The role of ablative therapy for primary and oligometastatic renal cell carcinoma

Abstract

Ablation therapy is emerging as a compelling alternate approach for the management of patients with renal cell carcinoma (RCC), particularly patients who are not surgical candidates. These treatment modalities provide an excellent local control and minimal toxicity, with potential to delay systemic therapy for patients with oligometastatic RCC. This review aims to provide an overview of the role of ablative therapies in the management of patients with localized and oligometastatic RCC.

Introduction

Renal cell carcinoma (RCC) is the most prevalent form of kidney cancer, affecting over 400,000 individuals worldwide annually, with incidence rates on the rise. ¹ The majority of RCC cases are diagnosed at a localized stage, where surgical intervention remains the gold standard of treatment, typically involving radical nephrectomy or partial nephron-sparing approaches. ² Nevertheless, a significant proportion of patients are not considered good candidates for surgical treatment due to factors such as advanced age, frailty, presence of comorbidities, or a compromised renal function. ³ Furthermore, a subset of patients will either be diagnosed with or progress to metastatic disease at a few sites(oligometastatic disease) and might also be amenable to surgical resection or locally ablative therapy. ⁴ In this context, ablative therapies emerge as a compelling alternative strategy for the management of localized or oligometastatic RCC.

Herein, we review the various ablative therapy modalities used in the management of RCC, with a focus on their indications and applications in both localized and oligometastatic disease.

The role of ablative therapy in primary RCC

It is beyond the context of this review to discuss the management of a small renal mass and when localized therapy is needed over a surveillance approach. However, in the context of localized RCC, ablative therapies have been shown to achieve clinical outcomes comparable to those achieved with surgery in appropriate patients while also offering the benefit of better preservation of renal function compared to a partial or radical nephrectomy.^5–7 Subsequently, current international guidelines support the consideration of thermal ablation (TA) as an alternate approach for managing patients with solid renal masses smaller than 3 cm.^8,9 TA should also be considered for patients with a solitary kidney who are at high risk of complete loss of renal function following surgical resection, patients with bilateral tumors or those with hereditary RCC. The National Comprehensive Cancer Network (NCCN) also recommends that a biopsy of lesions should be conducted either before or during the ablation procedure.

Thermal ablative therapies encompass a diverse array of modalities, including cryoablation, radiofrequency ablation (RFA), and microwave ablation (MWA). These methods employ distinct mechanisms to induce cell death, utilizing extreme temperatures or focused energy delivery to selectively target and eradicate malignant cells, while preserving adjacent healthy tissues. Tumor size and tumor location have been shown to be strong predictors of outcomes for renal masses, highlighting the need for appropriate patient selection and TA modality selection.^10,11

Radiofrequency ablation (RFA) involves delivering a high frequency alternating current to the target tissue using a monopolar or bipolar probe. Recent studies have shown that RFA is highly effective for renal masses smaller than 3 cm. However, larger masses may not be fully ablated and may need multiple probes or repeated ablation sessions. RFA is less effective for centrally located tumors due to the “heat sink” effect of nearby large hilar vessels, making lateral tumors the preferred location for optimal RFA outcomes.^12–14

Microwave ablation works by emitting electromagnetic energy through a probe to generate intense heat, causing coagulative necrosis and cell death. MWA has been shown to achieve larger ablation zones than RFA with a shorter treatment time. ¹⁵

Cryoablation can induce cell death by delivering extreme cold through a probe to the target tissue, resulting in the formation of an ice ball, that can be visualized easily and monitored in real time. While all 3 TA modalities are effective for cortical tumors smaller than 3 cm, cryoablation seems to provide better outcomes for larger tumors (>4 cm), especially those centrally located. ¹⁵ Optimal tumor size and location for each modality are summarized in Figure 1.

Figure 1.

Ablative therapy modalities in localized renal cell carcinoma.

Ultimately, there are ongoing debates regarding the appropriate use of ablation for a small renal mass. While it has been shown to be comparable to surgical resection for local disease control in management of a small renal mass, a surveillance approach can still be considered. For patients with tumors measuring ≥4 cm (T1b) who are not good surgical candidates, treatment options are needed and are more limited. In this context, stereotactic body radiotherapy (SBRT) has emerged as a compelling alternative, challenging the historical perception of RCC as a radioresistant tumor. ¹⁶ As defined by ASTRO, SBRT is an external beam radiation used to deliver a high dose of radiation to target specific tumor sites accurately with minimal damage to surrounding healthy tissues. ¹⁷ Evidence from observational and early phase clinical trials have demonstrated that SBRT is a safe and effective treatment for managing T1b or T1c RCC, with a notable local control rate of 95%, minimal toxicity, and a modest impact on renal function (a decrease in eGFR of around 7 ml/min post-SBRT).^18–21 Current NNCN Guidelines support the consideration of SBRT for the management of medically inoperable patients with stage I or stage II/III kidney cancer. Compared to TA, SBRT is particularly advantageous for larger tumors that are centrally located or near critical structures such as vasculature and renal collecting system. Additionally, as a noninvasive modality, SBRT is a suitable treatment approach for elderly or frail patients and those on anticoagulation therapy.

The role of ablative therapy in oligometastatic RCC

Oligometastatic RCC is characterized by a limited number of metastases, typically fewer than five. ²² This relatively confined spread provides the opportunity for localized treatment strategies with the intent to delay systemic therapy or even cure the disease. This subset of patients can potentially achieve a status termed M1 NED (No Evidence of Disease), indicating that no active disease is detectable following the treatment of metastatic sites. ²³ From this perspective, although the traditional treatment paradigm for oligometastatic RCC includes systemic therapy, metastasis-directed therapy (MDT) has recently gained ground. This is especially true given the pattern of disease recurrence in the era of immunotherapy with data from Checkmate 214 showing higher incidence of new disease in single organ site for those achieving a response to nivo/ipi and then progressing than those receiving suntinib alone. ²⁴ MDT can be performed using surgical resection of the metastasis, metastasectomy, or ablation therapy.^25–27 Data from observational studies suggest that metastasectomy can improve outcomes in a subset of patients with oligometastatic RCC, particularly those with isolated RCC.^28,29 Conversely, for patients with multiple metastasis, bone involvement, and patients who are less likely to be considered for surgical resection, ablative therapies might be a plausible alternative for localized treatment.

Subsequently, in recent years, there has been compelling evidence suggesting that SBRT may have a role in the management of patients with oligometastatic RCC. In fact, studies have shown that SBRT can achieve an excellent local control with minimal toxicity. In a meta-analysis of 28 studies including 1602 patients (SABR ORCA), Zaorsky et al. reported a 1-year local control rate of 89.1% and 90.1% for extracranial and intracranial disease, respectively, with an incidence of any grade 3–4 toxicity of 0.7% and 1.1% for extracranial and intracranial disease, respectively. ³⁰

Moreover, evidence from prospective and retrospective studies suggest SBRT may help delay the need for systemic therapy without compromising survival.^31–33 In a phase 2 trial, Tang et al. evaluated the feasibility and efficacy of radiotherapy to defer systemic therapy in 30 patients with oligometastatic RCC. At a median follow-up of 17.5 months, the authors reported a 1-year progression-free survival and systemic therapy–free survival of 64% and 82%, respectively, with minimal toxicity. Zhang et al. retrospectively looked at a cohort of 47 patients with oligometastatic RCC treated with SBRT and reported a two-year local control rate of 91.5% and no significant toxicity. The median time to systemic therapy after the first SBRT was 15.2 months. This deferral can be crucial in preserving quality of life of patients and reducing treatment-related burdens.

Recent advancements have shed light on the immunomodulatory effects of radiotherapy, paving the way to rational combination of SBRT with immunotherapy to increase responses. In an analysis of resected SBRT-treated RCC, Chow et al. found intratumoral immune remodeling following radiation. ³⁴ From this perspective, multiple retrospective and prospective studies have investigated the combination of SBRT to metastatic sites with systemic therapy (Table 1).^35–38 Evidence from those trials suggest that this combination is safe and may potentiate the efficacy of immunotherapy in patients with RCC. Moreover, there are currently two ongoing trials CYTOSHRINK (NCT04090710) and SAMURAI (NCT05327686) evaluating if SBRT for primary RCC cytoreduction can improve outcomes in patients with metastatic RCC receiving immunotherapy.^39,40The concept of oligoprogressive disease has been defined to describe cases where there is disease progression in one site while the overall systemic disease remains controlled. In these cases, SBRT can be employed to delay the switch from an otherwise successful systemic therapy, providing a strategic advantage in the management of RCC.^41,42 In a phase 2 trial, Cheung et al. reported outcomes of 37 patients with oligoprogressive metastatic renal cell carcinoma (mRCC) who underwent SBRT while receiving tyrosine kinase inhibitor (TKI) therapy. The 1-year local control rate of the irradiated tumors was 93%. Overall, 47% of patients required a change in systemic therapy within one year, with a median time to change of 12.6 months. The one-year OS rate was 92%, with no reported grade 3–5 SBRT-related toxicities. In another phase 2 trial, Hannan et al. demonstrated that SBRT extended the duration of ongoing systemic therapy by more than 6 months in 70% of patients with oligoprogressive RCC.

Table 1.

Clinical trials evaluating the safety and efficacy of the combination of SBRT and systemic therapy in oligometastatic RCC.

Author (Year)	Clinical trial number	Phase	Intervention / Treatment	Patients enrolled	Primary endpoint	Secondary endpoint	Outcomes
Dengina et al. (2019)	NCT02864615	Ib	SBRT in patients with stable disease on TKI or IO	17	SBRT-related AE	ORR of target lesion	No grade 2 or higher AE ORR 76%
Siva et al (2022)	NCT02855203	I/II	1 fraction SBRT + Pembrolizumab	30	Safety	OS; DPFS; ORR; DCR; Time to local progression	Grade 3 AE 13%; DCR 83%; 2-yr FFLP 92%; 2-yr OS 74%; 2-yr PFS 45%
Hannan et al (2022)	NCT01896271	II	1 or 3 fractions SBRT + HD IL-2	30	ORR	OS; PFS; Toxicity; treatment related tumor specific immune response	ORR 16%; Median PFS 2 months; Median OS 37 months
Masini et al (2022)	NCT0346971	II	3 fractions SBRT + Nivolumab	69	ORR	PFS; OS; DCR; safety	ORR 17%; DCR 55%; Median PFS 5.6 months; Median OS 20 months
Hall et al (2022)	NCT05327686	II	IO-based combination with or without SBRT to the primary tumor	Accrual ongoing	nrPFS	ORR; rPFS; OS	Accrual ongoing
Lalani et al (2023)	NCT04090710	II	IPI/NIVO with or without SBRT to the primary tumor	-	PFS	OS; ORR; safety; quality of life	Estimated study completion date 2025

Abbreviations: OS: overall survial; PFS: progression-free survival; ORR: objective response rate; DCR: disease control rate; FFLP: freedom from local progression; nrPFS: nephrectomy and radiographic progression-free survival; AE: adverse event; TKI: tyrosine kinase inhibitor; IO: immunotherapy; mo: months.

Additionally, ablation therapy offers a promising option for expanding the treatment arsenal for patients with non-clear cell RCC (nccRCC), notably those with chromophobe RCC. Historically, managing these patients has been very challenging due to a poor prognosis and a lack of effective systemic treatment options. ⁴³ Currently, there are no approved treatment regimens and treatment options for this patient population is based on extrapolating results from clear cell RCC trials or from retrospective data. Therefore, the NCCN strongly recommends enrolling patients with nccRCC in clinical trials to explore new and potentially more effective therapies.

Conclusion

In summary, ablation therapy is emerging as a compelling alternate approach for the management of patients with RCC. For patients with localized RCC who are not surgical candidates and are felt to need local disease control, ablative treatments, including TA or SBRT, can be an effective options in select patients achieving excellent local control with minimal toxicity. In the setting of oligometastatic RCC, SBRT can help delay the need for systemic therapy or be used in combination with immunotherapy to potentiate its efficacy. In patients who present with oligoprogression, SBRT should be considered to delay the switch from an otherwise successful systemic therapy.