Salvage Surgery for Advanced Renal Cell Carcinoma

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1 European Urology Supplements European Urology Supplements 3 (2004) 2 8 Salvage Surgery for Advanced Renal Cell Carcinoma Gerald H. Mickisch * Center of Operative Urology Bremen, Robert-Koch-Str. 34a, D Bremen, Germany Abstract Objective: Treatment of choice for non-disseminated disease 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. Salvage surgery in this context is considered to be experimental therapy, and this rapidly evolving field needs the definition of accepted treatment standards. Methods: A literature search using Medline sources was carried out to obtain evidence-based information. Results: Treatment options in advanced disease include nephrectomy, sometimes in combination with metastasectomy in selected cases, alone or cytoreductive surgery followed by immunotherapy. Alternatively, one may apply immunotherapy initially and perform salvage nephrectomy in the case of a response, or proceed to immunotherapy as a monotherapy. Nevertheless, long-term survival ranges merely from 5 to 10% depending strongly on patient selection criteria. Conclusion: Concepts and progress in this field appear to be of major interest for modern uro-oncologists following the advent of immunotherapeutic strategies that require a surgical intervention at some stage of the treatment cascade. # 2004 Elsevier B.V. All rights reserved. Keywords: Renal cancer; Advanced disease; Tumor nephrectomy; Lymphadenectomy; Immunotherapy; Randomized trials 1. Introduction Approximately 2 3% of all malignant tumors in adults develop in the kidney. In 85% of them, the tumor originates from cells of the proximal tubules and is known as Grawitz tumor, hypernephroma or a renal cell carcinoma (RCC). In the Netherlands, the annual incidence of this, since recently, second most common urological tumor is about 11 per 100,000 inhabitants. Men are twice as often afflicted as women, most often in the fifth to seventh decades. The incidence of RCC has gradually increased over the years and 5-year survival rates in contemporary series reach 60%. However, for patients with metastatic disease, two-year survival is between 0% and 20% [1]. * Tel. þ ; Fax: þ address: gerald.mickisch@coub.de (G.H. Mickisch). At the time of diagnosis, about 20% of patients have disseminated disease and another 25% will have locally advanced disease. Since approximately one third of all patients with tumor limited to the kidney at the time of diagnosis will subsequently develop metastatic disease postoperatively, some 50% of all patients with RCC will, sooner or later, present with disease that requires complex treatment decisions. Radical nephrectomy is still the treatment of choice in organ-confined stages [2]. However, because curative surgery is almost impossible in disseminated disease, the role of surgery in a metastasized patient has been disputed. With the advent of modern immunotherapeutic strategies, albeit with limited efficacy, the time may have come to critically re-evaluate our standard approach to surgical approaches in metastatic RCC [3]. Since RCC metastasizes by both blood-borne and lymphatic routes, surgery for loco-regional deposits and/or for distant metastasis will be discussed /$ see front matter # 2004 Elsevier B.V. All rights reserved. doi: /j.eursup

2 G.H. Mickisch / European Urology Supplements 3 (2004) Lymphadenectomy for RCC It is a well-known fact that nodal involvement is one of the major factors influencing the prognosis of cancer patients, including carcinoma of the kidney. In the various series reported in the literature the overall 5-years survival rates for stage I renal cell carcinoma (tumor confined to the kidney) range from 56 to 82% and for stage II renal cell carcinoma (extension to perirenal fat but within Gerota s fascia) from 43 to 100% [1]. These survival rates decrease considerably when lymph node metastases are present. For review see [4]. In a reported series the overall 5-year survival rates for lymph node positive disease range from 8 to 35%. In older series, the incidence of lymph node metastases in renal cancer ranges from 13 to more than 32%. The incidence of lymph node involvement increases with the stage of the tumor. Giuliani and associates found a 6% incidence of lymph node metastases in tumors confined to the kidney, a 46.4% incidence in locally advanced tumors, a 61.9% incidence in the patients with distant metastases and a 66.6% incidence of lymph node metastases in patients with both vascular infiltration and distant metastases. Lymph node dissection (LND) has resulted in the finding of lymphatic metastases in % of patients who have no other evidence of metastatic disease and there is little doubt about the value of regional LND as a staging procedure. Since renal carcinoma can metastasize by lymphatic routes only, regional lymphadenectomy has been proposed as a method of improving the results of surgical therapy. However, the therapeutic value of lymphadenectomy for renal cell carcinoma is still controversial. LND may improve the prognosis of renal cell carcinoma, but factors such as distribution of lymph node metastases, the extent of the LND, the possibly increased operative morbidity and mortality, and the relation between histologic type, and the incidence of nodal metastases were also to be investigated in a well planned prospective study (EORTC 30881). Preliminary results of this study have been published [5]. From May until September 1991, 772 patients with a clinically locally confined adenocarcinoma of the kidney were entered into the study. 389 patients were randomized to have a radical nephrectomy without a LND. 383 patients were randomized to undergo a radical nephrectomy with a complete LND. Fortyone patients were not eligible, mainly due to an incorrect disease stage or histopathology, thus leaving 731 eligible patients, 369 in the no LND group and 362 in the group having a LND. Patients who had clinically detectable lymph node metastases or distant metastases before surgery were ineligible and excluded from the study. There was virtually no difference between the two treatment groups in the number of complications. There is a slightly larger number of patients with blood loss during operation among the patients who had a LND, but the differences are not statistically significant (Chi-square test). Thus the extension of the operation caused by the LND had no real impact on the complication rate. In 336 patients information on the lymph node status is available. 43 of these patients had palpable lymph nodes during surgery. Almost 97% of the patients had no lymph node metastases on pathological examination of the resected lymph nodes. Of the patients who underwent a nephrectomy without LND, 29 of 346 patients (8.4%) had palpable lymph nodes during surgery. Only 6 of these 29 patients had lymph node metastases at biopsy of the glands. As only 17% of the patients entered have progressed or died, based on a median follow-up of 5 years, it is too early to elude on treatment efficacy. There are some points that might have contributed to the differences in survival found in older, non-randomised series and that may be arguments against lymphadenectomy. First, the number and location of the involved nodes were not specified in any of the reported series. It is possible that the survivors were the patients with only one or several microscopically involved lymph nodes in the renal hilum. These nodes would also have been removed by a standard radical nephrectomy without an extensive lymphadenectomy. Secondly, one has to take into account the potentially increased morbidity and mortality from the extended operation in the light of the small improvement in survival reported in most series. Thirdly, many patients with negative lymph nodes may die of disseminated tumor, indicating that blood-borne metastases are perhaps more common causes of death from renal carcinoma than are lymphatic metastases. So, lymphadenectomy can only be justified if lymphatic metastases is the only extent of tumor dissemination. In summary it can be concluded from this large study that an LND combined with a radical nephrectomy does not increase morbidity or mortality, but a longer follow-up is needed to make conclusions on its efficacy in terms of prolonged tumor-free survival. 3. Adjuvant immunotherapy In the case of a macroscopically radical tumor resection for RCC, adjuvant immunotherapies have

3 4 G.H. Mickisch / European Urology Supplements 3 (2004) 2 8 been advocated to reduce the recurrence rate. Current reviews on this topic concluded, however, that this approach must be considered experimental therapy [6], since all six randomized trials so far, including the large Delta-P-protocol, were negative and did not demonstrate a survival benefit. Nevertheless, all these trials were not statistically powerful enough to detect small differences at a low event rate so as not to permit firm conclusions. In this situation, the EORTC went on to develop a protocol randomizing between one cycle of adjuvant triple drug (IFNa, IL-2, 5 FU) therapy versus watchful waiting in a group of patients considered to be at higher risk for a relapse after a potentially curative tumor resection (such as positive lymph nodes, positive surgical margins or macroscopic/microscopic venous tumor invasion). Until results from EORTC will become available, adjuvant immunotherapy should only be applied in the context of controlled clinical trials. 4. Advanced disease It is common knowledge that a nephrectomy in a patient with metastatic spread of an RCC almost certainly cannot bring cure, and that the patient will die of these metastases rather than from his primary tumor. In fact, the only rationale in favor of a nephrectomy in the presence of metastases may be a potential survival benefit, or the improvement of the quality of the survival. In contrast, it is clear that a nephrectomy in the disseminated disease stage needs an operation with its proper morbidity and sometimes mortality. Arguments pro and contra surgery in metastatic RCC are summarized in Table 1. Prolongation of life can only be achieved when a better tumor control is obtained with a tumor nephrectomy. Nephrectomy will reduce the tumor burden and remove the source of new metastases. For many years, there were no prospectively randomized trials to demonstrate the postulated survival benefit (see below). In addition, it was suggested that nephrectomy could induce spontaneous regression of metastases. Reports on this phenomenon were reviewed [7] and concluded that the overall incidence was about 0.7%, whilst the mortality of nephrectomy in this situation amounted to 1 5%. Furthermore, spontaneous regression of metastatic lesions may also occur without surgery. Moreover, prior nephrectomy is said to potentially enhance the response to systemic therapy, an issue that has rested quite controversial [8]. Inastudyon55 patients with metastatic RCC, triple drug immunotherapy resulted in a 32% objective response rate in those after nephrectomy, whereas the same regimen reached only a response rate of 4.7% with the primary tumor in situ. However, these results do not necessarily demonstrate a biological effect of nephrectomy, because patients in this series who were not offered a nephrectomy were almost certainly of poor performance score and thus represented a negative selection bias. Only prospectively randomized trials such as EORTC may adequately settle the question whether surgery improves on response to immunotherapy. The second aim of a nephrectomy in metastatic RCC is to improve on quality of life by obtaining relief of symptoms, mainly hematuria, pain or systemic manifestations. Hematuria can be quite impressive, necessitate transfusion and be responsible for death. However, not only nephrectomy, but also embolization could effectively treat this symptom. Pain caused by the primary tumor can result from tumor necrosis, eventually hemorrhage and evacuation of blood clots with renal colic. In these cases a symptomatic improvement can be expected from the nephrectomy. Mostly, however, pain is due to direct involvement of nerves or bony structures, where surgery will be difficult and not very rewarding. The systemic manifestations of metastatic RCC are general deterioration of performance score, anemia, anorexia, weight loss, fever, hypertension, and hyper- Table 1 Surgery for metastatic renal cell carcinoma Pro Treatment/prevention of tumor complications (hematuria, bleeding, flank pain) Spontaneous regression of metastases Remove source of new metastases Reduction of tumor burden Removes trap for trafficking lymphocytes Psychology/quality of life??? Contra Treatment alternatives available (embolization/irradiation) Useless (waste of time) Dangerous (perioperative morbidity/mortality) No survival benefit ever proven May compromise immune system Psychology/quality of life??? Arguments pro and contra nephrectomy in metastatic renal cell carcinoma.

4 G.H. Mickisch / European Urology Supplements 3 (2004) calcemia. These symptoms, partly paraneoplastic, are very likely to show amelioration after nephrectomy, when no metastases are present. In disseminated patients the effect on these systemic sequelae of RCC will often not be influenced by nephrectomy unless metastases are treated at the same time. Nevertheless, many metastatic patients will experience a short-lived general improvement after nephrectomy that can be well appreciated by patient and family because it temporarily declines the progressive deterioration under expectant management [9]. Also, the intention to prevent symptoms caused by spontaneous rupture and bleeding or pain is not a valuable argument for nephrectomy in metastatic RCC, since these symptoms can still be treated adequately when they arise. Finally, when either leaving the primary tumor behind or performing an otherwise useless major surgical procedure, psychological factors can become important in the quality of life. The decision for surgery or surveillance often depends on the urologist s ability to face advanced cancer patients and the willingness to inform the patient on the stage of the disease. Undoubtedly, only well designed randomized trial with quality of life assessment may answer the question of utility of nephrectomy in the metastatic patient. 5. Surgical considerations The surgery only approach is often hampered by the fact that metastases present usually multiple and invade more than one organ. Only a small minority is solitary, and the resection of these may be beneficial to the patient. In a contemporary series of 141 patients who underwent a curative metastasectomy for their first recurrence of RCC, 44% experienced a 5-year overall survival rate [10] whereas patients with incomplete surgery or non-surgical treatment did considerably worse (14% and 11% 5-year overall survival rate, respectively). Favorable predictors of survival by multivariate analysis included a single organ of first recurrence, curative resection of first-metastasis, a long disease-free interval (>12 months), a solitary site of first metastasis, and a metachronous presentation with recurrence. Admittedly, the drawback of all published studies so far is that they are retrospective and concern relatively small number of patients. Cure after metastasectomy remains uncommon; however, selected patients with recurrent RCC who can undergo a curative resection of their disease have a good opportunity for long-term survival, particularly those with a single site of recurrence and/or a long disease-free interval. The role of cytoreductive surgery before immunotherapy in patients with metastatic RCC as well as the search for more genetically-tailored systemic therapies [11] needed to be defined. Nephrectomy alone in these patients is not thought to extend survival. Theoretical advantages of nephrectomy in this situation include the presence of fewer cancer cells to treat, removal of a trap for trafficking lymphocytes, prevention of complications during systemic treatment, the ability to harvest tumor infiltrating lymphocytes and tumor cells for analysis and use in experimental therapies, and reduction of a large, potentially immunosuppressive tumor burden. Other practical considerations comprise a proposed potential improvement in patient performance score, allowing better tolerance and probability of response to immunotherapy, elimination of the primary tumor as a possible source of hemorrhage, discomfort or propagation of metastases, and the fact that responses to immunotherapy in the primary have been rare. Disadvantages of this approach include growth of metastatic disease during the recovery period, which could preclude treatment, and the morbidity associated with a major operation. When evaluating the controversial issue of cytoreductive surgery prior to immunotherapy, the questions that must be asked are whether patients with metastatic disease tolerate the operation well enough to receive systemic treatment postoperatively and whether removal of the primary tumor increases the likelihood of an objective response to immunotherapy at metastatic sites. The ability to provide a scientifically valid answer was seriously hampered by the lack of prospective randomized trials. Comparison of previous non-randomized trials concurs that the surgical procedure in experienced hands involves acceptable mortality and limited morbidity [12,13]. However, these reports also indicate that from 38% to 77% of the patients [12,14] failed to receive immunotherapy, usually due to rapid disease progression. Obviously, patient selection becomes most critical for this approach. In an effort to limit debulking nephrectomy to patients most likely to benefit from the combined treatment strategy, strict enrollment criteria were established. Those with inadequate cardiac or pulmonary function, central nervous system metastases or concurrent illness were excluded because they would have been ineligible for immunotherapy a priori. In addition, patients were eliminated whose chance of response would not be significantly improved by removing the primary tumor due to disease distribution

5 6 G.H. Mickisch / European Urology Supplements 3 (2004) 2 8 (bone, liver, or contralateral kidney), extent of metastases or nonclear-cell tumor histology and whose risk of rapid symptomatic progression following surgery was increased. Applying these criteria enabled 87.3% [15] or, more recently, 93% [16] of selected patients to recover from nephrectomy and to receive immunotherapy. This subset represented 33% or 55% of patients presenting at the respective institution with metastatic RCC. Objective response rates (CR þ PR) in all series ranged from 12.6 to 39% with a vast majority being incomplete. Because these data are from non- randomized studies, any prolongation of survival remains inconclusive. Ultimately, the clinical role of cytoreductive nephrectomy in immunotherapy protocols remained conjecture. As is the case with many salient issues in immunotherapy for RCC, a lack of properly designed trials had left much confusion. A randomized trial comparing immunotherapy in patients who have undergone nephrectomy to those with the primary tumor in place was necessary. One such trial, EORTC a joint protocol with SWOG 8949, has been closed for patient entry in summer of 1998 due to reaching the recruitment targets. This large study was designed to answer the question whether prior nephrectomy increases the chance of response to immunotherapy (response rates) and whether combined treatment may result in prolongation of time to progression and, most importantly, in a survival benefit. The EORTC was the first cooperative group to report preliminary results from this major trial effort [17]. Others followed and provided similar evidence [18] albeit at reduced efficacy. In the EORTC study, 85 patients were included from June 1995 to July Two proved to be ineligible, one on each treatment. Of the remaining 83, 41 were randomized to arm 1 (surgery plus immunotherapy) and 42 to receive immunotherapy alone (arm 2). All patients had a histologically proven metastatic RCC, were progressive at entry, and signed an informed consent. In the case of therapy 1, surgery was performed within 4 weeks after randomization and immunotherapy started between 2 and 4 weeks after the day of the operation. In the case of therapy 2, Interferon-alpha immunotherapy started within one working day after randomization. Followup visits were monthly with a projected treatment duration of one year. Dosage of Interferon-alpha in both arms was units/m 2, 3 times a week. An intent to treat analysis was carried out. Distribution of patients between arms 1 and 2 was evenly with respect to age, gender, WHO performance score (0, 1), tumor type, venous invasion, lung metastases only (stratification factor), liver metastases, bone metastases and co-morbidity. 20 patients were younger than 50 years, 12 older than 70 years. 4 patients in arm 1 received no tumor nephrectomy and went on immunotherapy whenever possible. There were 6 perioperative surgical complications, and only one of them did not receive immunotherapy. Toxicity such as myelotoxicity, nausea, anorexia and neurologic/psychologic disorders was equally distributed between treatment arms, led to a dose modification in 32% of evaluable patients, but was generally considered to be manageable in an outpatient setting. 50% of all patients received more than 16 weeks of Interferon-alpha treatment. There were 5 complete responses in arm 1, and only 1 in arm 2. Partial responses and stable diseases were similarly distributed between treatment arms. The overall objective response rate (CR þ PR) was 19 versus 12%, respectively (log rank p ¼ 0:38), not reaching statistical significance. However, both primary end points, time to progression (log rank p ¼ 0:04) and duration of survival (log rank p ¼ 0:03), were in favor of the combined treatment arm. The estimate for the median survival shifted from 7 months to 17 months. Hence, in the context of Interferon-alpha based immunotherapy, preceding cytoreductive tumor nephrectomy significantly delays time to progression and improves on overall survival in metastatic RCC patients presenting with a good performance status. Suffice to say that laparoscopic removal of the tumor-bearing kidney may also be attempted in suitable cases [19], awaiting further analysis in randomized trials. 6. Immunotherapeutic considerations and the role of salvage surgery While some retrospective data suggested improved response rates of immunotherapy in nephrectomized patients which was not confirmed in the prospective randomized trial [17], not all responders have had prior removal of the primary tumor [20]. Nevertheless, of 51 patients treated at the NCI with the kidney in place an objective response rate of merely 6% with no responses in the primary was noted [21]. Even if multimodality treatment of metastatic RCC consisting of surgery and immunotherapy has been accepted in most large tumor centers worldwide to be worthwhile in selected patients, the timing and impact of adjuvant nephrectomy (primary or delayed) remains controversial. Several arguments may support the use of immunotherapy with the primary tumor in situ. Everybody who at the time of diagnosis is fit enough to receive systemic

6 G.H. Mickisch / European Urology Supplements 3 (2004) therapy will be treated by the only means that might cure the patient at this time not amenable to radical resection of disseminated disease. Patients who respond to therapy are identified, and those are probably the only ones who may benefit. Therefore, patients unlikely to profit avoid a major operation. Also, shrinkage of the primary tumor by initial immunotherapy may make nephrectomy less challenging technically. Some authors even suggested that surgery impairs the immune system of the patient, making postoperative immunotherapy less effective [14]. To assess the issue, a single institutional report appeared comparing retrospectively 37 patients with initial nephrectomy to 25 patients who received initial immunotherapy and scheduled delayed nephrectomy in the event of a response using the same selection criteria [22]. Eight patients (22%) were unable to enter induction of immunotherapy and three patients (8%) showed an objective response. Three patients demonstrated an objective response under initial immunotherapy and were then rendered tumor-free by salvage nephrectomy. Median survival reached 12 or 14 month, respectively. More recently, the same institution described a highly selected group of 14 patients with metastatic RCC [23] who responded to initial immunotherapy and underwent subsequently a radical resection of all tumor masses. The cancer specific survival rate at 3 years amounted to impressive 81.5%. Nevertheless, the gist remains whether or not overall patient survival is better achieved by surgical selection or, alternatively, by medicinal selection. Given the known morbidity and survival data, it appears logical to conclude that more patients might be better served by first administering immunotherapy and then operating to eradicate residual soft-tissue disease only in those patients whose peripheral lesions regressed significantly. This question would probably be best answered in a prospective randomized trial. Modern immunotherapy has been advocated for metastatic RCC. Many adequately controlled studies have been performed and appeared in the peerreviewed literature. Objective response rates for firstline therapies such as Interferon-alpha and/or Interleukin-2 ranged from 2 to 39% [24,25] with a small minority of patients experiencing long-term remissions. Second-line therapy after failure of immunotherapy is largely ineffective [26]. Prolongation of survival due to cytokine therapy remains a matter of debate [8,27,28]. However, most of these trials comprised patients after nephrectomy and the treatment option immunotherapy alone (i.e. with the primary tumor in situ) still is with the exception of patients presenting with a good performance score [17] not authoritatively evaluated given the lack of prospective and randomized analysis [21]. 7. Conclusion In metastatic patients willing and fit enough to undergo anticancer treatment, four modalities are available in principle: (1) nephrectomy and/or metastasectomy only; (2) cytoreductive surgery followed by immunotherapy; (3) initial immunotherapy followed by salvage nephrectomy in responders; and (4) immunotherapy alone. So far, only option 2 (cytoreductive surgery followed by immunotherapy) is authoritatively evaluated and approved. It constitutes standard therapy currently. Quality of life issues under therapy need further exploration as well as the continuing search for more active systemic therapies. Monotherapeutic approaches such as surgery alone or immunotherapy alone should either only be applied in a small minority of patients with radically resectable disease, or remains incompletely evaluated so as not to permit a legitimate use outside ethically acceptable treatment protocols. At present, multimodality treatment consisting of surgery and immunotherapy in a complex clinical situation, such as in a patient with advanced RCC, deserves our attention and should have priority in clinical research on RCC. Timing and impact of nephrectomy needs further investigation as well as the continuing search for more active treatment regimens. However, in either management scheme, surgery is required to ensure that all disease has been eradicated. Therefore, a central role for a modern oncologic urologist can easily be justified in the management of metastatic RCC. 8. Take-home messages Multimodality treatment of mrcc is superior to monotherapeutic strategies. It prolongs time to progression. It extends overall survival. It has acceptable morbidity and mortality in experienced hands. Timing of nephrectomy needs further attention. The search for more active systemic therapies continues.

7 8 G.H. Mickisch / European Urology Supplements 3 (2004) 2 8 References [1] Mickisch GHJ. Principles of nephrectomy for malignant disease. BJU Int 2002;89: [2] Mickisch GHJ. Surgical approaches to organ-confined renal cell carcinoma. Onkologie 2000;23: [3] Mickisch GH, Carballido J, Hellsten S, Schulze H, Mensink H. Guidelines on renal cancer. Eur Urol 2001;40: [4] Mickisch GHJ. Lymph node dissection for renal cell carcinoma the value of operation and adjuvant therapy. Urologe (A) 1999;38: [5] Blom JHM, van Poppel H, Marechal JM, Jacqmin P, Sylvester R, Schröder FH, et al. members of the EORTC-GU group. Radical nephrectomy with and without lymph node dissection: preliminary results of the EORTC randomised phase III protocol Eur Urol 1999;36: [6] Bukowsky RM. Natural history and therapy of metastatic renal cell carcinoma. Cancer 1997;80: [7] De Riese W, Goldenberg K, Allhoff E. Metastatic renal cell carcinoma: Spontaneous regression. long-term survival and late recurrence. Int Urol Nephrol 1991;23: [8] Mickisch GHJ. Rational selection of a control arm for randomized trials in metastatic renal cell carcinoma. Eur Urol 2003;43: [9] van Brussel J, Mickisch GH. Prognostic factors in renal cell and bladder cancer. Br J Urol 1999;83: [10] Kavolius JP, Mastorakos DP, Pavlovich C. Resection of metastatic renal cell carcinoma. J Clin Oncol 1998;16: [11] Noordzij MA, Mickisch GHJ. The genetic make up of renal tumors. Urol Res, in press. [12] Walther MM, Yang JC, Pass Hl. Cytoreductive surgery before high dose interleukin-2 based therapy in patients with metastatic renal cell carcinoma. J Urol 1997;158: [13] Tigrani VS, Reese DM, Small EJ, Presti Jr JC, Carroll PR. Potential role of nephrectomy in the treatment of metastatic renal cell carcinoma: a retrospective analysis. Urology 2000;55: [14] Bennett RT, Lerner SE, Taub HC. Cytoreductive surgery for stage IV renal cell carcinoma. J Urol 1995;154:32 4. [15] Taneja SS, Pierce W, Figlin R. Immunotherapy for renal cell carcinoma: the era of interleukin-2 based treatment. Urology 1995; 45: [16] Fallick ML, McDermott DF, LaRock D. Nephrectomy before interleukin-2 therapy for patients with metastatic renal cell carcinoma. J Urol 1997;158: [17] Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R. Radical nephrectomy plus Interferon-alpha based immunotherapy compared with interferon-alpha alone in metastatic renal cell carcinoma: a randomized trial. Lancet 2001;358: [18] Flanigan RC, Salmon S, Blumenstein BA, Bearman SI, Roy V, McGrath PC, et al. Nephrectomy followed by interferon alpha-2b compared with interferon alpha-2b alone for metastatic renal cell cancer. New Engl J Med 2001;345: [19] Walther MM, Lyne JC, Libutti SK, Linehan WM. Laparoscopic cytoreductive nephrectomy as preparation for administration of systemic interleukin-2 in the treatment of metastatic renal cell carcinoma: a pilot study. Urology 1999;53: [20] Fleischmann JD, Kim B. Interleukin-2 immunotherapy followed by resection of residual renal cell carcinoma. J Urol 1991;145: [21] Wagner JR, Walther MM, Linehan WM, White DE, Rosenberg SA. Interleukin-2 based immunotherapy for metastatic renal cell carcinoma with the kidney in place. J Urol 1999;162:43 5. [22] Rackley R, Novick AC, Klein EA. The impact of adjuvant nephrectomy on multimodality treatment of metastatic renal cell carcinoma. J Urol 1994;152: [23] Krishnamurthi V, Novick AC, Bukowski RM. Efficacy of multimodality therapy in advanced renal cell carcinoma. Urology 1998; 51: [24] Negrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C, et al. Recombinant human interleukin-2, recombinant human interferon alpha-2a, or both in metastatic renal cell carcinoma. New Engl J Med 2000;338: [25] Atzpodien J, Kirchner H, Illiger HJ, Metzner B, Ukena D, Schott H, et al. IL-2 in combination with IFN-alpha and 5-FU versus tamoxifen in metastatic renal cell carcinoma: long-term results of a controlled randomized clinical trial. Br J Cancer 2001;85: [26] Vis AN, Gaast vda, Rhijn vbwg, Catsburg TK, Schmidt C, Mickisch GHJ. A phase II trial of methotrexate-human serum albumin (MTX-HSA) in patients with metastatic renal cell carcinoma who progressed under immunotherapy. Cancer Chemother Pharmacol 2002;49: [27] Motzer RJ, Mazumdar M, Bacik J, Russo P, Berg WJ, Metz EM. Effect of cytokine therapy on survival for patients with advanced renal cell carcinoma. J Clin Oncol 2000;18: [28] Medical Research Council Renal Cancer Collaborators. Interferon-a and survival in metastatic renal cell carcinoma: early results of a randomised controlled trial. Lancet 1999;353:301 5.