Stereotactic radiosurgery and stereotactic body radiation therapy (SBRT) have led to a resurgence of the use of radiotherapy in the management of advanced renal cell carcinoma (RCC). These techniques provide excellent local control and palliation of metastatic sites of disease with minimal toxicity. Additionally, SBRT to the primary tumor may be efficacious and well tolerated in select patients that are not surgical candidates. Emerging data suggest that SBRT may potentiate the immune response, and current and future study will evaluate if SBRT can improve survival outcomes in patients with metastatic RCC.
Key points
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The role of radiotherapy in advanced renal cell carcinoma has been increasing since the advent of high-dose-per-fraction treatment techniques.
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Excellent local control rates with minimal toxicity are possible with the use of stereotactic radiosurgery for intracranial metastases and stereotactic body radiation therapy (SBRT) for oligometastases to bone and visceral sites.
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Data are emerging supporting the efficacy and safety of SBRT as management of the primary tumor in select nonsurgical patients.
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Current research is focused on combining SBRT with immune checkpoint inhibitors in patients with metastatic renal cell carcinoma in an effort to potentiate the immune response and improve survival outcomes.
Introduction
Historically the role of radiotherapy (RT) in the management of renal cell carcinoma (RCC) was limited given several negative trials evaluating the effect of RT on survival in the neoadjuvant , and adjuvant , settings for patients with localized disease, and early in vitro studies reporting that RCC is a relatively radioresistant histology. However, as higher-dose-per-fraction treatments became possible through the advent of stereotactic radiosurgery (SRS) for intracranial sites and stereotactic body radiation therapy (SBRT; synonymous with stereotactic ablative RT) for extracranial sites, there has been a resurgence of interest in RT for RCC. There are now published experiences showing the utility of RT in the treatment of RCC in a variety of clinical scenarios, including SBRT for RCC limited to the kidney, , SBRT for locally advanced (LA) RCC, , SRS for brain metastasis from RCC, and SBRT for extracranial metastasis from RCC. This article reviews the role of RT in patients with advanced RCC, including LA disease (≥T3 or >N0, M0) as well as metastatic RCC (mRCC), and ongoing efforts to optimize the incorporation of RT into the multimodality treatment paradigm for patients with mRCC to improve survival outcomes.
Radiotherapy in locally advanced renal cell carcinoma
Approximately 16% of patients with RCC present with LA, stage III disease. Upfront radical nephrectomy remains the standard of care, followed by adjuvant sunitinib in select cases with clear cell histology. However, recurrences after nephrectomy can be seen in up to 40% of LA RCC, with a predominantly distant pattern of recurrence. Treatment options for recurrent RCC include further surgery or radiation if local recurrence or systemic therapy.
RT has a limited role in LA RCC given the negative historical trials in this patient population. The role of neoadjuvant radiation therapy for surgical downstaging was investigated in the 1960s and 1970s, including 2 prospective clinical trials that compared neoadjuvant radiation therapy and upfront surgery. Both studies did not show an overall survival benefit at 5 years. , Similarly, the role of adjuvant radiation therapy was explored in 2 prospective clinical trials and failed to show a survival benefit, at least in part because of significant complication rates. , In a more recent meta-analysis including these trials and other retrospective studies, adjuvant radiation therapy was associated with a significant reduction in locoregional failure, but no survival benefit. However, this analysis is limited by many of the included studies using outdated RT techniques and only a few studies being prospective. However, based on these data, current guidelines do not support routine fractionated radiation therapy in the neoadjuvant and adjuvant settings.
More recently, advanced radiation techniques have been evaluated in the treatment of RCC. Intraoperative radiation therapy (IORT) allows precise localization of the tumor bed while minimizing radiation dose to the surrounding normal organs. This approach was studied in multiple retrospective series, the largest of which was a multicenter cohort of 98 patients, 71% of whom had T3 to T4 disease. More than half of these patients received either neoadjuvant or adjuvant external beam RT, and 5-year disease-free survival was favorable compared with surgery alone, although in general isolated local recurrence is a rare event even in patients with LA RCC. Given the lack of prospective evidence and no indication of an overall survival benefit, IORT is not routinely indicated in current guidelines.
Prospective data are emerging to support consideration of SBRT to the primary tumor as an option for patients with LA RCC who are not operable candidates. Treatment of the primary RCC tumor with SBRT is associated with excellent rates of local control for T1 to T2 lesions (local control rates of 70%–100% in a systematic review) and thus has been gaining interest in recent years for early-stage disease. However, extrapolation of this technique to LA RCC should be done with caution because it is not as well characterized in this patient population. One phase I dose escalation study included patients with up to T3 tumors, and none of the 15 patients with evaluable response had progressive disease, although outcomes for the subset with T3 tumors were not reported. Most other prospective studies of SBRT for localized RCC did not report T stage, , , although some of these studies did include tumors larger than 5 cm , , and thus possibly some LA cases.
Data for SBRT specifically in T3 or greater tumors is largely restricted to reported outcomes in the small subset of LA patients included in some cohorts. In a dose escalation study of SBRT for RCC, 1 patient with T4 disease had local progression 11 months after treatment with SBRT (8 Gy in 5 fractions), which was successfully salvaged with repeat irradiation to the same dose and fractionation. Three patients with T3 disease in 2 other studies showed no disease progression after follow-up of greater than 1 year. , The largest series of patients with LA tumors was published by Wang and colleagues, who evaluated the efficacy of SBRT for patients with asynchronous bilateral RCC who previously had nephrectomy and developed a second primary in the contralateral kidney. Of the 4 patients with T3a tumors included, 3 had no local relapse at 3, 6, and 29 months of follow-up and 1 had local relapse at 12 months. One patient with T4 disease was included, who experienced local failure 6 months after treatment. However, the study is limited by its small fractionation size (3–5 Gy/fraction) with an extended fractionation scheme (10–17 fractions) and use of a gamma body irradiator.
Although small retrospective and prospective studies are accumulating to support a role for SBRT to the primary tumor in early-stage RCC, data for patients with LA RCC are therefore limited, and the potential toxicities associated with treating these larger tumors have not been well described. Responses in the reported cases suggest that SBRT may provide a benefit in terms of local control and palliation of symptoms in LA RCC, although further studies are warranted.
Radiotherapy in metastatic renal cell carcinoma
Management of Central Nervous System Metastasis
Although the rate of brain metastasis development in all patients with mRCC is approximately 2%, up to 16% of patients with thoracic and bone metastasis develop intracranial metastasis. The development of brain metastases is associated with clear cell histology, sarcomatoid differentiation, larger tumor size, and node-positive disease at diagnosis. In an epidemiologic evaluation of intracranial RT use in mRCC, the frequency of SRS use for brain metastasis from RCC increased from 27% in 2005 to 44% in 2014, and this trend was associated with improved overall survival.
Local control rates with SRS for RCC brain metastasis are excellent, and generally approach or exceed 90% at 1 year ( Table 1 ). , The largest study to date evaluating SRS for RCC brain metastasis is reported by Kano and colleagues, who examined 531 lesions treated in 158 patients. With a median marginal dose of 18 Gy (range 10–22 Gy), the local control at 1 year was 87%, although survival at 1 year was only 38%. No studies are available evaluating survival of patients treated with SRS for RCC brain metastasis who are receiving modern systemic therapy (either ipilimumab/nivolumab or pembrolizumab/axitinib), but improved survival would be expected in this setting because most deaths in patients receiving radiosurgery for brain metastasis are attributable to non-neurologic causes, particularly for patients with limited (<4) brain metastasis. ,
| Author (Year) | Patients (Number of Lesions) | Sites Treated | Marginal Dose in Gy (Range) | Median Follow-up (mo) | 1-y LC (%) | Toxicity |
|---|---|---|---|---|---|---|
| Schöggl et al, 1998 | 23 (44) | Brain | Median 18 (8–30) | NR | NR (crude rate 100) | 9% peritumoral edema 4% radionecrosis |
| Goyal et al, 2000 | 29 (66) | Brain | Median 18 (7–24) | 7 | 85 | 14% radiation necrosis |
| Payne et al, 2000 | 21 (37) | Brain | Mean 20 (11–40) | NR | NR (crude rate 100) | 0% radiation toxicity |
| Amendola et al, 2000 | 22 (131) | Brain | Mean 18 (15–22); unknown whether marginal | NR | NR (crude rate 91) | 5% radiation necrosis |
| Ikushima et al, 2000 | 10 (24) | Brain | All 42 Gy in 7 fractions to isocenter | 5 | 90 | 0% acute or late toxicity |
| Hernandez et al, 2002 | 29 (92) | Brain | Median 17 (13–30) | 7 | 100 | NR |
| Hoshi et al, 2002 | 42 (113) | Brain | Median 25 (20–30) | 10 | 91 | 1 mortality secondary to tumor hemorrhage |
| Noel et al, 2004 | 28 (65) | Brain | Median 17 (11–22) to isocenter | 14 | 93 | 4% radionecrosis 4% seizure 4% tumor hemorrhage |
| Muacevic et al, 2004 | 85 (376) | Brain | Median 21 (15–35) | 11 | 94 | 4% grade V toxicity caused by tumor hemorrhage 13% symptomatic radiation toxicity |
| Samlowski et al, 2008 | 32 (71) | Brain | NR (15–24) | NR | 86 | 6% symptomatic radiation necrosis |
| Shuto et al, 2010 | 105 (444) | Brain | Mean 22 (8–30) | 7 | 71 | 2% tumor hemorrhage requiring surgery 5% peritumoral edema |
| Fokas et al, 2010 | 68 (81) | Brain | Median 19 (15–22) | NR | 83 | 2% grade III acute toxicity with SRS only, 3% with SRS + WBRT, overall 3% acute toxicity 4% grade III late toxicity with SRS only, 5% with SRS + WBRT, overall 6% late toxicity |
| Kano et al, 2011 | 158 (531) | Brain | Median 18 (10–22) | 8 | 87 | 7% symptomatic adverse effects 6% tumor hemorrhage |
| Staehler et al, 2011 | 51 (135) | Brain | Median 20 (20–20) | 16 | 100 | 4% grade II tumor hemorrhage 6% grade II convulsions |
| Cochran et al, 2012 | 61 (124) | Brain | Median 20 (13–24) | 9 | 93 | 10% radiation-induced edema or necrosis 3% hemorrhage |
| Kim et al, 2012 | 46 (99) | Brain | Mean 21 (12–25) | NR | NR (crude rate 85) | 2% symptomatic tumor hemorrhage 2% hydrocephalus |
| Meyer et al, 2018 a | 82 (120) | Brain | Median BED 3 75.1 Gy (SD 21.2) | 13 | 82 | Including extracranial metastasis 50% grade I–II toxicity (asthenia, nausea, dyspnea, headache) 5% grade III toxicity (esophageal fistula, seizure, intratumoral hemorrhage, and increased ICP) |
| Stenman et al, 2018 a | 31 (167) | Brain | Median 22 Gy (16.5–35.5) | 63 (for all patients) | NR (crude rate 96) | NR for entire cohort For all patients receiving targeted agents, 30% grade II–III toxicity (seizure, fatigue, pneumonitis most common) |
| Gerszten et al, 2005 | 48 (60) | Spine | Mean 16 Gy in 1 fraction | 37 | 96 | 0% radiation toxicity |
| Wersall et al, 2005 | 50 (154) | 117 lung, 6 adrenal gland, 12 kidney metastases, 5 thoracic wall, 4 bone, 3 mediastinum, 3 abdominal lymph gland, 2 liver, 1 spleen, 1 pancreas | Modal: 32 Gy in 4 fractions, 40 Gy in 4 fractions, and 45 Gy in 3 fractions | 37 | 99 | 40% any toxicity 2% grade V toxicity |
| Svedman et al, 2006 | 26 (77) | 63 lung/mediastinum, 5 kidney metastases, 5 adrenal, 4 thoracic wall, 3 abdominal glands, 3 liver, 1 pelvis, 1 spleen | 40 Gy in 4 fractions | 52 | 100 | 58% grade I–II toxicity 4% Grade V toxicity |
| Teh et al, 2007 | 14 (23) | Orbits, head and neck, lung, mediastinum, sternum, clavicle, scapula, humerus, rib, spine, abdominal wall | Modal 24 Gy in 3 fractions | 9 | 81 | No grade 2 or higher toxicity |
| Nguyen et al, 2010 | 48 (55) | Spine | Modal 27 Gy in 3 fractions | 13 | 80 | No grade 3 or 4 neurologic toxicity 23% grade I fatigue 13% grade II fatigue 11% grade II nausea 7% grade II vomiting 2% grade III pain 2% grade III anemia |
| Staehler et al, 2011 | 55 (105) | Spine | Median 20 Gy in 1 fraction | 33 | 94 | 2% grade I abdominal pain |
| Balagamwala et al, 2012 | 57 (88) | Spine | Median 15 Gy in 1 fraction (unknown whether marginal) | 5 | 50 | 33% any toxicity 10.5% grade 1 fatigue 2% grade 3 nausea/vomiting 8% pain flare |
| Jhaveri et al, 2012 | 18 (24) | 14 spine, 4 ribs/clavicle, 6 pelvis | Modal 40 Gy in 5 fractions | 10 | NR | 6% grade I toxicity |
| Zelefsky et al, 2012 | 55 (105) | 59 spine, 22 pelvic bones, 14 other, 9 femur, 1 lymph node | Modal 24 Gy in 1 fraction | 12 | 72 | 4% grade 2 dermatitis 7% fractures 2% grade 4 erythema |
| Ranck et al, 2013 | 18 (39) | 11 bone, 10 abdominal lymph node, 7 mediastinum/hilum, 4 lung, 2 kidney metastases, 2 adrenal, 2 liver, 1 soft tissue | Modal 50 Gy in 10 fractions, (unknown whether marginal) | 16 | 96 | 61% grade I fatigue 11% grade 1 rib fracture 6% grade 2 radiculitis 6% grade 2 bone pain |
| Wang et al, 2017 | 84 (184) | 49 abdomen, 42 spine, 35 thorax, 25 nonspine, 16 soft tissue, 5 kidney, 3 spinal cord | Median 11 Gy in median 3 fractions | 16 | 91 | 4% acute grade 3 toxicity (progressive pain and UTI) 2% late grade 3 toxicity (gastrointestinal bleed, compression fracture, and radiculopathy) |
| Meyer et al, 2018 a | 109 (132) | 75 spine, 11 nonspine bone and soft tissue, 46 visceral metastases | Median BED 3 90.6 Gy (SD 55.1) including brain metastasis | 13 | 84 | Including brain metastasis 50% grade I–II toxicity (asthenia, nausea, dyspnea, headache) 5% grade III toxicity (esophageal fistula, seizure, intratumoral hemorrhage, and increased ICP) |
| Stenman et al, 2018 a | 65 (117) | 68 lung, 18 lymph node, 7 adrenal, 5 kidney, 5 liver, 5 soft tissue, 4 bone, 4 local recurrence, 1 other | Modal 45 Gy in 3 fractions, unknown whether marginal) | 63 (for all patients) | NR (crude rate 76) | NR for entire cohort For all patients receiving targeted agents, 30% grade II–III toxicity (seizure, fatigue, pneumonitis most common) |
| Franzese et al, 2019 | 58 (73) | 39 lungs, 19 lymph nodes, 7 bone, 5 adrenal, 3 liver | Median 45 Gy in 5 fractions | 16 | 90 | 12% acute grade 1 toxicity (fatigue, pain, and nausea) 7% late grade 1–2 pneumonitis |
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