Systemic therapy for renal cell carcinoma

PURPOSE: We review the status of systemic therapy for patients with advanced renal cell carcinoma. MATERIALS AND METHODS: A literature search was performed on MEDLINE and CANCERLIT to identify results of systemic therapy for patients with renal cell carcinoma published from January 1990 through December 1998. Treatment results of chemotherapy agents, immunotherapy, combination programs and adjuvant therapy were reviewed. RESULTS: No chemotherapy agent has produced response rates that justify its use as a single agent. Interferon-alpha and interleukin (IL)-2 demonstrated low response rates ranging from 10% to 20%. The results of 2 randomized trials suggest that treatment with interferon-alpha compared to vinblastine or medroxyprogesterone achieves a small improvement in survival. Response rates in patients treated with low dose IL-2 are similar to those achieved with a high dose bolus schedule but whether the responses are as durable is being addressed in an ongoing randomized trial. A randomized trial of interferon-alpha plus IL-2 compared to monotherapy with either agent showed increased toxicity but no improvement in survival. In 3 randomized trials no survival benefit was associated with adjuvant interferon-alpha therapy following complete resection of locally advanced renal cell carcinoma. CONCLUSIONS: Despite extensive evaluation of many different treatment modalities, metastatic renal cell carcinoma remains highly resistant to systemic therapy. A few patients exhibit complete or partial responses to interferon and/or IL-2 but most do not respond, and there are few long-term survivors. Preclinical research, and clinical evaluation of new agents and treatment programs to identify improved antitumor activity against metastases remain the highest priorities in this refractory disease.     

Systemic therapy for chromophobe renal cell carcinoma: A systematic review

Background: Chromophobe renal cell carcinoma (chRCC) subtype accounts for almost 5% of total RCC cases. It carries the best prognosis among the rest of RCC types. However, patients with metastatic chRCC disease have worse prognosis than patients with advanced clear cell RCC. Furthermore, available data regarding systemic therapy for chRCC patients are scarce and confusing. Aim: The aim of this systematic review is to search for and critically appraise studies that investigate the results of systemic therapies in patients diagnosed with metastatic chRCC disease. Methods: Search strategy included PUBMED, CENTRAL, clinicaltrials.gov databases, and abstracts of major conferences with a focus on urologic oncology (till March 2019). Studies investigating patients that were treated with systemic therapy for advanced chRCC disease were included. Primary outcomes were progression-free survival and objective response rate. Secondary outcome was overall survival. Screening of available studies was carried out by 2 groups of reviewers, as well as the quality assessment of the included studies. Results: The systematic search yielded 369 studies, of which 15 studies (2 randomized control trials and 13 cohort studies), involving 183 patients, met the eligibility criteria. The 2 randomized control trials that directly compared sunitinib vs. everolimus, suggested an advantage for sunitinib without being statistically significant. Furthermore, sunitinib seems to be superior than sorafenib at least in terms of objective response rate. Regarding mTOR inhibitors, they may have a role in a specific subset of chRCC patients, that needs to be further explored. Finally, as far as immunotherapy is concerned, available data suggest that chRCC seems to be resistant to recent immune check point inhibitors, since just a few tumor responses were observed with the administered immunotherapy regiments. Conclusion: The optimum therapy for metastatic chRCC is still missing, as results from ongoing trials are awaited. More studies, of high quality and adequate sample size, that will be based on the specific biology of chRCC, have to be carried out in order to identify the best treatment.     

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.     

Chemoimmunotherapy in the systemic treatment of advanced renal carcinoma

Polychemotherapy and immunomodulating treatment using IL-2 and/or IFN-alpha produce objective responses in a proportion of advanced renal cell carcinoma patients. The goals of an improved cost effectiveness and therapeutic index of interleukin-2 and/or Interferon-alpha in combination with chemotherapeutic agents require the design of risk factor adapted individual therapeutic strategies for the outpatient setting. High dose i. v. IL-2 therapy in metastatic renal cell carcinoma has been proven effective [11]. Other modalities of applying IL-2 have been described [12-14] (Table 1). A cumulative risk-score identified three risk-groups with significant differences in median survival [16]. The SC use of IL-2 and INF-alpha has been established in the treatment of RCC [16, 23]. It appears that combination chemoimmunotherapy including p. o. retinoic acid is far more effective than single agent treatment. Further studies will have to be designed to improve therapeutic index and cost effectiveness in systemic combination therapy in metastatic RCC.     

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.     

Adoptive Immunotherapy of Patients with Metastatic Renal Cell Cancer Using Lymphokine-Activated Killer Cells, lnterleukin-2 and Cyclophosphamide: Long-Term Results

Background Initial results of adoptive immunotherapy using lymphokine-activated killer (LAK) cells and interleukin-2 (IL-2) appeared to offer promise for treating renal cell cancer (RCC). However, lower response rates were seen in subsequent trials, and the long-term results of this treatment method have not been fully reported. In this study, we examine long-term results of adoptive immunotherapy using LAK cells, IL-2, and cyclophosphamide (LAK/IL-2/CPM therapy). Methods We administered 10 courses of therapy to 9 patients with advanced RCC. One patient had liver and para-aortic lymph node metastases; the others had only lung metastases. The clinical effects were initially evaluated 4 weeks after therapy and follow-up was continued for periods of 43 to 76 months. Results The 4-week evaluation revealed 3 complete responses (CR), 3 partial responses (PR), 1 minor response (MR), 1 patient with no change in disease status (NC), and 2 patients whose disease progressed (PD). One CR patient remained apparently free of disease for 43 months. After tumors recurred in the lung of another CR patient further disease progression was suppressed by IL-2 administration until the patient died from other causes at 46 months. The third CR patient showed tumor recurrence in the lung and was re-treated with the sameLAK/CPM/IL-2 therapy. Lung tumors decreased in size (PR), but the patient died due to brain metastasis 2 months after the second round of treatment. The 2 initial PR patients, as well as the MR and NC patients, developed regrowth or new metastatic lesions within 2 to 15 months following therapy. The 2 PD patients died 2 and 9 months after therapy. Conclusion Long-term effects ofLAK/IL-2/CPM therapy were not correlated with the maximal response observed 4 weeks after therapy. AlthoughLAK/IL-2/CPM therapy appears suitable for use as induction therapy in RCC, our data suggest that long-term suppression will require surgical removal of remnant tumors or more intensive maintenance therapy.     

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.     

Interleukin-2 in the treatment of unresectable or metastatic renal cell cancer: a systematic review and practice guideline

Objective

We performed a systematic review of randomized controlled trials (RCTs) to assess the efficacy of interleukin-2 (IL-2) for the treatment of patients with unresectable or metastatic renal cell carcinoma (RCC).

Methods

We searched the literature to identify RCTs or meta-analyses of RCTs comparing treatment regimens with IL-2 to those without. Outcomes of interest included overall or progression-free survival, response rate, toxicity and quality of life.

Results

We identified 36 RCTs, and 6 met the eligibility criteria (1098 patients). We studied IL-2 alone and in combination with other agents, including interferon-alpha (IFN-a), 5-fluorouracil (5-FU), and 13-cis-retinoic acid or tamoxifen. No trials comparing high-dose IL-2 to non-IL-2 regimens were identified. A meta-analysis of 1-year mortality data from the 6 trials did not show a difference between IL-2-based regimens and non-IL-2 controls. Two of the 6 trials detected statistically significant longer survival with IL-2 combined with IFN-a and 5-FU. Of the 4 trials that assessed progression-free survival, 3 reported significantly longer progression-free intervals with IL-2-based regimens. Five trials reported response rates; pooling the rates from these trials gave an overall weighted response rate of 13.3% (range 9%–39%) and 5.3% (range 0%–20%) for IL-2-containing regimens and non-IL-2 regimens, respectively. IL-2-based regimens were more toxic than were non-IL-2 controls; the most frequently reported grade 3–4 toxicities were hypotension (range 6%–68%), fever (2%–56%), nausea or vomiting or both (6%–34%), diarrhea (1%–28%) and cardiac toxicity (11%–25%). None of the trials reported health-related quality-of-life data.

Conclusion

Non-high-dose IL-2 containing regimens do not provide superior treatment efficacy over non-IL-2-based regimens, with added toxicity, and therefore should not be used as standard treatment for patients with unresectable or metastatic RCC. High-dose IL-2 should only be used by experienced physicians in the context of a clinical trial or investigative setting.Renal cell carcinomas (RCCs) account for 3% of all adult solid malignancies.¹ In 2006, it was estimated that 4600 patients would be diagnosed with the disease in Canada.² According to Bukowski, at the time of first diagnosis, 45% of patients will present with localized disease, 25% will have locally advanced disease with lymph node or local organ involvement and the remaining 30% will present with metastases.³ Patients with meta-static disease have a 5-year life expectancy of less than 10% and a median survival time of less than 12 months. However, survival can be quite variable, depending on several prognostic factors, including performance status, lactate dehydrogenase (LDH), hemoglobin and calcium levels, and the absence of prior nephrectomy.⁴For patients presenting with inoperable or metastatic disease, cure is rarely possible, and treatment efforts often focus on effectively controlling symptoms and offering a chance at improved survival. Clinical trials of chemotherapy in the metastatic setting have shown RCCs to be resistant to currently available chemotherapeutic agents.⁵ Immunotherapy agents, however, have shown activity in RCC. Interleukin-2 (IL-2) has been evaluated extensively in the setting of advanced RCC. Various doses and modes of delivery have been studied, attempting to maximize efficacy and decrease the significant toxicities that can be associated with high-dose IL-2 therapy. High-dose IL-2 has been defined as IL-2 administered as an intravenous bolus of at least 600 000 IU/kg every 8 hours, or a dose exceeding 65 mu/m² daily. IL-2 at 18 mu/m² days 1–4 or 5 intravenously is not considered high-dose IL-2.Since its approval by the United States Food and Drug Administration (FDA), high-dose IL-2 has been used in patients with advanced RCC as a standard therapy at many comprehensive cancer centres in the US. This has likely contributed to the paucity of trials without an IL-2 arm. IL-2 was also approved by Health Canada in 2003, but its use has been very sporadic and limited. Because interferon-alpha (IFN-a) is associated with a real, if modest, survival benefit in the randomized setting⁶ and because it is accessible to and tolerated by most RCC patients, it has become a de facto standard of care in Canada.To clarify the role of IL-2 in the treatment of RCC and to develop appropriate recommendations for treatment, the Genitourinary Cancer Disease Site Group (GU DSG) of Cancer Care Ontario''s Program in Evidence-based Care (PEBC) systematically reviewed evidence from randomized controlled trials (RCTs) of IL-2 in patients with unresectable or meta-static RCC.     

Combined cytoreductive laser therapy and immunotherapy for palliation of metastatic renal cell carcinoma to the head and neck

Interleukin-2 (IL-2) remains the mainstay of treatment for metastatic renal cell carcinoma (RCC), but minimally invasive surgical techniques have provided new options for the combined treatment of RCC. Two patients with metastatic RCC to the head and neck treated by combined laser-induced thermal therapy and IL-2 were described in this case report. Both patients had an extended survival compared to the historical survival of 10 months for metastatic RCC but eventually succumbed to progressive disease. The authors’ initial experience with metastatic RCC suggests that laser thermoablation and immunotherapy in selected patients with metastatic RCC is warranted as a palliative treatment, but a larger study with long-term follow-up is necessary to determine the effectiveness of this approach.     

Combination of surgery and immunotherapy in metastatic renal cell carcinoma

The treatment of choice for non-disseminated renal cell cancer (RCC) is surgery. However, the 5-year survival rates for all stages do not exceed 60%, even in contemporary series. Further improvement will most likely have to await the development of a more effective systemic therapy and the application of combined treatment modalities to counter the relatively high number of patients presenting with advanced stages. Whereas textbook belief up to the 1990s suggested refraining from surgical antitumor-therapy in the case of metastatic RCC, current strategies clearly advocate debulking tumor nephrectomy in the context of modern immunotherapies. This dramatic change of attitude stemmed from two randomized phase III trials conducted by EORTC and SWOG, including a combined analysis of both studies, in which cytoreductive tumor nephrectomy conveyed a significant survival benefit over immunotherapy alone. Concepts and progress in this field appear to be of major interest for modern oncologic urologists following the advent of immunotherapeutic strategies that require surgical intervention at some stage of the treatment cascade.     

Role of targeted therapy in combination with surgery in renal cell carcinoma

Surgical complete resection is the only curative treatment of renal cell carcinoma including patients with locally advanced disease and those with limited metastatic disease. Patients at high risk of recurrence after complete resection might theoretically benefit from adjuvant and neoadjuvant systemic treatment strategies to prolong disease‐free survival and ultimately overall survival. Another rationale for using targeted therapy includes downsizing/downstaging of surgically complex locally advanced renal cell carcinoma to facilitate complete resection or primary tumors to allow for nephron‐sparing strategies. Unfortunately, a considerable percentage of patients are diagnosed with metastatic disease at first presentation. Although large population‐based studies consistently show a survival benefit after cytoreductive nephrectomy in the targeted therapy era, confounding factors preclude definite conclusions for this heterogeneous patient group until ongoing phase III trials are published. Presurgical targeted therapy has been proposed to identify patients with clinical benefit and potentially long‐term survival after cytoreductive nephrectomy. Recently, the use of targeted therapy before or after local treatment of metastases has been reported in small retrospective series. The present review revisits the current evidence base of targeted therapy in combination with surgery for the various disease stages in renal cell carcinoma.     

Outcome and survival with nonsurgical management of renal cell carcinoma

OBJECTIVE: To document long-term survival in patients with renal cell carcinoma (RCC) in whom the primary tumour was left in situ and treatment limited to palliative and symptomatic measures. PATIENTS AND METHODS: All patients with a diagnosis of RCC from January 1994 to January 1999 and in whom the primary tumour was left in situ were identified from hospital records (nine women and 16 men, mean age 69 years). The tumour stage was T1-T4. RESULTS: The mean survival overall was 19.3 months; patients with locally advanced disease, i.e. stage >or= T3a, had a mean survival of 16.9 months. CONCLUSIONS: There is renewed interest in the management of advanced RCC, with data supporting cytoreductive nephrectomy with systemic biological therapy. These results confirm that such patients with or without metastatic disease can survive for a considerable period with no aggressive surgical or systemic measures, and such intervention may offer no significant advantage in outcome and survival over supportive treatment alone.     

Therapeutic dendritic cell vaccination of patients with renal cell carcinoma

OBJECTIVE: Dendritic cell (DC) vaccination against cancer is a new specific immunotherapeutic approach given with either therapeutic or adjuvant intent. We provide a review of DC vaccination as a treatment for metastatic renal cell carcinoma (RCC). METHOD: A total of 197 patients with metastatic RCC were treated with DC vaccination in 14 phase I/II clinical trials. Different vaccine preparations, administration routes, and treatment schedules have been tested in these trials. Clinical response and immune response were analysed. RESULTS: Seventy-three (37%) patients had clinical response with 4 complete responses, 8 partial responses and 61 disease stabilisations, whereas 4 patients had mixed response, but most of these responses have not been transformed into durable clinical effects. Immune responses were observed in a subset of the treated patients but were not always associated with a clinical response. Only mild toxicity was observed in these trials. CONCLUSION: DC vaccination therapy in patients with metastatic RCC is currently experimental but the results are encouraging with achievement of tumour regression and induction of antigen-specific immune response combined with minimal toxicity in a subset of the treated patients. Future emphasis should be placed on therapy in the adjuvant setting because patients with minimal residual disease are more likely to benefit from the treatment. Combination approaches with DC vaccination and immune-enhancing therapies or antiangiogenic therapy should be further investigated to develop new and more efficient treatment strategies for patients with RCC.     

Recurrent metastatic renal cell carcinoma presenting as a bleeding gastric ulcer after a complete response to high-dose interleukin-2 treatment

Immunotherapy with high-dose recombinant interleukin-2 is an effective therapy for selected patients with metastatic renal cell carcinoma (RCC). Objective responses (complete or partial) are observed in about 15% of treated patients. The overall and disease-free survival of patients with a complete response are significantly prolonged. Although RCC is known to spread hematogenously, isolated RCC metastasis to the stomach is a rare event. Recurrent RCC, after a complete response to interleukin-2, presenting clinically as an isolated gastric metastasis, has not been reported to date. In this report, we describe the clinical course of a patient with metastatic RCC who had a complete response to high-dose interleukin-2 and was disease free for 4 years before presenting with massive upper gastrointestinal hemorrhage due to an isolated gastric metastasis. The patient remained disease free for 3 years after resection of the metastasis. Metastatic RCC to the stomach, although rare, should be suspected in any patient with a history of RCC who presents with gastrointestinal symptoms. In the absence of diffuse disease, aggressive therapy, including surgical resection, is appropriate for isolated gastric metastasis, because prolonged survival is possible.     

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.     

Surgical intervention in patients with metastatic renal cancer: metastasectomy and cytoreductive nephrectomy

For patients with metastatic renal cancer, prognostic factors defined in systemic therapy clinical trials stratify patients into good, intermediate, and poor risk groups with median survival varying from 4 to 13 months. These same factors also stratify patients whose renal cancers were initially resected completely and who then developed subsequent metastatic disease. Metastasectomy performed in low-risk patients was significantly associated with enhanced survival when compared with low-risk patients not undergoing metastasectomy. Two randomized, prospective clinical trials demonstrated a modest survival advantage of approximately 6 months for patients undergoing cytoreductive nephrectomy followed by interferon alfa-2b. Once effective systemic agents are developed, both metastasectomy and cytoreductive nephrectomy will play greater roles in consolidating clinical responses.     

Renal cell carcinoma - innovative medical treatments

PURPOSE OF REVIEW: This review highlights recent innovations of medical treatments in advanced renal cell carcinoma. Because of significant toxicity many patients do not benefit from standard systemic cytokine therapy using interleukin-2, interferon-alpha, or both. Their median progression-free survival is about 2 months and their overall survival is poor. Here we report improvements in patient outcome, focusing on overall survival, progression-free survival and quality of life to meet their needs. RECENT FINDINGS: Rating treatment results requires analysis of patient selection and risk stratification. In well-selected patients systemic interleukin-2 therapy as well as combinations of cytokines (interleukin-2 and interferon-alpha) improve outcome, induce long-term survival and, in a minority of patients, even produce long-lasting complete remissions. Within the group of patients who are not candidates for systemic cytokines, interleukin-2 for pulmonary metastases given locally by inhalation achieves long-term progression-free survival and long-term overall survival similar to high-dose systemic interleukin-2 but without the toxicity associated with it. In patients at high risk for metastatic disease progression-free survival is prolonged by autologous tumor vaccine as reported in a recent randomized study. However, in established metastatic disease no clear benefit has been demonstrated by any of the many recent vaccine protocols. Chemotherapeutic agents and thalidomide generally fail to improve patient outcome but produce significant and sometimes irreversible toxicity. SUMMARY: Cytokine-based immunotherapy can be considered standard in the treatment of metastatic renal cell carcinoma today. Long-term survival and sometimes even cure seems possible in patients using systemic and local (inhaled) applications of interleukin-2 alone or in combination with interferon-alpha. Noncytokine treatment approaches are scientifically interesting but still disappointing from a patient's perspective.     

Should radical nephrectomy be performed in the face of surgically incurable disease?

The role of cytoreductive nephrectomy in the management of metastatic renal cancer remains controversial. Recent trials, like SWOG 8949 have suggested the usefulness of this approach at least in selected patients with good performance status and other favorable indicators. The timing of cytoreductive nephrectomy has also been controversial and remains so to this time.CommentaryAn estimated 30,000 new cases of renal cell carcinoma (RCC) are detected annually in the U.S. In approximately one-third of these cases, metastatic disease is diagnosed at presentation. Multi-modality treatment combines biologic response modifier (BRM) therapy with surgery in an attempt to improve survival with either form of treatment alone. The optimal timing of surgery relative to BRM therapy continues to be debated.Prior to the advent of multi-modality therapy, there were relatively few indications for nephrectomy in patients with metastatic RCC. The incidence of spontaneous regression of metastatic RCC following removal of the primary tumor is only 1–4% and, therefore, nephrectomy on this basis is not justified. There is a palliative role for nephrectomy in selected patients with metastatic RCC who are experiencing severe disability from associated local symptoms; however, some patients in this category can be managed with percutaneous renal angioinfarction. A small subset of patients with a solitary metastasis may benefit from nephrectomy and resection of the metastatic lesion based on reported 5-year survival rates of up to 30–35%.There has been controversy concerning the appropriate timing of adjuvant or cytoreductive nephrectomy in the multi-modality approach to treatment of metastatic RCC. Many protocols have involved preliminary removal of the primary tumor before the administration of BRM therapy. The rationale for this has been to enhance response rates to BRM therapy by reducing tumor volume and, in some cases, to provide immunoreactive cells for treatment. A drawback of this approach was that many patients underwent nephrectomy without subsequently receiving BRM therapy due to postoperative morbidity/mortality or rapid tumor progression. This prompted interest in an alternative approach of delayed adjuvant nephrectomy wherein BRM therapy was administered initially and nephrectomy was subsequently performed only in those patients who demonstrated a response to systemic therapy.The relative merits of initial versus delayed adjuvant nephrectomy in conjunction with BRM therapy for metastatic RCC have recently been clarified through two phase III prospective multicenter clinical trials conducted in Europe (EORTC) and the United States (SWOG). The results of both of these carefully done studies have indicated improved survival with initial nephrectomy followed by BRM therapy. The latter comprised interferon monotherapy in both studies, which opens the studies to criticism, however the essential observation of extended survival with preliminary nephrectomy appears to be valid. On this basis, there is now objective evidence to suggest that initial cytoreductive nephrectomy is the preferred approach in patients with metastatic RCC who are candidates for multi-modality therapy. The most appropriate candidates for such therapy remain patients with good performance status and low-volume (preferably pulmonary) metastatic disease. The ability to perform cytoreductive nephrectomy laparoscopically in some of these patients, with reduced morbidity, is a further development that has strengthened the argument in favor of initial nephrectomy.Andrew C. Novick, M.D.     

Adjuvant therapy in renal cancer

Summary Surgery is the therapy of choice for patients with local renal cancer, but the results are unsatisfactory if the disease is locally advanced or systemic disease is present. As for the stage-related prognosis, patients with local disease (T1–2 N0 M0) show good prognosis, with a 5-year survival of 90–100% after nephrectomy. In these patients the indication for adjuvant treatment is limited; it is almost impossible to document the statistically significant efficacy for adjuvant treatment, even when this therapy results in a long-term complete remission rate of more than 50% of the patients with metastatic disease. If such a drug were available, survival would be improved by 5%, but more than 1200 patients would have to be included in this protocol to reveal any significance. Patients with locally advanced disease (T3–4) or with nodal or distant metastases (N1–3, M1) have a worse prognosis, even if the tumor can be completely removed surgically; the 5-year survival rates are 60%, 25% and 5%, respectively. For these patients it is reasonable to start prospective statistical studies concerning adjuvant treatment after surgery. The aims of the investigations should be survival, local or systemic progression of the disease, and quality of life. However, the number of prospective trials is still limited and the results are disappointing: hormone therapy, chemotherapy, immunotherapy and radiotherapy in metastatic renal cancer have reached response rates above 30%; a complete response has been seen in less than 10% of all cases and only for a short period of time. Therefore, we do not recommend any kind of adjuvant treatment after radical nephrectomy. Even adjuvant surgery (complete lymph-node dissection) cannot be recommended as a routine procedure, until the benefit for the patients has been proven by prospective trials.     

Efficacy of Multimodality Therapy in Advanced Renal Cell Carcinoma

Objectives. The integration of systemic biologic response modifier (BRM) therapy and surgery to treat metastatic renal cell carcinoma (RCC) is an evolving approach. The purpose of this study was to evaluate the efficacy of this form of multimodality therapy in patients with metastatic RCC.Methods. Between 1988 and 1996, 14 patients at our institution underwent initial BRM therapy followed by surgical resection of primary and metastatic RCC lesions. Patient records were reviewed to determine the response to BRM therapy, progression-free survival rate, and overall survival rate. The mean follow-up for the entire group was 43.5 months.Results. After BRM therapy, 9 patients manifested an objective response and 5 patients had stable disease. All patients were then rendered disease-free by surgical excision of residual or recurrent metastatic lesions and the primary tumor. The cancer-specific survival rate at 3 years was 81.5%. Currently, 7 patients are alive and disease-free (mean follow-up 41.4 months), 3 patients are alive with recurrent disease (mean survival 48.3 months), 3 patients died of metastatic disease (mean survival 27.9 months), and 1 patient died of an unrelated cause 54.4 months after therapy.Conclusions. The results of this study suggest that adjunctive surgery after BRM therapy can extend the survival of selected patients with metastatic RCC. Aggressive surgical resection of stable or responding lesions after BRM therapy should be considered in the management of these patients.