Cytoreductive Nephrectomy vs Medical Therapy in RCC
Cytoreductive Nephrectomy vs Medical Therapy in RCC
Background: Renal cell carcinoma (RCC) can be considered as two distinct entities: localized and metastatic disease.
Methods: We conducted a review of the scientific literature published within the past decade pertaining to cytoreductive nephrectomy for metastatic RCC.
Results: Retrospective data and historical prospective series have demonstrated the survival benefit of debulking nephrectomy in well-selected RCC patients. New medical therapies, including vascular endothelial growth factor and mTOR pathway blocking drugs, are active biological agents, with survival improvement and potential regression of metastatic and primary tumors. Our current therapeutic challenge is the optimal integration of multimodal therapy consisting of systemic therapy and surgery including cytoreductive nephrectomy, debulking, and metastasectomy. Empiric data to guide this decision are limited.
Conclusions: The decision concerning whether medical or surgical therapy should be the primary treatment approach selected must be made on an individual basis, taking into account patient performance status, clinical parameters, and physician expertise and recommendations, thus making each case a unique therapeutic challenge.
Fortunately, the current era is one in which a variety of medical and surgical innovations are in active development in renal cell carcinoma (RCC). From the medical side, the emphasis is on targeted therapies, with currently approved drugs that impact the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and Raf pathways, as well as mTOR protein expression. Furthermore, additional investigational applications including other growth-factor receptor tyrosine kinases and downstream proteins, as well as increasing complex immune manipulations, beyond cytokines, are similarly promising. From the surgical and locally directed therapy standpoint, technical novelties such as laparoscopic, robotic, and energy-intense modalities (radiofrequency ablation, cryoablation and potentially high-intensity frequency ultrasound) increasingly demonstrate comparable nephron-preservation potential, with minimal morbidity, and comparable treatment-specific short-term outcomes. Definitive local control of the primary is always a goal in localized disease but is conceptually less important in the context of established metastatic disease where debulking is the primary goal. The psychologic impact of primary tumor resection is a further dimension in a patient's decision-making process.
However, compelling prospective trials attribute a survival advantage to nephrectomy itself, in the face of metastatic disease. Among patients selected for suitability for nephrectomy despite radiographically evident metastatic disease, those assigned to nephrectomy followed by interferon treatment had a median survival of 13.6 months compared with 7.8 months in patients assigned to interferon alone. Similarly, from a retrospective outlook, nephrectomy status is a major factor in clinical prognostic stratification, along with performance status, hemoglobin level, serum calcium level, and lactate dehydrogenase (LDH) measurement. Other factors that were prognostic in the databases of the Southwest Oncology Group (SWOG) and the European Organisation for Research and Treatment of Cancer (EORTC) included Eastern Cooperative Oncology Group (ECOG) performance status, serum alkaline phosphatase level, and lung-only pattern of metastatic spread.
These experiences predate targeted drug availability for RCC. The extent to which these historical series parallel our treatment-specific outcomes with these novel agents is unclear. Similarly, the optimal integrations of these experiences were not evaluated directly against the new drugs. The optimal integration of surgery and medical therapy is yet to be elucidated. Nevertheless, clinical scoring systems identify good-risk subsets of patients significantly greater median survival (22 to 30 months) compared with the subjects in this nephrectomy trial, but the extent to which these data are applicable to patients already stratified is uncertain.
Patients with kidney cancer, particularly those with metastatic disease, are heterogeneous with respect to tumor histology, age at presentation, performance status, and anatomic pattern of spread. To whom should nephrectomy be offered? Before or after medical treatment, or permanently deferred? Should our experience with metastatic RCC, consisting predominantly of clear cell histology tumors (~ 75%), be extrapolated to the papillary RCC (10% to 15%) and the 12 rarer subtypes of kidney tumors defined in the 2004 WHO classification simply because they originate from the same organ of origin? How does the answer change with the introduction of the targeted drug era? A variety of clinical and laboratory parameters can help tailor the approach for an individual patient, leading to the central question of strategic integration of nephrectomy with targeted therapy for the patient with metastatic RCC at presentation.
With about one-third of incidentally detected kidney cancers being metastatic at presentation, as well as the presence of locally advanced disease, the issue of initial anticancer treatment by medical or surgical intervention is a frequent topic of discussion. Patients with stage IV disease, however, are a heterogeneous group, even after assignment to a risk stratification category. For some patients, the extent of metastatic disease is detectable but miniscule, or obvious symptoms are directly attributable to the primary tumor, such as hematuria and abdominal pain. The circumstances that contribute to an easy decision to consider upfront cytoreductive nephrectomy can be considered in two aspects: one is a general medical context of good reserve of renal function in the contralateral kidney (or in a noninvolved, salvageable component of the ipsilateral kidney); the other is data demonstrating survival advantage attributable to nephrectomy, from experience preceding the targeted drug era.
At the other extreme, compromising situations such as high relative metastatic bulk (compared to the primary), multiple medical comorbidities, frailty that raises operative and perioperative risk, histologic subtype that is not clear cell in which the majority of our clinical experience lies, or limitations on renal functional reserve, nephrectomy must be deferred either temporarily or permanently.
What is the best approach for a fit patient, with a technically resectable primary tumor, who has metastatic disease? Will new agents control the primary to an extent that obviates the benefit attributable to cytoreductive nephrectomy? How are risk stratifications based on postnephrectomy patients relevant to a nephrectomy decision? Of specific concern, there is a middle ground, with a technically resectable primary tumor, good anticipated postsurgical renal functional reserve, and perhaps mild or moderate symptoms, possibly raising the question of a durable response with high-dose intravenous interleukin-2 (IL-2). What sequence strategy is optimal in this specific clinical scenario?
As the urologic oncology experience accumulates, more medical and surgical options — each of which individually has demonstrated oncologic benefits in terms of symptom-control, progression-free survival (PFS), and overall survival — the physician integrating a multidisciplinary treatment plan is faced with a treatment dilemma: can the benefit be increased through strategic sequencing and combinations? An empiric change in our treatment paradigm is naturally slower to develop than the identification of benefit in isolated drug-specific clinical trials. The decision of nephrectomy and metastatectomy vs medical treatment is a unique application of the sequencing question.
At present, factors that influence our decision about the initial therapy include ECOG performance prior to surgery, clinical characteristics of the tumor, psychologic outlook of the patient about the operation, and expected perioperative morbidity and convalescence. As discussed below, the clinical factors that influence the individualized decision process are derived from a variety of independent experiences and challenge the multidisciplinary team to reach a personalized treatment decision algorithm.
Abstract and Introduction
Abstract
Background: Renal cell carcinoma (RCC) can be considered as two distinct entities: localized and metastatic disease.
Methods: We conducted a review of the scientific literature published within the past decade pertaining to cytoreductive nephrectomy for metastatic RCC.
Results: Retrospective data and historical prospective series have demonstrated the survival benefit of debulking nephrectomy in well-selected RCC patients. New medical therapies, including vascular endothelial growth factor and mTOR pathway blocking drugs, are active biological agents, with survival improvement and potential regression of metastatic and primary tumors. Our current therapeutic challenge is the optimal integration of multimodal therapy consisting of systemic therapy and surgery including cytoreductive nephrectomy, debulking, and metastasectomy. Empiric data to guide this decision are limited.
Conclusions: The decision concerning whether medical or surgical therapy should be the primary treatment approach selected must be made on an individual basis, taking into account patient performance status, clinical parameters, and physician expertise and recommendations, thus making each case a unique therapeutic challenge.
Introduction
Fortunately, the current era is one in which a variety of medical and surgical innovations are in active development in renal cell carcinoma (RCC). From the medical side, the emphasis is on targeted therapies, with currently approved drugs that impact the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and Raf pathways, as well as mTOR protein expression. Furthermore, additional investigational applications including other growth-factor receptor tyrosine kinases and downstream proteins, as well as increasing complex immune manipulations, beyond cytokines, are similarly promising. From the surgical and locally directed therapy standpoint, technical novelties such as laparoscopic, robotic, and energy-intense modalities (radiofrequency ablation, cryoablation and potentially high-intensity frequency ultrasound) increasingly demonstrate comparable nephron-preservation potential, with minimal morbidity, and comparable treatment-specific short-term outcomes. Definitive local control of the primary is always a goal in localized disease but is conceptually less important in the context of established metastatic disease where debulking is the primary goal. The psychologic impact of primary tumor resection is a further dimension in a patient's decision-making process.
However, compelling prospective trials attribute a survival advantage to nephrectomy itself, in the face of metastatic disease. Among patients selected for suitability for nephrectomy despite radiographically evident metastatic disease, those assigned to nephrectomy followed by interferon treatment had a median survival of 13.6 months compared with 7.8 months in patients assigned to interferon alone. Similarly, from a retrospective outlook, nephrectomy status is a major factor in clinical prognostic stratification, along with performance status, hemoglobin level, serum calcium level, and lactate dehydrogenase (LDH) measurement. Other factors that were prognostic in the databases of the Southwest Oncology Group (SWOG) and the European Organisation for Research and Treatment of Cancer (EORTC) included Eastern Cooperative Oncology Group (ECOG) performance status, serum alkaline phosphatase level, and lung-only pattern of metastatic spread.
These experiences predate targeted drug availability for RCC. The extent to which these historical series parallel our treatment-specific outcomes with these novel agents is unclear. Similarly, the optimal integrations of these experiences were not evaluated directly against the new drugs. The optimal integration of surgery and medical therapy is yet to be elucidated. Nevertheless, clinical scoring systems identify good-risk subsets of patients significantly greater median survival (22 to 30 months) compared with the subjects in this nephrectomy trial, but the extent to which these data are applicable to patients already stratified is uncertain.
Patients with kidney cancer, particularly those with metastatic disease, are heterogeneous with respect to tumor histology, age at presentation, performance status, and anatomic pattern of spread. To whom should nephrectomy be offered? Before or after medical treatment, or permanently deferred? Should our experience with metastatic RCC, consisting predominantly of clear cell histology tumors (~ 75%), be extrapolated to the papillary RCC (10% to 15%) and the 12 rarer subtypes of kidney tumors defined in the 2004 WHO classification simply because they originate from the same organ of origin? How does the answer change with the introduction of the targeted drug era? A variety of clinical and laboratory parameters can help tailor the approach for an individual patient, leading to the central question of strategic integration of nephrectomy with targeted therapy for the patient with metastatic RCC at presentation.
With about one-third of incidentally detected kidney cancers being metastatic at presentation, as well as the presence of locally advanced disease, the issue of initial anticancer treatment by medical or surgical intervention is a frequent topic of discussion. Patients with stage IV disease, however, are a heterogeneous group, even after assignment to a risk stratification category. For some patients, the extent of metastatic disease is detectable but miniscule, or obvious symptoms are directly attributable to the primary tumor, such as hematuria and abdominal pain. The circumstances that contribute to an easy decision to consider upfront cytoreductive nephrectomy can be considered in two aspects: one is a general medical context of good reserve of renal function in the contralateral kidney (or in a noninvolved, salvageable component of the ipsilateral kidney); the other is data demonstrating survival advantage attributable to nephrectomy, from experience preceding the targeted drug era.
At the other extreme, compromising situations such as high relative metastatic bulk (compared to the primary), multiple medical comorbidities, frailty that raises operative and perioperative risk, histologic subtype that is not clear cell in which the majority of our clinical experience lies, or limitations on renal functional reserve, nephrectomy must be deferred either temporarily or permanently.
What is the best approach for a fit patient, with a technically resectable primary tumor, who has metastatic disease? Will new agents control the primary to an extent that obviates the benefit attributable to cytoreductive nephrectomy? How are risk stratifications based on postnephrectomy patients relevant to a nephrectomy decision? Of specific concern, there is a middle ground, with a technically resectable primary tumor, good anticipated postsurgical renal functional reserve, and perhaps mild or moderate symptoms, possibly raising the question of a durable response with high-dose intravenous interleukin-2 (IL-2). What sequence strategy is optimal in this specific clinical scenario?
As the urologic oncology experience accumulates, more medical and surgical options — each of which individually has demonstrated oncologic benefits in terms of symptom-control, progression-free survival (PFS), and overall survival — the physician integrating a multidisciplinary treatment plan is faced with a treatment dilemma: can the benefit be increased through strategic sequencing and combinations? An empiric change in our treatment paradigm is naturally slower to develop than the identification of benefit in isolated drug-specific clinical trials. The decision of nephrectomy and metastatectomy vs medical treatment is a unique application of the sequencing question.
At present, factors that influence our decision about the initial therapy include ECOG performance prior to surgery, clinical characteristics of the tumor, psychologic outlook of the patient about the operation, and expected perioperative morbidity and convalescence. As discussed below, the clinical factors that influence the individualized decision process are derived from a variety of independent experiences and challenge the multidisciplinary team to reach a personalized treatment decision algorithm.
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