Extracranial oligometastatic renal cell carcinoma: current management

Review

014

Extracranial oligometastatic renal cell carcinoma: current management and future directions

Jasmin Loh1, Ian D Davis2, Jarad M Martin1 & Shankar Siva*,3,4

1

4

2 1 7 /

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astatic nt man-

ture , UK

Abstract: The term ‘oligometastases’ was formulated to describe an intermediate state between widespread metastases and locally confined disease. The standard of care in metastatic renal cell carcinoma is systemic therapy; however, in patients with solitary or limited metastases, aggressive local therapies may potentially prolong survival. The literature suggests a survival benefit with surgical metastasectomy, with a reported 5-year survival as high as 45% in those who achieve complete resection. More recently, an expanding body of evidence supports the role of stereotactic ablative body radiation therapy for the treatment of oligometastatic renal cell carcinoma and early results demonstrate comparable local control rates with surgery. There is also increasing interest in the abscopal and immunologic effects of localized radiation. With the proliferation of newer targeted agents and immunomodulatory agents, current work is addressing the optimization of patient selection and avenues towards sequencing and combining the various treatment options. The concept of oligometastases, introduced by Hellman and Weichselbaum in 1995 describes an intermediate state of metastases in which the number and site of metastatic tumors are limited [1] . This clinical state includes two groups of patients: those with widespread and incurable, but mostly subclinical metastatic, disease; and those with truly limited metastatic disease and who may be potentially curable. The clinical implication of this hypothesis is that patients with overt metastases have distinct clinical and biological characteristics enabling them to be treated effectively with local ablative measures. The absolute number of metastatic lesions that defines the oligometastatic state is controversial. The precise definition has varied among the different studies. In general, oligometastases is defined as one to five metastases, involving either single or multiple organs, and are potentially amenable to local therapy with the aim of achieving long-term survival. There have been further suggestions by researchers from the University of Chicago (IL, USA) to distinguish between the different clinical scenarios that may exist within the concept of oligometastatic disease [2] . They include patients with:

Keywords

• immunotherapy • metastasectomy • oligometastases • renal cell carcinoma • stereotactic

ablative body radiation therapy • targeted therapy

●● De novo oligometastases or synchronous disease: those that initially present with limited m etastases,

although they may or may not also have more widespread subclinical metastatic disease [2] ; ●● Induced oligometastases or oligoprogressive disease: those who initially present with more wide-

spread metastases and who respond to systemic therapy, resulting in limited, but persistent, metastases [2] or differential limited progression in the face of good systemic control of other metastatic disease [3] ; Department of Radiation Oncology, Calvary Mater Hospital, Edith Street, Waratah NSW 2298, Australia Monash University Eastern Health Clinical School, Level 2, 5 Arnold Street, Box Hill, Melbourne, VIC 3128, Australia 3 Department of Radiation Oncology, Peter MacCallum Cancer Centre, Lansdowne Street, East Melbourne VIC 3002, Australia 4 Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, Melbourne, VIC, Australia *Author for correspondence: Tel.: +61 3 9656 1111; Fax: +61 3 9656 1424; [email protected] 1 2

10.2217/FON.14.40 © 2014 Future Medicine Ltd

Future Oncol. (2014) 10(5), 761–774

part of

ISSN 1479-6694

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Review Loh, Davis, Martin & Siva ●● Recurrent oligometastases or metachronous

disease: those who initially present with and are treated curatively for locoregional disease and subsequently develop further limited meta stases [4] . Niibe and Hayakawa coined the term oligorecurrence to describe an oligometastatic state where the primary site is controlled [5] . Approximately 25–30% of patients with newly diagnosed renal cell carcinoma (RCC) have metastatic disease at the initial presentation and approximately a third with clinically localized primary tumor at diagnosis will subsequently develop metastatic disease [6] . Historically, patients with metastatic RCC (mRCC) have a poor prognosis, with 5-year survival rates of ≤10% [6] . However, prolonged survival has been noted in patients with solitary or oligometastatic disease amenable to resection. With improved and more sensitive imaging methods, the oligometastatic state is increasingly being identified and, thus, the optimal management strategy in these patients warrants revisiting. RCC is often considered resistant to older conventional treatments including cytotoxic chemotherapy, conventionally fractionated radiation therapy and cytokine-based immunotherapy. This has led to surgery being considered as the only potential curative means in these patients. However, another local therapy is now available. Stereotactic ablative body radiation therapy (SABR) is able to deliver much higher biological doses of radiation therapy using high-precision techniques. Therefore, the conventional paradigm of surgical management of oligo-mRCC is now being challenged. The management of intracranial metastases has previously been published and, therefore, this review will focus exclusively on extracranial oligo-mRCC [7,8] . Biology of metastases Paget hypothesized in his ‘seed and soil hypothesis’ that metastases depend on interactions between tumor cell and target organ [9,10] . Certain tumors have a predilection to metastasize to particular organs and successful colonization of the target organ is owing to a complex interaction between the host, tumor microenvironment and genetic instability of the tumor cells. The discrete steps in the biological cascade of metastasis have been well described and have provided a framework to categorize the genes involved in each step of the metastatic process [11] . Adding to this complexity is the recently

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demonstrated intratumor heterogeneity by multiregion sequencing [12] . This implies that there are primary tumor subpopulations that only have a limited capability to metastasize, therefore, resulting in the oligometastatic state. The molecular fundamentals of oligometastases are still largely unknown. A panel of genes have been identified that were differentially expressed between patients with aggressive and nonaggressive RCC, but were not significantly different between aggressive primary and mRCC. These findings suggest that gene expression alterations that result in aggressive behavior and metastatic potential can be identified in the primary tumor [13] . Gene-expression profiling of resected pulmonary metastases from 18 patients with RCC using DNA microarrays found differential expression of 135 genes stratifying patients with fewer (≤8) versus multiple (≥16) metastases [14] . Furthermore, gene ontology enrichment analysis demonstrated upregulation of genes that positively regulate the cell cycle in those with multiple metastases, indicating increased growth potential in multiple metastases versus fewer metastases and hence implying a fundamental biological difference between these two clinical scenarios. More recently, miRNA expression has demonstrated the potential to identify patients most likely to remain oligometastatic after metastases-directed treatment [15] . Imaging Technological advances in imaging modalities have increased the frequency and likelihood of detecting oligometastatic disease. Routine use of cross-sectional imaging, such as computed tomography (CT) scanning, has improved the early detection of metastases. MRI has been shown to be highly sensitive and more specific compared with bone scintigraphy, with improved detection of bone metastases, as well as soft tissue disease [16] . Fluorine-18 fluorodeoxyglucose PET combined with CT has increased the detection of metastases, with the majority of cases reporting sensitivity close to a 100% for metastatic disease [17] . There is further work currently being carried out to assess utility of other molecular imaging, such as PET with novel radiolabelled isotopes. For example, cG250 is a monoclonal antibody targeting the carbonic anhydrase IX antigen, which is expressed in more than 90% of clear cell RCC and have preliminary data not only for diagnosis of primary and mRCC, but also as a therapeutic strategy [18] .

future science group

Extracranial oligometastatic renal cell carcinoma: current management & future directions Together, these imaging modalities improve the accuracy of detecting an oligometastatic state, not only by detecting occult metastases, but also by detecting additional disease that would reclassify a patient into the broadly metastatic category. Metastasectomy There is a long history of surgery in the locally aggressive management of mRCC. Regarding extracranial lesions, the first pulmonary metastasectomy reported in 1945 [19] , with the patient dying 23 years after metastasectomy without evidence of recurrence . Resections for mRCC have been performed for solitary or limited metastatic disease to provide long-term disease control and a potential cure; recurrent disease, again with a view to long-term control or cure, or for palliation; symptomatic disease for local control and palliation of symptoms; and selected cases of limited residual disease following response to systemic therapy. The metastasectomy literature consists mainly of retrospective studies that are sometimes contradictory and suffer from selection biases; there has not been any published prospective randomized trial to date. Metastasectomy, in appropriately selected patients, has been shown to be feasible and with acceptable surgical morbidity. Pulmonary metastasectomy The lung is the most common site of metastases in mRCC. The 5-year overall survival rate after pulmonary metastasectomy ranges from 31 to 39% (Table 1) , and on subgroup analyses, complete resection has been consistently shown to be the strongest predictor of survival with reported survival rates up to 45% at 5 years [20–24] . Other prognostic factors associated with a favorable outcome include fewer number and/or smaller size of metastases, metachronous (versus synchronous) metastatic disease and negative hilar or mediastinal lymph node involvement at time of metastasectomy. Repeat thoracotomies for recurrent pulmonary metastases were not associated with an increase in morbidity or mortality and no survival difference was observed in these patients compared with those who were operated on only once, although patient selection would clearly be important [20,22,24] . Bone metastasectomy The second most common distant metastatic site of RCC is bone, with incidence rates of 20–25%


Review

at the time of initial presentation of metastatic disease [30] . The 5-year survival rates have been reported to be between 13 and 38% after resection of solitary osseous metastases (Table 1) , and patients with solitary metastases survive longer on average than those with multiple metastases [25–29] . Studies have shown conflicting results for the prognostic significance of the extent of surgery (radical vs marginal resection), localization of the osseous metastases (axial vs appendicular skeleton), timing of onset of metastases (synchronous vs metachronous) and presence of pathological fracture. The Fuhrman grade of the primary renal cell tumor was not found to be predictive of long-term survival in bone metastases [28,29] . Resection of other extracranial sites of metastasis Oligometastases to other extracranial sites, such as the thyroid, liver and pancreas, in RCC are uncommon. Published data on metastasectomy to these sites are, therefore, limited and there are no established guidelines for management. In a retrospective series of 45 patients, the 5-year survival rate following thyroid metastasectomy for mRCC was 51% [31] . Reported 5-year survival rates following liver metastasectomy for mRCC range from 26 to 62.2%, and prognostic factors that have been associated with improved survival include clear resection margins, metachronous rather than synchronous metastases, low grade of primary tumor, male sex and metastases diameter of ≤5 cm [32–34] . Several studies have reported 5-year survival rates of above 80% following pancreatic metastasectomy [35] , and a combined analysis of 15 studies reported a 5-year survival rate of 66% [36] . Data from the available literature support the role of resection of limited mRCC. However, these predominantly retrospective studies warrant validation in a prospective randomized manner. The prognostic significance of histological subtype on metastasectomy outcomes remains unclear. The predominant subtype is clear cell RCC, and the remaining subtypes including papillary, chromophobe, collecting duct and medullary cell types are grouped together as nonclear cell RCC. Most studies do not distinguish between clear and nonclear cell types. The limited retrospective data report contradictory findings. One study reported that the overall survival following pulmonary metastasectomy was not influenced by the histologic subtype (clear

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Review Loh, Davis, Martin & Siva Table 1. Pulmonary and bone metastasectomy series for renal cell carcinoma. Study (year)

Study period (years)

Total patients Nephrectomy Extrapulmonary†/ (complete performed extraosseous‡ resection), n metastases (patients, %)

Pulmonary metastases Pfannschmidt 1985–1999 191 (149) et al. (2002)

Complete resection, negative LN involvement, number of metastases: ≤7, DFI: >23 months Complete resection, number of metastases: ≤6 Complete resection, negative LN involvement, number of metastases: 3 metastases) NA

NA

NA

All grade 1–2 toxicity

Toxicity

NA

72% at 1 year

49% at 1 year

NA

NA

None reported during the follow-up period

4% grade 3 toxicity (pain and fatigue). No grade 3–4 neurologic toxicity observed

Most common toxicity is grade 1 fatigue (10.5%). One case of grade 3 nausea and vomiting. No grade 4 toxicity

NA

No grade 2 or higher toxicity with RTOG/EORTC toxicity criteria

Two cases of grade 2 dermatitis, four developed fractures, one case of grade 4 erythema 32 months 96% had grade 1–2 toxicity. One death (patient treated for large metastatic lesion in lung close to pleura died 10 weeks after SABR after admission with electromechanical dissociation) NA 40% had grade ≥1 toxicity, majority had grade 3 toxicity. One death (fatal gastric hemorrhage 4 months after SABR for metastasis in pancreas adjacent to stomach and duodenum)

NA

NA (median 85% at DFS: 2-years 12.7 months)

Median survival

† Prospective trial. EORTC: European Organisation for Research and Treatment of Cancer; DFS: Disease-free survival; NA: Not available; RTOG: Radiation Therapy Oncology Group; SABR: Stereotactic ablative body radiation therapy.

48 (60)

Gerszten et al. (2005)

NA

Cervical (6), thoracic (26), lumbar (23)

Lung (63), kidney, adrenal, thoracic wall, abdominal glands, liver, pelvis, spleen Lung (117), kidney, renal bed, adrenal, pancreas, spleen, mediastinum, thoracic wall, bone, abdominal lymph nodes Orbits, head and neck, lung, mediastinum, sternum, clavicle, scapula, humerus, rib, spine, abdominal wall, primary kidney tumor Extracranial metastases (171) Primary kidney tumors (33) Spine

Osseous, abdominal lymph nodes, mediastinum/hilum, lung, kidney, adrenal, liver, soft tissue Pelvic bones, femur, spine, lymph nodes

Treated sites (treated lesions), n

Nguyen et al. 2002–2007 48 (55) (2010)

57 (88)

1997–2005 92 (204)

NA

Balagamwala NA et al. (2012)

Gilson et al. (2006)

Teh et al. (2007)

Wersall et al. 1997–2003 58 (162) (2005)

Svedman et al.† (2006)

Zelefsky et al. 2004–2010 55 (105) (2012)

Ranck et al. (2013)

Patients (treated lesions), n 2006–2010 18 (39)

Study (year) Study period

Table 2. Stereotactic ablative body radiation therapy trials in renal cell carcinoma.

[48]

[47]

[46]

[45]

[44]

[43]

[42]

[41]

[40]

Ref.

Extracranial oligometastatic renal cell carcinoma: current management & future directions

Review

767

Review Loh, Davis, Martin & Siva Table 3. Targeted therapy trials in renal cell carcinoma. Targeted agents

Mechanism of action

Trials

Objective response rates (%)

Median progression-free survival (months)

Median overall survival (months)

Ref.

Multikinase inhibitor targeting VEGFR, PDGFR, c-KIT Angiogenesis inhibitor targeting VEGFR, PDGFR and c-KIT mTOR inhibitor

Sunitinib vs IFN-α

31 vs 6

11.0 vs 5.0

26.4 vs 21.8 (ns)

[52]

Pazopanib vs placebo Pazopanib vs sunitinib

30 vs 3 31 vs 25

11.1 vs 2.8 8.4 vs 9.5

NA 28.4 v 29.3

[54]

Temsirolimus vs IFN-α vs both Bevacizumab plus IFN-α vs placebo plus IFN-α Bevacizumab plus IFN-α vs IFN-α Sorafenib vs IFN-α

9 vs 5 vs 8‡

3.8 vs 1.9 vs 3.7‡

10.9 vs 7.3 vs 8.4‡

[55]

31 vs 12

10.2 vs 5.4

23.3 vs 21.3 (ns)

[56]

26 vs 13

8.5 vs 5.2

18.3 vs 17.4

[57]

68 vs 39

5.7 vs 5.6

NA

[58]

Everolimus vs placebo Axitinib vs sorafenib

1 vs 0 (ns) 19 vs 9

4.0 vs 1.9 6.7 vs 4.7

14.8 vs 14.4 (ns) Data not mature

[60]

Sorafenib vs placebo

NA

5.5 vs 2.8

19.3 vs 15.9

[61]

First-line therapy Sunitinib† Pazopanib† Temsirolimus† Bevacizumab† Sorafenib§

Monoclonal antibody targeting VEGFR Small molecule that inhibits multiple isoforms of intracellular serine/threonine kinase and other receptor tyrosine kinases

[53]

Second-line therapy Everolimus† Axitinib† Sorafenib†

mTOR inhibitor Second-generation VEGFR inhibitor Second-generation VEGFR inhibitor

[59]

National Comprehensive Cancer Network category 1 recommendation. Statistically significant results between temsirolimus versus IFN-α only. National Comprehensive Cancer Network category 2A recommendation. NA: Not available; ns: Not statistically significant; PDGFR: PDGF receptor; VEGFR: VEGF receptor. † ‡

§

metastases. Most patients had undergone nephrectomy before targeted therapy in the trials that demonstrated the benefits of targeted agents (Table 3) . Cytoreductive nephrectomy, therefore, continues to be performed in appropriately selected patients. Two ongoing prospective randomized trials (the CARMENA trial [68] and the SURTIME trial [69]), investigating the role and timing of cytoreductive nephrectomy in patients receiving targeted therapy, respectively, are addressing this question. Similarly, there is paucity of data on the efficacy of metastasectomy in the targeted therapy era. A retrospective study by Johannsen et al. investigated discontinuation of targeted therapy in mRCC patients after a duration of therapy ranging from 4 to 26 months. The study focused on patients who achieved complete response with either targeted therapy alone or a combined approach of additional resection of residual metastases. These approaches were followed by recurrence in 66.7% of patients and re-exposure to targeted therapy was effective in 86.9% of cases. The median time without targeted therapies was 7 months [70] . A potential benefit of the

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combined approach is to enable patients a period of time without targeted therapies and thereby mitigate the duration of the sometimes debilitating associated side effects. The evidence for safety with combined modality management with surgery and systemic targeted agents is limited. This evidence is largely retrospective in nature. Increased risk of wound-related complications have been reported in a retrospective study of patients treated with various targeted agents prior to cytoreductive nephrectomy [71] . A prospective Phase II study that investigated the use of two to three cycles of sunitinib prior to cytoreductive nephrectomy reported surgical complication rates of 27% [72] . The majority (16%) had delayed wound healing and there was one death due to respiratory failure. An 18% postoperative complication rate was reported in a retrospective study of patients who underwent metastasectomy of various sites after receiving at least one cycle of targeted therapy [73] . The majority developed chylous ascites after retroperitoneal surgery. There were no bleeding or wound complications seen.


Extracranial oligometastatic renal cell carcinoma: current management & future directions There is potential scope for integration of SABR with targeted therapy for synergistic effect. A Phase II trial investigating the feasibility of concurrent sunitinib and hypofractionated radiation therapy in 25 patients with oligometastases from various primary tumors reported local control rates of 75% at 18 months. The incidence of acute grade ≥3 toxicities was 28%, most commonly myelosuppression, bleeding and abnormal liver function test and there was one grade 5 hemorrhage. Caution will need to be used in these settings as many of the targeted therapies are radiosensitizers. A dose reduction is recommended for sunitinib when used concurrently with radiation therapy, and caution is advised in patients on any form of anticoagulation. Furthermore, the irradiation of large volumes particularly over sensitive structures such as small bowel with concurrent targeted agents is likely to increase the risk of toxicity [74] . Therefore, validation of clinical benefit of concurrent use compared with either SABR or targeted therapy alone in randomized trials is essential. Treatment of a lesion progressing on targeted therapy while other lesions remain controlled is reasonable in the light of the biological differences between metastases in the same patient. This approach also enables the patient to continue on that particular targeted agent and achieve the maximum clinical benefit before moving on to second-line therapy [3] . Conversely, if toxicities from systemic therapies are proving difficult to tolerate, consolidative radiation therapy to residual disease following response to targeted therapy may allow patients a drug holiday. Immunotherapy Defects in many aspects of the immune response are common in RCC [75] . Established tumors in the human host are capable of effective evasion of the tumor-directed immune response. In this setting, radiation therapy has been shown to elicit reactivation of the tumor-directed immune system [76] . The ‘abscopal effect’ is a bystander effect of radiation therapy observed as tumor regression remote from the site of irradiation. The abscopal effect is a rare event, but has been documented in a variety of tumors, including RCC [77] , and can occur with conventionally fractionated radiation therapy as well as SABR. A recent case report of an abscopal effect in a patient with melanoma treated with ipilimumab (an inhibitor of immunologic checkpoint on


Review

T cells) and radiation therapy has further fueled interest in this area [76] . Our own group has demonstrated abscopal effects secondary to SABR of a pulmonary metastasis in the context of nonsmall-cell lung cancer [78] . One series reported on four cases of RCC with an abscopal response out of 28 cases treated with SABR. In three out of the four cases, untreated metastatic disease completely regressed with no evidence of relapse at the time of reporting that ranged from 2 to 4 years post-therapy [79] . One of the proposed mechanisms for the abscopal effect of radiation therapy is the release of antigens and cytokines that can then inhibit tumor growth [80] . The primary driver of increased immune mediated cell death is an enhanced capacity to recognize and mount an adaptive immune response to the established tumor. Direct ionizing radiation elicits innate immune recognition of tumor, in the absence of a pathogen, through the liberation of cellular stress signals collectively termed, ‘danger signals’ [81,82] . In this context, radiation has been shown to profoundly augment T-cell priming and activation in human subjects, leading to elimination of cancer cells in a CD8 + T-cell-dependent manner [83] . Recent evidence suggests that ablative doses of radiation evoke a particularly strong immune response. Lee et al. demonstrated that T cells are required to elicit tumor responses after ablative radiation therapy [84] . Survival after ablative radiation therapy was decreased by more than 75% in mice deficient in CD8 + cells (the major killer T cells). Inhibition of tumor growth was more pronounced with a single dose of 20 Gy compared with a nonablative dose of 5 Gy in four fractions delivered over 2 weeks. These results suggest that a radiation therapy-induced adaptive immune response can be a dose-dependent phenomenon and may result in additional tumor cell kill beyond direct radiation damage to DNA. Conventionally fractionated radiation therapy and adjuvant chemotherapy are speculated to be potentially immunosuppressive [84] . In the former, the fractionated low-dose radiation therapy may deplete radiosensitive T cells over time leading to suppression of the adaptive immune response. In the latter, chemotherapy abolished priming of the CD8 + T cells and forestalled cytotoxic T-cell proliferation, which may lead to increased rates of recurrence. By contrast, immunotherapy given in conjunction with radiation therapy amplified the radiation-mediated immune responses [84] .


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Review Loh, Davis, Martin & Siva These findings have caused a resurgence of interest in exploring immunotherapy in RCC [85] . Recent work has demonstrated that immune tolerance of host tissues including cancer is actively regulated through various ‘immune checkpoint’ molecules, which act to inhibit immune responses including autoimmunity against cancer [85] . There are many such molecules and those of key clinical interest at present include CTLA-4 and PD-1. CTLA-4 moves rapidly to the cell surface on activation of T cells and inhibits T-cell activation. By contrast, PD-1 is expressed mainly on activated lymphocytes and, thus, is relevant at the time the T cell encounters the target it is meant to kill [86] . Activation of PD-1 at that time will protect the cancer from an effective immune response. Ligands for PD-1, such as PD-L1 and PD-L2, are expressed by many tissues including cancer cells. Antibodies against CTLA-4 are now approved for use (e.g., ipilimumab [Yervoy ®, Bristol-Myers Squibb, NJ, USA]) or under development (e.g., tremelimumab [Pfizer Inc./ Medimmune, NY, USA]). Antibodies against PD-1 (e.g., nivolumab [Bristol-Myers Squibb]) or PD-L1 (e.g., BMS-936559/MDX-1105 [BristolMyers Squibb] or MPDL3280A [Roche, NJ, USA]) are also under development. Nivolumab treatment led to objective responses in 27% of RCC patients with an acceptable adverse event profile in a Phase I study [87] . The complementary actions of CTLA-4 and PD-1 make it logical to combine therapies blocking these pathways or to combine them with other therapies. This approach has been shown to be effective in several clinical trials in a range of cancer types [87–90] . These approaches act on the host immune system and there is every reason to be confident that they will be effective in multiple tumor types. Several strategies are of relevance to RCC. For example, the trial that compares the anti-PD-1 antibody nivolumab with the mTOR inhibitor everolimus and has now completed accrual [91] . The anti-CTLA-4 antibody ipilimumab has demonstrated efficacy in RCC [92] . Interestingly, there may be other indirect interactions between therapies for RCC and the immune system. For example, sunitinib has been shown to decrease numbers of immune cells with immunosuppressive effects, prevent development of T-cell unresponsiveness, alter cytokine-expression profiles in favor of an anti-tumor effect, and improve survival of tumor-bearing mice [93] . This study used tumor models other than RCC, but is relevant due to

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the common use of sunitinib in RCC. At least one clinical trial is investigating various combinations of therapies including that of nivolumab plus sunitinib or pazopanib [94] . Other forms of cancer immunotherapy are also relevant in RCC. The cellular immunotherapy AGS-003 has shown promising results in a Phase II trial and a Phase III trial is under development. Seung et al. reported on a Phase I study of metastatic melanoma and RCC patients, in which patients were treated with SABR with one, two or three doses of 20 Gy per fraction followed by IL- 2 administration [95] . Response rates in nonirradiated lesions were higher than expected with combination treatment compared with IL-2 alone. These observations have led to intensified efforts to combine radiation therapy with an immune modifier to increase the effects of radiation therapy through immune responses, such as this trial investigating SABR and anti-CTLA-4 therapy [96] . Conclusion Although mRCC has in the past been associated with poor prognosis, some patients with solitary or limited metastatic disease can survive for long periods. Oligo-mRCC may, in some cases, be a biologically distinct entity with limited capacity to metastasize further. If that is the case then local aggressive therapy may lead to long-term disease control and potential cure. Currently surgery remains at the forefront of potentially curative locally ablative modalities for oligo-mRCC, but with increasing experience in SABR, the dogma that only surgery can afford a potential cure is being challenged. A key challenge continues to be the correct identification of patients who are most likely to benefit from aggressive local therapy. Although advances in imaging techniques have improved the detection of patients with a truly oligometastatic state, the incorporation of molecular classifiers of oligometastases can have a potential role in increasing the accuracy of the identification of such patients. High local control rates are seen with SABR and reported toxicity rates are low. However, in the absence of randomized data, the benefits of SABR or surgery have yet to be validated. Although randomized controlled trials provide the strongest evidence, due to the uncommon scenario and variety of presentations of the oligometastatic state, it can be difficult to conduct such studies in this patient population. Other trial designs that may be more realistic and reflective of the heterogeneity of RCC and its presentations


Extracranial oligometastatic renal cell carcinoma: current management & future directions include N of 1 studies, tissue-based approaches, propensity matched analyses and adaptive design methods. The optimal strategies for combining the different modalities of treatment (surgery, SABR and systemic therapy) in mRCC have yet to be established and current trials are ongoing. Future perspective With increasing use and experience, and in the right context, SABR may be a viable alternative to surgery as local therapy in the management

Review

of oligo-mRCC, particularly as follow-up data matures and the high local control rates are maintained. However, the current experience with SABR is still limited and the duration of patient follow-up is shorter compared with surgery. It is imperative to ensure that careful validation of SABR is performed, including documentation of practice, outcomes, and quality measures; and that appropriate clinical trials are performed in order to provide high-level evidence of its effect before SABR is widely adopted. Further opportunities to

Executive summary Definition ●●

Oligometastases describes an intermediate state of cancer spread in which the number and site of metastatic tumors are limited. The clinical implication of this is that local therapy may be potentially curative.

●●

The clinical entity of oligometastatic renal cell carcinoma is increasingly being recognized, and a subset of patients can potentially achieve long-term survival with aggressive local therapy.

Metastasectomy ●●

Surgical metastasectomy has a long history of use in oligometastatic disease, with the data demonstrating high local control rates and potential survival advantage.

●●

Completeness of resection is a predictor for improved survival.

●●

Stereotactic ablative body radiation therapy results are promising, with high local control rates and low toxicity reported.

●●

However, the stereotactic ablative body radiation therapy experience is still limited with short duration of follow-up compared with surgery.

●●

Currently no randomized evidence exists to support either surgery or stereotactic ablative body radiation therapy in this setting, and clinical decision-making is based on individual patient and tumor characteristics, and clinical judgment.

Targeted therapy ●●

Molecularly targeted agents that act by blocking signal transduction pathways associated with renal cell carcinoma

tumor growth and angiogenesis have demonstrated higher objective response rates compared with cytokine therapy. ●●

The role of local therapies to the primary tumor or metastases in the era of targeted therapy remains undefined. Randomized trials are ongoing.

Immunotherapy ●●

There is increasing recognition of immunologic effects of high-dose radiation, with ongoing research in this area to try to improve the therapeutic ratio with combined treatment.

Challenges ●●

Local aggressive therapies may not benefit all patients, therefore, it is imperative to identify potentially suitable cases.

●●

Selection of the optimal local therapy should be informed by an understanding of the advantages/disadvantages of the different treatment modalities.

●●

The optimal sequencing or integration of systemic and local therapies in this patient cohort is not yet fully understood.

Future perspective ●●

There is a clear need for well controlled prospective evidence to inform treatment options in patients oligometastatic renal cell carcinoma.



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Review Loh, Davis, Martin & Siva improve outcome will arise from combining SABR with other modalities of treatment, including targeted therapies and immunotherapies. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a 11 Gupta GP, Massague J. Cancer metastasis:

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