBRT. In the group of 64, the site of failure at the time of first extracranial progression was in initial sites of disease only in 64%, new sites only in 9% and both old and new in 27%. These indicate two important points. One is that perhaps 10% of patients with metastatic NSCLC would be eligible for SBRT-based ablative therapies in NSCLC. The other is that the patterns of failure indicate that significant gains in progression-free survival (PFS) might accrue from SBRT to all sites of initial disease. Fairchild et al. [38] carried out a combined analysis of 13 randomised controlled trials testing lower versus higher doses of radiotherapy for palliation in patients with advanced NSCLC. They described an overall survival at 1 year after higher dose radiotherapy versus lower dose radiotherapy of 26.5% versus 21.7%, respectively (P ¼ 0.002). This again suggests that there might be an effect on survival with the systematic addition of radical radiotherapy or SBRT to all sites of disease in the first-line setting.

Staging for Patients with Oligometastatic Disease There are clearly limitations on the ability of current imaging modalities to rule out micrometastases. Current imaging modalities allow us to see into where we previously could not, often with excellent tumour versus nontumour resolution. Nevertheless, for this group of patients in particular, more attention should be paid to the search for metastases than normal. As an example in NSCLC, all patients who are to be treated as oligometastatic should be staged with a positron emission tomography/computed tomography and a magnetic resonance imaging scan of the brain. Studies investigating the utility of imaging strategies are being set-up or are underway [39]. But perhaps novel methods of disease assessment beyond conventional imaging may hold the key. Perhaps, blood-based biomarkers, such as circulating free DNA, may better select patients with presumed oligometastatic disease for SBRT [40]. At present,

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Table 1 Summary of selected baseline characteristics from studies by Griffioen et al. [42] and De Ruysscher et al. [43] on the use of radiotherapy in oligometastatic non-small cell lung cancer

Local stage (ignoring M1 status) I II IIIA IIIB Number of metastatic sites 1 2 3

De Ruysscher et al.

Griffioen et al.

n 4 6 9 20 n 34 4 1

n 11 12 38

18% 20% 62%

n 50 9 2

82% 15% 3%

10% 15.4% 23.1% 51.3% 87.2% 10.3% 2.6%

studies of SBRT for oligometastatic disease should include a defined staging strategy and this may help inform imaging strategies surrounding oligometastatic disease and patient selection for SBRT treatment [41].

Ablative Strategies in Oligometastatic Nonsmall Cell Lung Cancer Regarding the radical treatment of patients with synchronous oligometastatic disease, a retrospective study of the radical treatment of 61 NSCLC patients with one to three synchronous metastatic deposits was reported by Griffioen et al. [42]. Patients included in the analysis were treated between 1999 and 2012 at two institutions and the reported 1 and 2 year overall survival rates were 54 and 38%, respectively, with PFS rates of 32 and 8%, respectively. Treatment was mainly delivered using radical radiotherapy or SBRT, but nine patients had surgical treatment of the primary site of disease. Selected baseline characteristics are shown in Table 1. De Ruysscher et al. [43] reported a single-arm prospective phase II trial investigating whether it would be possible to obtain a significant 2 and 3 year survival in patients with synchronous oligometastases when treated radically. Selected baseline characteristics are shown below. These are of direct interest to synchronous oligometastatic trial design as they indicate the proportion of patients who would probably require conventional radiotherapy to the primary and nodes (at least 75%) versus SBRT to the primary only (maximum 25%). Also, the vast majority of patients in this study had only one visible metastasis, by far the highest proportion being brain metastases. Thus, this suggests that in any future trial of SBRT for synchronous metastases in NSCLC, a large proportion of the treatments to metastases will be for solitary brain metastases. With a median followup of 27.7 months, the median overall survival was 13.5 months (95% confidence interval 7.6e19.4). The 1 year overall survival was 56.4%, the 2 year 23.3% and the 3 year 17.5%. The median PFS was 12.1 months (95% confidence interval 9.6e14.3). The 1 year PFS was 51.3%, both the 2 and

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3 year PFS were 13.6%. It should be noted that PFS in systemic therapy-only trials is in the order of 8 months [44]. The University of Rochester reported median survivals of patients with limited initial stage IV metastatic NSCLC treated with SBRT similar to that of stage III NSCLC patients with a 5 year survival of 14% [45]. Twenty-five patients from the University of Chicago with a median of two extracranial metastases underwent SBRT and had median survival similar to stage III patients of 23 months and an 18 month overall survival of 53% [46]. Those treated with prior systemic therapy, those progressing through chemotherapy immediately before SBRT and non-adenocarcinoma histology were associated with worse outcomes. The NCCTG initiated a randomised phase III study to test the hypothesis that radiotherapy to all known sites of disease after four to six cycles of systemic therapy in NSCLC patients with one to three metastatic sites would result in improved overall survival [47]. After the completion of nonstandardised systemic therapy, patients were randomised to observation or radiotherapy to all known sites of disease. The radiotherapy schema was 60 Gy in 2 Gy fractions or 45 Gy in 3 Gy fractions. The study was closed due to poor accrual. Important lessons can be learnt from these studies for future trial design. Specifically, the study population must be enriched to include only those most likely to be randomised. Exclusion criteria and subgroup analyses must account for those negative prognostic factors that are either intuitive or found in multiple studies [48]. Furthermore, in addition to the known predictors of outcome after SBRT for oligometastatic disease, biomarkers for response or toxicity should be developed to complement existing clinical criteria for patient selection and radiotherapy treatment planning [49]. Results from open studies such as the SABRCOMET study (Stereotactic Ablative Radiotherapy for Comprehensive Treatment of Oligometastatic Tumors, NCT01446744) and the MD Anderson Consolidative Therapy for NSCLC Oligometastatic Disease study (NCT01725165) as well as the start of both the SARON and CORE studies, among others, are all eagerly awaited [50].

Stereotactic Body Radiotherapy for Tumours other than Non-small Cell Lung Cancer We have discussed the role of SBRT for NSCLC, but similar principles apply in the treatment of oligometastatic disease from primary tumour types other than NSCLC [51]. Treatment of oligometastases from the primary tumour sites of colorectal cancer, breast cancer, prostate cancer, renal cell carcinoma, melanoma, sarcoma and head and neck cancers using SBRT has been reported [34,37,52e58]. Each primary tumour type will have distinctive patterns of spread, with an associated variation in clinical outcome and an associated impact on the existence of an oligometastatic state. Although no direct comparison exists, outcomes after SBRT treatment to lung metastases from colorectal carcinoma seem to be poorer than outcomes after

SBRT to lung metastases from other primary tumour types, particularly with reference to local control [59]. This relatively poor outcome may represent colorectal tumours with inherent poorer prognostic features by virtue of being metastatic to the lung alone and with no involvement of the liver. Hence, as stated earlier, tumour and patient factors will probably be the main determinants of clinical outcome. The challenge for researchers is to determine whether to approach the use of SBRT in oligometastatic disease from a primary tumour type perspective or from an organ perspective.

Which Ablation Strategy to Use for Oligometastatic Disease? If the principle of oligometastatic disease is accepted and if local ablative therapy is effective, the question then arises as to whether one ablation therapy is more effective than another? Given the paucity of data for the effectiveness of SBRT in oligometastatic disease, needless to say few comparisons of SBRT with other ablative strategies exist. In a systematic review comparing the treatment of adrenal metastases with SBRT as compared with adrenalectomy or percutaneous catheter ablation, higher control rates after surgery were observed [60]. This may represent case selection, with surgery reserved for those with a better performance status and for those with solitary adrenal metastases. In an overview of the treatment of liver metastases, SBRT to the liver showed comparable local control rates to surgical resection [51]. However, it should be noted that the follow-up for SBRT is on the whole less mature than for the surgical series to date. In a single institutional study of lung oligometastases treated with surgery or SBRT, both local control and overall survival were comparable [61]. Studies such as these provide suggestive evidence that SBRT is comparable in efficacy with surgery, but it is unlikely that any randomised comparison of SBRT versus surgery will occur, given the difficulty in undertaking comparisons of SBRT versus surgery in early stage NSCLC [62]. As is the case with conventionally fractionated radiotherapy and for most organs receiving treatment, SBRT usually allows retention of most of the irradiated organ’s function, which may not always be possible after surgery. Furthermore, it has been suggested that SBRT may trigger an immune response, which may lead to immune destruction of non-irradiated micrometastases in an abscopal-type manner [63,64]. If this phenomenon is clinically significant, then SBRT may have biological advantages over surgery in the treatment of oligometastases.

Oligo-recurrence and Oligo-progression This review does not aim to give clinical recommendations on what to do in various scenarios. Each must be judged on its merits and hopefully some scenarios will have an evidence base. One particular scenario is that patients

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with metastatic disease sometime progress in an oligometastatic manner with stability in most metastatic sites, yet progression in a small number of disease locations. The idea that these patients should continue to be treated with ablation therapy to the sites of oligo-progression as long as clinical benefit is obtained has been explored in NSCLC and melanoma [65e67]. SBRT is certainly likely to be an easier strategy for patients to undergo than repeat surgery or indeed starting cytotoxic chemotherapy. It remains to be seen how much we will be able to extrapolate from the currently planned studies, but it is likely that much of what we learn in the first-line setting will come to be applied at subsequent occasions of relapse.

Stereotactic Body Radiotherapy for Oligometastatic Disease and Systemic Therapy Given the ablative nature of SBRT and relatively high dose delivered, there is the potential for increased overlapping toxicity as well an enhanced anti-tumour effect with the co-administration of systemic therapy. In mitigation of this concern, the highly focused nature of SBRT radiotherapy dose delivery may permit more effective delivery in conjunction with systemic therapy. SBRT has been safely delivered after induction cytotoxic chemotherapy with no excessive toxicity [68]. Of particular concern is the delivery of anti-angiogenic therapy soon after SBRT (less than 2 months) and the risk of gastrointestinal perforation [69,70]. In contrast, a phase II study of sunitinib (a multitargeted tyrosine kinase inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFR, c-kit, FLT3 and ret) in conjunction with SBRT did not show any enhanced toxicity at or near the sites irradiated as a result of the combination [71]. As discussed above, a number of early phase studies have examined the role of SBRT delivered alongside systemic therapy to treat oligo-progression. In the study by Iyengar et al. [67], in which SBRT was delivered for the treatment of oligoprogressive disease, co-administration of the EGFR inhibitor erlotinib did not result in any excess toxicity. In a similar early phase study of SBRT administered alongside gefitinib, no excessive toxicity was noted [72]. Thus, it seems that many of the novel anti-EGFR agents used in the treatment of advanced NSCLC may be safe when delivered with SBRT. Therefore, it may be possible to avoid stopping such systemic therapy during radiotherapy, thus avoiding the risk of tumour flare off the drug. Of emerging interest is the role that immunotherapy may have when delivered with SBRT. As eluded to earlier, there is growing preclinical data and a number of case reports that suggest the presence of abscopal effects when radiotherapy is delivered during co-administration with immune checkpoint inhibitors, suggesting that this combination may lead to an enhanced tumour response outside of the primary treatment field [63,64]. Of particular interest is the combination of anti-PD-1 antibodies with radiotherapy. The unique role of PD-1 in down-regulating the immune response to inflammation suggests that turning off this

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pathway in combination with radiotherapy delivery may lead to an enhanced response beyond that seen with antiPD-1 therapy alone [73]. In a mouse glioma model, the combination of a constructed anti-PD-1 antibody and stereotactic radiotherapy leads to long-term survival supporting the efficacy of this combination [74]. Controlled clinical studies of the combination of immune modulating agents and SBRT are awaited. Hence, where the oligometastatic state is complicated by the presence of subclinical micro-metastases, the co-administration of systemic therapy and in particular immunotherapy, with SBRT is an exciting new paradigm shift that may lead to long-term control or cure and thus has the potential to transform the management of patients with metastatic disease.

Conclusion Oligometastatic disease seems to be a distinct clinical entity with the possibility of long-term survival after local treatment in appropriately selected patients with NSCLC. Trials testing the utility of SBRT in the treatment of oligometastatic disease are being set-up in the UK for patients with NSCLC and other primary tumour types. It is hoped that these studies will provide much needed information on both appropriate patient selection for SBRT treatment and the effect of SBRT for patients with oligometastatic disease.

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