Metastatic renal cell carcinoma (RCC): Spontaneous regression,long-term survival and late recurrence

We report 4 cases of metastatic renal cell carcinoma (RCC) with long-term survival either following radical nephrectomy alone or in combination with radio- or hormonal therapy. Two patients with lymph node metastases showed a long-term survival of 12 or more years following radical tumour nephrectomy (with lymphadenectomy) and radiotherapy. One of them exhibited a histologically proven tumour recurrence nearly 12 years after primary surgical treatment and died shortly later; the other one is still without any evidence of metastatic disease. Two other patients exhibited spontaneous regression of pulmonary metastases: one regression occurred after radical tumour nephrectomy alone, the other one after successful primary hormonal treatment and subsequent radical tumour nephrectomy. The following important aspects are emphasized: 1. Renal cell carcinoma is a very unpredictable tumour. Once the diagnosis of renal cell carcinoma is proved, a patient can never be considered cured. 2. Although adjuvant palliative nephrectomy has produced contradictory results in several reports, radical tumour nephrectomy either alone or in combination with other adjuvant therapies such as radiotherapy, hormonal or immunological treatment, can be worthwhile. Cases with long-term survival and spontaneous regression of distant metastases are proof of this. Besides, if carefully selected, the mortality rate of different adjuvant therapies is not significantly higher in patients with metastatic disease than in patients without metastases. The world literature on this subject is reviewed.     

PULMONARY NODULES IN PATIENTS WITH A HISTORY OF RADICAL NEPHRECTOMY FOR RENAL CELL CARCINOMA

Background:
Nine patients with a history of radical nephrectomy for renal cell carcinoma underwent surgical removal of newly detected pulmonary nodules at the Hiroshima University Hospital. Six patients had metastatic lung tumors two patients had bronchogenic primary carcinomas and one had a granulomatous infection.
Methods:
To determine if any characteristics can distinguish a new primary carcinoma from metastatic renal cell carcinoma, we reviewed the nine patients described above. The patients with pulmonary metastases and those with new primary lung cancers did not differ in age, sex, history of smoking, clinical stage and pathological findings of the renal primary site, on the location and size of the pulmonary nodules.
Results:
Only the interval between the nephrectomy and the appearance of the new pulmonary lesion may be a predictive factor. This interval was 48 and 51 months for the patients with new primary lung cancers but varied from 0 to 39 months for the patients with metastatic renal cell carcinoma. A solitary nodule had an equal chance of being metastatic or primary. Conclusions: These results indicate that a solitary nodule that is detected at a longer inferval after radical nephrectomy may be a new primary lung cancer. Once new pulmonary nodules are identified in a patient with a history of radical nephrectomy for renal cell carcinoma, surgical excision is required for a final diagnosis before initiating therapy for metastases.     

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.     

Multi-modal treatment for metastatic renal cancer: the role of surgery

Surgical intervention in the patients with metastatic renal cancer can occur in two settings: (1) to render a patient clinically free of all sites of primary disease and metastases, termed nephrectomy/metastasectomy, or (2) to resect the primary tumor in the face of unresectable metastatic disease prior to the initiation of systemic therapy, termed cytoreductive nephrectomy. Carefully selected patients with good performance status undergoing nephrectomy and subsequent metastasectomy may experience prolonged survival in the range of 30 months, which could be attributed to a combination of patient selection factors and the surgical resections. Randomized clinical trials from the United States and Europe have demonstrated a small but significant survival benefit to cytoreductive nephrectomy and cytokine therapy versus cytokine therapy alone which is measured in the range of 3–6 months and associated with overall survival of approximately 12 months. The precise mechanism by which cytoreductive nephrectomy improves survival is not known but may relate to reduction in the large primary immunosuppressive burden. Patient selection factors including performance status and serum factors (Hgb, corrected Ca++, LDH) stratify metastatic patients into risk groups, which are strongly associated with survival time in both medically and surgically treated patients with metastatic renal cancer. The development of multi-kinase and mTOR inhibitors has markedly improved survival in treatment naïve and previously treated patients with metastatic renal cancer , and these agents are currently under active clinical investigation in the neo-adjuvant and adjuvant setting.     

The natural history of metastatic renal cell carcinoma: a computer analysis.

Survival factors of 86 patients with metastatic renal cell carcinoma were studied by computer analysis. Cumulative survival was 53 per cent at 6 months, 43 per cent at 1 year, 26 per cent at 2 years and 13 per cent at 5 years. Survival was influenced favorably by confinement of metastases to the lungs, by the absence of local recurrence or persistence of tumor and by a longer interval free of disease after removal of the primary tumor. Medical therapy improved survival during the first year after diagnosis of metastases but no objective regression of tumor was observed. Excision of metastatic foci significantly improved survival for up to 5 years (p less than 0.05 and p less than 0.02) after which most patients died of recurrence. Palliative or adjunctive nephrectomy in patients with metastases was associated with a 6 per cent mortality rate but it increases survival over other patients with metastases at the time of diagnosis of renal carcinoma who did not undergo nephrectomy. This difference was owing to patient selection and survival of those who had adjunctive nephrectomy was no greater than that of the study population as a whole. However, based on the factors that were associated with improved survival palliative nephrectomy may be beneficial when a limited number of metastases treatable by excision or radiation therapy are present, when effective systemic therapy exists or when the primary tumor produces severe symptoms.     

Neoadjuvant treatment of renal cell carcinoma

Renal cell carcinoma is a potentially devastating cancer, and when metastatic, remains incurable with currently available systemic therapy. Surgical nephrectomy remains the only proven modality which can offer curative options for patients with resectable disease. Further, cytoreductive nephrectomy continues to play a role in the metastatic disease setting. The use of targeted therapy as an adjunct to surgical resection is beginning to be explored in both of these clinical scenarios. Immediate questions regarding preoperative treatment with VEGF pathway targeted therapy include issues surrounding the safety of these agents in use in the perioperative time period, the expectations for response in the primary tumor, the optimal duration of therapy, and the clinical settings in which this therapy may be most beneficial. This review will discuss the current experience with neoadjuvant or preoperative therapy in locally advanced or metastatic renal cell carcinoma and will overview the challenges and opportunities which lie ahead for this form of multimodality therapy.     

Long-term survival under maintenance gemcitabine chemotherapy for metastatic transitional cell carcinoma

We report a case of a 74-year-old patient who received 41 courses of maintenance therapy with gemcitabine over a length of 28 months for metastatic transitional cell carcinoma. One year earlier the patient had received three cycles of adjuvant cisplatin-based combination chemotherapy after nephro-ureterectomy for a locally advanced urothelial cancer of the right renal pelvis. This case demonstrates a paradigm shift in the palliative treatment of advanced urothelial cancer, with the implementation of more tolerable agents such as gemcitabine. Even elderly patients with impaired renal function may benefit in terms of tumor reduction and survival from systemic chemotherapy, which may be applied over a prolonged period of time.     

The role of cytoreductive nephrectomy in the management of metastatic renal cell carcinoma

Cytoreductive nephrectomy can be an important and effective component of a multidisciplinary treatment approach to metastatic renal cell carcinoma in carefully selected patients. The results of retrospective single institution series and randomized multicenter phase III trials suggest that removal of the primary tumor, even in the setting of metastatic disease, can significantly prolong survival and delay time to progression. It may also enhance the response to systemic therapy in the postoperative period. When employing initial cytoreductive nephrectomy as part of an overall treatment approach, careful patient selection is critical to success. A poor performance status (ECOG performance status less than 1), significant comorbidities that make surgical intervention high risk, or high-volume metastatic disease, and the presence of brain, liver, or bone metastases, or of atypical (sarcomatoid) histology have all been shown to be associated with an extremely poor prognosis. Patients exhibiting these clinical phenotypes should not be considered for initial cytoreductive nephrectomy as part of their treatment paradigm. Instead, they should receive some form of upfront systemic therapy (immunotherapy or novel therapy) and then be considered for delayed nephrectomy as part of a surgical consolidation approach after an interval of treatment if their disease kinetics demonstrate stable or regressing disease in response to systemic therapy. Patients who do not demonstrate these poor prognostic features should be considered for upfront cytoreductive nephrectomy as part of their overall treatment approach because of the potential it offers for palliation from local tumor symptoms, a delay in the time to disease progression, an improved response to systemic therapy, and improved overall survival.     

Management of locally recurrent renal cell carcinoma after partial nephrectomy

While partial nephrectomy can provide effective treatment for selected patients with renal cell carcinoma, postoperative local tumor recurs in approximately 10 per cent of the cases. We describe 4 patients in whom tumor recurred in a solitary renal remnant after partial nephrectomy for renal cell carcinoma 1 to 6 years previously. The original tumor was pathological stage I in 2 patients and stage III in 2. Neither of the patients with stage I renal cell carcinoma had metastatic disease when locally recurrent carcinoma was noted. A second partial nephrectomy was done in these patients and they are alive 1 and 10 years later. Both patients with stage III renal cell carcinoma also had metastatic disease when locally recurrent carcinoma was noted. One patient died 1 year later and the other is alive 1 year later. Patients who undergo partial nephrectomy for renal cell carcinoma should be followed closely to allow for early detection of local tumor recurrence. When this occurs, secondary surgical treatment may be possible with complete tumor excision and the opportunity for extended survival.     

Partial nephrectomy for renal cell carcinoma

Although radical nephrectomy must still be considered optimal curative therapy for patients with localized renal cell carcinoma and a normal opposite kidney, partial nephrectomy is the treatment of choice when localized renal cell carcinoma is present bilaterally or in a solitary functioning kidney. In such patients, partial nephrectomy allows complete surgical excision of the primary tumor while preserving sufficient renal parenchyma to avoid the need for renal replacement therapy. Parenchyma-sparing techniques are detailed in this article.     

Failure of immunotherapy for metastatic renal cell carcinoma

Prompted by reports of tumor regression among patients with metastatic renal cell carcinoma treated by injection of an aggregated autologous or allogeneic tumor antigen with a nonspecific adjuvant, we studied the efficacy of this therapy in 23 patients. Following nephrectomy or excision of a metastatic lesion 16 patients were treated with an aggregated autologous tumor antigen combined with Candida albicans antigen. There were only 2 minimal responses. Seven patients judged unsuitable for an operation were treated with an aggregated allogeneic antigen. There were no objective responses. We conclude that these treatment regimens have minimal activity against metastatic renal cell carcinoma.     

Infarction-nephrectomy for metastatic renal carcinoma. Southwest oncology group study

Thirty patients with metastatic renal cell cancer were treated by renal infarction, followed by delayed nephrectomy. All cases were collected over an eighteen-month period, with a minimum follow-up of one year. There were no complete remissions and only one partial remission, which lasted twenty-one months before progression of disease. Three patients had stable disease for at least six months, but eventually all patients showed evidence of progression. After tumor progression was documented patients were treated with intramuscular medroxyprogesterone acetate (Depo-Provera) 800 mg per week. No patient responded to this therapy. Overall, a 28 per cent one-year survival and a seven-month median survival were realized, which is similar to other series in which no therapy or palliative nephrectomy was performed. We conclude that infarction and nephrectomy is not an effective modality in the treatment of metastatic renal cell carcinoma. In addition, medroxyprogesterone was not shown to be significantly active against renal cancer in this study.     

Management of isolated renal fossa recurrence following radical nephrectomy

PURPOSE: Local recurrence of renal cell carcinoma in the renal fossa without distant metastatic disease is an infrequent occurrence. Management of this lesion can be challenging, with relatively few series in the literature. We describe our use of surgical extirpation with adjuvant intraoperative radiation. MATERIALS AND METHODS: The University of California, San Francisco Urologic Oncology database and the University of California, San Francisco Radiation Oncology database were queried for all patients with locally recurrent renal fossa recurrence. Only patients with recurrence of renal cell carcinoma in the renal fossa were included. Survival, complications and the use of adjuvant therapy in the form of intraoperative radiation therapy were noted. RESULTS: A total of 14 patients were treated for this lesion between 1990 and 2003. Mean time to recurrence was 40 months (range 5 to 180). Only 1 patient was symptomatic preoperatively, while in 13 disease had been detected on routine computerized tomography followup. Mean size of the recurrent tumor was 6.35 cm (range 2 to 17). 9 patients died of progressive, metastatic disease after a mean of 17 months (range 1 to 56) and 5 are alive with a mean survival of 66 months (range 14 to 86). The time to recurrence after nephrectomy approached statistical significance (p =0.06) when comparing the patients who were alive vs those who died of disease. Additionally, there was no statistical difference in size of mass recurrence between these 2 groups. There was no difference in survival due to adjuvant intraoperative radiation therapy. Local fossa re-recurrence developed in 2 patients. Survival was 40% at 2 years and 30% at 5 years from surgery. Complications, including minor complications, occurred in 42% of patients and there was no perioperative mortality. CONCLUSIONS: Selected patients with isolated local recurrence in the renal fossa may have favorable and durable outcomes following surgical resection and possibly adjuvant intraoperative radiation therapy for isolated renal fossa recurrence following radical nephrectomy. Development of novel and effective systemic therapy is needed in high risk patients with renal cancer.     

Integrating metastasectomy in the management of advanced urological malignancies-where are we in 2005?

PURPOSE: In the past patients with metastatic cancer were considered incurable and they were not candidates for surgical management of metastases. However, experience with testicular cancer has shown that metastasectomy can often be the final, critical step in achieving disease-free status. We summarized the most current data on metastasectomy for advanced urological malignancies. MATERIALS AND METHODS: We performed an extensive review of the literature from 1990 to the present using MEDLINE. Only original reports were included with an emphasis on specific malignancies and specific sites of metastasis. RESULTS: There is increasing evidence that patients with metastatic renal cell carcinoma and bladder carcinoma can be cured by surgical resection of metastases, usually combined with systemic therapy. The ideal patient has responded to systemic therapy and has few metastatic sites. CONCLUSIONS: Metastasectomy should frequently be done in patients with advanced testicular cancer and it should increasingly be considered in patients with metastatic renal cell carcinoma or bladder carcinoma. This technique may be used for cure and palliation. Specific patient factors determine the likelihood and degree of potential benefit.     

Indications for and results of nephrectomy for metastatic renal cell carcinoma

We find that, when metastases are present, a nephrectomy for renal cell carcinoma is not justified in the vast majority of cases. The only noncontroversial indication is for palliative nephrectomy which is performed to relieve intractable symptoms in the properly chosen patient. However, it is unusual to see a patient with tumor-related symptoms that cannot be conservatively managed. A relative indication for nephrectomy is found in the patient with osseous metastases only, as some studies have demonstrated a prolongation of survival by adjunctive nephrectomy in this setting. Another relative indication is in the patient with limited metastases that are amenable to surgical or radiation ablation coupled with nephrectomy; patients in whom the metastasis appears years after the nephrectomy have the best chance for a successful outcome. When therapy that is effective against metastatic tumor is eventually found, adjunctive nephrectomy as a debulking procedure may become indicated; until then, surgery is not justified. On the basis of data presently available, adjunctive nephrectomy in the hope of inducing spontaneous regression of metastases is never indicated.     

Clinical study on surgical treatment of renal cell carcinoma with pulmonary metastases]

This study reviewed the surgical therapy for lung metastatic foci of renal cell carcinoma. During the 14 years from 1977 to 1991, lung metastatic foci were removed in 10 patients with renal cell carcinoma at our hospital. Six of them died of cancer and four are alive. The prognosis tended to be better the longer the interval from nephrectomy to lung metastasis. Neither the number of metastatic foci nor the surgical technique produced any difference in the prognosis. The prognosis tended to be better for patients with clear cell tumors than for those with granular cell tumors. For the treatment of lung metastasis of renal cell carcinoma, since we have no better therapy than surgical removal at the present, it is our duty to attempt to improve the prognosis of patients by the resection of metastatic foci whenever possible. However, the use of adjuvant therapy such as interferon should be considered, and the indications for operation and the timing of surgery reviewed.     

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.     

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.     

Laparoscopic cytoreductive nephrectomy as preparation for administration of systemic interleukin-2 in the treatment of metastatic renal cell carcinoma: a pilot study

OBJECTIVES: Cytoreductive nephrectomy is commonly performed in patients with metastatic renal cell carcinoma before systemic interleukin-2 (IL-2) therapy. Open nephrectomy is associated with prolonged recovery during which metastatic disease can progress. The feasibility of laparoscopic cytoreductive surgery in these patients with large renal tumors was examined. The role of tumor morcellation in reducing the recovery period and allowing earlier treatment with IL-2 was investigated. METHODS: Patients with metastatic renal cancer underwent either open nephrectomy (group 1, n = 19) or laparoscopic cytoreductive nephrectomy (n = 11; 6 with tumor morcellation [group 2], 5 with removal of the tumor through a small incision [group 3]). The three groups were compared to evaluate relative recovery, suitability for treatment with IL-2, and laparoscopic port site seeding. RESULTS: A group of 19 patients underwent open nephrectomy (group 1). Eleven patients with a median tumor volume of 377 cm3 (median tumor diameter 9 cm) underwent laparoscopic cytoreductive nephrectomy. Six of these patients underwent tumor morcellation (group 2) and 5 underwent laparoscopic assisted nephrectomy (group 3). There was no difference in patient age, sex, sites of metastatic disease, ECOG status, size of renal tumor, or surgical complication rates among groups. Patients whose tumor was morcellated had reduced postoperative parenteral narcotic requirements and were discharged sooner than patients undergoing open cytoreductive nephrectomy. Time to treatment with IL-2 was shortest in the morcellation group (median time to treatment 37 days). No port site seeding was observed. CONCLUSIONS: Laparoscopic cytoreductive nephrectomy in patients with bulky renal disease is a safe procedure in selected patients. This pilot study demonstrated a significant association of laparoscopic tumor morcellation with less postoperative pain, faster time to discharge, and shorter time to treatment with IL-2. A randomized study is warranted to determine the role of laparoscopic cytoreductive nephrectomy with tumor morcellation.     

Outcome of isolated renal cell carcinoma fossa recurrence after nephrectomy

PURPOSE: Local recurrence of renal cell carcinoma in the renal fossa after complete radical nephrectomy is uncommon. We characterize and determine outcome in a small subset of patients. MATERIALS AND METHODS: From 1970 to 1998 the incidence of isolated renal bed recurrence among 1,737 T1-3N0M0 unilateral nephrectomy cases was 1. 8% (standard error [SE] 0.4) at 5 years. There were 30 patients in whom isolated local fossa carcinoma recurred after complete radical nephrectomy without evidence of metastatic disease. Patients with any nodal involvement at radical nephrectomy were excluded from study as were those who had undergone any form of partial nephrectomy. Patient charts were reviewed for clinical presentation, stage, treatment, development of metastatic disease and survival. Pathological stage was assigned according to the 1997 TNM staging system. Recurrence was identified in 12 (40%) patients during routine followup and the remaining 18 (60%) presented with symptoms related to the recurrent tumor. Patients were divided into 3 treatment groups of observation (9), therapy excluding surgical extirpation (11) and complete surgical resection alone or in conjunction with additional therapy (10). Mean time from local recurrence to development of metastatic disease was calculated. Survival from local recurrence to overall death and disease specific death was estimated using the Kaplan-Meier method. Survival curves for the different treatment groups were then compared. RESULTS: There were 30 patients identified with an ipsilateral renal fossa recurrence of renal cell carcinoma after complete nephrectomy in the absence of disseminated disease. Mean followup was 3.3 years (range 0.006 to 14.8) and no patient was lost to followup. The T stage of the primary tumor was T1/T2 in 13 cases, T3a in 4, T3b in 12, and T3c in 1, and all were node negative. Mean time to metastasis was 1. 6 years (range 0.006 to 7.3) in the 19 patients who had documented interval metastatic disease after local recurrence. There were 26 deaths, of which 25 were disease specific. Estimated overall crude and cause specific survival at 1 and 5 years was 66% and 28%, respectively. Calculating survival among symptomatic and asymptomatic patients revealed no discernible difference in outcome (p = 0.94). The 5-year survival rate with surgical resection was 51% (SE 18) compared to 18% (12) treated with adjuvant medical therapy and only 13% (12) with observation alone. The differences in cause specific survival were significant (p 相似文献