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INTRODUCTION

Renal cell carcinoma—cancer of the kidney and renal pelvis—is the 8^th most common malignancy in the United States (U.S.) and represents 4.2% of all new cancer cases. This equates to an estimated 73,820 new cases and 14,770 deaths in 2019 alone.¹ The most effective treatment modality for this type of cancer is surgery and the least effective treatment is cytotoxic chemotherapy.² 

The median age at diagnosis of renal cell carcinoma is 64 years. Patients can present with a variety of symptoms at any stage, and some patients are even asymptomatic when the cancer is discovered.³ When symptoms are present, they are commonly mistaken for a urinary tract infection or kidney stones. The classic triad of symptoms includes hematuria, flank pain, and a palpable abdominal mass. Although this triad only occurs in 9% of patients with renal cell carcinoma, when present, it strongly suggests regional or metastatic disease.⁴

Fortunately, symptoms commonly prompt a thorough examination and work-up early in the disease course. Once infection is ruled out, evaluation of these symptoms commonly includes imaging with ultrasound or computed tomography scan, which can identify a renal mass. The majority (65%) of renal cell carcinoma cases are diagnosed when the disease is confined to the primary site and is curable with surgery. The 5-year survival rate for localized disease is approximately 93%. The remaining 35% of patients are nearly evenly divided between regional disease (spread to the lymph nodes) and metastatic disease. The 5-year survival rates for these patients are 69% and 12%, respectively. The extent of disease spread continues to be the most significant predictor of prognosis and is the primary guide to selecting therapy.³

To further evaluate prognosis, patients with metastatic renal cell carcinoma (mRCC) are divided into low-risk, intermediate-risk, and poor-risk groups on the basis of the number of prognostic factors present, which are outlined in Table 1.⁵ Recent clinical trials report that most patients (60%-70%) have an intermediate-risk prognosis, and the remaining patients are evenly distributed between low-risk (favorable-risk) and poor-risk groups.^6,7 A recent survival analysis, which included treatment with modern therapies, resulted in 3-year overall survival rates of 47% for intermediate-risk patients, 76% for favorable-risk patients, and 13% for poor-risk patients.⁸

A partial or complete nephrectomy is used in most cases to obtain tissue for histologic diagnosis and molecular studies. The most common histology is clear cell, which makes up 70% of cases of renal cell carcinoma, followed by papillary (chromophilic), which accounts for 10% of cases. Chromophobe, oncolytic, and collecting duct tumors are rare, less common histologies. The importance of histology as it relates to prognosis is debated. Individual institutions have reported that clear cell tumors have worse cancer-specific survival than any other histology; however, a multi-institutional study failed to find a survival difference among histology types.⁴

The signaling pathology among histology types appears to be different, and it has been well characterized for clear cell histology, which has led to targeted drug therapy. Briefly, clear cell histology tumors have aberrant von-Hippel Lindau signaling, which triggers hypoxia signaling, including increased production of vascular endothelial growth factor (VEGF).⁹ Targeted therapies blocking VEGF signaling have become a mainstay of treatment for renal cell carcinoma with this histology.

TREATMENTS FOR RENAL CELL CARCINOMA

Treatment for renal cell carcinoma depends on the location and size of the tumor, its stage, and patient-specific factors. Survival data is incomplete related to many of the treatment options, as several studies are ongoing, but some data are available to guide the selection of first- and second-line therapies.

Resectable tumors

Surgery is a mainstay of treatment for all patients who can tolerate the procedure. For stage I and II disease (i.e., large tumor limited to the kidney without nodal involvement), removal of the kidney and the tumor is almost always curative and no adjuvant therapy is indicated. Select patients may have a partial nephrectomy. Patients who have stage III disease (i.e., nodal involvement or a large tumor that has invaded major veins or perinephric tissues but not grown beyond Gerota’s fascia) are ideally treated with radical nephrectomy. Patients with stage III clear cell disease and a high risk of recurrence may be treated with adjuvant therapy.¹⁰ The U.S. Food and Drug Administration (FDA) has approved sunitinib as adjuvant therapy for high-risk patients with clear cell histology. However, as revealed in the phase III adjuvant trials (Table 2), targeted therapies seem to have marginal, if any, benefit for disease-free survival.^11-13 The ongoing phase III immunotherapy trials are attractive, but results are not expected until 2022.

Metastatic tumors

The majority of patients with mRCC still undergo surgical removal of the affected kidney. This practice was based on the concept that the primary tumor was producing cytokines, which suppress the immune system and act as essential growth factors for tumors that allow them to grow and proliferate. An early clinical trial demonstrated superior outcomes with nephrectomy plus interferon versus interferon alone. Even in the current immunotherapy era, nephrectomy is performed in approximately three-fourths of patients with renal cell cancer. However, the benefits of nephrectomy with targeted therapy and immunotherapy remains unclear. Retrospective data and subgroup analyses from prospective trials indicate that there is value to removing the kidney, but this difference may be explained by patient-selection bias.¹⁴ A prospective study examined this question directly by comparing sunitinib with or without nephrectomy and did not find an advantage to removing the kidney.¹⁵ Still, surgery remains a standard approach.² 

Systemic therapy for advanced renal cell carcinoma has undergone significant changes over the last decade. The discovery and successful targeting of the VEGF pathway, as well as the development of immune checkpoint inhibitors, have led to significant improvements in survival. When Motzer et al first reported a survival and prognostic stratification for advanced renal cell carcinoma in 1999, favorable-risk patients had an overall survival of 20 months; intermediate-risk patients, 10 months; and poor-risk patients, 4 months.⁵ The current prognoses for these groups are 43 months, 23 months, and 8 months, respectively.¹⁶ Recent data evaluating combination regimens including immunotherapy appear to raise survival to an even higher degree. A summary of key trials of first-line therapies is presented in Table 3.^6,7,17,18

First-line immunotherapy versus VEGF tyrosine kinase inhibitor (TKI) therapy is currently being debated. Different conclusions can be reached by different studies because of the immature overall survival data, the interpreted value of progression-free survival (PFS), the VEGF-TKI used, and the sequence of regimens.^19-21 There are 3 FDA-approved first-line VEGF-TKIs: sunitinib, pazopanib, and cabozantinib. The randomized trial comparing pazopanib and sunitinib showed no difference in efficacy between the agents; however, the head-to-head comparison of cabozantinib and sunitinib demonstrated that cabozantinib is superior (PFS 8.2 months vs. 5.6 months; p=0.012).^22,23 Due to the timing of the trial, sunitinib was the comparator for the immunotherapy trials, so it is inconclusive if immunotherapy would have achieved better results if compared to cabozantinib. It is also unclear if cabozantinib added to immunotherapy would be better than axitinib added to immunotherapy. Furthermore, it is unclear how first-line VEGF inhibition and immunotherapy impacts second-line treatment selection and efficacy. Randomized trials will be required to determine the best TKI to add to immunotherapy and to see if the combination is better than cabozantinib.

An analysis of the available data indicates that selecting nivolumab and ipilimumab as first-line therapy (CheckMate 214 trial) makes the selection of second-line therapy with a VEGF-TKI an easier decision. The consideration from this trial is that the favorable-risk population did numerically better with sunitinib than with immunotherapy.⁶ However, a recent abstract suggests that the gap in response rate and PFS that favored sunitinib is narrowing and the differences are not statistically significant,²⁴ though the findings do not specifically address this population of patients. The National Comprehensive Cancer Network (NCCN) guidelines list sunitinib or pazopanib as preferred first-line treatments for favorable-risk patients, but, at this time, the guidelines do not include the new axitinib-plus-immunotherapy results.¹⁰

Utilizing programmed death-ligand 1 (PD-L1) expression to select patients to receive first-line immunotherapy does not appear to be impactful. In the nivolumab/ipilimumab study, a subgroup analysis comparing patients with PD-L1-positive and PD-L1-negative (<1%) tumors demonstrated a prognostic difference favoring the PD-L1-positive patients, but both populations performed better than the patients who received sunitinib.⁷ Similarly, in the avelumab-plus-axitinib trial, the PD-L1-positive group did better than the PD-L1-negative group, but both groups did better than the sunitinib group.⁶ In the pembrolizumab-plus-axitinib trial, the PD-L1-positive group did better than the sunitinib group; the results from the PD-L1-negative group numerically favored immunotherapy but were not statistically significant (death: hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.34-1.03).¹⁷ Given the results of the subgroup analysis, it seems unnecessary to test for PD-L1. 

The best first-line regimen for advanced renal cell carcinoma remains unclear (Table 4), but the data for a VEGF-TKI plus immunotherapy or combined immunotherapy is superior to sunitinib monotherapy. On the basis of the published literature, it appears that most treatment-naïve advanced renal cell carcinoma patients will be treated with an immunotherapy-containing regimen. Assuming that immunotherapy does not induce resistance mechanisms to a VEGF-TKI, the nivolumab/ipilimumab regimen, philosophically, would be the best first-line approach for intermediate-risk and poor-risk populations, preserving the VEGF-TKIs for second-line therapy. Survival data with longer follow-up of these trials will help clarify the best treatment.