Commentary on “Cytoreductive radiofrequency ablation in patients with metastatic renal cell carcinoma (RCC) with small primary tumours treated with sunitinib or interferon-α.” Tsimafeyeu I,Zart JS,Chung B,Kidney Cancer Research Bureau,Moscow, Russian Federation.: BJU Int 2013; 112(1):32–8. [Epub 2013 Jun 7]. doi: 10.1111/bju.12107.

ObjectivesTo evaluate the role of cytoreductive radiofrequency ablation (cRFA) in patients with metastatic renal cell carcinoma (RCC) with small primary tumours treated with immuno- or targeted therapy. To assess the efficacy of sunitinib in patients with metastatic RCC with unresected small primary tumours.Patients and methodsThree parallel single-arm prospective studies were conducted. Eligibility criteria were nearly identical for all trials and included: histopathologically confirmed RCC; metastatic measurable disease; size of primary tumour <5 cm; good or intermediate prognosis according to the Memorial Sloan-Kettering Cancer Center model; and no previous therapy. Study 1: Patients were treated with percutaneous cRFA under computed tomography guidance followed by interferon (IFN)-α, 9 MIU, s.c., three times per week. Study 2: Patients received cRFA followed by sunitinib in repeated 6-week cycles of 50 mg/day orally for 4 weeks, then 2 weeks off treatment. Study 3: Patients with unresected primary RCC received sunitinib alone. The primary endpoint was progression-free survival (PFS).ResultsBaseline patient characteristics (age, gender, histology, Eastern Cooperative Oncology Group performance status, metastatic sites, primary tumour size) were similar in all three studies. Efficacy data for 114 evaluable patients showed an objective response rate of 8% (95% confidence interval [CI] 4.5, 10.5) for study 1, 28.9% (95% CI 15.2, 34) for study 2, and 31.6% (95% CI 20.3, 38.9) for study 3. The median (95% CI) PFS times were 9.1 (6.9, 10.2), 13.4 (9.8, 14.4) and 12.7 (11.3, 13.5) months for studies 1, 2 and 3, respectively. Objective response rate was significantly higher and PFS significantly longer in the sunitinib trials than in study 1 (P<0.01 all differences); no differences were found between studies 2 and 3 (objective response rate, P = 0.1; PFS, P = 0.6). Study 1 met its primary endpoint, showing that PFS was significantly longer than the expected 5 months (P = 0.02). The median (95% CI) objective survival (OS) times were greater in study 2 (cRFA/sunitinib) and study 3 (sunitinib-alone) than in study 1 (IFN-α) at 27.2 (22.6, 31.8) and 22.5 (20.7, 24.3) vs 19.5 (16.3, 22.7) months, respectively. Differences were significant (study 1 vs 2, hazard ratio [HR] = 0.55; P = 0.003; study 1 vs study 3 HR = 0.6, P = 0.01). OS was significantly longer in the cRFA/sunitinib group compared with the sunitinib-alone group (HR = 0.71; P = 0.04). There were no unexpected toxicities of medical treatment or complications of cRFA.ConclusionscRFA is a safe and effective approach for select patients with metastatic RCC treated with immunotherapy. The cRFA technique did not improve PFS in patients treated with sunitinib; cRFA probably has impact on OS in these patients. This needs to be tested in a larger trial. Sunitinib was effective in patients with metastatic RCC with unresected small primary tumours.     

Efficacy of multikinase inhibitors in the treatment of advanced renal cell cancer. A snapshot

Due to the chemoresistance of renal cell cancer, cytokine-based therapeutic approaches were considered the standard treatment for patients with metastatic disease. At present, data that are available from a few phase II/III studies, dealing both with the first- and second-line treatment of patients suffering from systemic progression of RCC, indicate the significantly higher clinical efficacy of multikinase inhibitors when compared with cytokine-based therapeutic regimens. In this context, sorafenib (Nexavar, BAY 43-9006) and sunitinib (Sutent, SU 011248) are the most frequently applied and most intensively investigated substances. In Germany, with regard to a phase III study reported at the ASCO congress in 2006, sunitinib received approval for the first-line therapy of metastatic RCC. The application of multikinase inhibitors follows the principle of targeting such mediators that are considered to be substantially involved in the pathogenesis and particularly progression of renal cell cancer within relatively well-defined molecular pathways. The aim of the present paper is to address and to critically discuss the clinical data that are currently available regarding the therapeutic efficacy of kinase inhibitors during the treatment of metastatic RCC.     

Wirksamkeit von Multikinaseinhibitoren in der Therapie des fortgeschrittenen Nierenzellkarzinoms

Due to the chemoresistance of renal cell cancer, cytokine-based therapeutic approaches were considered the standard treatment for patients with metastatic disease. At present, data that are available from a few phase II/III studies, dealing both with the first- and second-line treatment of patients suffering from systemic progression of RCC, indicate the significantly higher clinical efficacy of multikinase inhibitors when compared with cytokine-based therapeutic regimens. In this context, sorafenib (Nexavar, BAY 43-9006) and sunitinib (Sutent, SU 011248) are the most frequently applied and most intensively investigated substances. In Germany, with regard to a phase III study reported at the ASCO congress in 2006, sunitinib received approval for the first-line therapy of metastatic RCC. The application of multikinase inhibitors follows the principle of targeting such mediators that are considered to be substantially involved in the pathogenesis and particularly progression of renal cell cancer within relatively well-defined molecular pathways. The aim of the present paper is to address and to critically discuss the clinical data that are currently available regarding the therapeutic efficacy of kinase inhibitors during the treatment of metastatic RCC.     

Treatment of Advanced and Metastatic Renal Cancer: A Revolution?

ContextA significant proportion of patients with renal cell carcinoma (RCC) will experience recurrence or tumour progression after surgical treatment. Nowadays, several treatment options, including immunotherapy and targeted therapies, are available for management of advanced and metastatic RCC.ObjectiveThis paper aims to give an overview of the current treatment options for patients with advanced and metastatic RCC.Evidence acquisitionThis paper is based on a presentation given at the 6th Meeting of the European Society of Oncological Urology 2009, held in Istanbul, Turkey. Data were retrieved from recent review articles, original articles, and abstracts on the treatment of advanced and metastatic RCC.Evidence synthesisThe potential role of adjuvant vaccines in treatment of patients with advanced RCC after nephrectomy has been suggested. With regard to the newly developed targeted agents for treatment of metastatic clear-cell RCC, sunitinib and bevacizumab plus interferon-α (INF-α) seem promising as first-line therapy for good- and intermediate-risk patients. Temsirolimus appears to be effective as first-line treatment in metastatic RCC (mRCC) patients with poor prognosis. Sorafenib and everolimus should be considered as second-line therapy in mRCC patients. Some targeted therapies have also demonstrated clinical activities in patients with metastatic non–clear-cell RCC. Although grade 1 and grade 2 treatment-related adverse events were common with targeted therapies, most were manageable. The effect of targeted agents in earlier stage disease is currently under investigation. Cytokine therapy was associated with a modest survival benefit in mRCC. A combined analysis, however, suggested that cytoreductive nephrectomy might improve survival in patients with mRCC treated with interferon immunotherapy.ConclusionsMore research on the use of adjuvant vaccines in treating patients with advanced RCC is warranted. Although the management of metastatic disease has undergone a revolution in recent years, a lot of questions still need to be answered.     

Metastatic non-clear cell renal cell carcinoma: current therapeutic options

Non-clear cell (ncc) renal cell carcinoma (RCC) accounts for approximately 25% of all patients with metastatic RCC. It is refractory to standard immuno(chemo)therapy and, to date, no specific trials have been reported to evaluate the efficacy of novel targeted drugs in the different subtypes of metastatic nccRCC. We review all available data from subgroup analyses of the global sorafenib and sunitinib expanded access programmes, current phase-III trials, and smaller multi- and single-centre studies focusing on the activity of targeted agents in these specific and rare RCC subtypes. Both sorafenib and sunitinib have significant activity in metastatic nccRCC, but the efficacy of each agent seems to vary between different nccRCC forms. Preliminary clinical data for temsirolimus appear to be promising but more extensive and long-term data are awaited. With the advent of novel therapeutic options, specific controlled multicentre trials are urgently needed to define their exact value and efficacy for treating the historically resistant nccRCC forms. The medium-term aim should be to tailor the most advantageous therapy for each patient with respect to his/her individual RCC subtype and physical condition.     

The promising role of radiotherapy in the treatment of advanced or metastatic renal cell carcinoma: a narrative review

Traditionally, renal cell carcinoma (RCC) has been regarded to be “radioresistant”. Conventional fractionated radiation (CFRT) has played a limited role in RCC as a palliative treatment to relieve pain and bleeding. Succeed to the rapid development of precise radiotherapy techniques, realizing safe delivery of high-dose radiotherapy, an increasing amount of convincing data suggests that the delivery of high-dose-per-fraction radiation through stereotactic radiosurgery (SRS) or stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR) can help to overcome resistance to radiotherapy. Herein, we summarized and analyzed the data from randomized controlled trials, retrospective and prospective studies, and meta-analyses relating to the treatment of advanced and metastatic RCC (mRCC) with CFRT, SBRT, or SBRT combined with systemic therapy. CFRT has a limited effect on local control (LC) of advanced RCC and mRCC, but it is a major palliative treatment which could obviously relieve pain caused by cancer. SBRT and SRS have the significant advantage of being able to precisely deliver a high dose of radiation to the target tissues. SBRT could cause a higher LC for advanced and metastatic RCC and could be used as an alternative to surgery for patients with oligometastatic RCC. The combination of SBRT with systemic therapy, such as targeted therapy or immunotherapy, is safe and tolerable. Concurrent immunotherapy and SBRT is a promising treatment strategy for patients with advanced or metastatic RCC. However, research on radiotherapy combined with systemic therapy is still limited and further studies to explore this treatment for RCC are urgently needed.     

Surgical considerations for patients with metastatic renal cell carcinoma

Among patients with renal cell carcinoma (RCC), 25–30% present with metastatic disease at the time of initial diagnosis. Despite the ever-increasing array of treatment options available for these patients, surgery remains one of the cornerstones of therapy. Proper patient selection for cytoreductive surgery is paramount to its effective use in the management of patients with metastatic RCC despite the decrease in reported morbidity rates. We explore the evolving role cytoreductive surgery in metastatic RCC spanning the immunotherapy era to the targeted therapy era. Despite significant advances in the management of patients with metastatic RCC, further evidence on the definitive role of cytoreductive surgery in the targeted therapy era is awaited through large randomized trials.     

Novel approaches in the therapy of metastatic renal cell carcinoma

Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, with approximately 40% of patients eventually dying of cancer progression. Approximately one third of patients present with metastatic disease, and up to 40% treated for localized disease have a recurrence. Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of RCC have paved the way for developments that may enhance early diagnosis, better predict tumor prognosis, and improve survival for RCC patients. The recent discovery of molecular tumor markers is expected to revolutionize the staging of RCC in the future and lead to the development of new therapies based on molecular targeting. Cytokine-based immunotherapy can be considered standard therapy in the treatment of metastatic RCC today. However, new therapies such as tumor vaccines, anti-angiogenesis agents, and small molecule inhibitors are being developed to improve efficacy and treat those patients who are unable to tolerate or are resistant to systemic immunotherapy. The aim of this review is to provide an update on current therapeutic approaches and targeted molecular therapy for metastatic RCC.     

Der Stellenwert der Targeted-Therapie beim Nierenzellkarzinom

Therapeutic approaches based solely on cytokine are meanwhile no longer recommended without restrictions as the primary therapy for metastatic renal cancer due to the reduced clinical response and the promising available data regarding molecular therapy. Several randomized controlled studies have been performed since the introduction of the so-called targeted therapies for metastatic renal cancer. Substantial data relevant for drug approval are available for the multikinase inhibitors sorafenib (Nexavar) and sunitinib (Sutent), the mTOR inhibitor temsirolimus (Torisel), and the monoclonal antibody bevacizumab (Avastin) in combination with interferon-alpha. Sunitinib, temsirolimus, and bevacizumab are approved for first-line treatment, whereas sorafenib was approved for second-line treatment in Germany.Clinical trials are currently investigating the questions of optimal timing, value of neoadjuvant or adjuvant treatment, form, and sequence of the molecular targeted therapy. Experimental investigations for a better understanding of signaling pathways will preferably allow preselecting patients for an individualized therapy in metastatic renal cell cancer (RCC). The aim of the present paper is to address and to critically discuss the clinical data that are currently available regarding"targeted" therapeutics during the treatment of metastatic RCC.     

Prognosefaktoren für das Überleben des metastasierten Nierenzellkarzinoms

Prognostic factors for the survival of patients undergoing immunotherapy for metastatic renal cell carcinoma (RCC) were first published in 1999 by Motzer et al. Since then several modifications of the prognostic model have been published. Even if not validated for targeted therapies stratification of RCC patients based on the prognostic factors provided the basis for recent clinical trials investigating the efficacy of sorafenib, sunitinib, temsirolimus, or bevacizumab/interferon. In order to compare the results of the trials and to generate treatment algorithms one has to carefully examine the prognostic factors used in the trials. The present article reviews the development of the prognostic models and their use in recent clinical trials. Furthermore, a reasonable algorithm for the treatment of patients with metastatic RCC is presented.     

Clinical efficacy and prognostic factors for overall survival in Japanese patients with metastatic renal cell cancer treated with sunitinib

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? A randomized prospective phase III clinical trial for systemic treatment‐naïve metastatic renal cell cancer (RCC) patients demonstrated the superiority of sunitinib over interferon with an acceptable safety profile. However, a commonly asked question is whether patients with RCC in clinical trials are representative of those with this disease being seen in ordinary clinical practice. To our knowledge, this is the first report of sunitinib for the Japanese patients with metastatic RCC in ordinary clinical practice. The estimated median PFS and OS in this study were 9.3 and 32.2 months, respectively. The application of the MSKCC model distinctly separated OS curves (P < 0.001), suggesting that MSKCC prognostic factors might be still valid to predict survival in metastatic RCC in the era of molecular targeted therapy.

OBJECTIVES

• ? To report the treatment efficacy and safety profile of sunitinib for patients with metastatic renal cell carcinoma (RCC) in ordinary clinical practice.
• ? In addition, to investigate the prognostic clinicopathological factors in these patients.

PATIENTS AND METHODS

• ? The present study consisted of native Japanese patients with metastatic RCC, comprising 29 pretreated and 34 systemic treatment‐naïve patients.
• ? Univariate and multivariate analyses were performed by the log‐rank test and the Cox proportional hazards model, respectively.

RESULTS

• ? Estimated median progression‐free survival and overall survival (OS) were 9.3 months (95% confidence interval, CI, 5.0–13.7) and 32.2 months (95% CI, 24.4–40.0), respectively.
• ? Among the patients pretreated before sunitinib, two patients were treated with initialized systemic therapy with sorafenib and the remaining 27 were initialized with interferon‐α.
• ? The OS from the initial systemic therapy of the patients in pretreated groups was 79.6 months (95% CI, 14.6–144.5).
• ? The application of the Memorial Sloan‐Kettering Cancer Center model distinctly separated the OS curves (P < 0.001).
• ? The most common grade 3 adverse events were fatigue (53%), thrombocytopaenia (48%), hand‐foot syndrome (16%), anaemia (20%), hypertension (10%) and leucopaenia (9%), although these events were manageable and reversible.

CONCLUSIONS

• ? Sunitinib has a favourable efficacy/safety profile for Japanese metastatic RCC patients in clinical practice.
• ? The estimated median OS was >2 years with acceptable tolerability.
• ? The median OS from the initial systemic therapy of the pretreated patients was >6 years.
• ? Memorial Sloan‐Kettering Cancer Center prognostic factors still appear to be valid for predicting survival in metastatic RCC in the era of molecular targeted therapy.

     

Integration of surgery and systemic therapy for renal cell carcinoma

Proper integration of surgery and systemic therapy is essential for improving outcomes in renal cell carcinoma (RCC). There is no current role for adjuvant therapy after nephrectomy for clinically localized disease. The potential benefits of neoadjuvant therapy for locally advanced nonmetastatic disease are in need of further study. In metastatic disease, the proper integration of cytoreductive surgery and systemic therapy remains to be elucidated. Presurgical targeted therapy is feasible and may be beneficial. Pending the results of randomized controlled trials, upfront cytoreductive nephrectomy in appropriate patients will likely continue as the paradigm of choice in metastatic RCC.     

Behandlung des metastasierten Nierenzellkarzinoms. Stellenwert der Immuntherapie gegenüber der Metastasenchirurgie

The prognosis for patients in whom metastatic renal cell carcinoma (RCC) is not treated is unfavorable, with a reported 5-year survival of 0-18%. Before the era of immunotherapy and in the absence of effective nonsurgical therapy, resection of metastases was the accepted way to prolong survival, giving a 5-year survival of 7-69%. Retrospective studies have shown that several clinical factors are associated with a relatively good prognosis. Some patients will benefit from resection of metastases, but most patients with metastatic RCC are not candidates for such aggressive surgery. The use of interleukin-2 has demonstrated that immunotherapy can produce durable remissions. Without randomized trials, it is difficult to know whether survival is longer than that in untreated patients, but there is clear evidence that immunotherapy improves survival and yields long-lasting remissions in selected patients. Many questions remain concerning quality of life and the benefit-to-risk ratio of immunotherapy, but it is the most effective treatment for metastatic RCC.     

High frequency of intracerebral hemorrhage in metastatic renal carcinoma patients with brain metastases treated with tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor

OBJECTIVES: To report the high incidence of intracerebral hemorrhage (ICH) in patients with metastatic renal cell carcinoma (RCC) treated with the tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor (VEGFR). METHODS AND RESULTS: Between October 2005 and December 2006, 67 patients with metastatic RCC were treated with sorafenib or sunitinib at the Montpellier Cancer Center in compassionate access programs. The medical records of five (7%) patients who died of ICH during therapy were reviewed retrospectively. Four of them had known brain metastases. Previous radiation therapy had been indicated in two patients. Two patients had a history of hypertension. Death from ICH occurred in the first 2 wk following the onset of treatment. Three other patients with brain metastases who received sorafenib or sunitinib during the same period did not experience ICH. CONCLUSIONS: The frequency of fatal ICH in RCC patients with brain metastases treated with tyrosine kinase inhibitors targeting the VEGFR seems high. Prospective clinical trials will be necessary for assessing the true incidence and predictive factors related to this toxicity.     

The Role of Metastasectomy in Renal Cell Carcinoma in the Era of Targeted Therapy

Despite contemporary innovations in systemic therapy and surgical treatment, renal cell carcinoma (RCC) remains the most lethal urologic malignancy. Still, around 20 % of patients with RCC present with metastases at diagnosis, and 40–50 % of those with localized advanced disease will ultimately progress to metastatic disease. Although the new, targeted therapy paradigms have changed the treatment of patients with advanced RCC and offer prolonged survival, cure is extremely uncommon in the absence of surgical resections. In this paper, the current role of metastasectomy is reviewed. Searches were carried out in the PubMed database and the Cochrane Library of Controlled Clinical Trials. While there is no randomized study available, recent large observational studies have better defined the prognosis of patients with metastatic RCC with or without metastasectomy. In multivariate analysis, independent predictive factors included male gender, disease-free interval > 1 year, single metastatic site and complete metastasectomy. Other reports from selected patient materials show 29–31 % 5-year overall survival rates. In patients with recurrent disease after resection of a lung metastasis, 60 % were able to undergo a subsequent resection, compared with 25 % with recurrent bone metastasis. Also, metastasectomy after initial systemic therapy gave partial or complete response in a majority of patients. In these patients, the median survival was 4.7 years and 21 % remained free of disease at last follow-up. Patients with metastatic renal cell carcinoma should be considered for multimodal therapy, including surgery of metastatic lesions. A proportion of patients will achieve long-term survival with aggressive surgical resection.     

Surgery for metastatic renal cell cancer

Renal cell carcinoma (RCC) often presents in its metastatic form, or progresses after curative treatment. While the management of metastatic RCC has historically been mainly surgical, contemporary approaches often incorporate systemic immunotherapy. This review examines the current indications and scope of surgical treatment of patients with metastatic RCC. Surgery is sometimes indicated for symptom palliation at either the primary or secondary sites. However, other less invasive therapies may be equally effective, and should be considered carefully. Cytoreductive surgery prior to immunotherapy appears to confer a survival advantage, but only selected patients are suitable for this treatment regimen. Primary immunotherapy followed by surgical removal of the tumour in partial responders is an alternative treatment strategy, which has not yet been evaluated as in randomized trials. As immunotherapy develops further, the precise timing and role of surgery in multimodality treatment will need to be carefully evaluated. Occasionally, the complete surgical excision of metastases, and the primary tumour, if present, is feasible and this may prolong survival. Empirically, it would seem that such patients should also be treated with adjuvant immunotherapy, as eventual relapse is frequent. Surgery with the aim of inducing spontaneous tumour regression is not justifiable, given the rarity of this phenomenon.     

Recent advances in molecular targeted therapy for metastatic renal cell carcinoma

Advanced renal cell carcinoma (RCC) is resistant to chemotherapy and radiotherapy. Immunotherapy is relatively effective against RCC. However, the response rate is approximately 15–20%. Therefore, new therapeutic approaches are necessary. Recently, molecular mechanisms responsible for the proliferation of RCC are identified, and molecular targeted therapy is developed. Bevacizumab, sorafenib, sunitinib, axitinib, temsirolimus, everolimus are promising molecular targeted therapeutic agents for metastatic RCC, and will be used widely in clinics in the near future. In addition, combination therapy with molecular targeted therapy and other therapies including immunotherapy may also be developed soon.     

Prediction of response to combined immunotherapy with interferon-α and low-dose interleukin-2 in metastatic renal cell carcinoma: Expression patterns of potential molecular markers in radical nephrectomy specimens

Objectives:   To evaluate the expression levels of multiple molecular markers in radical nephrectomy specimens from patients with metastatic renal cell carcinoma (RCC) who received combined immunotherapy with interferon-α (IFN-α) and low-dose interleukin-2 (IL-2) and to identify factors predicting susceptibility to this therapy.
Methods:   This study included 40 patients with metastatic clear cell RCC undergoing combined immunotherapy with IFN-α and low-dose IL-2 following radical nephrectomy. Expression levels of 10 markers, including Aurora-A, Bcl-2, clusterin, heat shock protein 27, heat shock protein 90, Ki-67, matrix metalloproteinase-2, matrix metalloproteinase-9, p53 and vascular endothelial growth factor, in RCC specimens were measured using immunohistochemical staining.
Results:   In this series, one, 10, 15 and 16 patients were diagnosed as showing complete response, partial response, stable disease and progressive disease, respectively. Expression levels of Bcl-2 and Ki-67 had significant impacts on the response to this therapy. Furthermore, cancer-specific survival was significantly associated with the expression levels of Ki-67 and Bcl-2 in addition to performance status, presence of metastases at diagnosis, metastatic organ and C-reactive protein on univariate analysis. Only the presence of metastases at diagnosis and Ki-67 expression level appeared to be independent predictors of cancer-specific survival on multivariate analysis.
Conclusions:   It would be useful to consider the expression levels of potential molecular markers, particularly Ki-67, in addition to clinical parameters, such as the presence of metastases at diagnosis, to select metastatic RCC patients likely to benefit from combined immunotherapy.     

Systemische Therapie des metastasierten Nierenzellkarzinoms

Cytokine-based immunotherapy was the only viable option in metastatic, nonresectable renal cell carcinoma (RCC) for many years. Systemic immunotherapy has become increasingly established as a standard therapy during the last 15 years. In this context, interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) turned out to be the most effective single agents in RCC. Subsequently, the approved subcutaneous application of these compounds was the preferred administration route in Germany. Response rates with cytokine combination therapy were almost similar to those of more aggressive concepts using additional chemotherapeutic agents.Currently, new compounds targeting specific signaling pathways are readily available and have passed clinical testing. Such small molecules like tyrosine kinase inhibitors, monoclonal antibodies, or the mTOR inhibitor CCI-779 may dramatically change the established concepts of systemic RCC treatment. This paper gives an overview of established, current, and evolving concepts of systemic therapy in RCC.     

Cytokine therapy in renal cell cancer

Despite extensive investigations with many different treatment modalities, metastatic renal cell carcinoma (RCC) remains a disease highly resistant to systemic therapy. The outlook for patients with metastatic RCC is poor, with a 5-year survival rate of less than 10%. Late relapses after nephrectomy, prolonged stable disease in the absence of systemic therapy, and rare spontaneous regression are clinical observations that suggest host immune mechanisms could be important in regulating tumor growth. Interleukin-2 (IL-2) and interferon- (IFN-) have been extensively studied in advanced RCC with responses in the 10 to 20% range. Two randomized trials suggest that treatment with IFN- compared with vinblastine or medroxyprogesterone results in a small improvement in survival. Prolonged responses with high-dose IL-2 is significant but is accompanied by formidable toxicity. Although the combination of IFN- and IL-2 compared with monotherapy with IFN- or IL-2 increases the response proportion, no improvement in survival could be demonstrated in a recent randomized trial. In addition, three randomized trials showed no survival benefit associated with IFN- therapy given as adjuvant therapy following complete resection of locally advanced RCC. Small numbers of patients exhibit complete or partial responses to IFN- and/or IL-2, but most patients do not respond and there are few long-term survivors. Clinical investigation of new agents and treatment programs to identify improved antitumor activity against metastases remain the highest priorities in this refractory disease.