Kidney Cancer Journal | Volume 2, Issue 2

Partial Nephrectomy is the Surgical Treatment of Choice for (Most) Complex Localized Renal Tumors

The decision to undergo partial nephrectomy (PN) versus radical nephrectomy (RN) for a localized renal mass should take various factors into consideration, including tumor characteristics, patient’s health status and preference, and risks and benefits of these each approach. PN represents a suitable surgical approach for small renal tumors in favorable locations. It may also better preserve long-term renal function, particularly in patients who may need surgery for a contralateral kidney mass or have pre-existing chronic kidney disease. Conversely, RN may be preferred in elderly patients with severe (non-renal related) comorbidities, in patients with an anatomically challenging tumor location, or for larger or locally advanced masses.

Diagnostic Imaging for Solid Renal Tumors: A Pictorial Review

The prognosis of renal tumors depends on histologic subtype. The increased use of abdominal imaging has resulted in an increase in the number of small renal incidentaloma in recent decades. Of these incidentally discovered tumors, 20% are benign lesions warranting conservative management, but most are renal cell carcinomas that warrant a more aggressive therapeutic approach due to their malignant potential. Dedicated diagnostic renal imaging is important for characterization of renal tumors to facilitate treatment planning. This review discusses the ability to detect and differentiate renal cell carcinoma subtypes, angiomyolipoma and oncocytoma based on ultrasound imaging, computed tomography, multiparametric magnetic resonance, and nuclear imaging. 

Reconciling the Role of Vascular Endothelial Growth Factor-Targeted Therapies in Adjuvant Renal Cell Carcinoma Treatment

Up to 40% of patients with high risk, localized RCC will relapse after nephrectomy and are at risk of eventually succumbing to the disease. Historically, phase 3 clinical trials failed to demonstrate meaningful benefit of adjuvant therapy in RCC, likely because these early trials used treatments that did not demonstrate meaningful clinical efficacy in mRCC. However, the clear clinical activity demonstrated by VEGF-TKIs in mRCC patients renewed the promise of adjuvant therapy. ASSURE, S-TRAC, and PROTECT are the first three trials to examine the clinical efficacy of 1 year of adjuvant VEGF-TKI therapy in patients with high-risk RCC following nephrectomy. In this review we reconcile the results of these studies and explore the future of adjuvant RCC therapy.

Intensity Modulated Radiotherapy is a Well-Tolerated and Effective Treatment for the Long-Term Control of Intra-Abdominal and Retroperitoneal Oligometastatic Renal Cell Cancer

Background: The use of conventionally fractionated intensity modulated radiotherapy (IMRT) in the management of oligometastatic renal cell carcinoma (RCC) is currently poorly characterised in the literature. Objective: To evaluate the safety and effectiveness of IMRT for intraabdominal and retroperitoneal RCC oligometastases. Methods: Retrospective analysis of 14 patients with oligometastatic RCC treated with IMRT with the aim of inducing long-term control. Indications for radiotherapy included bleeding abdominal mass (5 patients), solitary renal bed recurrence (5 patients) and isolated, asymptomatic pancreatic mass (4 patients). The prescribed radiotherapy dose was 50 Gray in 20 to 25 fractions. Patients were followed up long-term using regular cross-sectional imaging and clinical review to assess local and distant disease control and treatment related toxicity. Results: At median follow up of 33.5 (6–68) months, 12 patients remain alive (86%), of whom 11 (92%) have no evidence of local recurrence. Six patients (43%) developed further metastatic disease, of whom 4 (67%) received systemic treatment. Median duration of local control was 33.5 months, and 1- and 3-year overall survival (OS) was 92.9% and 85.7% respectively. No treatment-related toxicities ≥ grade 3 and no long-term sequelae were observed. Conclusions: IMRT to intra-abdominal and retroperitoneal metastasis in oligo-metastatic RCC can be delivered safely, provide durable responses and excellent longer-term survival if given to a sufficiently high dose over a conventionally fractionated course. Our study is the first to date with long-term follow up to evaluate the role of IMRT in such cases and has important implications for treatment of oligometastatic RCC. 

Optimal First-Line Treatment of Metastatic Renal-Cell Carcinoma: A Network Meta-Analysis

Background: First-line treatment of metastatic renal cell carcinoma (mRCC) has incrementally evolved over the past decade. Most recently, promising clinical trials for first-line cabozantinib, nivolumab plus ipilimumab, and bevacizumab plus atezolizumab were reported. However, the comparator arm in all of these trials was sunitinib, so no head-to-head comparison exists for contemporary first-line treatments. Objective: To provide an indirect comparison of first-line treatments for mRCC that are currently approved or likely soon to be approved. Methods: Pivotal phase 2/3 clinical trials comparing currently approved first-line agents and novel regimens of nivolumab plus ipilimumab and bevacizumab plus atezolizumab were included if they reported overall survival (OS), progression-free survival (PFS), or objective response rate (ORR). Network meta-analysis of OS, PFS, and ORR was conducted in the context of Bayesian hierarchical log-linear models with both within and between study variance components. Results: For OS, evidence suggests nivolumab plus ipilimumab may be the best first-line treatment available for mRCC (probability best 52%). In contrast, cabozantinib may be superior to other first-line treatments for PFS (probability best 69%) and ORR (probability best 95%). Conclusion: For first-line treatment of mRCC, cabozantinib appears superior to other agents for PFS and ORR, whereas, nivolumab plus ipilimumab may be the best treatment for OS. No single agent was superior to comparators across all endpoints. First-line treatment for mRCC should be tailored to individual cases based on the unique characteristics of each treatment regimen.

What Survival Benefits are Needed to Make Adjuvant Sorafenib Worthwhile After Resection of Intermediate- or High-Risk Renal Cell Carcinoma? Clinical Investigators’ Preferences in the SORCE Trial

Background: Decisions about adjuvant therapy involve trade-offs between possible benefits and harms. Objective: We sought to determine the survival benefits that clinical investigators would judge as sufficient to warrant treatment with adjuvant sorafenib in the SORCE trial after nephrectomy for apparently localised renal cell carcinoma (RCC). Methods: A subset of clinical investigators in the SORCE trial completed a validated questionnaire that elicited the minimum survival benefits they judged sufficient to warrant one year of adjuvant sorafenib in scenarios with hypothetical baseline survival times of 5 years and 15 years, and baseline survival rates at 5 years of 65% and 85%. Results: The 100 participating SORCE investigators had a median age of 42 years, and 74 were male. For one year of sorafenib versus no therapy, the median benefits in survival times the investigators judged sufficient to warrant treatment were an extra nine months beyond five years and an extra 12 months beyond 15 years; the median benefits in survival rates were an extra 5% beyond baseline survival rates of both 65% and 85% at five years. The patients recruited in the SORCE trial by these investigators judged smaller benefits sufficient to warrant adjuvant sorafenib for both survival rate scenarios (p ≤0.0001). The survival benefits the investigators judged sufficient to warrant one year of adjuvant therapy with sorafenib for RCC were similar to those of other clinicians considering three months of adjuvant chemotherapy for lung cancer, but smaller than those of clinicians considering six months of adjuvant chemotherapy for breast cancer. Conclusion: SORCE investigators judged larger benefits necessary to warrant adjuvant sorafenib than their patients. The benefits required by the investigators were similar or smaller than those other clinicians considered sufficient to warrant adjuvant chemotherapy for other cancers. Clinicians should recognise that their patients and colleagues may have preferences that differ from their own when considering the potential benefits and harms of adjuvant treatment. 

Positive Surgical Margins After Partial Nephrectomy: A Systematic Review and Meta-Analysis of Comparative Studies

Objective: We performed an update of previous reviews of the literature to provide an overview on incidence, predictive factors, management and prognosis of positive surgical margins (PSMs) after partial nephrectomy (PN) including recent surgical series and studies comparing different approaches and techniques. Material and methods: A literature search was performed from January 2013 to January 2018 using the Medline database. The search strategy included a free-text protocol using the term “nephron-sparing surgery” OR “partial nephrectomy” AND “positive surgical margins” across the title and abstract fields of the records. From each selected study, we extracted the following data: number of analyzed patients, study design, approach and surgical technique used, PSMs rate, pathological features, type of PSMs treatment, mean (median) follow-up duration and final patient status. Meta-analysis was conducted using Review Manager software v. 5.2 (Cochrane Collaboration, Oxford, UK). Results: We selected a total of 36 (48%) studies. All studies were retrospective and the best statistical method used for comparison was the matched-pair analysis (level 4). Overall, 45,786 patients treated with PN were included in the selected studies. PSMs were reported in a total of 3,093 (6.7%) patients. The mean estimated PSMs rate was 7%, 5% and 4.3% in patients who underwent robot-assisted PN (RAPN), laparoscopic PN (LPN) and open PN (OPN), respectively. Comparative studies showed a significant advantage in favor of OPN compared with minimally invasive approach, while RAPN showed more favourable PSMs risk compared with LPN (odds ratio 3.02, 95% confidence intervals 2.05–4.45). No differences were detected stratifying data according to other surgical or tumor-related factors. Tumor size, nuclear grading and pT3a stage represent the most important predictors of PSMs. In 6,809 patients, follow-up data were available. Only 101 (1.4%) local recurrences and 88 (1.3%) distant recurrences were observed both in PSMs and negative surgical margins subgroups. PSMs were associated with a significant increased risk of local recurrence with a significant impact on local recurrence-free survival and metastasis-free survival. However, a significant impact on cancer-specific and overall survival could not be demonstrated. Conclusions: Studies published in the last 5 years confirmed that PSMs after PN are a rare condition. Although PSMs increase the risk of local and distant recurrence, their influence on cancer-specific and overall survival seems to be limited. Close surveillance should be strongly recommended as initial treatment of patients with PSMs after PN. 

Nutritional Predictors of Perioperative Complications and Mortality Following Nephrectomy for Renal Malignancies: A Population-Based Analysis

Introduction and Objective: Conflicting data exists regarding the impact of body mass index (BMI) on postoperative outcomes following surgery for renal malignancies (RM). Herein, we investigated associations between obesity, hypoalbuminemia, and/or significant weight loss in the preoperative period, and risk complications and mortality within 30 days of radical (RN) or partial nephrectomy (PN). Materials and Methods: Review of the American College of Surgeons National Surgical Quality Improvement Program database identified 8,618 patients treated with PN or RN for RM between 2005 and 2012. Univariate and multivariable logistic regression models were developed to assess associations between hypoalbuminemia (<3.5 g/dl), >10% weight loss within 6 months of surgery, obesity (BMI >30 kg/m2 ), and 30-day major complications and mortality. Results: Median BMI was 29.2 kg/m2 with 24.9%, 11.9%, and 8.2% having class I, II, and III obesity, respectively. Weight loss of >10% was observed in 2.6% and 15.4% had preoperative albumin<3.5 g/dl. There were 1,802 complications (20.9%) and 88 deaths within 30 days (1.0%). On multivariable analysis, BMI ≥40 kg/m2 (OR 1.3, p  = 0.04), >10% weight loss (OR 1.9, p  < 0.001) and hypoalbuminemia (OR 1.5, p  < 0.001) were independently associated with 30-day complications, while only >10% weight loss was independently associated with 30-day mortality (OR 2.4, p  = 0.03). Conclusions: Extreme obesity, hypoalbuminemia, and significant weight loss were independently associated with risk of significant complications following PN or RN while only significant preoperative weight loss was associated with early mortality, underscoring the need to further understand the utility of moderating these risk factors in the perioperative period. 

Clinical Trials Corner

A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Pembrolizumab (MK-3475) as Monotherapy in the Adjuvant Treatment of Renal Cell Carcinoma Post Nephrectomy (KEYNOTE-564)

While strides have been made in the treatment of metastatic RCC, there remains no standard adjuvant systemic therapy that has demonstrated an overall survival benefit in the non-metastatic setting. Most patients with intermediate- to high-risk advanced RCC will progress within 3 years following nephrectomy. Pembrolizumab, an anti-PD-1 antibody, has demonstrated benefit in treating metastatic RCC. It is thought that there may be benefit to immune checkpoint inhibitor therapy after resection of localized disease, the hypothesis being that such therapy may allow for eradication of micrometastatic disease and thus translate to improvements in disease-free (DFS) and overall survival (OS).