Nazli Dizman

Metastasis in renal cell carcinoma: Biology and implications for therapy

Although multiple advances have been made in systemic therapy for renal cell carcinoma (RCC), metastatic RCC remains incurable. In the current review, we focus on the underlying biology of RCC and plausible mechanisms of metastasis. We further outline evolving strategies to combat metastasis through adjuvant therapy. Finally, we discuss clinical patterns of metastasis in RCC and how distinct systemic therapy approaches may be considered based on the anatomic location of metastasis.

Advances in treatment of metastatic renal cell carcinoma.

Purpose of review Multiple agents, including vascular endothelial growth factor (VEGF) inhibitors and mammalian target of rapamycin inhibitors have been approved over the past decade for the treatment of metastatic renal cell carcinoma (mRCC). Here, we focus on nivolumab, cabozantinib, and lenvatinib plus everolimus, agents that have recently emerged with positive clinical data leading to ‘Food and Drug Administration approval or pending approval in mRCC. We also review the development of novel agents of interest showing promise in mRCC as part of combination therapy’. Recent findings Nivolumab and cabozantinib both offer improved survival over everolimus in the second-line treatment of mRCC. Lenvatinib plus everolimus has similarly shown encouraging survival benefits in a phase II trial for the second-line setting. Novel combinations in mRCC, including dual immune checkpoint blockade, VEGF and programmed death 1 inhibition, VEGF and vaccine therapy, dual angiogenic blockade, and VEGF-directed therapy with nanoparticle-containing camptothecin have shown promising activity in early-phase trials. Summary Multiple promising agents are available in the treatment of mRCC. The appropriate sequencing of agents in the treatment of mRCC may become further elucidated by future studies that prospectively analyze potential biomarkers to identify patients who will derive the greatest benefit from VEGF, mammalian target of rapamycin, or checkpoint inhibitors.

Association of Circulating Tumor DNA (ctDNA) Detection in Metastatic Renal Cell Carcinoma (mRCC) with Tumor Burden

Background: In a series of 224 patients with advanced renal cell carcinoma (RCC), we have previously reported circulating tumor DNA (ctDNA) detection in 79% of patients. Clinical factors associated with detection are unknown. Methods: Data was obtained from patients with radiographically confirmed stage IV RCC who received ctDNA profiling as a part of routine clinical care using a CLIA-certified platform evaluating 73 genes. Detailed clinical annotation was performed, including assessment of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, previous and current treatments and calculation of tumor burden using scan data most proximal to ctDNA assessment. Tumor burden was equated to the sum of longest diameter (SLD) of all measurable lesions. Results: Thirty-four patients were assessed (18 male and 16 female) with a median age of 62 (range, 34–84). Twenty-six patients, 4 patients and 4 patients had clear cell, sarcomatoid and papillary histologies, respectively. IMDC risk was good, intermediate and poor in 14, 19 and 1 patient, respectively. ctDNA was detected in 18 patients (53%) with a median of 2 genomic alterations (GAs) per patient. No associations were found between IMDC risk, histology or treatment type and presence/absence of ctDNA. However, patients with detectable ctDNA had a higher SLD compared to patients with no detectable ctDNA (8.81 vs 4.49 cm; P = 0.04). Furthermore, when evaluated as a continuous variable, number of GAs was correlated with SLD (P = 0.01). Conclusions: With the caveat of a limited sample size, it appears that SLD (a surrogate for tumor burden) is higher in mRCC patients with detectable ctDNA. Confirmation of these findings in larger series is ongoing and may suggest a capability for ctDNA to either complement or supplant radiographic assessment.

Exceptional Response to Nivolumab Rechallenge in Metastatic Renal Cell Carcinoma with Parallel Changes in Genomic Profile

A 44-yr-old man was noted to have headaches, and computerized tomography imaging of the brain revealed a 1.6-cm frontal lesion. Complete staging revealed a 7.5-cm left-sided renal mass and extensive retroperitoneal adenopathy. The patient received a craniotomy and nephrectomy, with pathology from both procedures revealing clear cell renal cell carcinoma (RCC). The patient received high-dose interleukin-2 approximately 1 mo thereafter (Fig. 1), but progressed within a span of 2 mo. He then received pazopanib, which stabilized his disease for approximately 5 mo. The patient then received bevacizumab monotherapy but progressed within 2 mo. He then received nivolumab/ ipilimumab in a phase 1 clinical trial with a marked radiographic response in retroperitoneal nodes with no new findings on neuroimaging [1]. However, he developed grade 3 hepatoxicity requiring cessation of immunotherapy and initiation of chronic steroids, ultimately tapered after 6 mo. In the intervening period, while off of systemic therapy, the patient developed 14 new brain metastases which were treated with stereotactic radiosurgery. Eighteen months after initial receipt of nivolumab/ ipilimumab, the patient developed further systemic progression and was rechallenged with bevacizumab. He progressed on bevacizumab monotherapy after 4 mo and then received bevacizumab in combination with trebananib [2]. He progressed on this regimen within 4 mo and then received radiation to retroperitoneal lymph nodes. After 8 mo, the patient developed further progression and was started on an investigational antibody drug conjugate. The patient had relatively rapid progression on this with new brain metastases. After craniotomy and stereotactic radiosurgery to these new lesions, the patient was started on cabozantinib. While he had some stabilization of disease with cabozantinib, his disease ultimately progressed after 11 mo. He was then rechallenged with nivolumab and once again developed grade 3 hepatoxicity after just two doses. Nivolumab was discontinued. However, after 3 mo, the

Letter by Dizman et al Regarding Article, “Periodontitis Increases the Risk of a First Myocardial Infarction: A Report From the PAROKRANK Study”

We have read the article “Periodontitis Increases the Risk of a First Myocardial Infarction: A Report From the PAROKRANK Study” by Ryden et al1 with great interest. We congratulate the authors for their meticulous work on such a controversial subject. In our opinion, the title …

Assessment of distress and quality of life in rare cancers

Rare cancers are a heterogeneous group of conditions that can be associated with emotional and physical impairments. In view of the dearth of research in this area, we investigated the quality of life and prevalence of distress in a cohort of patients diagnosed with a rare cancer, classified by the RARECARE definition.

Assessment of Treatment Patterns for Metastatic Renal Cell Carcinoma in Brazil

Background Although multiple therapies have emerged for the treatment of metastatic renal cell carcinoma (mRCC), it is unclear whether application of these agents is consistent in developed and developing countries. We sought to determine patterns of care for mRCC in Brazil as a representative developing country. Material and Methods A commercial database was used to acquire information pertaining to patients with mRCC receiving treatment at private or public hospitals in Brazil between March 2013 and October 2016. Basic clinical and demographic criteria were available, as well as information to ascertain the International Metastatic Renal Cell Carcinoma Database Consortium risk. Treatment-related data across multiple lines of therapy were collected. Results Of 4,379 patients assessed, 3,990 (91%) had metastatic disease, and 26%, 48%, and 26% of patients had good, intermediate, and poor International Metastatic Renal Cell Carcinoma Database Consortium risk disease, respectively. Although 3,149 patients (79%) received first-line therapy, only 641 (20%) and 152 (5%) received second- and third-line therapy, respectively. In the first-line setting, vascular endothelial growth factor–directed agents represented the most commonly used therapy, whereas in the second-line setting, vascular endothelial growth factor– and mammalian target of rapamycin–directed agents were used with similar frequency. Marked differences were seen in receipt of systemic therapy on the basis of treatment in private or public hospitals. Conclusion Relative to developed countries, marked attrition is noted between each subsequent line of therapy in Brazil. Patterns of care also vary greatly in private and public settings, pointing to financial constraints as a potential cause for discordances in treatment.

Concomitant Radioembolization and Immune Checkpoint Inhibition in Metastatic Renal Cell Carcinoma

This case represents the challenge and creativity necessary when treating patients with metastatic renal cell carcinoma who have been exposed to multiple lines of therapy. At present, treatment with immune checkpoint inhibition has stabilized and improved the metastatic disease of this patient with the exception of hepatic lesions. This isolated progression within the liver led the employment of radioembolization, which successfully treated those metastases. This is the first documented case of metastatic renal cell carcinoma controlled with concurrent use of immune checkpoint inhibition and radioembolization for both extrahepatic and hepatic metastases, respectively. This case can be construed as a potential example of the abscopal effect and may provide the basis for understanding this type of response in select patients.

Cytoreductive nephrectomy: A medical oncologist’s perspective

The role of cytoreductive nephrectomy (CN) was firmly established in the cytokine era on the basis of 2 randomized studies employing adjunctive interferon therapy. However, systemic therapy for metastatic renal cell carcinoma has evolved markedly over the past decade, with targeted therapies representing the standard of care in the front-line setting. The preponderance of retrospective data generated to date appears to suggest that the benefit of CN is maintained in the targeted therapy era. However, these studies are inherently prone to selection bias and cannot substitute prospective evidence. Herein, we discuss ongoing prospective studies evaluating CN and propose novel strategies to evaluate this surgical technique in the context of an evolving therapeutic landscape.

Therapeutic Sequencing in Metastatic Renal Cell Carcinoma

The influx of multiple novel therapeutic options in the mRCC field has brought a challenge for treatment sequencing in this disease. In the past few years, cabozantinib, nivolumab and the combination of lenvatinib and everolimus have been approved in the second-line setting. As there is no direct comparison between these agents and the studies have failed to show improved benefit among a biomarker-selected patient population, appropriate patient selection based on clinical factors for individualized therapy is critical. Herein we provide a comprehensive overview of current data from each agent through the discussion of disease biology, clinical trials, potential biomarkers and distilling future perspectives in the field.