Brian F. Chapin

The Impact of Targeted Molecular Therapies on the Level of Renal Cell Carcinoma Vena Caval Tumor Thrombus

BACKGROUND Targeted molecular therapies (TMTs) previously have demonstrated oncologic activity in renal cell carcinoma (RCC) by reducing the size of primary tumors and metastases. OBJECTIVE To assess the cytoreductive effect of TMTs on inferior vena cava tumor thrombi. DESIGN, SETTING, AND PARTICIPANTS A multi-institutional database of patients treated with TMTs for RCC was reviewed. The subset with in situ level II or higher caval thrombi (above renal vein) was assessed for radiographic response in thrombus size and level. Pre- and posttreatment characteristics of this population were assessed for predictors of response in height, diameter, and level of the tumor thrombi. MEASUREMENTS The main outcome measured was a change in the clinical level of tumor thrombus following TMT. We also measured radiographic responses in thrombus size and location before and after TMT. RESULTS AND LIMITATIONS Twenty-five patients met the inclusion criteria. Before TMT, thrombus level was II in 18 patients (72%), III in 5 patients (20%), and IV in 2 patients (8%). The first-line therapy was sunitinib in 12 cases; alternative TMTs were administered in 13. The median duration of therapy was two cycles (range: one to six cycles). Following TMT, 7 patients (28%) had a measurable increase in thrombus height, 7 (28%) had no change, and 11 (44%) had a decrease. One patient (4%) had an increase in thrombus-level classification, 21 (84%) had stable thrombi, and in 3 (12%) the thrombus level decreased. There was only one case (4%) where the surgical approach was potentially affected by tumor thrombus regression (level IV to III). No statistically significant predictors of tumor thrombus response to TMTs were found. Limitations include the descriptive and retrospective study design. Because TMTs were initiated according to physician and/or patient preferences, and not all patients were treated in anticipation of surgery, no conclusions could be drawn regarding selection and duration of therapy. Thus it may not be appropriate to extrapolate our experience to all patients with locally advanced RCC. Although this is the largest reported experience with in situ caval tumor thrombi treated with TMT, this series lacks sufficient statistical power to assess the usefulness of TMTs adequately in tumor thrombus cytoreduction. CONCLUSIONS TMT had a minimal clinical effect on RCC tumor thrombi. Only patients treated with sunitinib had clinical thrombus regression; however, the clinical magnitude and relevance of this effect is not clear and should be investigated prospectively.

Improved Survival With Prostate Radiation in Addition to Androgen Deprivation Therapy for Men With Newly Diagnosed Metastatic Prostate Cancer

PURPOSE There is growing interest in the role of local therapies, including external beam radiotherapy (RT), for men with metastatic prostate cancer (mPCa). We used the National Cancer Database (NCDB) to evaluate the overall survival (OS) of men with mPCa treated with androgen deprivation (ADT) with and without prostate RT. METHODS The NCDB was queried for men with newly diagnosed mPCa, all treated with ADT, with complete datasets for RT, surgery, prostate-specific antigen (PSA) level, Gleason score, and Charlson-Deyo comorbidity score. OS was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched analyses. RESULTS From 2004 to 2012, 6,382 men with mPCa were identified, including 538 (8.4%) receiving prostate RT. At a median follow-up of 5.1 years, the addition of prostate RT to ADT was associated with improved OS on univariate (P < .001) and multivariate analysis (hazard ratio, 0.624; 95% CI, 0.551 to 0.706; P < .001) adjusted for age, year, race, comorbidity score, PSA level, Gleason score, T stage, N stage, chemotherapy administration, treating facility, and insurance status. Propensity score analysis with matched baseline characteristics demonstrated superior median (55 v 37 months) and 5-year OS (49% v 33%) with prostate RT plus ADT compared with ADT alone (P < .001). Landmark analyses limited to long-term survivors of ≥1, ≥3, and ≥5 years demonstrated improved OS with prostate RT in all subsets (all P < .05). Secondary analyses comparing the survival outcomes for patients treated with therapeutic dose RT plus ADT versus prostatectomy plus ADT during the same time interval demonstrated no significant differences in OS, whereas both therapies were superior to ADT alone. CONCLUSION In this large contemporary analysis, men with mPCa receiving prostate RT and ADT lived substantially longer than men treated with ADT alone. Prospective trials evaluating local therapies for mPCa are warranted.

Safety of Presurgical Targeted Therapy in the Setting of Metastatic Renal Cell Carcinoma

BACKGROUND In patients with metastatic renal cell carcinoma (mRCC), the timing of systemic targeted therapy in relation to cytoreductive nephrectomy (CN) is under investigation. OBJECTIVE To evaluate postoperative complications after the use of presurgical targeted therapy prior to CN. DESIGN, SETTING, AND PARTICIPANTS A retrospective review of all patients who underwent a CN at The University of Texas M.D. Anderson Cancer Center from 2004 to 2010 was performed. Inclusion in this study required documented evidence of mRCC, with treatment incorporating CN. INTERVENTIONS Patients receiving presurgical systemic targeted therapy prior to CN were compared to those undergoing immediate CN. MEASUREMENTS Complications were assessed using the modified Clavien system for a period of 12 mo postoperatively. RESULTS AND LIMITATIONS Presurgical therapy was administered to 70 patients prior to CN (presurgical), while 103 patients had an immediate CN (immediate). A total of 232 complications occurred in 57% of patients (99 of 173). Use of presurgical systemic targeted therapy was predictive of having a complication>90 d postoperatively (p=0.002) and having multiple complications (p=0.013), and it was predictive of having a wound complication (p<0.001). Despite these specific complications, presurgical systemic targeted therapy was not associated with an increased overall complication risk on univariable or multivariate analysis (p=0.064 and p=0.237) and was not predictive for severe (Clavien ≥3) complications (p=0.625). This study is limited by its retrospective nature. As is inherent to any retrospective study reporting on complications, we are limited by reporting bias and the potential for misclassification of specific complications. CONCLUSIONS Despite an increased risk for specific wound-related complications, overall surgical complications and the risk of severe complications (Clavien ≥3) are not greater after presurgical targeted therapy in comparison to upfront cytoreductive surgery.

Treatment of the Primary Tumor in Metastatic Prostate Cancer: Current Concepts and Future Perspectives

CONTEXT Multimodal treatment for men with locally advanced prostate cancer (PCa) using neoadjuvant/adjuvant systemic therapy, surgery, and radiation therapy is being increasingly explored. There is also interest in the oncologic benefit of treating the primary tumor in the setting of metastatic PCa (mPCa). OBJECTIVE To perform a review of the literature regarding the treatment of the primary tumor in the setting of mPCa. EVIDENCE ACQUISITION Medline, PubMed, and Scopus electronic databases were queried for English language articles from January 1990 to September 2014. Prospective and retrospective studies were included. EVIDENCE SYNTHESIS There is no published randomized controlled trial (RCT) comparing local therapy and systemic therapy to systemic therapy alone in the treatment of mPCa. Prospective studies of men with locally advanced PCa and retrospective studies of occult node-positive PCa have consistently shown the addition of local therapy to a multimodal treatment regimen improves outcomes. Molecular and genomic evidence further suggests the primary tumor may have an active role in mPCa. CONCLUSIONS Treatment of the primary tumor in mPCa is being increasingly explored. While preclinical, translational, and retrospective evidence supports local therapy in advanced disease, further prospective studies are under way to evaluate this multimodal approach and identify the patients most likely to benefit from the inclusion of local therapy in the setting of metastatic disease. PATIENT SUMMARY In this review we explored preclinical and clinical evidence for treatment of the primary tumor in metastatic prostate cancer (mPCa). We found evidence to support clinical trials investigating mPCa therapy that includes local treatment of the primary tumor. Currently, treating the primary tumor in mPCa is controversial and lacks high-level evidence sufficient for routine recommendation.

Can a Durable Disease-Free Survival be Achieved With Surgical Resection in Patients With Pathological Node Positive Renal Cell Carcinoma?

PURPOSE Patients with isolated regional nodal metastases from renal cell carcinoma are a distinct cohort for which resection of involved lymph nodes may be therapeutic. We assessed the outcomes of patients treated at our institution with pathological node positive renal cell carcinoma without concomitant metastatic disease (T(any)N+M0). MATERIALS AND METHODS A total of 2,521 patients with nonmetastatic renal cell carcinoma (T(any)N(any)M0) of any histological subtype treated with nephrectomy were identified between 1995 and 2009. Pathological regional node positive disease in the absence of clinically detectable metastases (T(any)N(1-2)M0) was present in 68 patients (2.7%) and these patients formed our study cohort. Patients were assessed for timing and location of recurrence, disease specific survival and overall survival. Multivariate Cox regression analysis was performed to define factors predictive of recurrence and overall survival. RESULTS Of the 68 patients with T(any)N(1-2)M0 renal cell carcinoma 22.1% were free of disease at a median followup of 43.5 months. In those patients experiencing recurrence, disease was detected within the first 4 months after surgery in 51% and was most commonly detected at multiple organ sites. The Kaplan-Meier estimated 5-year overall survival and disease specific survival was 37% and 39%, respectively. Predictors of a favorable outcome included an Eastern Cooperative Oncology Group performance status of 0, single node involvement, absence of sarcomatoid features and papillary histology. CONCLUSIONS Nephrectomy with lymph node dissection can provide a durable disease-free survival in a proportion of patients with regionally advanced renal cell carcinoma and limited lymph node metastases.

Discerning the survival advantage among patients with prostate cancer who undergo radical prostatectomy or radiotherapy: The limitations of cancer registry data

The objective of this study was to compare the overall survival of patients who undergo radical prostatectomy or radiotherapy versus noncancer controls to discern whether there is a survival advantage according to prostate cancer treatment and the impact of selection bias on these results.

Radical Prostatectomy for Locally Advanced Prostate Cancer: Current Status.

In the past, prostate cancer (PC) could only be detected clinically, and delayed diagnosis of locally advanced or metastatic disease at presentation was common. Prostate-specific antigen testing and magnetic resonance imaging led to PC detection in a much earlier stage. However, controversy about the best treatment for locally advanced PC remains. Recent refinements in surgery and radiation therapy have improved outcomes, but no comparative study has yet conclusively determined superiority of one option over the other. In this review, we present the most recent evidence about the role of radical prostatectomy for locally advanced PC treatment from a surgeons perspective.

Renal Cell Carcinoma: What the Surgeon and Treating Physician Need to Know

OBJECTIVE The multimodality approach to treating both localized and metastatic renal cell carcinoma has led to a demand for improved imaging evaluation. We review the information needed from the radiologic studies used to determine treatment strategies. CONCLUSION Adequate preoperative radiologic assessment provides the treating physician with information critical in determining the sequence of treatments, role of nephron-sparing surgery, surgical approach, and timing of systemic therapy for metastatic disease.

Disease reclassification risk with stringent criteria and frequent monitoring in men with favourable‐risk prostate cancer undergoing active surveillance

To determine the frequency of disease reclassification and to identify clinicopathological variables associated with it in patients with favourable‐risk prostate cancer undergoing active surveillance (AS).

The RENAL Nephrometry Nomogram: Statistically Significant, But Is It Clinically Relevant?

There are multiple treatment options for managing patients with renal cell carcinoma (RCC), particularly for those with a small renal mass (SRM). Surgical removal is the gold standard for treatment of localized RCC, whereas energy-ablative therapies and active surveillance are reasonable options in patients with significant comorbid medical conditions. The objective of preoperative prognostic stratification is to tailor an individual’s therapy based on anticipated outcomes of a specific biologic factor. Preoperative identification of two such factors, malignancy or high-grade malignancy, would be useful when counseling a patient with a newly diagnosed SRM. An individual’s risk can be assessed based on a single variable or through integration of multiple variables and calculating risk using a nomogram. The use of nomograms in urologic oncology has been driven by the allure of providing individualized medicine and optimizing clinical decision making based on a multitude of patient-specific variables rather than by simplistic grouping according to risk level. Although these nomograms calculate a probability of an outcome based on a population, we must keep in mind that there is still a significant amount of subjective interpretation prior to obtaining the objective prediction. It is important when assessing the utility of a specific nomogram to be aware of the variability of the model to predict for an outcome when applied to an individual patient (ie, confidence score) and to determine what each individual variable in a nomogram adds to the overall predictive ability [1]. A second important consideration when assessing a nomogram for practical use is determining if the predicted outcome will truly alter clinical decision making. In other words, is this information useful, and at what probability would decisions be altered? In this edition of European Urology, Kutikov et al [2] have attempted to use their previously published standardized renal mass quantification system, RENAL nephrometry [3], in conjunction with two additional clinical variables to develop a nomogram to predict for the presence of malignancy and high-grade disease. Several groups have previously attempted to develop clinical nomograms to determine the probability of renal masses being malignant or high grade, but they have had only modest success [4,5]. First and foremost, the group from Fox Chase Cancer Center should be congratulated on the development of the RENAL nephrometry score, which, along with PADUA score and C-index, was one of the first scoring systems originally created with the intention of providing a standardized descriptive system for renal masses based on radiologic findings. The initial goal of this stratification system was to compare surgical outcomes and practice patterns across institutions. Although this system is proving useful as an anatomic descriptor, its value for use in a predictive