Neoadjuvant Nivolumab and Ipilimumab for Nonmetastatic Renal Cell Carcinoma with Tumor Thrombus

Cases of renal cell carcinoma (RCC) with tumor thrombus are highly complex. If left untreated, mortality outcomes are dismal for both metastatic and nonmetastatic disease.^[1,2] The surgical treatment of RCC with level IV tumor thrombus often requires aggressive maneuvers such as a sternotomy and cardiac bypass. Interest in neoadjuvant treatment options for RCC with tumor thrombus persists, although effective regimens are scarce. Here, we present a case of neoadjuvant therapy with a combination of checkpoint inhibitors, nivolumab and ipilimumab, for nonmetastatic RCC with tumor thrombus. Case details, clinical and surgical decision-making, treatment effects, and important considerations are discussed. The patient provided written informed consent to participate in this study.

A 67-year-old man presented to the urologic oncology clinic after an incidental finding on a computed tomography angiogram. A 4.3 × 3.9 × 3.7 cm partially exophytic, solid enhancing mass was seen arising from the lower pole of the right kidney with filling defect into the renal vein and inferior vena cava (IVC), suspicious for tumor thrombus (Fig. 1). Echocardiogram and ultrasound imaging confirmed the presence of a thin tumor extending from the renal mass into the IVC and culminating into a rounded thrombus in his right atrium (Fig. 2). Biopsy of the mass demonstrated clear cell RCC. Additional imaging demonstrated no evidence of metastasis.

The patient was referred to medical oncology for neoadjuvant treatment to potentially shrink the tumor and alleviate the morbidity associated with level IV thrombus treatment. Dual checkpoint inhibitor immunotherapy (CII) was initiated, consisting of nivolumab (3 mg/kg/dose) and ipilimumab (1 mg/kg/dose) intravenous infusions every 3 weeks for four cycles. Repeat echocardiogram showed continued presence of thrombus. The patient then began nivolumab monotherapy (480 mg) for eight more cycles. While on the therapy, the patient did experience hypothyroidism and generalized pruritus managed well with levothyroxine and topical triamcinolone. The patient otherwise tolerated treatment well; did not experience any severe immune adverse events, renal insufficiency, hematuria, or proteinuria; and did not require systemic steroid treatment.

Following a year of CII (four cycles of nivolumab and ipilimumab, eight cycles of nivolumab), the thrombus had decreased in size but failed to regress below the right atrium (Fig. 3). Given that the patient appeared to achieve maximum benefit from the therapy, surgery was next pursued. The patient was presented with two options: a median sternotomy, atriotomy with tumor thrombectomy while on cardiac bypass, and concurrent nephrectomy and vacuum extraction of the thrombus from the IVC at the level of the renal vein. The patient opted for the latter with conversion to a more invasive treatment if necessary.

Intraoperatively, the IVC tumor thrombus was palpated through the vena cava by the surgeon, who estimated the thrombus was a cordlike structure of only 2–3 mm in thickness. An incision into the renal vein revealed a white-appearing thrombus. The tumor thrombus was grasped with a clamp, and, with steady traction, the entire thrombus was caudally extracted with minimal resistance. The vacuum device was used to remove any residual tumor and was followed by radical nephrectomy.

Histology (Fig. 4) demonstrated clear cell RCC (World Health Organization [WHO] grade 3) with viable tumor cells in the kidney and renal vein with negative margins. The IVC thrombus demonstrated therapy-related changes with no residual viable tumor and associated hyalinization, myxoid changes, and microcalcifications. This was in contrast to the primary tumor within the kidney and renal vein, which showed classic features of clear cell RCC. Final staging was pT3c pNx.

The patient is now more than a year out from surgery and has no evidence of recurrence on routine imaging. He has experienced no complications related to his surgery.

Nivolumab and ipilimumab combination therapy is recommended in advanced and metastatic RCC.^[3] Its indication for patients with RCC with tumor thrombus is less clear and limited to a few case reports, primarily for metastatic disease.^[4–9] However, to the best of our knowledge, the present case represents only the second published report for nivolumab and ipilimumab combination therapy for nonmetastatic RCC with tumor thrombus. Preoperative use of this combination resulted in posttreatment changes in thrombus histology and alleviation of surgical complexity, morbidity, and mortality associated with sternotomy and cardiac bypass. Furthermore, the regimen used in this case (four combination cycles and eight nivolumab monotherapy cycles) is unique compared with its use in other related case reports.

In many malignancies, neoadjuvant therapies are used to downstage tumors, ease surgical removal, and improve survival. However, ineffectiveness of neoadjuvant chemotherapy and radiation have limited their use in RCC.^[10] Increased understanding of the ability of RCC to escape tumor immunity by altering autoantigens (i.e., downregulation of major histocompatibility complex class I molecules or changes in antigen presentation) and inducing immunosuppression via cytokines has inspired new therapeutics.^[11] The emergence of novel immunotherapies has shifted the treatment paradigm and has expanded available options for neoadjuvant treatment.^[12–15] For RCC with tumor thrombus specifically, neoadjuvant treatments, such as avelumab and axitinib, stereotactic ablative radiotherapy, pazopanib, sunitinib, and sorafenib, have been explored with varying efficacy in downstaging tumor staging and thrombus level.^[15–20] More recently, nivolumab and ipilimumab have emerged as intriguing options in the RCC and RCC with tumor thrombus treatment arsenal.

Nivolumab is a monoclonal antibody directed against program death 1 (PD-1), inhibiting its interaction with program death ligand 1 (PD-L1). Blocking PD-1 and PD-L1 interaction effectively enhances antitumor responses and delays tumor growth.^[21] Ipilimumab is a monoclonal antibody directed at cytotoxic T-lymphocyte associated protein 4 (CTLA-4), which is responsible for downregulation of T-cell responses. By disrupting CTLA-4, T-cell activation, restoration, and amplification are achieved to enhance antitumor responses.^[22] Although nivolumab and ipilimumab have had positive results when used in isolation for multiple tumors, nivolumab and ipilimumab combination therapy has demonstrated increased efficacy. When compared with sunitinib in advanced RCC (Phase 3 CheckMate 214 Trial), the combination resulted in significantly higher overall survival rates when used in previously untreated advanced RCC.^[23] Nivolumab and ipilimumab combination therapy is now first-line therapy for patients with advanced and metastatic RCC.^[3,6,7]

Dual therapy with nivolumab and ipilimumab has been used in RCC with tumor thrombus, although primarily in metastatic disease. In several reports, neoadjuvant nivolumab and ipilimumab combination therapy resulted in various degrees of tumor thrombus regression in patients with metastatic RCC with tumor thrombus.^[4,5,7–9] The use of nivolumab and ipilimumab in nonmetastatic RCC with tumor thrombus, as in this case, has been scarcely reported. In a report by Labbate et al,^[6] four cycles of combination therapy followed by four cycles of nivolumab monotherapy successfully downstaged a level IV tumor thrombus to level III in locally advanced RCC. Similarly, in our case, the thrombus failed to regress below the level of the hepatic veins, resulting in a negligible effect of nivolumab and ipilimumab on surgical outcome and approach. The patient still required a cardiac surgical operating room instead of a general surgical operating room, which is much more costly. Fortunately, open sternotomy was avoided in this case. The ability to grasp and cleanly pull the thrombus back in this case is abnormal because it is usually affixed to the walls of the IVC. It is additionally noteworthy that there was no malignancy histologically in the thrombus itself because this is a likely effect of the systemic therapy. The lack of malignancy identified in the thrombus but continued presence in the primary tumor is similar to the case by Labbate et al,^[6] attributed to the heterogeneity of the microenvironments. Although systemic therapy resulted in no identifiable malignancy in the thrombus, surgery was still necessary to prevent thrombus dislodgement and pulmonary embolism.

These aforementioned cases demonstrate the varying success of different regimens of neoadjuvant nivolumab and ipilimumab combination therapy used in patients with RCC with tumor thrombus to help facilitate tumor thrombectomy and nephrectomy.^[6–8] For metastatic disease, cytoreductive nephrectomy and thrombectomy can improve symptoms and prolong survival.^[24] Moreover, 5-year survival for patients with nonmetastatic RCC with tumor thrombus is greater than 50% versus ∼ 10% for complete versus incomplete resection, respectively.^[24] This drastic difference in survival, highly dependent on radical surgical resection, highlights the interest in neoadjuvant treatments aimed at tumor debulking and growth restriction. However, as seen in our case, systemic therapy may fail to resolve the entirety of the tumor, emphasizing the importance of surgical intervention in patients with RCC with tumor thrombus. Furthermore, neoadjuvant immunotherapy in RCC with tumor thrombus also has the potential to prolong acceptable preoperative waiting time. Patients with high-risk RCC (i.e., T3, T4) are recommended to undergo surgery within 30 days,^[25] with higher risk cases such as RCC with tumor thrombus being encouraged even sooner if possible. By allowing more time from diagnosis to operation, increased nutritional and functional status can potentially be achieved, which may have prognostic benefits for patients with RCC undergoing nephrectomy and tumor thrombectomy.^[26–28]

RCC with tumor thrombus is associated with high morbidity and mortality. Neoadjuvant immunotherapy with nivolumab and ipilimumab combination therapy for RCC with tumor thrombus may decrease tumor burden and associated operative and oncologic risks. Prospective clinical trials evaluating the efficacy of neoadjuvant immunotherapy in patients with RCC with tumor thrombus should be conducted to further identify appropriate patient selection and use of such interventions.