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RENAL AND UROLOGICAL PROBLEMS: Edited by Fred Saad

The emerging roles of stereotactic ablative radiotherapy for metastatic renal cell carcinoma

Cheung, Patricka; Thibault, Isabellea; Bjarnason, Georg A.b

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Current Opinion in Supportive and Palliative Care: September 2014 - Volume 8 - Issue 3 - p 258-264
doi: 10.1097/SPC.0000000000000074
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Abstract

INTRODUCTION

Historically, renal cell carcinoma (RCC) has been labelled as a radio-resistant tumour. As such, the role of radiotherapy in the management of metastatic RCC, if given at all, has been limited to a palliative measure to improve or prevent patient symptoms. This is clearly reflected in the published guidelines regarding the management of kidney cancer [1,2]. Conventional low-dose radiotherapy has been used to treat symptomatic bone metastases, brain metastases, thoracic metastases, or any other symptomatic metastases [3–5]. Typical palliative radiotherapy doses include 8 Gy in 1 fraction, 20 Gy in 5 fractions, or 30 Gy in 10 fractions, depending on the body site and clinical scenario. Such doses are not meant to be ablative, and tumours often re-grow after a period of time.

Stereotactic ablative radiotherapy (SABR), also known as stereotactic body radiotherapy (SBRT), is defined as ‘the precise delivery of highly conformal and image-guided hypofractionated external-beam radiotherapy, delivered in a single or a few fraction(s), with doses at least biologically equivalent to a conventional radical course of treatment’ [6]. In other words, this is a very intense and focused radiotherapy delivered in 1–5 fractions. The goal of such treatment is to eradicate the treated tumour or provide long-term local control. With SABR, the dose delivered per fraction is much higher than the typical 1.8–2.5 Gy per fraction used in conventional high-dose radical radiotherapy. Despite the very high doses of radiation delivered to the tumour by SABR, there is significant sparing of adjacent normal tissues, making such treatment very well tolerated in the majority of cases. In patients with medically inoperable stage I lung cancer, SABR has become the new standard of care as an alternative to surgical resection. SABR is also being increasingly used in patients with limited lung, liver, adrenal, and bone metastases, and has become a standard treatment option for patients with limited number of brain metastases [7▪,8,9].

Given the convenience and high therapeutic ratio of SABR in treating tumours in almost every body site, there has been increasing interest in using SABR to treat metastatic tumours in certain clinical scenarios. The purpose of this article is to illustrate the emerging roles of SABR for patients with metastatic RCC. Specifically, the use of SABR will be discussed in the following scenarios: to improve local control and provide more effective and longer term palliation of symptomatic RCC metastases, to treat oligometastatic RCC, to treat oligoprogressive RCC, and to improve the effectiveness of immunotherapy for metastatic RCC.

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Box 1:
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STEREOTACTIC ABLATIVE RADIOTHERAPY TO IMPROVE LOCAL CONTROL AND PROVIDE MORE EFFECTIVE PALLIATION OF SYMPTOMATIC RENAL CELL CARCINOMA METASTASES

There is now a wealth of published literature documenting the high local control rates obtained with SABR. Most of the experience comes from treating stage I lung cancer with curative intent, in which long-term local control rates are in the order of at least 90% [10,11]. Similarly, pulmonary metastases are increasingly being treated with SABR, again revealing similar local tumour control rates [12–14]. In one retrospective study of 110 patients comparing surgical resection and SABR for lung metastases, neither local control nor overall survival was different between the two treatments [15▪]. Favourable local control rates are also seen in liver metastases [16–21] and adrenal metastases [22–27] treated with SABR. Use of stereotactic radiotherapy in patients with or less four brain metastases is already an established treatment option, providing superior local control and better neurocognition compared with conventional palliative whole-brain radiotherapy alone [9]. There is even evidence that stereotactic radiotherapy may be beneficial in patients with 5–10 brain metastases [28▪].

Another body site where SABR is increasingly being used is the spine. Given the proximity of the spinal cord, the ability of SABR to spare adjacent structures whilst delivering a high dose to the tumour is critical to prevent radiation myelopathy. When delivered carefully with strict dose limits to the spinal cord and appropriate dose fractionation schemes, SABR to the spine is well tolerated and effective [29–32]. In one prospective trial, spine SABR was associated with significant and prolonged pain relief for patients with spine metastases without spinal cord compression [32]. An ongoing, prospective, phase 2 and 3 trial (RTOG 0631) is randomizing patients with spine metastases to SABR and conventional palliative radiotherapy to determine whether SABR improves pain control. A similar proposed randomized phase 2 trial in Canada (NCIC CTG SC.24) will use complete pain response in 3 months as its primary endpoint. It would be reasonable to hypothesize that the potential clinical benefits of SABR to the spine would likely translate to other skeletal bone metastases.

Table 1 lists the published SABR experience specific to metastatic RCC body targets. A good number of studies has reported on spine metastases only, whereas others include multiple body sites treated with SABR. Overall, the crude local control rates are high and consistent with other SABR reports which include multiple cancer histologies. A recent review summarizing the SABR literature for early-stage primary RCC in the kidney treated with curative intent also reveals high local control rates of approximately 90% [33]. All of these data support the notion that RCC tumours respond to SABR and are not as radio-resistant as previously thought.

Therefore, it is logical to consider using SABR to treat metastatic RCC tumours, in which long-term local control is desirable. This may include body sites where recurrent uncontrolled cancer would cause significant morbidity and where re-treatment is difficult. Intracranial metastases, spine metastases, and central hilar and mediastinal metastases are good examples. Using SABR upfront to palliate symptomatic tumours may also be beneficial if the degree and duration of symptom relief is improved compared with conventional, low-dose palliative radiotherapy.

STEREOTACTIC ABLATIVE RADIOTHERAPY TO ERADICATE OLIGOMETASTATIC RENAL CELL CARCINOMA

Oligometastases refers to a cancer disease state between local-regional disease and widespread metastatic disease, in which the number of metastatic tumours is truly limited in number and location [34]. The use of SABR to treat oligometastases has been a topic of great interest. There are now multiple published reviews describing the existing literature and rationale [19,35,36▪]. In essence, SABR can potentially mimic the effects of surgical resection of metastases and offer a chance at prolonged disease-free survival or even ‘cure’ in some patients with limited number of metastases. This is highly relevant for metastatic RCC patients, as surgical resection of oligometastatic disease is already an established and accepted treatment option [37,38].

The largest published prospective experience of using SABR to treat oligometatases enrolled 121 patients who had or less 5 metastases [39]. All solid tumour histologies were allowed. All tumours were treated with SABR, and the 6-year overall survival and freedom from widespread distant metastases rates were 20 and 21%, respectively. Breast cancer patients had significantly better outcomes than other patients. Another prospective trial reported on the outcomes of 61 patients with or less 5 metastases treated with SABR, resulting in a 2-year overall survival and progression-free survival rates of 57 and 22%, respectively [40]. Both of these trials had very few patients with oligometastatic RCC. Kao et al.[41] reported on the outcomes of 46 patients with oligometastatic cancer of various histologies (13% had RCC) who were enrolled onto a prospective trial. These patients had 1–5 sites of metastatic disease and received concurrent sunitinib and SABR to all tumour sites. This study is especially relevant as sunitinib (an antiangiogenic agent) is a commonly used systemic agent for metastatic RCC. The 4-year local control, distant control, progression-free survival, and overall survival were 75, 40, 34, and 29%, respectively. Patients with RCC and prostate cancers had superior overall survival compared with other histologies. Concurrent administration of sunitinib and SABR appeared to be well tolerated. There is an ongoing multinational randomized phase 2 trial Stereotactic Ablative Radiotherapy for Comprehensive Treatment of Oligometastatic Tumors (SABR-COMET) for patients with or less five metastases comparing comprehensive SABR to all tumours against the standard of care without SABR, with overall survival as the primary endpoint. All solid cancer histologies are eligible, but patients must have their primary tumour treated with no evidence of local recurrence [42].

There are a few published reports of using SABR to treat multiple tumour sites in patients with metastatic RCC (see bottom half of Table 1) [48–53]. However, only one study specifically reported on outcomes in the oligometastatic setting with all tumours treated with SABR. Ranck et al.[52] reported the outcomes of 18 patients with 39 metastatic RCC lesions. The 2-year local control of the treated tumours was 91.4%, and overall survival was 85%. In 12 patients with no prior exposure to systemic therapy, all tumour sites were treated with SABR. The 2-year local control and distant control rates were 100 and 35.7%, respectively. A shorter interval from diagnosis to SABR predicted distant progression. Freedom from any post-SABR therapy was 64.2% at 1 year.

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Table 1:
Summary of the published literature on stereotactic ablative radiotherapy exclusively in metastatic renal cell carcinoma patients

Given the high local control rates obtained with SABR, it would seem reasonable to hypothesize that outcomes of oligometastatic RCC patients treated with SABR would be similar to those whose metastases are surgically resected. It is also likely that the prognostic factors predicting superior outcomes after surgical resection of RCC metastases will apply to patients treated with SABR. A recent review of the surgical experience indicates that those who will benefit most from ablation of RCC metastases are those with primary tumour T-category less than 3, primary tumour Fuhrman grade less than 3, pulmonary metastases only, disease-free interval greater than 12 months, and solitary organ involvement [38]. SABR has the advantage of being a noninvasive modality which would make it more suitable than surgery for patients at high operative risk. Furthermore, RCC tumours are very vascular and associated with an increased risk of intraoperative haemorrhage or they may require preoperative embolization which could delay surgery. SABR also allows for the ablation of metastatic tumours in body sites not easily amenable to surgical resection. If surgery or SABR is used to eradicate all sites of oligometastatic RCC, systemic therapy may be delayed and only started if patients developed widespread metastatic disease. Combining current targeted systemic agents used for metastatic RCC with SABR appears to be well tolerated, with no significant increase in toxicities [54].

STEREOTACTIC ABLATIVE RADIOTHERAPY TO TREAT OLIGOPROGRESSIVE RENAL CELL CARCINOMA

The management of metastatic RCC may include surveillance in asymptomatic or minimally symptomatic patients with indolent disease [55] or systemic therapy using targeted antiangiogenic agents in patients with progressing disease [56,57]. In patients being observed or treated with systemic therapy, oligoprogression is a relatively new term used to describe the clinical situation in which a solitary or a few metastatic tumours progress, whereas all other metastases are stable or responding. The usual practice would be to start or change systemic therapy at this point, but another approach is to locally ablate the ‘rogue’ metastases and continue on surveillance or the same systemic therapy. This is a new approach for this clinical situation, and the evidence for this is very limited.

Straka et al.[58▪] published a case report of a patient with metastatic RCC who developed a solitary area of progression in an adrenal metastasis whilst taking sunitinib. Instead of switching to another line of systemic therapy, the progressing tumour was treated with SABR. The patient was then able to stay on sunitinib for another 8 months before more widespread progression occurred. Such an approach has also been reported in patients taking crizotinib for metastatic nonsmall cell lung cancer who have ALK-positive tumours. In a retrospective review of 33 patients who progressed on crizotinib, 14 had extra-cranial progression in four or less tumour sites which were treated SABR. Crizotinib was continued after SABR to the progressing lesions. The 1-year local control rate was 86%. Median overall time taking crizotinib in those treated with SABR before more widespread progression was 28 months, compared with 10.1 months in those who had widespread progression not suitable for SABR. Those patients who are able to continue taking crizotinib for more than 12 months had significantly higher overall survival [59▪].

A Canadian, multiinstitutional, single-arm, prospective, phase 2 trial (OZM-053) is being conducted to study the use of SABR in metastatic RCC patients who develop oligoprogression whilst taking first-line sunitinib therapy. SABR will be used to treat up to five progressing tumours, with no more than three progressing soft-tissue metastases. Concurrent administration of sunitinib with SABR is not allowed, but sunitinib will be resumed after completion of SABR. The primary endpoint is local control of the irradiated lesions at 1 year, but an important secondary endpoint will be the added progression-free survival after SABR and staying on the same systemic therapy.

The concept of oligoprogression has a biological rationale. A recent study has shown that there can be significant genetic heterogeneity within the primary tumour and between different metastatic tumours in the same patient with metastatic RCC, suggesting that systemic therapies targeting a single mutation or pathway may not be as effective for all metastatic sites in the same individual [60]. This provides a sound biological basis for the mixed response to a targeted systemic agent seen in clinical practice and for the use of SABR to treat those ‘rogue’ tumours.

STEREOTACTIC ABLATIVE RADIOTHERAPY TO ELICIT THE ABSCOPAL EFFECT OF RADIOTHERAPY AND IMPROVE THE EFFECTIVENESS OF IMMUNOTHERAPY FOR METASTATIC RENAL CELL CARCINOMA

The abscopal effect of radiotherapy refers to the rare phenomenon of tumour shrinkage at sites distant from the irradiated area. Increasing evidence indicates that radiotherapy recruits biological effectors outside the treatment field and has systemic effects via the immune system [61]. Such an effect has been reported in patients with metastatic RCC [62,63]. With the development of novel immunotherapies for metastatic RCC [57], there is an opportunity to potentially improve the effectiveness and duration of response of these new agents by exploiting the immune-modulated abscopal radiotherapy effect that may be related to neoantigens produced after SABR.

Such a strategy has already been described for patients with melanoma. Postow et al.[64] published a case report of a patient with metastatic melanoma taking the immune activation drug ipilimumab who had a symptomatic pleural-based tumour treated with SABR. Afterwards, nonirradiated metastases in the right hilum and spleen both decreased in size. There are multiple, ongoing, phase 1 and 2 trials in metastatic melanoma which combine SABR with immunotherapy to better define the safety and efficacy of such an approach [65]. Given the new immune-modulating drugs being tested in metastatic RCC patients, prospective studies to evaluate the safety and efficacy of adding SABR are warranted.

CONCLUSION

SABR is a novel radiotherapy technique which delivers very focused ablative doses of radiation, resulting in high rates of local tumour control in almost every body site. RCC tumours are not radio-resistant when exposed to the large fraction sizes typical of SABR. Given the high response and local control rates, SABR is increasingly being used in metastatic RCC patients to improve the efficacy and duration of palliating symptomatic metastases. SABR also provides a noninvasive alternative and complement to surgical resection in the management of oligometastatic RCC for patients who are medically inoperable or who have disease not easily amenable to resection. Use of SABR in the oligoprogression setting may significantly delay the need to initiate or change systemic therapy, potentially leading to improved long-term outcome. Combining SABR with the new immunotherapies for metastatic RCC may enhance the effect and duration of treatment response given the abscopal effect of radiotherapy. As exciting as these emerging roles seem, well designed prospective clinical trials are urgently needed to confirm these benefits.

Acknowledgements

None.

Conflicts of interest

Disclosures: The authors have no conflicts of interest to declare.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

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            Keywords:

            abscopal effect; kidney cancer; oligometastases; oligoprogression; stereotactic body radiotherapy

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