Manuel Caitano Maia

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.

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.

Case Discussion: Systemic Therapy for Metastatic Renal Cell Carcinoma

First-line systemic therapy for patients with metastatic renal cell carcinoma should largely entail the use of targeted agents. Depending on the clinical factors, VEGF- or mTOR-directed agents may be appropriate.

Efficacy and Safety of Docetaxel in Elderly Patients With Metastatic Castration-Resistant Prostate Cancer

Purpose Limited data are available about the tolerability and clinical outcomes of elderly patients with metastatic castration-resistant prostate cancer (mCRPC) who are treated with docetaxel. We evaluated the efficacy and safety of docetaxel as first-line chemotherapy for patients with mCRPC who were treated in our institution. Materials and Methods We retrospectively identified patients with mCRPC and a Karnosfky performance status of 60% or greater treated with docetaxel on any schedule as first-line chemotherapy between 2008 and 2013. The primary end point was a comparison of median overall survival (OS) according to age in this population. Secondary end points were comparisons of the rates of severe toxicities, prostate-specific antigen (PSA) decline of 50% or greater, and time to progression (TTP). Results were stratified by three age groups: younger than 65 years, 65 to 74 years, and 75 years or older. Results Among the 197 patients included, 68 (34%) were younger than 65 years, 85 (43%) were 65 to 74 years, and 44 (22%) were 75 years or older. The mean number of comorbidities was not different among groups (1.19 v 1.32 v 1.43; P = .54). Patients younger than 65 years received a higher cumulative dose of docetaxel (450 mg/m2 v 382 mg/m2 v 300 mg/m2; P = .004). The rates of PSA decline of 50% or greater (41% v 47% v 36.4%; P = .51) and the median TTP (5.13 v 5.13 v 4.7 months; P = .15) were comparable among all groups. The median OS was longer in the group of patients younger than age 65 years (19.6 v 12.4 v 12.3 months; P = .012). Rates of any grade 3 or higher adverse event were not different among groups (63.2% v 71.8% v 54.5%; P = .14). Conclusion Administration of docetaxel in elderly patients who had good performance status was well tolerated. Rates of PSA decline and TTP were similar to those of younger patients, but median survival was lower.

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.

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.

Subset Analyses from CheckMate 025: A Challenge to Current Clinical Dogma?

Arguably the most contentious debate in metastatic renal cell carcinoma (mRCC) 5 yr ago was whether axitinib or everolimus represented optimal second-line therapy. In the absence of any randomized trials comparing the two directly, investigators were left to juxtapose efficacy and toxicity across two independent phase 3 trials [1,2]. Subset analyses from each trial were used to invoke comparisons of progression-free survival (PFS) and response rate in VEGFtyrosine kinase inhibitor (TKI) pretreated patients. Despite differences in eligibility, many attempts were made to infer from the separate phase 3 data sets which drug has the superior safety profile [3,4]. Fast forward to 2017. For the moment, the nature of firstline therapy remains unchanged. Sunitinib and pazopanib remain the agents most commonly used in this setting; although there is no consensus as to which is superior, comparative data do exist to guide the patient and clinician in decision-making [5]. However, second-line therapy has evolved entirely with the reporting of two phase 3 and one phase 2 clinical trial. CheckMate 025 compares the PD-1 inhibitor nivolumab to everolimus in patients with one to three prior lines of treatment [6]. In this issue of European Urology, subset analyses from this study are described. METEOR assesses the TKI cabozantinib, which has affinity not only for VEGF but also for MET and AXL, two putative oncogenic drivers [7]. Finally, a randomized phase 2 study compares the multikinase inhibitor lenvatinib to everolimus and to the combination of drugs. At recent meetings it has been evident that clinicians have aligned primarily with either cabozantinib or nivolumab in the second-line setting. Despite compelling PFS data