Matthew T. Campbell

Outcomes of unselected patients with metastatic clear-cell renal cell carcinoma treated with first-line pazopanib therapy followed by vascular endothelial growth factor receptor tyrosine kinase inhibitors or mammalian target of rapamycin inhibitors: a single institution experience

To explore the efficacy and safety of pazopanib in a ‘real‐world’ setting in unselected patients, as data regarding unselected patients with metastatic clear‐cell renal cell carcinoma (ccRCC) treated with first‐line pazopanib are limited.

Front-line Treatment with Gemcitabine, Paclitaxel, and Doxorubicin for Patients with Unresectable or Metastatic Urothelial Cancer and Poor Renal Function: Final Results from a Phase II Study

OBJECTIVE To estimate the response rate of gemcitabine, paclitaxel, and doxorubicin in patients with advanced urothelial carcinoma, we conducted a phase II clinical trial. Patients with renal insufficiency cannot receive standard cisplatin-based chemotherapy for urothelial carcinoma, and carboplatin-based regimens have proved unsatisfactory. Secondary end points for this study included overall survival, safety of the regimen, and safety of same-day pegfilgrastim dosing. METHODS A two-stage design was chosen with target response rate of 40%. Key inclusion criteria were metastatic or unresectable urothelial carcinoma, no prior chemotherapy, glomerular filtration rate <60 mL/min, and no dialysis. Gemcitabine (900 mg/m(2)), paclitaxel (135 mg/m(2)), and doxorubicin (40 mg/m(2)) were administered on day 1 of each 14-day cycle. Pegfilgrastim was given with every cycle on either day 1 or optionally day 2. RESULTS Forty patients were enrolled and 39 were treated. Median age was 72 years (range 51-89). There were 7 complete and 15 partial responses, for a response rate of 56.4% (95% confidence interval, 39.6-72.2). Most cycles (82.8%) were given with same-day pegfilgrastim. Notable grade 3 and 4 nonhematologic toxicities were fatigue and mucositis (10.3% each). There were 4 episodes of neutropenic fever (4 of 198 cycles [2%]; 4 of 39 patients [10.3%]) and no treatment-related deaths. Median overall survival was 14.4 months. CONCLUSION The combination of gemcitabine, paclitaxel, and doxorubicin is effective first-line chemotherapy for patients with advanced urothelial carcinoma and renal insufficiency. Neutropenic prophylaxis was acceptable whether pegfilgrastim was given immediately or 24 hours after chemotherapy.

Outcomes of Patients With Metastatic Non-Clear-Cell Renal Cell Carcinoma Treated With Pazopanib.

Micro‐Abstract Outcomes data in patients with metastatic non–clear‐cell renal cell carcinoma (RCC) treated with pazopanib are limited. We identified 29 patients with non–clear‐cell metastatic RCC who received pazopanib (9 in the front‐line setting, and 20 in the salvage setting). Median overall survival was 31 months (95% confidence interval [CI], 9.2‐NA [not available]) in the front‐line group compared with 13.6 months (95% CI, 6.4‐NA) in the salvage group. Background: Pazopanib is associated with increased progression‐free survival (PFS) in clear‐cell renal cell carcinoma (RCC) and has become a standard of care in this disease. The drug is used in metastatic non–clear‐cell RCC, but data on outcomes in this setting are limited. Patients and Methods: We conducted a retrospective data analysis of records of consecutive metastatic non–clear‐cell RCC patients who received pazopanib in front‐line and salvage settings between November 2009 and November 2012. Tumor response rate was assessed by a blinded radiologist using Response Evaluation Criteria in Solid Tumors version 1.1. PFS and overall survival (OS) times were estimated using Kaplan–Meier methods. Results: Twenty‐nine patients were identified with non–clear‐cell metastatic RCC, 9 received pazopanib in the front‐line setting, 20 in the salvage setting after progression of disease with other targeted therapies. Seven patients (24%) had papillary RCC, 4 (14%) had chromophobe, 5 (17%) had unclassified histopathology, and 13 (45%) had other subtypes including collecting duct, translocation Xp11.2, and various subtypes with sarcomatoid differentiation. All patients discontinued pazopanib before analysis. Median PFS was 8.1 months (95% CI, 5.7‐NA [not available]) in the front‐line group, and 4 months (95% CI, 2.1‐9.9) in the salvage group. Median OS was 31 months (95% CI, 9.2‐NA) in the front‐line group, and 13.6 months (95% CI, 6.4‐NA) in the salvage group. Conclusion: Pazopanib showed efficacy in patients with metastatic non–clear‐cell RCC in the front‐line and salvage settings. Toxicity was mild to moderate and manageable. Further studies are needed to evaluate pazopanibs role in non–clear‐cell RCC in terms of efficacy and safety.

Phase I trial of sunitinib and temsirolimus in metastatic renal cell carcinoma

BACKGROUND Preclinical data suggest that anti-vascular endothelial growth factor agents combined with mammalian target of rapamycin inhibitors yield synergistic antitumor effects. A phase I trial with a 3+3 dose escalation design of S with T was stopped after the first dose pair led to 2 of 3 patients experiencing dose-limiting toxicity (DLT). PATIENTS AND METHODS To explore multiple potential dosing pairs of S and T, a 2-stage outcome-adaptive Bayesian dose-finding method was designed. The primary objective was to find the MTD of S and T in patients with advanced renal cell carcinoma. A 3-week treatment cycle consisted of daily S, 2 weeks of treatment, 1 week without treatment, and weekly T. RESULTS Twenty patients received study drugs; the median number of previous therapies was 1. The number of patients (S and T doses in mg) was: 2 (S, 12.5; T, 6), 1 (S, 25; T, 12.5), 1 (S, 12.5; T, 8), 8 (S, 12.5 alternate 25; T, 9), 2 (S, 25; T, 6), 2 (S, 25 alternate 37.5; T, 6), 2 (S, 37.5; T, 6), and 2 (S, 37.5; T, 8). Six patients required dose reduction, 3 because of Grade 3 stomatitis, 2 because of Grade 3 thrombocytopenia; the mean number of cycles was 6.6 ± 5.3, the mean time during study was 159 ± 120 days. One patient experienced a DLT in cycle 1 and was nonevaluable, 1 had a partial response, 16 had stable disease, and 2 had progressive disease as best response. There were 21 Grade 3/4 adverse events but no treatment-related deaths. CONCLUSION The MTD of S and T were not determined because of premature trial closure. S 37.5 mg/d, 2 weeks of treatment, 1 week with no treatment, and T 8 mg to 10 mg weekly are close to the MTD.

Intratumoral heterogeneity and chemoresistance in nonseminomatous germ cell tumor of the testis

Background Nonseminomatous germ cell tumor of the testis (NSGCT) is largely curable. However, a small group of patients develop refractory disease. We investigated the hypothesis that intratumoral heterogeneity contributes to the emergence of chemoresistance and the development of refractory tumor subtypes. Results Our institutions records for January 2000 through December 2010 included 275 patients whose primary tumor showed pure embryonal carcinoma (pure E); mixed embryonal carcinoma, yolk sac tumor, and teratoma (EYT); or mixed embryonal carcinoma, yolk sac tumor, seminoma, and teratoma (EYST). Patients with EYST had the highest cancer-specific mortality rate (P = .001). They tended to undergo somatic transformation (P = .0007). Two of 5 patients with clinical stage I EYST who had developed recurrence during active surveillance died of their disease. Materials and Methods In this retrospective study, we evaluated consecutive patients who had been diagnosed with the three most common histological phenotypes of NSGCT. Chemoresistance was defined as the presence of teratoma, viable germ cell tumor, or somatic transformation in the residual tumor or the development of progressive or relapsed disease after chemotherapy. In a separate prospective study, we performed next-generation sequencing on tumor samples from 39 patients to identify any actionable genetic mutations. Conclusions Our data suggest that patients with EYST in their primary tumor may harbor a potentially refractory NSGCT phenotype and are at increased risk of dying from disease. Despite intratumoral heterogeneity, improved patient selection and personalized care of distinct tumor subtypes may optimize the clinical outcome of patients with NSGCT.

Optimizing management of upper tract urothelial carcinoma

Upper tract urothelial cancer (UTUC) is a rare cancer of the urothelium, comprising only a fraction of cases as compared to urothelial tumors of the bladder. As a result, systemic treatment approaches in bladder cancer are often applied to patients with UTUC. Given the anatomical location of these tumors, the age, the comorbid conditions of these patients with UTUC, and the need for radical nephroureterectomy for treatment, most patients have substantial impairment of renal reserve. There is growing evidence for the benefit of perioperative chemotherapy in this disease. Patients with UTUC have high rates of microsatellite instability and fibroblast growth factor receptor 3 mutations as compared to their bladder counterparts presenting unique, important subsets in UTUC. Immune checkpoint inhibitors targeting the programmed death receptor 1 and ligand have provided a new second-line treatment option for patients with UTUC and appear particularly well suited for patients with microsatellite instability. More work in understanding the molecular gene signatures and its relationship to response to chemotherapy, immunotherapy, and targeted therapy is needed to continually optimize care for patients with all stages of disease. Advances in UTUC are possible, when one accounts for the unique clinical and biological features of this disease.

The state of immune checkpoint inhibition in urothelial carcinoma current evidence and future areas of exploration

AbstractImmune checkpoint inhibition will be the first treatment breakthrough in recurrent and metastatic urothelial carcinoma since the introduction of combination chemotherapy more than 30 years ago. Monoclonal antibodies that target cytotoxic T-lymphocyte antigen 4, programmed death receptor 1, and programmed death receptor ligand 1 are furthest along in clinical development. Specific antibodies targeting either programmed death receptor 1 or programmed death receptor ligand 1 have demonstrated significant single-agent activity with impressive safety and tolerability for heavily pretreated patients in early-phase clinical trials. In our review, we discuss the rationale for immunotherapy in urothelial cancer, completed and ongoing studies with immune checkpoint therapy, the development of molecular subtypes of urothelial carcinoma with the potential impact of immunotherapy in these new groupings, and future directions of exploration with these agents in both early- and late-stage disease.

Long-term survivorship in patients (pts) with metastatic renal cell cancer (mRCC): A retrospective study from the MD Anderson Cancer Center (MDACC).

510 Background: The overall survival (OS) of pts with mRCC has improved since the introduction of targeted therapies (TT). We sought to characterize the baseline characteristics, management, and outcomes of pts who survived > 4 yrs from date of diagnosis of metastatic disease (Met Dx). Methods: We retrospectively reviewed medical records of consecutive pts who were diagnosed with mRCC and evaluated at MDACC from 1/1/2001 to 12/31/2008. Descriptive statistics and Kaplan-Meier methods were used to estimate OS times. Results: For 729 mRCC pts identified, median OS was 2.3 years (95% CI: 2.1, 2.5); 219 (30.0%) pts have survived >4 yrs, and 167 (22.9%) pts have survived >5 yrs. For pts diagnosed in the cytokine era (2000 to 2004) median OS was 2.3 yrs (95%CI: 2-2.6) compared to median OS 2.4 yrs (95%CI: 2.0-3.0) for pts diagnosed in the targeted era (2005-2008). Of the 219 pts, 205 pts had adequate baseline information. Conclusions: Since 2000, approximately 30% of mRCC pts have survived >4 yrs and 23% have su...

Current and Future Applications of Novel Immunotherapies in Urological Oncology: A Critical Review of the Literature

CONTEXT Immunotherapies promote anticancer responses with varying levels of success based on the tumor type. OBJECTIVE In this narrative review article, we searched the literature regarding immunotherapies in genitourinary malignancies to define the state of the field, explore future applications of immune checkpoint inhibitors, cytokines, vaccines, and cellular therapies in urological oncology and evaluate possible strategies to improve the selection of patients who might benefit from such approaches. EVIDENCE ACQUISITION We reviewed related literature, with a focus on recent studies about immunotherapies, predictors of response, and ongoing clinical trials. EVIDENCE SYNTHESIS Immunotherapies based on immune checkpoint blockade are approved as first- and second-line therapies for urothelial carcinoma (UC) and second-line therapies for renal cell carcinoma with limited success in prostate cancer. Programmed death-ligand 1 is the most commonly used predictive biomarker outside of UC; however, a substantial proportion of patients with tumors negative for programmed death-ligand 1 expression benefit from checkpoint inhibition, limiting its sensitivity. A high mutational load and molecular subtypes of UC are emerging as additional potential predictors. Genomic sequencing and gene expression analysis associate alterations of genes implicated in DNA repair pathways, such as BRCA1 and BRCA2, with immune checkpoint therapies. In prostate cancer, the vaccine, sipuleucel-T, is the only Food and Drug Administration-approved immunotherapy. CONCLUSIONS Immunotherapies are emerging as exciting new treatment options with a tolerable toxicity profile in urological cancers. Checkpoint inhibitors are effective only in a subset of patients, demanding personalized approaches that consider various clinical and molecular parameters to predict patient response. Clinical trials investigating the optimal timing, sequence, and combination of immunotherapies with standard of care and novel agents will guide therapy choices and improve patient outcome. PATIENT SUMMARY Clinical data supports the safety and efficacy of immune checkpoint inhibitors alone or in combination with other therapies in urological cancers.

Recent developments in the management of germ cell tumors

Purpose of review In the present review, we summarize the recent developments in the management of germ cell tumors (GCTs). Recent findings Treatment-related acute and late-onset toxicity remains a key challenge in the management of GCTs. Recent data show that patients with large retroperitoneal lymph node metastases are at increased risk of venous thromboembolism and may benefit from prophylactic anticoagulation. Predictive models have been developed to identify patients with residual retroperitoneal lymph node masses who are more likely to benefit from surgical resection. However, their clinical use remains hampered by relatively low accuracy. There are currently multiple conventional-dose chemotherapy (CDCT) options for salvage therapy in patients with refractory or recurrent disease. In addition, more efficacious high-dose chemotherapy (HDCT) regimens continue to be developed. The role of salvage CDCT versus HDCT is currently being prospectively investigated. Finally, intratumoral heterogeneity is a common finding in cancer and an obvious observation in GCTs. Despite intratumoral heterogeneity, recent studies on nonseminomatous GCT have identified distinct histological subgroups and a potentially lethal clinical phenotype. Importantly, comprehensive molecular profiling so far has not elucidated the biologic basis or the clinical underpinnings of intratumoral heterogeneity in GCTs. Summary Remaining challenges to be addressed include minimizing therapeutic toxicity and improving outcomes in patients with refractory/recurrent GCTs or malignant transformation of teratomas.