A 73-Year-Old Man With a Late Isolated Brain Metastasis of Clear Cell Renal Cell Carcinoma Following a Durable Complete Response to Lenvatinib-Pembrolizumab, Resulting in Deferred Cytoreductive Nephrectomy

Introduction

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cell carcinoma (RCC), and RCC accounts for most malignant kidney tumors [1]. Patients can present with flank pain, hematuria, an abdominal mass, constitutional symptoms, or paraneoplastic findings, although many renal tumors are detected incidentally by cross-sectional imaging [1]. Diagnosis is based on radiological evaluation, pathological confirmation when clinically required, and staging to assess local extension, venous tumor thrombus, nodal disease, and distant metastases [1]. Management depends on disease stage and includes surgery, systemic therapy, and local treatment for selected metastatic sites [1].

Lenvatinib is an oral multikinase inhibitor that targets vascular endothelial growth factor receptors and other proangiogenic and oncogenic pathways [2,3]. Pembrolizumab is an anti-programmed death-1 immune checkpoint inhibitor that restores antitumor T-cell activity [4]. The combination of lenvatinib and pembrolizumab is an established first-line systemic option for advanced RCC and can produce deep tumor responses in selected patients [2].

A complete response (CR) refers to disappearance of measurable malignant disease, and durable CR indicates sustained disappearance of measurable malignant disease over time, including in some patients after treatment de-escalation or modification [5]. In metastatic RCC, durable systemic responses have renewed interest in deferred cytoreductive nephrectomy (dCN), in which systemic therapy is given first and surgery is considered only after favorable biological selection [6–11]. Previous reports have described successful deferred cytoreductive nephrectomy after immune checkpoint inhibitor-based therapy, including lenvatinib plus pembrolizumab [7,8,12,13]. However, late isolated central nervous system (CNS) relapse after prolonged extracranial complete response remains insufficiently characterized [14–16].

This report describes the case of a 73-year-old man with a late isolated brain metastasis of clear cell renal cell carcinoma following a durable complete response to lenvatinib-pembrolizumab, resulting in deferred cytoreductive nephrectomy.

Case Report

A 73-year-old man presented with right flank pain. Contrast-enhanced computed tomography (CT) revealed a right renal mass with a level II inferior vena cava (IVC) tumor thrombus and multiple bilateral pulmonary metastases, consistent with cT3bN0M1 disease (Figure 1). Baseline brain CT showed no evidence of intracranial metastasis. Laboratory studies showed elevated C-reactive protein and mild anemia, and the patient was classified as intermediate risk according to the International Metastatic Renal Cell Carcinoma Database Consortium criteria.

Because of the metastatic burden and the presence of an IVC tumor thrombus, systemic therapy with lenvatinib plus pembrolizumab was initiated before surgery. Lenvatinib was started at 20 mg once daily and was later reduced stepwise to 10 mg because of hypertension and fatigue. After 2 cycles, follow-up imaging showed marked regression of the primary renal tumor, substantial reduction of the IVC tumor thrombus, and near-complete resolution of the pulmonary metastases (Figure 2).

Following this favorable response, deferred cytoreductive nephrectomy with IVC thrombectomy was performed. The operative time was 268 min, and the estimated blood loss was 1000 mL. Histopathological examination showed clear cell renal cell carcinoma with extensive treatment-related necrosis and focal residual viable tumor (Figure 3). The postoperative course was uneventful except for transient renal dysfunction.

Lenvatinib was resumed at 8 mg after surgery but was discontinued soon afterward because of worsening renal function. Pembrolizumab monotherapy was continued without immune-related adverse events. Serial CT examinations during follow-up showed persistent complete extracranial radiographic remission and no extracranial recurrence.

More than 2 years after achieving systemic CR, the patient developed mild headache. Brain magnetic resonance imaging (MRI) revealed a solitary lesion in the left occipital lobe, whereas systemic imaging showed no evidence of extracranial disease (Figure 4). Stereotactic radiotherapy (SRT; 30 Gy in 3 fractions) was administered and achieved good local control. At the most recent follow-up, no further systemic recurrence was observed.

Discussion

This case provides 2 main clinical lessons. First, lenvatinib-pembrolizumab can induce marked downstaging of metastatic ccRCC with an IVC tumor thrombus and enable dCN in a carefully selected responder. Second, durable extracranial CR does not eliminate the possibility of late isolated CNS relapse, suggesting that the brain may remain a clinically relevant sanctuary site.

The role of cytoreductive nephrectomy in metastatic RCC has changed substantially after trials that questioned routine upfront nephrectomy in patients requiring systemic therapy [9,10]. Current strategies increasingly use initial systemic therapy as a selection tool to identify patients with favorable tumor biology who may benefit from delayed surgery [8,11]. The present case is consistent with this approach: regression of both the primary tumor and IVC tumor thrombus after lenvatinib-pembrolizumab converted a technically complex presentation into an operable condition. Similar reports have described successful dCN after lenvatinib-pembrolizumab and favorable clinical or pathological outcomes after immune checkpoint inhibitor-based therapy [7,8].

Pathological examination in our patient showed extensive treatment effect with only focal residual viable tumor, supporting substantial cytoreduction at the primary site. Moreover, complete extracranial remission persisted after lenvatinib discontinuation because of renal dysfunction. This course is compatible with previous observations that some patients with deep responses to immunotherapy-based treatment can maintain prolonged disease control after treatment de-escalation [14].

The distinctive feature of this case is the late isolated brain metastasis after more than 2 years of extracranial CR. Brain metastases from RCC are clinically important because they can cause neurological morbidity, and intracranial efficacy of systemic regimens remains less well defined than extracranial efficacy [15,16]. The CNS can be a relative sanctuary site because of the blood-brain barrier and a distinct immune microenvironment [15–17]. Therefore, occult micrometastatic disease can persist intracranially despite durable extracranial control.

In patients treated with immune checkpoint inhibitors, new neurological symptoms also require careful differential diagnosis, including brain metastasis, cerebrovascular events, and immune-related neurologic adverse events. A recent American Journal of Case Reports case of sintilimab-associated encephalitis and myocarditis illustrates that ICI-related neurological toxicity can mimic or coexist with oncologic complications, reinforcing the need for prompt neurological assessment and appropriate brain imaging in symptomatic patients [18].

Local therapy remains central for limited brain metastasis from RCC. Stereotactic radiosurgery or stereotactic radiotherapy can provide local control, and combined use with immune checkpoint inhibition has been associated with prolonged disease control in selected cases [15,19]. In our patient, SBRT achieved durable local control without subsequent extracranial relapse, supporting timely local treatment when CNS-only progression is detected.

This case does not establish a universal indication for routine brain surveillance in asymptomatic long-term responders. However, it supports careful neurological assessment during long-term follow-up and a low threshold for brain MRI when new neurological symptoms occur. In selected high-risk clinical contexts, individualized CNS imaging may be considered, but its optimal timing and impact on outcomes require further study.

Conclusions

Lenvatinib-pembrolizumab enabled marked tumor regression and deferred cytoreductive nephrectomy in a patient with metastatic clear cell renal cell carcinoma and an inferior vena cava tumor thrombus, resulting in durable extracranial complete response. However, late isolated brain metastasis occurred without systemic recurrence. Long-term responders should be monitored carefully for neurological symptoms, and brain magnetic resonance imaging should be performed promptly when clinically indicated.