ACRT Journal

Introduction

Renal carcinoma is diagnosed in 25% of cases in advanced stage due to the presence of synchronous metastases [1,2]; however, the survival of patients (pts) with metastatic renal cell carcinoma (mRCC)  has increased significantly with the advent of TKIs and immunotherapy-based combinations, as demonstrated by different studies [3-6]. Several regimens are available for mRCC, providing clinicians the possibility to select the best regimen for the individual patient according both on patient’s and disease characteristics. In this regard, the Memorial Sloan Kettering Cancer Center (MSKCC) score and the International Metastatic RCC Data base Consortium (IMDC) score (or Heng’s prognostic system) are currently used to stratify mRCC pts in three different risk classes associated to different survivals [7,8]. Cytoreductive surgery (CN) in pts with metastatic renal carcinoma has always been considered as an additional strategy to systemic therapy. However, as shown in Table 1, the changes in standard therapies that have occurred over time have affected the clinical benefit of this therapeutic strategy. Studies by Flanigan et al and Mickisch et al showed that nephrectomy followed by interferon therapy led to a longer survival among pts with mRCC compared to interferon alone, suggesting the role of upfront CN in improving these pts’ outcome during the interferon-era [9,10].

This approach was completely reassessed with the introduction of TKIs, based on the results of CARMENA trial in which median overall survival (OS) of pts receiving upfront CN followed by sunitinib was even worse compared to sunitinib alone [11]. Furthermore, in SURTIME trial deferred nephrectomy did not guarantee a benefit in progression-free survival (PFS), although OS was higher with the deferred CN approach [12].

The role and timing of CN has then been strongly reconsidered in the era of immunotherapy both for clinical and biological reasons and further studies are ongoing to define the optimal sequence of multimodal approaches. Here we report the case of a young patient diagnosed with oligometastatic RCC undergoing multimodal treatment, and we discuss the role and timing of CN based on literature data with a look on emerging evidence from recent studies.

Table 1: Summary of trials investigating the role of CN in mRCC in pre-immunotherapy era.

Case Report

In March 2023, a 24-year-old Bangladeshi man in good clinical condition and without significant comorbidities came to the emergency room due to the onset of right lumbar and testicular pain and hematuria. He underwent a thoracic and abdominal CT (computed tomography) scan that revealed the presence of a right renal lesion of 8 centimeters in the largest diameter, infiltrating the fourth hepatic segment, the intercostal posterior muscles, and the ascending colon. In addition, a single metastatic lesion of the second lumbar vertebra was found, which was also confirmed on bone scintigraphy.

The patient was admitted to the urology unit where staging was completed with a brain CT scan, which was negative, and on 03/27/2023 he underwent a needle biopsy of the right renal lesion that diagnosed high-grade renal carcinoma with diffuse positivity for PAX8, racemase and high molecular weight cytokeratins on immunohistochemistry.

The case was discussed at a multidisciplinary meeting where, considering the oligometastatic disease and the patient’s age, we chose a multimodal approach, which would have included systemic therapy, CN and stereotactic radiotherapy on the single bone lesion.

On 04/18/2023, we started a first-line systemic treatment based on the combination of an antiangiogenic agent, cabozantinib 40 mg/day, and an immune-checkpoint inhibitor, nivolumab 240 mg every 14 days. Treatment was initially well tolerated with the onset of mild diarrhea and nausea that were managed with adequate support therapy, hypertension that required the introduction of antihypertensive therapy with amlodipine, and hypothyroidism that required thyroid replacement therapy with levothyroxine. However, two months later, a high-grade hand-foot syndrome (HFS) occurred: cabozantinib was then temporarily discontinued and subsequently reintroduced with a dose reduction (20 mg/day). The CT scan performed on 07/24/2023 showed a partial response of the right renal lesion with less infiltration of adjacent organs, while the lesion of the second lumbar vertebra was stable.

Considering the radiological response, the multidisciplinary team confirmed the initial program. On 09/06/2023 the patient underwent a right nephrectomy without complications. Histological examination diagnosed unclassifiable high-grade renal carcinoma characterized by post- iatrogenic alterations and large necrotic areas, with invasion of the renal pelvis and without involvement of surgical margins. On 10/04/2023, a stereotactic radiotherapy was performed on the second lumbar vertebra (a total dose of 24 Grays in three daily fractions with the Cyberknife technique). The patient returned to the oncology unit to resume systemic treatment with cabozantinib 20 mg/day plus nivolumab 240 mg every 14 days, which is still ongoing and well tolerated. The patient was free from progression at the last CT scan performed in September 2024.

Discussion

The use of CN in treating metastatic renal carcinoma, which was a common practice during the interferon era [9,10] and was later questioned with the advent of anti-angiogenic therapies [11,12], deserves to be reconsidered during the era of immunotherapy (Table 2).

The clinical case presented here shows the efficacy of a multimodal approach based on an excellent response to the combination treatment with TKI and immunotherapy followed by effective surgery. The results of the sequential approach taken in this case are consistent with the data from the National Cancer Data base (NCD). In this study, pts who responded to immunotherapy and then underwent deferred nephrectomy achieved a better survival advantage than those who received upfront nephrectomy [13]. Moreover, the CheckMate214 post hoc analysis conducted by Shirotake et al, who retrospectively investigated the clinical outcomes of Japanese pts treated with deferred CN after nivolumab plus ipilimumab for mRCC, showed higher objective response rate (ORR) and an OS gain adopting this strategy [14]. Similarly, the retrospective study conducted by Yoshino et al showed that pts receiving deferred CN after responding to immunotherapy achieved tumor shrinkage in both primary and metastatic lesions with a meaningful OS gain compared to pts who underwent upfront CN [15]. Results from the multicenter study by Gross et al also demonstrated that, when added to immunotherapy, CN is independently associated with longer OS and a 67% reduction in terms of mortality for all causes [16].

Table 2: Summary of trials investigating the role of CN in mRCC in the immunotherapy era.