RCC 2018: Top advances in treatment of localized, advanced disease

Editor’s note: Urology Times asked key opinion leaders in kidney cancer for what they felt were the most noteworthy developments in the field in 2018. We thank Amr A. Elbakry, MBBCh, MSc, Ketan K. Badani, MD, and Alexander Kutikov, MD, for their responses. Dr. Elbakry and Dr. Badani's summary follows. To read the overview authored by Dr. Kutikov, click here.

Dr. Elbakry is associate researcher of urology at Icahn School of Medicine and Dr. Badani is professor of urology at Icahn School of Medicine, director of the Comprehensive Kidney Cancer Center, vice chair of urology and robotic operations, and director of robotic surgery at Mount Sinai Health System, New York.

2018 was an exciting and productive year for kidney cancer research. Continued efforts have been made through research to optimize the treatment approach for localized disease and to improve strategies and treatment options for advanced and metastatic disease. Although there is much to discuss on this topic, we will highlight several of the important headlines in kidney cancer research over the course of 2018.

Localized disease

Functional outcome following surgery for kidney tumors

Preservation of renal function after kidney surgery was a hot topic of investigation this past year. In addition to oncologic outcome, renal function preservation should remain a primary outcome measure during the management of localized kidney tumors. In 2018, efforts to better understand and identify the factors predicting renal functional outcome following different management options for localized renal tumors were studied.

Antonelli et al reviewed data from a large series of 700 cases of partial nephrectomy (J Urol 2018; 199:927-32). They identified surgical approach (open and laparoscopic vs. robot assisted) and pedicle clamping methods as modifiable surgical factors that can predict early renal impairment. Diabetes mellitus was the primary factor that predicted late renal impairment.

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However, Beksac et al found that neither hypertension nor diabetes mellitus was associated with long-term renal impairment in patients with normal baseline estimated glomerular filtration rate (GFR) (Int J Urol 2019; 26:120-5). Another study suggested mathematically calculated contact surface area of the tumor as a better predictor of functional outcome than RENAL score (J Urol 2018; 199:649-54). The calculation was based on tumor radius and tumor depth to calculate the contact surface area, which assumes all renal tumors have a regular spherical shape, which is not true. They also used the estimated GFR at 30-day postoperative to assess the renal function outcome.

Therefore, future studies should reassess the concept of contact surface area as a predictor of functional outcome with the use of software-calculated contact surface area and long-term follow-up data regarding renal function.

A significant limitation of the previously mentioned studies is that they identified individual factors as predictors of renal function outcome after partial nephrectomy. However, two other studies opted to create models that take into consideration that renal function outcome is a collective result of multiple factors. Bhindi et al created two models that can predict early postoperative renal impairment and long-term renal functional outcome following radical and partial nephrectomy using data from more than 3,000 patents (Eur Urol Nov. 23, 2018 [Epub ahead of print]). The rationale for developing such models is to provide the patient with reliable information about renal function outcome and expectations after treatment. However, they included only preoperative features in their models, and also excluded tumor and kidney volumetric measurements from the models to make them simple, practical, and convenient to be used in the outpatient clinic.

Our group (Martini et al) developed a nomogram model to predict estimated GFR reduction following partial nephrectomy (Eur Urol 2018; 74:833-9). This model also includes postoperative factors; importantly, acute kidney injury, and predicts up to 1 year postoperatively. However, this nomogram is limited to only partial nephrectomy, unlike the models from the previous study. The models from both studies need to be externally validated, and potentially can be adopted as a useful tool during preoperative counseling of patients with renal tumors.

Next: Optimizing preoperative planning to improve partial nephrectomy outcomeOptimizing preoperative planning to improve partial nephrectomy outcome

Partial nephrectomy (PN) is the standard of care for cT1 renal tumors and has expanded to select patients with cT2 tumors. Preoperative planning and feasibility of partial nephrectomy is determined by the level of understanding of the anatomy of the tumor and its relation to the renal hilum and collecting system.

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A number of studies looked into the role of virtual 3-D modeling and physical modeling using 3-D printing of renal tumors in preoperative planning of PN procedures. Porpiglia et al reported using 3-D printing technology for 10 cases of renal tumor in planning of PN that were carried out during an international urology meeting (World J Urol 2018; 36:201-7). All procedures were broadcast in live surgery sessions by a group of world-renowned expert urologists. The authors evaluated the usefulness of 3-D modeling in understanding tumor anatomy and complexity, surgical planning, and potential role in surgical training using questionnaires that were filled out by 144 attendees.

Another group from Korea published a similar study with the participation of smaller group urologists and medical students (Int Braz J Urol 2018; 44:952-7). They reported a similar outcome regarding usefulness of 3-D printed models in surgical planning and educational purposes. Fan et al from China applied the same concept of using physical 3-D printed models in surgical planning of five PN procedures for completely endophytic renal tumors (Sci Rep 2018; 8:582).

In a video article, Wake et al described their ongoing three-arm study comparing physical printed 3-D models, digital 3-D models viewed with augmented reality, and conventional imaging in preoperative planning and intraoperative decision-making in robotic partial nephrectomy (Urology 2018; 116:227-8). They mentioned that the cost for printing a physical 3-D model is $500 to $1,000, and the cost for the headset used in viewing the digital 3-D model in augmented reality was $3,000.

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There are many questions that need to be answered regarding this subject, such as to what extent cost containment will allow wider adoption of this technology? Will the cost be justifiable? And is the digital 3-D modeling more efficient and more cost-effective than physical printed 3-D models? One aspect is that the digital models can layer anatomic details in real time with the ability to subtract different part of the model to focus on artery, collecting system and tumor, which is far more challenging with a physical model. The studies may find that the potential benefit of these technologies is best suited for a subset of patients with complex tumors, complex renal vascular anatomy, or ectopic kidneys with unusual anatomy.

Next:Active surveillanceActive surveillance

Active surveillance for small (<2 cm) and Bosniak 3/4 cystic renal masses should be considered as a valid option, especially when the risk of intervention outweighs the oncologic benefit (J Urol 2017; 198:520-9). Uzosike et al reviewed the imaging of more than 300 patients who were undergoing active surveillance (J Urol 2018; 199:641-8). They observed a high variability of tumor size in the first 6 months, which did not reflect true growth of the tumor. However, a relatively higher growth rate-that was not statistically significant-in the first 6 months was seen in the group of patients who underwent delayed intervention.

Jang et al studied the difference in the growth pattern of different histopathologic types of renal tumors (BJU Int 2018; 121-732-6). They found that the overall growth rate was not predictive of tumor pathology. These findings may indicate that we need to shift our focus to other approaches rather than tumor growth pattern.

Radiomics was suggested as a potentially more accurate alternative that can differentiate between different histopathologic subtypes of renal tumors by providing quantitative analysis of the imaging. In their review, de Leon et al described the potential roles of radiomic analysis in different aspects of kidney cancer management (Magn Reson Imaging Clin N Am 2019; 27:1-13). Further studies are needed to better assess this exciting application.

Metastatic disease

Advances in the treatment of advanced and metastatic renal tumors

Recently, the widely publicized results from the CARMENA trial (a phase III randomized clinical trial) were published (N Engl J Med 2018; 379:417-27). The results showed that systemic targeted therapy sunitinib (Sutent) alone was not inferior to cytoreductive nephrectomy followed by sunitinib, deemed the standard of care for metastatic renal tumors.

However, Massari et al argued that the results of CARMENA should not be generalized, although it is the first large prospective randomized trial to compare those two approaches (Target Oncol 2018; 13:705-14). They found in their systemic review and meta-analysis that further subgrouping of patients with metastatic disease according to metastasis location and performance status may reveal the benefit of cytoreductive nephrectomy in patients with non-brain metastasis and good performance status.

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Novel immunotherapeutic agents acting via immune checkpoint inhibition showed promising results in the management of metastatic renal cell carcinoma in the terms of progression-free and overall survival. In addition, the fact that these drugs are well tolerated by the patients encouraged the idea of combination therapy using either two immunotherapeutic agents or immunotherapy plus targeted therapy.

CheckMate 214 is a phase III prospective randomized trial comparing the combination of nivolumab (Opdivo), a programmed cell death 1 (PD-1) inhibitor antibody, and ipilimumab (Yervoy), an anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) antibody, versus sunitinib in the management of advanced RCC. The combination immunotherapy showed a significantly higher overall survival and number of complete responses (N Engl J Med 2018; 378:1277-90).

In another phase II trial (CABOSUN), the MET, AXL, and VEGFR2 inhibitor cabozantinib (CABOMETYX) was found to be superior to sunitinib in regard to progression-free survival when used as a first-line treatment in advanced RCC with intermediate- or poor-risk disease (Eur J Cancer 2018; 94:115-25). More studies are required, and will be done, to better identify the most effective and yet tolerable combination therapy that might lead to a breakthrough in the management of advanced and metastatic renal tumors.

Neoadjuvant therapy is also on the list of topics for locally advanced kidney cancer. The phase III PROSPER study, a randomized trial comparing perioperative nivolumab versus observation in patients with localized RCC undergoing nephrectomy, continues to enroll patients to assess the role of PD-1 inhibition (nivolumab) with the primary tumor in place to further augment the immune response prior to nephrectomy. We look forward to these results when they become available.