(UroToday.com) The 2023 American Society of Clinical Oncology (ASCO) annual meeting held in Chicago, IL between June 2nd and June 6th was host to an oligometastatic renal cell carcinoma (RCC) session. Dr. Raquibul Hannan discussed the role of stereotactic ablative body radiotherapy in this setting.
Dr. Hannan began with a case presentation of a 64-year-old female with an incidentally found 8 cm renal mass. On staging work-up with a CT scan, the patient was found to have a 2 cm rib lesion, that was biopsy-confirmed clear cell RCC. The patient was also found to have a single pulmonary metastatic lesion in the left lung lower lobe. By the International Metastatic RCC Database Consortium (IMDC) risk criteria, the patient was deemed IMDC intermediate risk (1 risk factor). Dr. Hannan suggested that treatment options in this setting include:
- Radical nephrectomy and stereotactic body radiation therapy (SBRT) to both remaining sites
- SBRT to all three sites
- Cytoreductive SBRT plus systemic therapy
RCC has historically been considered a radio-resistant malignancy. However, this only be applicable to historical conventionally fractionated, low-dose regimens. This does not apply to SBRT, however, which relies on high ablative tumor-killing doses, that are administered in a precise and focused fashion that minimizes surrounding toxicity (<5%). SBRT is typically administered in 1-5 fractions/settings, and is a non-invasive, convenient, and cost-effective modality in clinical practice with high control rates of >90% for both primary and metastatic RCC.1,2
What is the safety and efficacy of SBRT for RCC metastases? A single institutional review of 175 lesions in 84 patients demonstrated that the local control rate is 91% with a median follow-up of 16.7 months. Acute and late grade 3 toxicities were 1.7% and 2.9%, respectively. Factors associated with worse local control included:3
- Spinal location
- Repeat irradiation
- Dosimetry (D99 and dose/fx)
- Receipt of prior systemic therapy
A systematic review of 28 studies (1,602 patients with 3,892 lesions treated with SBRT) similarly demonstrated that the pooled local control rate at one year is 89% (95% CI: 84% - 94%). Any grade 3-4 toxicity occurred in 0.7% of patients (95% CI: 0 – 2.1%). One of the main limitations of these studies is the lack of long-term follow-up with local control and toxicity rates only evaluable in the short-term setting (1-3 years).
What is the rationale for metastasis-directed therapy (MDT) for oligometastatic RCC? It is clear that not all metastatic RCC patients fare the same. The IMDC risk stratification of metastatic RCC patients receiving VEGF-targeted therapies clearly demonstrated that favorable-intermediate risk patients can have median overall survivals in excess of 3 years.4 Similarly, Rini et al. have demonstrated that active surveillance for select metastatic RCC patients is feasible with a median delay to systemic therapy of 14.9 months.5 As such, it is clear that there is a subset of metastatic RCC patients that have favorable prognoses and that can be managed with MDT in the form of SBRT. This is further supported by results of a systematic review that demonstrated that a complete metastasectomy is associated with superior overall survival outcomes compared to no or incomplete metastasectomies.6
What is the role of SBRT, specifically, for these patients with oligometastatic RCC? A single center analysis of 47 patients (88 metastatic sites) with IMDC favorable and intermediate risk disease who underwent SBRT alone to all gross disease and sequential SBRT to treat additional metastatic sites was performed, with 1st line systemic therapy used to salvage untreated SBRT failures demonstrated the following:7
- Overall survival of 93% and 85% at one and two years, respectively
- Median time from SBRT to start of 1st line systemic treatment was 15.2 months
- Freedom from progression once starting 1st line systemic therapy was 15.2 months and 8.8 months for sunitinib and pazopanib, respectively.
A subsequent phase II trial by Dr. Hannan’s group published in The Journal of Clinical Oncology in 2021 enrolled 23 patients, who underwent 57 SBRT treatments. The 1-year freedom-from systemic rate was 91.3%, with 1-year progression-free survival, cancer-specific survival, and overall survival rates of 91.3%, 82.6%, and 95.7%, respectively.8 Evaluation of patient reported outcomes (PROs) from this trial demonstrated that SBRT in this setting was associated with minimal adverse effects on quality-of-life outcomes.
A similar single arm, phase II trial from the MD Anderson Cancer Center by Tang et al. evaluated SBRT in lieu of systemic therapy for patients with oligometastatic RCC. This study included 30 patients with 5 or less metastatic sites, who were treated with sequential radiation (SBRT + intensity-modulated radiotherapy). Of note, 30% of patients had received prior systemic therapy. The median PFS was 22.7 months, and the 1-year OS was 100%. There were two grade 3 and one grade 4 adverse event recorded.9
The EA8211 SOAR trial is a randomized phase III non-inferiority trial of SBRT versus systemic therapy for oligometastatic RCC that will open for enrolment in August 2023. This study will randomize patients with IMDC favorable and intermediate-risk, oligometastatic RCC with 2-5 metastatic sites, prior nephrectomy, and with all metastases amenable to SBRT to either SBRT followed by standard of care (SOC) systemic therapy or SOC systemic therapy alone. The co-primary endpoints are OS and the rate of grade 3 or worse adverse events.
What is the role of SBRT in oligoprogressive RCC in the setting of systemic therapy? It has been suggested that SBRT in this setting may allow for the destruction of systemic therapy-resistant clones, facilitating prolonged responses to systemic therapy. In an analysis of 51 metastatic RCC patients with oligoprogression on systemic therapy and who received SBRT to 71 sites (median follow-up 19 months), it was demonstrated that addition of SBRT in this setting was associated with a median increase in PFS of 8.6 months. This benefit was even more pronounced in patients receiving IO therapy, with a significantly longer median PFS at 28 months (p=0.007).10 This findings suggests that there may be a potential synergistic mechanism of action between SBRT and IO therapy.
A prospective, multicenter phase II trial evaluated the role of SBRT in 37 patients (57 tumors) with evidence of oligoprogression with tyrosine kinase inhibitors (TKIs). This analysis demonstrated a 1-year local control rate of 93%, with a median PFS of 9.3 months. Significantly, the median time to change of systemic therapy was 12.6 months. There were no grade 3-5 toxicities.11 A similar phase II trial in 20 patients with oligoprogression on systemic therapy by Dr. Hannan’s team demonstrated that the median extension of systemic therapy PFS with SBRT was 11.1 months. This study also demonstrated that there appears to be an even more significant PFS benefit in patients receiving IO-based therapy.12
Finally, what about the of SBRT for cytoreduction of the primary site? The best evidence in this disease space originates from the individual patient data meta-analysis from the IROCK (International Radiosurgery Consortium of the Kidney). In this meta-analysis, 190 patients with small renal masses were treated with SBRT. The median tumor diameter was 4 cm, and the median follow-up was 5 years. The cumulative local failure rate was 5.5% (i.e., local control was 94.5%). Single fraction SBRT was associated with lower local failure rates (p=0.02) There were no grade 3 toxicities, but one patient developed a grade 4 duodenal ulcer. There was an eGFR decline of 14.2 ml/min by year five post-SBRT.2
Currently there are two ongoing trials evaluating SBRT for primary RCC cytoreduction in patients receiving IO-based systemic therapy:
Dr. Hannan concluded his presentation with the following take-home messages:
- SBRT is safe and effective for RCC and preserves patient quality of life
- Ideal oligometastatic RCC candidates for SBRT for sequential disease control to delay systemic therapy include patients with:
- IMDC favorable-intermediate risk disease, indolent disease, solitary metastases, metachronous (>1 year from diagnosis of primary) metastases
- The current evidence is based on retrospective and phase 2 data; phase 3 trials are ongoing
- Oligoprogressive metastatic RCC treated with SBRT:
- Evidence of Responsiveness to ongoing systemic therapy
- IO-based therapy may have increased PFS in this setting compared to TKI-based therapy
- Only retrospective and phase 2 data to inform this; no phase 3 trials yet
- Evidence of Responsiveness to ongoing systemic therapy
- Future directions/unanswered questions
- What is the role of cytoreductive SBRT to the primary lesion in the IO setting?
- For oligometastatic RCC patients at higher risk of systemic failure (e.g., IMDC poor risk, sarcomatoid), is there a role for concurrent SBRT + systemic therapy?
Presented by: Raquibul Hannan, MD, PhD, Professor, Chief of Genitourinary Radiation Oncology, Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023.References:
- Correa RJM, et al. The Emerging Role of Stereotactic Ablative Radiotherapy for Primary Renal Cell Carcinoma: A Systematic Review and Meta-Analysis. Eur Urol Focus, 2019.
- Siva S, et al. 5-year outcomes after stereotactic ablative body radiotherapy for primary renal cell carcinoma: an individual patient data meta-analysis from IROCK (the International Radiosurgery Consortium of the Kidney). Lancet Oncol, 2022.
- Wang CJ, et al. Safety and Efficacy of Stereotactic Ablative Radiation Therapy for Renal Cell Carcinoma Extracranial Metastases. Int J Radiat Oncol Biol Phys, 2017.
- Heng DYC, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol, 2013.
- Rini BI, et al. Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. Lancet Oncol, 2016.
- Dabestani S, et al. Local treatments for metastases of renal cell carcinoma: a systematic review. Lancet Oncol, 2014.
- Zhang Y, et al. Stereotactic Ablative Radiation Therapy (SAbR) Used to Defer Systemic Therapy in Oligometastatic Renal Cell Cancer. Int J Radiat Oncol Biol Phys, 2019.
- Hannan R, et al. Phase II Trial of Stereotactic Ablative Radiation for Oligoprogressive Metastatic Kidney Cancer. J Clin Oncol, 2021.
- Tang C, et al. Definitive radiotherapy in lieu of systemic therapy for oligometastatic renal cell carcinoma: a single-arm, single-centre, feasibility, phase 2 trial. Lancet Oncol, 2021.
- Schoenhals JE, et al. Stereotactic Ablative Radiation Therapy for Oligoprogressive Renal Cell Carcinoma. Adv Radiat Oncol,, 2021.
- Cheung P, et al. Stereotactic Radiotherapy for Oligoprogression in Metastatic Renal Cell Cancer Patients Receiving Tyrosine Kinase Inhibitor Therapy: A Phase 2 Prospective Multicenter Study Eur Urol, 2021.
- Hannan R, et al. Phase II Trial of Stereotactic Ablative Radiation for Oligoprogressive Metastatic Kidney Cancer. Eur Urol Oncol, 2022.