Safety and Efficacy of Stereotactic Ablative Radiation Therapy for Renal Cell Carcinoma Extracranial Metastases

doi:10.1016/j.ijrobp.2017.01.032

International Journal of Radiation OncologyBiologyPhysics

Volume 98, Issue 1, 1 May 2017, Pages 91-100

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https://doi.org/10.1016/j.ijrobp.2017.01.032 Get rights and content

Purpose

Renal cell carcinoma is refractory to conventional radiation therapy but responds to higher doses per fraction. However, the dosimetric data and clinical factors affecting local control (LC) are largely unknown. We aimed to evaluate the safety and efficacy of stereotactic ablative radiation therapy (SAbR) for extracranial renal cell carcinoma metastases.

Methods and Materials

We reviewed 175 metastatic lesions from 84 patients treated with SAbR between 2005 and 2015. LC and toxicity after SAbR were assessed with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Predictors of local failure were analyzed with χ², Kaplan-Meier, and log-rank tests.

Results

In most cases (74%), SAbR was delivered with total doses of 40 to 60 Gy, 30 to 54 Gy, and 20 to 40 Gy in 5 fractions, 3 fractions, and a single fraction, respectively. The median biologically effective dose (BED) using the universal survival model was 134.5 Gy. The 1-year LC rate after SAbR was 91.2% (95% confidence interval, 84.9%-95.0%; median follow-up, 16.7 months). Local failures were associated with prior radiation therapy (hazard ratio [HR], 10.49; P<.0001), palliative-intent radiation therapy (HR, 4.63; P=.0189), spinal location (HR, 5.36; P=.0041), previous systemic therapy status (0-1 vs >1; HR, 3.52; P=.0217), and BED <115 Gy (HR, 3.45; P=.0254). Dose received by 99% of the target volume was the strongest dosimetric predictor for LC. Upon multivariate analysis, dose received by 99% of the target volume greater than BED of 98.7 Gy and systemic therapy status remained significant (HR, 0.12 and 3.64, with P=.0014 and P=.0472, respectively). Acute and late grade 3 toxicities attributed to SAbR were observed in 3 patients (1.7%) and 5 patients (2.9%), respectively.

Conclusions

SAbR demonstrated excellent LC of metastatic renal cell carcinoma with a favorable safety profile when an adequate dose and coverage were applied. Multimodality treatment with surgery should be considered for reirradiation or vertebral metastasis. A higher radiation dose may be required in patients who received previous systemic therapies.

Introduction

The standard of care for metastatic renal cell carcinoma (mRCC) is systemic therapy, whereas local treatment still remains controversial. A surgical series suggested that selected patients receiving curative-intent metastasectomy survived with a longer disease-free interval compared with patients who had not received it (1). Another series showed improved survival after resections of multiple limited metastases (2). The Mayo Clinic reviewed 887 mRCC patients and found improved cancer-specific survival with complete metastasectomy compared with less aggressive surgery, especially for pulmonary metastases (3). These findings suggested that selected patients with oligometastatic mRCC disease (4) can survive longer with improved quality of life when treated with complete metastasectomy (5).

Radiation therapy has historically been used for palliative purposes, and its practice in renal cell carcinoma (RCC) has been limited by perceived radioresistance to conventional fractionation (6). “Radioresistance” may be overcome with dose escalation, particularly by increasing the dose per fraction (7), as suggested by studies in preclinical models of human RCC xenografts (8). Stereotactic ablative radiation therapy (SAbR), or stereotactic body radiation therapy, has shown encouraging efficacy in mRCC 9, 10. SAbR relies on sophisticated image guidance and immobilization devices to deliver highly conformal ablative radiation doses to the tumor while sparing surrounding organs. However, factors associated with failure in mRCC are poorly understood. We report the safety and efficacy of SAbR and highlight its limitations for extracranial mRCC.

Section snippets

Patients

We retrospectively reviewed patients with extracranial mRCC treated with SAbR between 2005 and 2015 at our institution with >2 months’ follow-up (to obtain a scan to assess efficacy). Conventional fractionated radiation therapy and intracranial lesions were excluded. Pathologic confirmation was required to establish metastases. Patients treated with SAbR were divided into 2 radiation therapy intent categories: “curative,” in which all progressing lesions were treated, and “palliative,” in which

Tumor characteristics and radiation therapy regimens

Lesions (N=175) were identified from 84 patients treated over 124 SAbR sessions (Table 1). Most patients (72.6%) had localized disease at initial presentation but later had metastases develop. Most lesions (90%) were detected in patients with favorable or intermediate International Metastatic Renal Cell Carcinoma Database Consortium prognosis groups at the time of diagnosis with metastatic disease. The median dose per fraction was 11 Gy, and the median fraction number was 3. The median target

Discussion

We conducted a detailed analysis of our institutional SAbR experience for extracranial mRCC and showed satisfactory LC rates, confirming SAbR's safety and efficacy as a local therapy. More than half of the analyzed lesions were located in regions with significant internal motion (eg, chest, abdomen, or kidney). Despite the internal motion, adequate LC was achieved, indicating that modern radiation therapy techniques can accurately treat moving targets. A recent experience from the University of

Conclusions

SAbR exerts favorable LC with minimum acute and late complications and should be considered a treatment modality in selected RCC patients with limited metastases. No failures were observed when SAbR regimens of 24 Gy in 1 fraction, 12 Gy in 3 fractions, or 8 Gy in 5 fractions were used with ≥95% PTV coverage. These regimens may have been underestimated, as longer follow-up periods may result in additional failures. Lesions in patients in whom systemic therapy failed may require a higher dose.

Acknowledgments

The authors thank Dr. Damiana Chiavolini for scientific editing of the manuscript.

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Stereotactic body radiation therapy is effective for the local management of oligometastases (at most five metastases) with a benefit in survival and local control. Most studies on the management of oligometastases focus on all oligometastatic sites in primary cancer and very few focus on a single oligometastatic site. In particular, there are few data on bone oligometastases, which represent one of the preferred sites for secondary cancer locations. This article focuses on the benefit of stereotactic radiotherapy for bone oligometastases of all cancers by histological types, and reviews the results of major studies in this field.
La radiothérapie stéréotaxique a fait ses preuves dans la prise en charge locale des oligométastases (au plus cinq métastases) avec un bénéfice sur la survie et le contrôle local. La plupart des études sur les oligométastases s’intéressent à l’ensemble des sites oligométastatiques d’un cancer primitif et très peu s’intéressent à un seul site oligométastatique. En particulier, il existe peu de données sur les oligométastases osseuses, qui représentent un des sites privilégiés de localisations secondaires cancéreuses. Cet article s’intéresse au bénéfice de la radiothérapie stéréotaxique des oligométastases osseuses tous cancers confondus et par types histologiques, et reprend les résultats des grands essais dans ce domaine.
Stereotactic Body Radiotherapy for Kidney Cancer: Ready for Prime Time?
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The standard treatment for renal cell carcinoma (RCC) is surgery. However, a number of patients will not be candidates for surgical treatment or will reject this therapeutic approach. Therefore, alternative approaches are required. Historically, radiotherapy has been considered an ineffective treatment for RCC due to the radioresistance of renal tumour cells to conventional fractionation and the increased rate of toxicity. Stereotactic body radiotherapy (SBRT) is a radiotherapy technique that provides a non-invasive ablative treatment with remarkable rates of local control in both primary tumours and metastases in several locations, with a low associated morbidity due to the highly conformal dose and the use of image-guided techniques. Current evidence shows that a higher dose per fraction, achieving a higher biological effective dose, can overcome the radioresistance of RCC cells. Therefore, SBRT, as well as the combination of SBRT and new emerging immune therapies, has a potential role in the local treatment of primary RCC and oligometastatic RCC patients.
French AFU Cancer Committee Guidelines - Update 2022-2024: management of kidney cancer
2022, Progres en Urologie
Citation Excerpt :
Surgery is not the first-line treatment for single brain metastases for which stereotactic radiotherapy is often chosen [313]. Stereotactic radiotherapy has demonstrated superiority over conventional fractionated radiotherapy with a high rate of local control (> 90%) and low morbidity [314–318]. In oligometastatic contexts (≤ 5 metastases), complete treatment of all metastatic sites with stereotactic radiotherapy could provide a benefit in progression-free survival and disease-specific survival compared to no treatment or incomplete treatment [319].
To update the recommendations for the management of kidney cancers.
A systematic review of the literature was conducted from 2015 to 2022. The most relevant articles on the diagnosis, classification, surgical treatment, medical treatment and follow-up of kidney cancer were selected and incorporated into the recommendations. Therefore, the recommendations were updated while specifying the level of evidence (high or low).
The gold standard for the diagnosis and evaluation of kidney cancer is contrast-enhanced chest and abdominal CT. MRI and contrast-enhanced ultrasound are indicated in special cases. Percutaneous biopsy is recommended in situations where the results will influence the therapeutic decision. Renal tumours should be classified according to the pTNM 2017 classification, the WHO 2022 classification and the ISUP nucleolar grade. Metastatic kidney cancer should be classified according to the IMDC criteria. Partial nephrectomy is the gold standard treatment for T1a tumours and can be performed by an open approach, by laparoscopy or by robot-guidance. Active surveillance of tumours less than 2 cm in size can be considered regardless of the patient's age. Ablative therapies and active surveillance are options in elderly patients with comorbidity. T1b tumours should be treated by partial or radical nephrectomy depending on the complexity of the tumour. Radical nephrectomy is the first-line treatment for locally advanced cancers. Adjuvant treatment with pembrolizumab should be considered in patients at intermediate and high risk for recurrence after nephrectomy. In metastatic patients: Immediate cytoreductive nephrectomy may be offered to oligometastatic patients in combination with local treatment of metastases if this can be complete and delayed cytoreductive nephrectomy can be proposed for patients with a complete response or a significant partial response. Medical treatment should be proposed as first-line therapy for patients with a poor or intermediate prognosis. Surgical or local treatment of metastases can be proposed in case of single or oligo-metastases. The recommended first-line drugs for metastatic patients with clear cell renal carcinoma are the combinations axitinib/pembrolizumab, nivolumab/ipililumab, nivolumab/cabozantinib and lenvatinib/pembrolizumab. Cabozantinib is the recommended first-line treatment for patients with metastatic papillary carcinoma. Cystic tumours should be classified according to the Bosniak classification. Surgical removal should be proposed as a priority for Bosniak III and IV lesions. It is recommended that patient monitoring be adapted to the aggressiveness of the tumour.
These updated recommendations are a reference that will allow French and French-speaking practitioners to improve kidney cancer management.
Mettre à jours les recommandations sur la prise en charge des cancers du rein.
Une revue systématique de la littérature a été faite sur la période allant de 2015 à 2022. Les articles jugés les plus pertinents concernant le diagnostic, la classification, le traitement chirurgical, le traitement médical et le suivi du cancer du rein ont été sélectionnés et incorporés aux recommandations. Les recommandations ont ainsi été actualisées en spécifiant le niveau de preuve (fort ou faible).
L’examen de référence pour faire le diagnostic et le bilan d’extension des cancers du rein est le scanner thoraco-abdominal injecté. L’IRM et l’échographie de contraste sont indiquées dans certains cas particuliers. La biopsie percutanée est recommandée dans les situations où ses résultats influenceront la décision thérapeutique. Les tumeurs du rein doivent être classées selon la classification pTNM 2017, la classification OMS 2022 et le grade nucléolaire de l’ISUP. Les cancers du rein métastatiques doivent être classés selon les critères de l’IMDC. La néphrectomie partielle est le traitement de références des tumeurs T1a et peut être faite par voie ouverte, laparoscopique ou robotique. La surveillance active des tumeurs de moins de 2 cm peut être proposée quel que soit l’âge du patient. Les thérapies ablatives et la surveillance active sont des options chez les patients âgés avec des comorbidités. Les tumeurs T1b doivent être traitées par néphrectomie partielle ou totale en fonction de la complexité tumorale. La néphrectomie totale est le traitement de première intention des cancers localement avancés. Le pembrolizumab est une option à considérer chez les patients à haut risque de récidive après chirurgie d’un cancer du rein localisé. Chez les patients métastatiques: la néphrectomie cytoréductrice peut être proposée en cas de bon pronostic et la néphrectomie de clôture peut être proposée chez les patients en réponse complète ou en réponse partielle majeure ; le traitement médical doit être proposé en première intention en cas de pronostic mauvais ou intermédiaire. Le traitement chirurgical ou local des métastases peut être proposé en cas de lésion unique ou d’oligo-métastases. Les molécules recommandées en première ligne chez les patients métastatiques atteints d’un carcinome rénal à cellules claires sont les associations axitinib/pembrolizumab, nivolumab/ipilimumab, nivolumab/cabozantinib et lenvatinib/pembrolizumab. Le cabozantinib est le traitement de première ligne recommandé chez les patients atteints d’un cancer papillaire métastatique. Les tumeurs kystiques doivent être classées selon la classification de Bosniak. L’exérèse chirurgicale doit être proposée en priorité aux lésions Bosniak III et IV. Il est recommandé de suivre les patients en adaptant les modalités à l’agressivité tumorale.
Ces recommandations actualisées sont un référentiel qui permettra aux praticiens français et francophones d’encadrer au mieux leur prise en charge des cancers du rein.
Recommendations for stereotactic body radiation therapy for spine and non-spine bone metastases. A GETUG (French society of urological radiation oncolgists) consensus using a national two-round modified Delphi survey
2022, Clinical and Translational Radiation Oncology
The relevance of metastasis-directed stereotactic body radiation therapy (SBRT) remains to be demonstrated through phase III trials. Multiple SBRT procedures have been published potentially resulting in a disparity of practices. Therefore, the french society of urological radiation oncolgists (GETUG) recognized the need for joint guidelines for metastasis-directed SBRT in order to standardize practice in trials carried out by the group.
After a comprehensive litterature review, 97 recommandation statements were created regarding planning and delivery of spine bone (SBM) and non-spine bone metastases (NSBM) SBRT. These statements were then submitted to a national online two-round modified Delphi survey among main GETUG investigators. Consensus was achieved if a statement received ≥ 75 % agreements, a trend to consensus being defined as 65–74 % agreements. Any statement without consensus at round one was re-submitted in round two.
Tweny-one out of 29 (72.4%) surveyed GETUG investigators responded to both rounds. Consensus was achieved for 91/97 statements (93.8%) allowing the edition of comprehensive guidelines encompassing all aspects of SBM and NSBM SBRT planning and delivery: patients selection (19 statements), treatment preparation (14 statements), target volume delineation (18 statements), dose and fractionation (11 statements), prescription and dose objectives (9 statements), organs at risk dose constraints (15 statements) and image guided radiation therapy (11 statements).
GETUG guidelines for SBM and NSBM SBRT were agreed upon using a validated modified Delphi approach. These guidelines will be used as per-protocol recommendations in ongoing and further GETUG clinical trials.
Definitive radiotherapy in lieu of systemic therapy for oligometastatic renal cell carcinoma: a single-arm, single-centre, feasibility, phase 2 trial
2021, The Lancet Oncology
The role of radiotherapy in metastatic renal cell carcinoma is controversial. We prospectively tested the feasibility and efficacy of radiotherapy to defer systemic therapy for patients with oligometastatic renal cell carcinoma.
This single-arm, phase 2, feasibility trial was done at one centre in the USA (The MD Anderson Cancer Center, Houston, TX, USA). Patients (aged ≥18 years) with five or fewer metastatic lesions, an Eastern Cooperative Oncology Group status of 0–2, and no more than one previous systemic therapy (if this therapy was stopped at least 1 month before enrolment) without limitations on renal cell carcinoma histology were eligible for inclusion. Patients were treated with stereotactic body radiotherapy (defined as ≤5 fractions with ≥7 Gy per fraction) to all lesions and maintained off systemic therapy. When lesion location precluded safe stereotactic body radiotherapy, patients were treated with hypofractionated intensity-modulated radiotherapy regimes consisting of 60–70 Gy in ten fractions or 52·5–67·5 Gy in 15 fractions. Additional rounds of radiotherapy were allowed to treat subsequent sites of progression. Co-primary endpoints were feasibility (defined as all planned radiotherapy completed with <7 days unplanned breaks) and progression-free survival. All efficacy analyses were intention-to-treat. Safety was analysed in the as-treated population. A second cohort, with the aim of assessing the feasibility of sequential stereotactic body radiotherapy alone in patients with low-volume metastatic disease, was initiated and will be reported separately. This study is registered with ClinicalTrials.gov, NCT03575611.
30 patients (six [20%] women) were enrolled from July 13, 2018, to Sept 18, 2020. All patients had clear cell histology and had a nephrectomy before enrolment. All patients completed at least one round of radiotherapy with less than 7 days of unplanned breaks. At a median follow-up of 17·5 months (IQR 13·2–24·6), median progression-free survival was 22·7 months (95% CI 10·4–not reached; 1-year progression-free survival 64% [95% CI 48–85]). Three (10%) patients had severe adverse events: two grade 3 (back pain and muscle weakness) and one grade 4 (hyperglycaemia) adverse events were observed. There were no treatment-related deaths.
Sequential radiotherapy might facilitate deferral of systemic therapy initiation and could allow sustained systemic therapy breaks for select patients with oligometastatic renal cell carcinoma.
Anna Fuller Foundation, the Cancer Prevention and Research Institute of Texas (CPRIT), and the National Cancer Institute.
Active Surveillance in Metastatic Renal Cell Carcinoma: Results From the Canadian Kidney Cancer Information System
2021, Clinical Genitourinary Cancer
Citation Excerpt :
In our study, we could not assess the role of ablative radiotherapy, as this information was not specifically captured in the CKCis database. Nevertheless, it is reasonable to conclude that ablative radiotherapy could provide similar results as previously reported in several retrospective analyses.16-18 In our study we found that there was no significant difference in the number of cytoreductive nephrectomies between patients on AS and those assigned for immediate therapy.
Active surveillance (AS) is a commonly used strategy in patients with slow-growing disease. We aimed to assess the outcomes and safety of AS in patients with metastatic renal cell carcinoma (mRCC).
We used the Canadian Kidney Cancer information system (CKCis) to identify patients with mRCC diagnosed between January 1, 2011, and December 31, 2016. The AS strategy was defined as (1) the start of systemic therapy ≥ 6 months after diagnosis of mRCC, or (2) never receiving systemic therapy for mRCC with an overall survival (OS) of ≥1 year. Patients starting systemic treatment <6 months after diagnosis of mRCC were defined as receiving immediate systemic treatment. OS and time until first-line treatment failure (TTF) were compared between the two cohorts.
A total of 853 patients met the criteria for AS (cohort A). Of these, 364 started treatment >6 months after their initial diagnosis (cohort A1) and 489 never started systemic therapy (cohort A2); 827 patients received immediate systemic treatment (cohort B). The 5-year OS probability was significantly greater for cohort A than for cohort B (70% vs. 33.6%; P < .0001). After adjusting for International Metastatic RCC Database Consortium risk criteria and age, both OS (hazard ratio [HR] = 0.58; 95% confidence interval [CI], 0.47-0.70; P < .0001) and TTF (HR = 0.72; 95% CI, 0.60-0.85; P = .0002) were greater in cohort A1 compared with B. For cohort A1, the median time on AS was 14.2 months (range, 6-71).
Based on the largest analysis of AS in mRCC to date, our data suggest that a subset of patients may be safely observed without immediate initiation of systemic therapy.

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: Note—An online CME test for this article can be taken at http://astro.org/MOC.

: Conflict of interest: none.

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Clinical InvestigationSafety and Efficacy of Stereotactic Ablative Radiation Therapy for Renal Cell Carcinoma Extracranial Metastases

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Patients

Tumor characteristics and radiation therapy regimens

Discussion

Conclusions

Acknowledgments

Lancet Oncol

Int J Radiat Oncol Biol Phys

J Urol

Eur Urol

Pract Radiat Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Lancet Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Radiother Oncol

Resection of metastatic renal cell carcinoma

J Clin Oncol

Clinical Investigation
Safety and Efficacy of Stereotactic Ablative Radiation Therapy for Renal Cell Carcinoma Extracranial Metastases