Dae Y. Kim

Role of metastasectomy for metastatic renal cell carcinoma in the era of targeted therapy

Numerous biological pathways are affected in renal cell carcinoma and the introduction of targeted agents has improved the survival of patients with advanced and metastatic disease. Durable and long-lasting cure is rarely achieved, and in select cases, the excision of metastatic deposits has shown to increase survival. Clinical trials of targeted agents are being explored as neoadjuvant and adjuvant therapies with the role of metastasectomy evolving in the treatment paradigm. This review examines published reports of metastasectomy and its developing role in the era of targeted therapy. A Medline search was conducted using keywords “metastasectomy,” “renal cell carcinoma,” and “targeted therapy,” and selected articles are discussed by examining prognostic stratification and metastasectomy in major anatomic regions. Most published reports span earlier periods of immunotherapy and chemotherapy, and henceforth, discussions are in historical context in this review. Although there is lack of Level 1 evidence, reports have suggested the prognostic value and survival benefit for metastasectomy in lesions that are amenable to complete resection after longer disease-free intervals in carefully selected patients with adequate performance status. Therefore, the role of metastasectomy must be further elucidated in the era of targeted therapy.

Preoperative Predictors of Pathological Lymph Node Metastasis in Patients with Renal Cell Carcinoma Undergoing Retroperitoneal Lymph Node Dissection

PURPOSE Patients with locally advanced renal cell carcinoma represent a subset that may benefit from retroperitoneal lymph node dissection. We identified preoperative clinical predictors of positive lymph nodes in patients with renal cell carcinoma without distant metastasis who underwent retroperitoneal lymph node dissection. MATERIALS AND METHODS We retrospectively analyzed data on a consecutive cohort of 1,270 patients with cTany Nany M0 renal cell carcinoma who were treated at a single institution from 1993 to 2012. Multivariate analysis was performed to determine preoperative predictors of pathologically positive lymph nodes in patients who underwent retroperitoneal lymph node dissection. A nomogram was developed to predict the probability of lymph node metastasis. Overall, cancer specific and recurrence-free survival was estimated using the Kaplan-Meier Method. RESULTS We identified 1,270 patients with renal cell carcinoma without distant metastasis who had (564) or did not have (706) retroperitoneal lymph node dissection performed. Of the 564 patients 131 (23%) and 433 (77%) had pN1 and pN0 disease, and 60 (37%) and 29 (7.2%) had cN1pN0 and cN0pN1 disease, respectively. ECOG PS, cN stage, local symptoms and lactate dehydrogenase were associated with nodal metastasis on multivariable analysis. A nomogram was developed with a C-index of 0.89 that demonstrated excellent calibration. Differences in overall, cancer specific and recurrence-free survival among pNx, pN0 and pN1 cases were statistically significant (p <0.001). CONCLUSIONS Local symptoms, ECOG PS, cN stage and lactate dehydrogenase were independent predictors of lymph node metastasis in patients who underwent retroperitoneal lymph node dissection. Our predictive nomogram using these factors showed excellent discrimination and calibration.

Treating the two extremes in renal cell carcinoma: management of small renal masses and cytoreductive nephrectomy in metastatic disease.

The incidental renal mass represents a heterogeneous group that contains both benign and malignant pathologies. The majority of renal cell carcinomas are discovered incidentally, without the presence of symptoms directly related to the mass, and are closely associated with the term small renal masses because of the discovery before the onset of symptoms. In general, small renal masses are defined as 4 cm or smaller, and may account for greater than half of renal cell carcinoma diagnosis. The use of renal mass biopsy may offer additional pathological information but the clinician must be reminded of the technical and diagnostic limitations of renal mass biopsy. Patient-dependent factors, such as life expectancy and comorbidities, guide the management of small renal masses, which include active surveillance, partial nephrectomy, radical nephrectomy, and ablative techniques (cryoablation and radiofrequency ablation). Partial nephrectomy has demonstrated durable oncologic control for small renal masses while preserving renal function and, if feasible, is the current treatment of choice. In the other extreme of the renal cell carcinomas spectrum and in the presence of metastatic disease, the removal of the renal primary tumor is termed cytoreductive nephrectomy. Two randomized trials (SWOG 8949 and EORTC 30947) have demonstrated a survival benefit with cytoreductive nephrectomy before the initiation of immunotherapy. These two studies have also been the motivation to perform cytoreductive nephrectomy in the targeted therapy era. Currently, there are two ongoing randomized prospective trials accruing to investigate the timing and relevance of cytoreductive nephrectomy in the contemporary setting of targeted therapy.

Editorial Comment to Growing teratoma syndrome: Clinical and radiographic characteristics

Growing teratoma syndrome (GTS) is a rare clinical entity that was first described by Logothetis et al. in 1982. It occurs in the setting of non-seminomatous germ cell tumors, and is defined as a metastatic tumor (retroperitoneal or otherwise) consisting of mature teratoma that is enlarging during or after systemic chemotherapy, in the setting of normal serum tumor markers. Complete surgical resection is the main treatment of teratomas, which are characteristically chemoresistant and radioresistant. The development of platinum-based chemotherapy regimens in the treatment of non-seminomatous germ cell tumors with long-term survival greater than 90% is a testament to the curability of most testicular tumors. Unfortunately, some patients will have continued growth of their metastatic sites even with normalization of serum tumor markers after chemotherapy, and this should make the treating clinician suspect the presence of GTS. Two hypotheses behind GTS development are that chemotherapy regimens either transform malignant cells into “benign” teratomatous elements, and/or chemotherapy regimens only destroy malignant cells, therefore leaving a chemoresistant teratoma behind. Although teratoma is described as histologically benign, these elements might grow to extreme sizes and compromise adjacent structures, and some might undergo malignant transformation. Novel oral therapies – such as cdk4/6 inhibitors – have been recently used in a small number of patients with GTS (reference 21 in manuscript), with some stabilization of disease noted, but no tumor regression, which is not surprising, as these drugs are mainly tumoristatic. The present study by Lee et al. describes the clinical, radiographic and surgical characteristics of GTS from two academic medical centers with expertise in the type of major surgery typically involved in the treatment of GTS. The small number of patients (n = 15) treated during this 7-year period attests to the rarity of this entity, which was similarly observed by Spiess et al. at 2.2% (9/408) over a 25-year period at another academic medical center. Even with the small number of patients in the current report, there are several notable and worthy observations that can be made. First, the discordant rates of teratoma between the resected metastatic specimen and the primary testicular tumor highlight the inability to predict GTS by simply assessing the percentage of teratoma in the primary tumor specimen. Second, there is no growth rate that specifically characterizes or defines GTS, or that correlates with patient outcomes after surgical resection. In a larger series with 30 patients over a 12-year period, the 5-year overall survival was noted as 90%. Third, the surgical morbidity might be high, which is not surprising given the size and locally invasive nature of GTS, suggesting that earlier intervention with complete resection, preferably at a major center by an experienced urological surgeon, could result in improved outcomes. At present, we should aim to recognize GTS as early as possible by using the clinical clues previously described, and treat the appropriate patients with GTS using aggressive and complete surgical resection by expert urological surgeons. Despite the description of GTS more than 30 years ago, the rarity of this entity makes it difficult to prospectively study this disease with rigorous statistical methods. However, major medical centers with expertise in this disease should seek the opportunity and join forces – in a multicenter and multidisciplinary approach – to investigate and better understand this orphan disease on a molecular, pathological, radiological, surgical and therapeutic level.

Editorial Comment to Growing teratoma syndrome

Growing teratoma syndrome (GTS) is a rare clinical entity that was first described by Logothetis et al. in 1982. It occurs in the setting of non-seminomatous germ cell tumors, and is defined as a metastatic tumor (retroperitoneal or otherwise) consisting of mature teratoma that is enlarging during or after systemic chemotherapy, in the setting of normal serum tumor markers. Complete surgical resection is the main treatment of teratomas, which are characteristically chemoresistant and radioresistant. The development of platinum-based chemotherapy regimens in the treatment of non-seminomatous germ cell tumors with long-term survival greater than 90% is a testament to the curability of most testicular tumors. Unfortunately, some patients will have continued growth of their metastatic sites even with normalization of serum tumor markers after chemotherapy, and this should make the treating clinician suspect the presence of GTS. Two hypotheses behind GTS development are that chemotherapy regimens either transform malignant cells into “benign” teratomatous elements, and/or chemotherapy regimens only destroy malignant cells, therefore leaving a chemoresistant teratoma behind. Although teratoma is described as histologically benign, these elements might grow to extreme sizes and compromise adjacent structures, and some might undergo malignant transformation. Novel oral therapies – such as cdk4/6 inhibitors – have been recently used in a small number of patients with GTS (reference 21 in manuscript), with some stabilization of disease noted, but no tumor regression, which is not surprising, as these drugs are mainly tumoristatic. The present study by Lee et al. describes the clinical, radiographic and surgical characteristics of GTS from two academic medical centers with expertise in the type of major surgery typically involved in the treatment of GTS. The small number of patients (n = 15) treated during this 7-year period attests to the rarity of this entity, which was similarly observed by Spiess et al. at 2.2% (9/408) over a 25-year period at another academic medical center. Even with the small number of patients in the current report, there are several notable and worthy observations that can be made. First, the discordant rates of teratoma between the resected metastatic specimen and the primary testicular tumor highlight the inability to predict GTS by simply assessing the percentage of teratoma in the primary tumor specimen. Second, there is no growth rate that specifically characterizes or defines GTS, or that correlates with patient outcomes after surgical resection. In a larger series with 30 patients over a 12-year period, the 5-year overall survival was noted as 90%. Third, the surgical morbidity might be high, which is not surprising given the size and locally invasive nature of GTS, suggesting that earlier intervention with complete resection, preferably at a major center by an experienced urological surgeon, could result in improved outcomes. At present, we should aim to recognize GTS as early as possible by using the clinical clues previously described, and treat the appropriate patients with GTS using aggressive and complete surgical resection by expert urological surgeons. Despite the description of GTS more than 30 years ago, the rarity of this entity makes it difficult to prospectively study this disease with rigorous statistical methods. However, major medical centers with expertise in this disease should seek the opportunity and join forces – in a multicenter and multidisciplinary approach – to investigate and better understand this orphan disease on a molecular, pathological, radiological, surgical and therapeutic level.

Surgical Treatment for Renal Cell Carcinoma

Systemic therapies for renal cell carcinoma have made modest improvements in patient survival but rarely offer durable cure. Thus, surgical excision of renal cell carcinoma is an integral component of oncologic management. The spectrum of renal cell carcinoma presentation from small renal masses, locally advanced disease, and in the presence of metastasis varies with the surgical armamentarium needed to treat this diverse group of patients. In general for small renal masses, a nephron-sparing approach is preferred if it can be completed safely with negative margins, and for locally advanced tumors, radical nephrectomy is preferred with excision of the affected kidney, lymph nodes, and venous thrombi if present. With metastatic disease, cytoreductive nephrectomy has been shown to prolong survival in carefully selected patients, usually with good performance status and with oligometastasis. The surgical nuances, indication, and motivation for each surgical technique will be discussed in this chapter.

Prognosticators and outcomes of patients with renal cell carcinoma and adjacent organ invasion treated with radical nephrectomy.

OBJECTIVE To study the natural history, prognosticators, and outcomes in patients with renal cell carcinoma (RCC) with extension of tumor beyond Gerota׳s fascia or invading contiguously into the adrenal gland (pT4) or both. PATIENTS AND METHODS From 1992 to 2012, we identified 61 patients who underwent radical nephrectomy and were found to have pT4 disease. Clinicopathologic variables were queried using univariate analysis to identify relevant prognostic variables. Cox proportional hazards model was used for multivariate analysis of predictors of cancer-specific survival. Survival plots were estimated using Kaplan-Meier method and survival analysis using log-rank test. RESULTS Median age was 56 years (interquartile range: 49-64) and 49 (81.7%) patients had Eastern Cooperative Oncology Group Performance Status 0 or 1. At diagnosis, 22 (36.1%) patients showed nonmetastatic and 39 (63.9%) patients showed metastatic RCC. Overall, 49 (80.3%) patients had clear cell RCC, 24 (39.3%) patients had sarcomatoid features, and 39 (69.6%) patients had Fuhrman grade 3 to 4. There were 26 (42.6%) patients with pN0, 16 (26.2%) patients with pN1, and 19 (31.1%) patients with pNx. Median cancer-specific survival was 37 months for patients with nonmetastatic and 8 months for patients with metastatic RCC. On multivariate analysis, preoperative lactate dehydrogenase and alkaline phosphatase, M stage, pN stage, and sarcomatoid dedifferentiation were significantly associated with survival. CONCLUSIONS Survival in patients with pT4 remains poor. The pT4 disease is associated with a locally and regionally invasive biology that requires specific attention and warrants careful study. Understanding the drivers of this unique phenotype would generate therapeutic interventions that can change the behavior of these uniquely aggressive tumors.

Outcomes and prognosticators in patients with pathologic T4 renal cell carcinoma.

514 Background: The 2010 American Joint Committee on Cancer (AJCC) TNM staging system defines pathological T4 renal cell carcinoma (RCC) as extension of tumor beyond Gerota’s fascia and/or invading contiguously into the adrenal gland. This subset of patients with the highest stage and locally advanced disease demonstrate poor outcomes with an estimated 5 year-survival rate of 20-30%. For this high-risk population, patient selection is imperative for proper patient counseling and to identify patients who would benefit from surgical intervention. Our objective was to study patient outcomes and determine prognostic variables predicting survival in pT4 RCC. Methods: From July 1992 to January 2012, we identified 64 patients at our institution who underwent radical nephrectomy and were found to have pT4 disease. The clinical and pathological variables were studied using univariate analysis to identify prognostic variables predicting survival using the Cox proportional hazards model. Survival plots were estimate...

For the RECORD, We Should SWITCH Our Treatment AXIS Before the SUNRISES and TARGET the BEST Treatments Before INTORSECTing with a GOLD METEOR: A Tale of Sequences and Combinations

Once limited to cytokine therapy, the treatment landscape for patients with metastatic renal cell carcinoma (mRCC) has seen tremendous growth over the last 9 yr. Since December 2005, the US Food and Drug Administration has approved a total of seven new targeted therapies for the treatment of mRCC. These drugs have been shown to improve the survival of our patients with mRCC and are currently used as standard therapies. Whenwe take a step back and read through Hanahan and Weinberg’s paper, ‘‘The Hallmarks of Cancer’’ [1], we can see a simplified framework unifying the neoplastic disease process, and this helps us organize the complexity of tumor development and metastasis. The original hallmarks included sustaining proliferative signaling, evading growth suppressors, activating invasion and metastasis, enabling replicative immortality, inducing angiogenesis, and resisting apoptosis. The authors recently revised this review, and two additional hallmarks were included [2]: metabolic pathway abnormalities and immune system evasion. Both are very timely and relevant to our field. For renal cell carcinoma (RCC), theelucidationofangiogenesispathwayshas led to the development of therapies that affect the vascular endothelial growth factor (VEGF) axis aswell as themammalian target of rapamycin (mTOR) pathway, which is involved in some of these hallmark pathways. These therapies, mainly single agents (with the exception of bevacizumab plus interferon-a), werewelcomed as a new paradigm for the treatment of patients with mRCC.

MP36-20 SURVIVAL AND PROGNOSTIC VARIABLES PREDICTING SURVIVAL IN T4 RENAL CELL CARCINOMA

Hybrid Tumors Single Histology P Value Total Masses 48 379 Mean Size (cm) 5.67 5.38 0.28 Mean Age 63.04 61.89 0.59 Male 38 214 pT1a 20 151 0.89 pT1b 7 102 0.15 pT2a 3 25 1 pT2b 3 15 0.45 pT3a 9 44 0.25 pT3b 3 28 1 pT3c 2 1 pT4 1 2 Mixed Histology Types Clear+ Papillary 23 Clear + Chromophobe 5 Clear + Other 7 Other Malignant 6 Onco + Clear 3 Onco + Papillary 3 Onco + Chromophobe 1 -