Diogo Assed Bastos

Treatment outcome with mTOR inhibitors for metastatic renal cell carcinoma with nonclear and sarcomatoid histologies

BACKGROUND The clinical trials that reported benefit of the rapalogs temsirolimus and everolimus in advanced renal cell carcinoma (RCC) were primarily conducted in patients with clear-cell histology (ccRCC). We assessed outcome with these mammalian target of rapamicin (mTOR) inhibitors in two subsets of kidney cancer: sarcomatoid variant ccRCC and nonclear-cell RCC. PATIENTS AND METHODS Baseline clinical features, information on prior treatment, and histologic subtypes were collected for patients previously treated with rapalogs for metastatic RCC of either nonclear phenotype or ccRCC with sarcomatoid features. Outcome was assessed centrally by a dedicated research radiologist for determination of tumor response, progression-free survival (PFS), and overall survival (OS). RESULTS Eighty-five patients received temsirolimus (n = 59) or everolimus (n = 26). Nonclear-cell phenotypes included papillary (n = 14), chromophobe (n = 9), collecting duct (n = 4), translocation-associated (n = 3), and unclassified (n = 32) RCC. Twenty-three patients had clear-cell histology with sarcomatoid features. The response rate in assessable patients (n = 82) was 7% (all partial responses); 49% of patients achieved stable disease, and 44% had progressive disease as their best response. Tumor shrinkage was observed in 26 patients (32%). Median PFS and OS were 2.9 and 8.7 months, respectively. Nine patients (11%) were treated for ≥1 year, including cases of papillary (n = 3), chromophobe (n = 2), unclassified (n = 3) RCC, and ccRCC with sarcomatoid features (n = 1). No tumor shrinkages were observed for patients with collecting duct or translocation-associated RCC. CONCLUSIONS A subset of patients with nonclear-cell and sarcomatoid variant ccRCC subtypes benefit from mTOR inhibitors, but most have poor outcome. Histologic subtype does not appear to be helpful in selecting patients for rapalog therapy. Future efforts should include the identification of predictive tissue biomarkers.BACKGROUND The clinical trials that reported benefit of the rapalogs temsirolimus and everolimus in advanced renal cell carcinoma (RCC) were primarily conducted in patients with clear-cell histology (ccRCC). We assessed outcome with these mammalian target of rapamicin (mTOR) inhibitors in two subsets of kidney cancer: sarcomatoid variant ccRCC and nonclear-cell RCC. PATIENTS AND METHODS Baseline clinical features, information on prior treatment, and histologic subtypes were collected for patients previously treated with rapalogs for metastatic RCC of either nonclear phenotype or ccRCC with sarcomatoid features. Outcome was assessed centrally by a dedicated research radiologist for determination of tumor response, progression-free survival (PFS), and overall survival (OS). RESULTS Eighty-five patients received temsirolimus (n = 59) or everolimus (n = 26). Nonclear-cell phenotypes included papillary (n = 14), chromophobe (n = 9), collecting duct (n = 4), translocation-associated (n = 3), and unclassified (n = 32) RCC. Twenty-three patients had clear-cell histology with sarcomatoid features. The response rate in assessable patients (n = 82) was 7% (all partial responses); 49% of patients achieved stable disease, and 44% had progressive disease as their best response. Tumor shrinkage was observed in 26 patients (32%). Median PFS and OS were 2.9 and 8.7 months, respectively. Nine patients (11%) were treated for ≥1 year, including cases of papillary (n = 3), chromophobe (n = 2), unclassified (n = 3) RCC, and ccRCC with sarcomatoid features (n = 1). No tumor shrinkages were observed for patients with collecting duct or translocation-associated RCC. CONCLUSIONS A subset of patients with nonclear-cell and sarcomatoid variant ccRCC subtypes benefit from mTOR inhibitors, but most have poor outcome. Histologic subtype does not appear to be helpful in selecting patients for rapalog therapy. Future efforts should include the identification of predictive tissue biomarkers.

Safety and Efficacy of Targeted Therapy for Renal Cell Carcinoma With Brain Metastasis

BACKGROUND Brain metastases are associated with a poor prognosis in patients with renal cell carcinoma (RCC). The role of targeted therapy in this setting is not well established. The primary objective was to assess overall survival (OS) and neurologic events in patients with brain metastasis treated with targeted agents. PATIENTS AND METHODS Patients with RCC treated with targeted agents for brain metastasis between 2002 and 2012 were retrospectively identified. Kaplan-Meier methodology and a Cox proportional hazards model were used to analyze the association between clinical features and OS. RESULTS Of 65 patients identified, 52 (80%) were treated with antiangiogenic agents and 13 (20%) received inhibitors of mTOR (mechanistic target of rapamycin [serine/threonine kinase]); 57 (88%) had local therapy for brain metastasis, including surgery in 3 (5%), radiation therapy in 36 (55%), and both surgery and radiotherapy in 18 (28%). Median follow-up was 12.3 months (1.1-58.8). Median treatment duration for targeted therapy as first-line therapy was 3.4 months (0.3-31.9). The median OS was 12.2 months (95% CI, 8.0-15.5). The risk group according to the Memorial Sloan Kettering Cancer Center (MSKCC) stratification (P = .001), the histology subtype (clear vs. other) (P < .0001), and the number of brain lesions (1 vs. ≥ 2) (P = .004) correlated with OS on multivariate analysis. Neurologic complications were identified in 5 patients (8%), including 2 with radiation necrosis and 3 with brain metastasis hemorrhage. CONCLUSION The use of targeted agents in the multimodal treatment of patients with RCC and brain metastasis was not associated with excessive neurologic adverse events. Clear cell histology, favorable MSKCC risk status, and solitary brain metastasis are associated with more favorable OS.

The role of high-dose chemotherapy in the management of germ cell tumors.

Purpose of review To discuss the current role and future perspectives of high-dose chemotherapy (HDCT) in the management of advanced germ cell tumors (GCTs). Recent findings Multiple studies have demonstrated the safety and efficacy of HDCT, consisting of carboplatin and etoposide followed by stem cell reinfusion, for the salvage treatment of GCTs. However, three randomized trials showed no benefit for HDCT over conventional dose chemotherapy in the first-line setting. Similarly, adding a third drug to etoposide with carboplatin does not seem to substantially improve treatment efficacy and may increase toxicity and mortality. Recent retrospective data from single centers and a large international collaboration demonstrated better outcomes with use of HDCT in the initial (rather than later) salvage setting as well as with sequential rather than single cycle regimens. However, randomized data are lacking. Prognostic factors for outcome to salvage HDCT were recently established and enhanced supportive measures such as growth factors and antibiotic prophylaxis have resulted in a dramatic decrease in morbidity and mortality. Summary HDCT plays an integral role in the salvage treatment of patients with advanced GCTs. However, optimal timing (initial vs. later salvage), dosing, number of high-dose cycles, and patient selection remain to be defined.

Treatment outcome with mTOR inhibitors for 65 cases of non-clear cell renal cell carcinoma: Association of long-term responses and oncogenomic events.

391 Background: Temsirolimus and everolimus are standard agents in the management of advanced renal cell carcinoma, but the registration trials primarily enrolled patients with clear cell histology. We assessed outcome in patients with non-clear cell RCC (ncRCC) treated with mTOR inhibitors at our center. METHODS Clinical features and histologic subtypes were characterized for ncRCC patients treated with single-agent temsirolimus or everolimus. Outcome was analyzed using the Kaplan-Meier method to determine progression free survival (PFS) and overall survival (OS). Genomic analysis of outliers with either durable or poor response was done by next-generation sequence analysis of tumor tissue and germline DNA. RESULTS 65 patients received temsirolimus (n = 46) or everolimus (n = 19). Histologic subtypes included papillary (n = 16), chromophobe (n = 9), collecting duct (n = 6), translocation-associated (n = 3), and unclassified (n = 31) RCC. Median follow-up for survivors is 29 mos. Median treatment duration for 52 patients, who continue therapy or stopped due to progression or death, is 2 mos. 8 patients (12.3%) were treated for ≥ 1 year (max. 37 mos), including papillary (n = 3), chromophobe (n = 2) and unclassified (n = 3) RCC. Tumor analysis identified genomic determinants of long term response in 2 unclassified RCC (complete functional loss of TSC1 and TSC2, respectively). No such changes were seen in 2 patients with chromophobe RCC and rapid progression on therapy. CONCLUSIONS A subset of ncRCC patients derives benefit from mTOR inhibitors, but most have poor outcome. Durable responses can be linked to oncogenomic alterations within the mTOR pathway, and future goals should include the identification and characterization of such predictive tissue biomarkers. [Table: see text].

Optimizing the treatment of metastatic castration-resistant prostate cancer: a Latin America perspective

Prostate cancer is a significant burden and cause of mortality in Latin America. This article reviews the treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) and provides consensus recommendations to assist Latin American prostate cancer specialists with clinical decision making. A multidisciplinary expert panel from Latin America reviewed the available data and their individual experience to develop clinical consensus opinions for the use of life-prolonging agents in mCRPC, with consideration given to factors influencing patient selection and treatment monitoring. There is a lack of level 1 evidence for the best treatment sequence or combinations in mCRPC. In this context, consensus recommendations were provided for the use of taxane-based chemotherapies, androgen receptor axis-targeted agents and targeted alpha therapy, for patients in Latin America. Prostate-specific antigen (PSA) changes alone, during treatment, should be treated with caution; PSA may not be a suitable biomarker for radium-223. Bone scans and computed tomography are the standard imaging modalities in Latin America. Imaging should be prompted during treatment where symptomatic decline and/or significant worsening of laboratory evaluations are reported, or where a course of therapy has been completed and another antineoplastic agent is under consideration. Recommendations and guidance for treatment options in Latin America are provided in the context of country-level variable access to approved agents and technologies for treatment monitoring. Patients should be treated with the purpose of prolonging overall survival and preserving quality of life through increasing the opportunity to administer all available life-prolonging therapies when 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.

Chemotherapy in a Patient With G6PD Deficiency and Advanced Testicular Cancer

G6PD is the most common enzymatic deficiency in humans,1,2 affecting approximately 5% of the worlds population.3 Currently, there are more than 180 reported genetic variants of G6PD and its expression can vary from a mild (class V) to a severe deficiency of the enzyme (class I).3 G6PD deficient erythrocytes have difficulties in handling oxidative stress and, subsequently, are more susceptible to lysis.3 Antimalarials (dapsone, primaquine, methylene blue) are the classic therapeutic agents associated with acute hemolytic anemia but several other drugs are deemed as possible causes of hemolysis in G6PD deficient patients.2,4,5 Until the present moment, little is known about the prevalence of G6PD deficiency in cancer patients, and data regarding the use and safety of chemotherapy treatments in this population in the literature is extremely scarce.6 Here we describe the case of a young man with advanced testicular germ cell tumor treated with cisplatin-based chemotherapy (bleomycin, etoposide and cisplatin).

Performance status (PS) in advanced germ cell tumors (aGCT): Clinical and prognostic value of an underreported important variable.

e16537Background: Although PS is a strong marker of adverse outcomes in most metastatic solid tumors, data of PS status are lacking in GCT, especially using validated scales such as Eastern Coopera...

Tumor Lysis Syndrome After Platinum-based Chemotherapy in Castration-resistant Prostate Cancer With a BRCA2 Mutation: A Case Report

Tumor lysis syndrome is a potentially fatal oncologic emergency, extremely rare in prostate cancer, with very few cases reported in the literature. Mutations concerning the homologous recombination system genes, mainly BRCA1/2, have been studied in prostate cancer as potential therapeutic targets. To our knowledge, our case is the first report of tumor lysis syndrome in a patient with BRCA2-mutated prostate cancer after platinum-based chemotherapy exposure. The purpose of this article is to raise awareness to the possibility of tumor lysis syndrome in advanced prostate cancer, mainly in the setting of more active and personalized treatment regimens.

Safety and efficacy of targeted therapy for renal cell carcinoma (RCC) with brain metastasis.

497 Background: Brain metastases (Bm) in RCC are associated with poor prognosis. The safety and efficacy of TT in this setting is not well established since patients (pts) with Bm were excluded from pivotal clinical trials. The primary objective was to assess safety and efficacy of TT in pts with Bm. Methods: Pts with mRCC treated with ≥ 28 days of TT after Bm diagnoses were retrospectively identified. Kaplan-Meier method and Cox proportional hazards model were used to analyze the association between clinical features and OS. Results: 65 pts were identified, including 52 (80%) treated with anti-angiogenic agents and 13 (20%) treated with mTOR inhibitors. Most pts had extracranial metastasis (98%) and 54% had ≥ 2 brain lesions. Fifty seven pts (88%) had local therapy for Bm before TT including surgery in 3 (5%), radiation therapy (RT) in 36 (55%) and both surgery and RT in 18 (28%). Median follow-up was 12.3 months (1.1 – 58.8). Median treatment duration was 3.4 months (0.3 – 31.9) for 1st line and 1.9 mon...