Advanced renal cell carcinoma management: the Latin American Cooperative Oncology Group (LACOG) and the Latin American Renal Cancer Group (LARCG) consensus update.

PURPOSE: Renal cell carcinoma is an aggressive disease with a high mortality rate. Management has drastically changed with the new era of immunotherapy, and novel strategies are being developed; however, identifying systemic treatments is still challenging. This paper presents an update of the expert panel consensus from the Latin American Cooperative Oncology Group and the Latin American Renal Cancer Group on advanced renal cell carcinoma management in Brazil. METHODS: A panel of 34 oncologists and experts in renal cell carcinoma discussed and voted on the best options for managing advanced disease in Brazil, including systemic treatment of early and metastatic renal cell carcinoma as well as nonclear cell tumours. The results were compared with the literature and graded according to the level of evidence. RESULTS: Adjuvant treatments benefit patients with a high risk of recurrence after surgery, and the agents used are pembrolizumab and sunitinib, with a preference for pembrolizumab. Neoadjuvant treatment is exceptional, even in initially unresectable cases. First-line treatment is mainly based on tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs); the choice of treatment is based on the International Metastatic Database Consortium (IMCD) risk score. Patients at favourable risk receive ICIs in combination with TKIs. Patients classified as intermediate or poor risk receive ICIs, without preference for ICI + ICIs or ICI + TKIs. Data on nonclear cell renal cancer treatment are limited. Active surveillance has a place in treating favourable-risk patients. Either denosumab or zoledronic acid can be used for treating metastatic bone disease. CONCLUSION: Immunotherapy and targeted therapy are the standards of care for advanced disease. The utilization and sequencing of these therapeutic agents hinge upon individual risk scores and responses to previous treatments. This consensus reflects a commitment to informed decision-making, drawn from professional expertise and evidence in the medical literature.

"Non-metastatic, Castration-resistant Prostate Cancer: Diagnostic and Treatment Recommendations by an Expert Panel from Brazil".

INTRODUCTION: Non-metastatic, castration-resistant prostate cancer (nmCRPC) is an important clinical stage of prostate cancer, prior to morbidity and mortality from clinical metastases. In particular, the introduction of novel androgen-receptor signaling inhibitors (ARSi) has changed the therapeutic landscape in nmCRPC. Given recent developments in this field, we update our recommendations for the management of nmCRPC. METHODS: A panel of 51 invited medical oncologists and urologists convened in May of 2021 with the aim of discussing and providing recommendations regarding the most relevant issues concerning staging methods, antineoplastic therapy, osteoclast-targeted therapy, and patient follow-up in nmCRPC. Panel members considered the available evidence and their practical experience to address the 73 multiple-choice questions presented. RESULTS: Key recommendations and findings include the reliance on prostate-specific antigen doubling time for treatment decisions, the absence of a clear preference between conventional and novel (i.e., positron-emission tomography-based) imaging techniques, the increasing role of ARSis in various settings, the general view that ARSis have similar efficacy. Panelists highlighted the slight preference for darolutamide, when safety is of greater concern, and a continued need to develop high-level evidence to guide the intensity of follow-up in this subset of prostate cancer. DISCUSSION: Despite the limitations associated with a consensus panel, the topics addressed are relevant in current practice, and the recommendations can help practicing clinicians to provide state-of-the-art treatment to patients with nmCRPC in Brazil and other countries with similar healthcare settings.

Consensus on the Treatment and Follow-Up for Metastatic Castration-Resistant Prostate Cancer: A Report From the First Global Prostate Cancer Consensus Conference for Developing Countries (PCCCDC).

PURPOSE: To present a summary of the recommendations for the treatment and follow-up for metastatic castration-resistant prostate cancer (mCRPC) as acquired through a questionnaire administered to 99 physicians working in the field of prostate cancer in developing countries who attended the Prostate Cancer Consensus Conference for Developing Countries. METHODS: A total of 106 questions out of more than 300 questions addressed the use of imaging in staging mCRPC, treatment recommendations across availability and response to prior drug treatments, appropriate drug treatments, and follow-up, and those same scenarios when limited resources needed to be considered. Responses were compiled and the percentages were presented by clinicians to support each response. Most questions had five to seven relevant options for response including abstain and/or unqualified to answer, or in the case of yes or no questions, the option to abstain was offered. RESULTS: Most of the recommendations from this panel were in line with prior consensus, including the preference of a new antiandrogen for first-line therapy of mCRPC. Important aspects highlighted in the scenario of limited resources included the option of docetaxel as treatment preference as first-line treatment in several scenarios, docetaxel retreatment, consideration for reduced doses of abiraterone, and alternative schedules of an osteoclast-targeted therapy. CONCLUSION: There was wide-ranging consensus in the treatment for men with mCRPC in both optimal and limited resource settings.

Harnessing cell-free DNA: plasma circulating tumour DNA for liquid biopsy in genitourinary cancers.

In the era of precision oncology, liquid biopsy techniques, especially the use of plasma circulating tumour DNA (ctDNA) analysis, represent a paradigm shift in the use of genomic biomarkers with considerable implications for clinical practice. Compared with tissue-based tumour DNA analysis, plasma ctDNA is more convenient to test, more readily accessible, faster to obtain and less invasive, minimizing procedure-related risks and offering the opportunity to perform serial monitoring. Additionally, genomic profiles of ctDNA have been shown to reflect tumour heterogeneity, which has important implications for the identification of resistant clones and selection of targeted therapy well before clinical and radiographic changes occur. Moreover, plasma ctDNA testing can also be applied to cancer screening, risk stratification and quantification of minimal residual disease. These features provide an unprecedented opportunity for early treatment of patients, improving the chances of treatment success.

Stool Microbiome Profiling of Patients with Metastatic Renal Cell Carcinoma Receiving Anti-PD-1 Immune Checkpoint Inhibitors.

Preclinical models and early clinical data suggest an interplay between the gut microbiome and response to immunotherapy in solid tumors including metastatic renal cell carcinoma (mRCC). We sought to characterize the stool microbiome of mRCC patients receiving a checkpoint inhibitor (CPI) and to assess treatment-related changes in microbiome composition over the course of CPI therapy. Stool was collected from 31 patients before initiation of nivolumab (77%) or nivolumab plus ipilimumab (23%) therapy, of whom 58% experienced clinical benefit. Greater microbial diversity was associated with clinical benefit from CPI therapy (p = 0.001), and multiple species were associated with clinical benefit or lack thereof. Temporal profiling of the microbiome indicated that the relative abundance of Akkermansia muciniphila increased in patients deriving clinical benefit from CPIs. This study substantiates results from previous CPI-related microbiome profiling studies in mRCC. Temporal changes in microbiome composition suggest potential utility in modulating the microbiome for more successful CPI outcomes. PATIENT SUMMARY: We compared the composition and diversity of the gut microbiome in patients receiving immunotherapy for renal cell carcinoma. We found that higher microbial diversity is associated with better treatment outcomes. Treatment response is characterized by changes in microbial species over the course of treatment.

Advanced renal cell carcinoma (RCC) management: an expert panel recommendation from the Latin American Cooperative Oncology Group (LACOG) and the Latin American Renal Cancer Group (LARCG).

PURPOSE: The outcome of RCC has improved considerably in the last few years, and the treatment options have increased. LACOG-GU and LARCG held a consensus meeting to develop guidelines to support the clinical decisions of physicians and other health professionals involved in the care of RCC patients. METHODS: Eighty questions addressing relevant advanced RCC treatments were previously formulated by a panel of experts. The voting panel comprised 26 specialists from the LACOG-GU/LARCG. Consensus was determined as 75% agreement. For questions with less than 75% agreement, a new discussion was held, and consensus was determined by the majority of votes after the second voting session. RESULTS: The recommendations were based on the highest level of scientific evidence or by the opinion of the RCC experts when no relevant research data were available. CONCLUSION: This manuscript provides guidance for advanced RCC treatment according to the LACOG-GU/LARCG expert recommendations.

Biomarkers in Non-Schistosomiasis-related squamous cell carcinoma of the urinary bladder: A review.

Non-urothelial (NU) histologies represent less than 10% of bladder cancers, with squamous cell carcinoma (SCC) being the most common subtype (approximately 5%). Bladder SCCs are subdivided into Schistosoma-related or non-Schistosoma-related tumors, with the latter being the most frequent subtype in the western world. Typically, these patients have been excluded or under-represented in clinical trials and thus little is known about treatment efficacy in bladder SCC. To address this paucity of data, extrapolation from urothelial carcinoma (UC) trials can be performed but this approach has inherent limitations. In the era of precision medicine, efforts to characterize the genomic and molecular profiles of bladder tumors may yield evidence to support new targets for effective therapies. We reviewed the available data on biomarkers of bladder SCC and provide suggestions on how these may influence therapeutic testing and clinical trials in the future.

Renal cell cancer treatment: an expert panel recommendation from the Latin American cooperative group-genitourinary and the Latin American renal cancer group: focus on surgery.

BACKGROUND: Renal cell cancer (RCC) is one of the 10 most common cancers in the world, and its incidence is increasing, whereas mortality is declining only in developed countries. Therefore, two collaborative groups, The Latin American Oncology Cooperative Group-Genitourinary Section (LACOG-GU) and the Latin American Renal Cancer Group (LARCG), held a consensus meeting to develop this guideline. METHODS: Issues (134) related to the treatment of RCC were previously formulated by a panel of experts. The voting panel comprised 26 specialists (urologists and medical oncologists) from the LACOG-GU/LARCG. A consensus was reached if 75% agreement was achieved. If there was less concordance, a new discussion was undertaken, and a consensus was determined by the most votes after a second voting session. RESULTS: The expert meeting provided recommendations that were in line with the global literature; 75.0% of the recommendations made by the panel of experts were evidence-based level A, 22.5% of the recommendations were level B, and 2.5% of the recommendations were level D. CONCLUSIONS: This review suggests recommendations for the surgical treatment of RCC according to the LACOG-GU/LARCG experts.

Current systemic therapies for metastatic renal cell carcinoma in older adults: A comprehensive review.

Physiological changes that occur during the aging process may impact drug metabolism and availability, consequently affecting treatment efficacy and tolerability. Despite being a disease of older adults, there is little data to guide treatment decisions for older patients with metastatic renal cell carcinoma (mRCC). The recent approval of many new agents for this disease poses a clinical challenge: how to best utilize these drugs in a population (older adults) who has been generally under-represented in clinical studies. Additionally, the presence of comorbid conditions, polypharmacy, frailty, and lack of social support place this group of patients in a very unique situation. In order to avoid under-treatment, international societies' guidelines recommend routine use of geriatric tools to assess patients' suitability for systemic treatments. Here we provide a thorough review of age-related metabolic differences, safety and efficacy data for each drug approved for mRCC, and cover specific considerations for the management of older adults with this disease.

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.

A comprehensive review of immunotherapies in prostate cancer.

Prostate cancer is the second most common malignant neoplasm in men worldwide and the fifth cause of cancer-related death. Although multiple new agents have been approved for metastatic castration resistant prostate cancer over the last decade, it is still an incurable disease. New strategies to improve cancer control are needed and agents targeting the immune system have shown encouraging results in many tumor types. Despite being attractive for immunotherapies due to the expression of various tumor associated antigens, the microenvironment in prostate cancer is relatively immunosuppressive and may be responsible for the failures of various agents targeting the immune system in this disease. To date, sipuleucel-T is the only immunotherapy that has shown significant clinical efficacy in this setting, although the high cost and potential trial flaws have precluded its widespread incorporation into clinical practice. Issues with patient selection and trial design may have contributed to the multiple failures of immunotherapy in prostate cancer and provides an opportunity to tailor future studies to evaluate these agents more accurately. We have reviewed all the completed immune therapy trials in prostate cancer and highlight important considerations for the next generation of clinical trials.

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.

Systemic Therapy for Non-Clear Cell Renal Cell Carcinoma.

Treatment options for metastatic clear cell renal cell carcinoma (ccRCC) have evolved markedly over the past decade, with multiple targeted therapies approved for the disease. In contrast, little improvement has been made in the management of metastatic non-clear cell RCC (nccRCC). Non-clear cell disease is an umbrella term that encompasses multiple biologically distinct entities, including but not limited to papillary, chromophobe, and sarcomatoid RCC. To date, prospective studies have largely explored treatments for ccRCC (e.g., VEGF- and mTOR-directed therapies) in trials that aggregate non-clear cell histologies. However, the studies do not acknowledge the varying biology of each non-clear cell subtype. Emerging studies in nccRCC should examine individual histologies and apply biologically relevant therapies. An example of this is SWOG 1500, a randomized phase II study that will compare a VEGF-inhibitor to one of three MET-directed therapies in patients with metastatic papillary RCC. Until the biologic diversity of nccRCC is appreciated, outcomes are likely to remain dismal.

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.

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.