Prognostic Factors and Survival after Pulmonary Resection ofmetastaticrenalcellcarcinoma

European Urology European Urology 48 (2005) 77 82 Kidney Cancer Prognostic Factors and Survival after Pulmonary Resection ofmetastaticrenalcellcarcinoma Hans-Stefan Hofmann*, Heinz Neef, Katharina Krohe, Petko Andreev, Rolf-Edgar Silber Department of Cardio-Thoracic Surgery, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06097 Halle, Germany Accepted 2 March 2005 Available online 20 March 2005 Abstract Objective: Pulmonary metastasectomy as well as immunotherapy have reproducible, albeit limited efficacy in advanced renal cell carcinoma (RCC). We examined whether metastasectomy improved overall survival compared with results of immunotherapy. Methods: Between 1975 and 2003, 64 patients (41 men, 23 women) underwent pulmonary resection of metastatic RCC. Only patients who met the criteria for potentially curative operation, that means, control of primary tumor, ability to resect metastatic disease and no other extrapulmonary metastases, were included. Results: The overall 5-year survival was 33.4% (median survival: 39.2 months). A significant longer survival was observed using multivariate analysis in patients with complete pulmonary resection (R0), with a 5-year survival of 39.9% and a median survival of 46.6 months in correlation to patients with incomplete resection (5-year survival 0%, median survival 13.3 months). In multivariate analysis patients with synchronous metastases had a significant worse prognosis in correlation to patients with metachronous metastases. The 5-year survival of curative resected patients with metachronous metastases was 43.7% versus 0% for synchronous metastases, respectively. In patients with solitary metastasis and R0 resection, we observed a 5-year survival of 49%, whereas the rate was 23% in patients with more than a single metastasis. When establishing prognostic groups as suggested by the International Registry based on the risk factors disease-free interval, number of metastasis and complete resection the group with the best prognosis showed a 5-year survival of 52% (median survival 75.2 months). Conclusion: Metastasectomy nowadays is the best treatment option in cases with technical resectable metastases with as much as possible good prognostic factors (metachronous metastases with long DFI, number up to 6 metastases). # 2005 Elsevier B.V. All rights reserved. Keywords: Lung metastasis; Renal cell carcinoma; Survival; Prognostic factors 1. Introduction Renal cell carcinoma (RCC) accounts for about 2% of all cancers, with a world-wide annual increase of 1.5 5.9% due to enhanced detection of tumors by expanded use of imaging techniques. A total of 25 30% of patients with RCC have overt metastases at initial presentation [1,2]. About one third of patients * Corresponding author. Tel. +49 345 557 2793; Fax: +49 345 557 2802. E-mail address: stefan.hofmann@medizin.uni-halle.de (H.-S. Hofmann). with tumor of the kidney at diagnosis will develop metastatic disease during the following time. Thus, nearly 50 60% of all patients with RCC will eventually present with metastatic disease that requires individual treatment decision. Patients with untreated metastatic disease have a 5-year survival of 0% to 18% [3]. The first resection of a pulmonary metastasis in a patient with RCC was performed by Barney and Churchill in 1939 [4]. Since than, surgery remains the only effective treatment for patients with isolated pulmonary metastases. The published 5-year survival rates after pulmonary metastasectomy of renal origin 0302-2838/$ see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2005.03.004

78 H.S. Hofmann et al. / European Urology 48 (2005) 77 82 range from 36 54%. Good prognostic factors for pulmonary resection are solitary metastasis and long disease free interval. While RCC responds poorly to single-agent chemotherapy or hormonal therapy, immunotherapy with subcutaneous recombinant interleukin-2 (IL-2) alone or in combination with recombinant interferone alpha (IFNa) yielded significant therapeutic efficacy in RCC. In the era of emerging effective systemic therapy (usually immunotherapy) the role and indications of surgery for RCC must be scrutinized and eventually again defined. This retrospective analysis of patients subjected to aggressive surgical management of lung metastasis after radical tumornephrectomy reinforces the need to find indications/contraindications for complete eradication of metastatic disease or conservative treatment with immunotherapy. 2. Patients and methods Table 1 Clinical and pathological characteristics of patients and their pulmonary metastases No. of patients 64 Mean age (yr) 60.0 8.8 Male/female ratio 41/23 Disease free interval (month) 40.9 40.6 Synchronous/metachronous 6/58 Uni-/bilateral 41/23 Access Sternotomy 10 16% Thoracotomy (unilateral) 44 68% Thoracotomy (bilateral) 10 16% Surgical Procedure PE/diagnostic thoracotomy 7 (11%) Atypical resection 48 (75%) Lobectomy 7 (11%) Pneumonectomy 2 (3%) Residual tumor situation R0 54 (84%) R1 2 (3%) R2 8 (13%) 64 patients (41 men, 23 women) with lung metastasis of RCC were operated on for curative purposes in our department between September 1975 and September 2003 (Table 1). The indications for the operation as well the operation itself were performed by the same surgeon. In all patients the primary RCC was treated by radical nephrectomy. Six patients had lung metastases at the same time as RCC diagnosis (synchronous metastastasizing). The mean disease free interval between primary resection of the kidney and pulmonary metastasectomy for patients with metachronous metastases was 40.9 months. Pulmonary metastases were bilateral in 22 patients and unilateral in 42 patients. Ten sternotomies, 10 staged bilateral and 44 unilateral thoracotomies were performed. In four patients with bilateral metastases the planed second lateral thoracotomy was not carried out because of incomplete resection (R1/ R2) after the first lateral thoracotomy. Wedge resection was performed in 48 patients, lobectomy in 7 and pneumonectomy in two patients. Because of miliare metastasizing seven patients had only biopsy. Finally, the resection was complete (R0) in 84% (n = 54). After metastasectomy, a microscopic residual tumor remained in two patients (R1) and a macroscopic residual tumor in 8 patients (R2). 14% (9/64) of the patients received adjuvant therapy as chemo- or immunotherapy. Those patients however did receive different schemes so no grouping for survival analysis depending on adjuvant treatment was possible. All patients were post-examined in our outpatient department. Survival was calculated from the time of metastasectomy. For analysis of follow-up data, life table curves were calculated with Kaplan-Meier methods, and survival distributions were compared by use of log-rank statistics. The Cox proportional hazards model was applied for multivariate analysis using the SPSS software program (SPSS Inc., Chiacago, U.S.). 3. Results There were no operative deaths. Follow-up of all patients ranged from 60 days to 13 years (median 23.2 month). Detectable recurrent disease occurred in 31 (57%) of the 54 patients with RO resection. Local recurrence in the lung occurred in eight and distant metastases in only one organ in 11 patients (kidney n = 4, brain = 3, liver n = 2, bone n = 1, thyroid n = 1), 12 patients suffered from multiple metastases. Of these, 25 patients died and 9 patients died without knowledge of recurrent disease during the follow-up. Overall estimated long term survival was 33% and 13% at 5 and 10 years, respectively. The median survival of all patients was 30 months. 4. Influence of prognostic factors 4.1. Synchronous versus metachronous metastases Of the 54 patients who underwent complete pulmonary resection (R = 0), 5 patients had synchronous pulmonary metastases at the time of RCC diagnosis. The other 49 patients developed the metachronous metastases during follow-up after nephrectomy. The 5-year survival of the patients with metachronous metastases was 43.7% (median survival 56.7 months). No patient with synchronous metastases survived the fourth year after thoracotomy (median survival 15.3 months). There was a significant difference between these two groups (p = 0.033). 4.2. Disease free interval The occurrence of metastasis can also be expressed as the time from treatment of the primary tumor to the development of pulmonary metastases disease free

H.S. Hofmann et al. / European Urology 48 (2005) 77 82 79 interval (DFI). Thirty-one patients with R0 resection had a DFI of less than three years with a 5-year survival of 32.6% (median survival 36.9 months). This was not significantly lower (p = 0.17) than the 5 year-survival of 49.8% (median survival 59 months) in the 23 patients with R0 resection, but with a longer disease free interval. 4.3. Localization of metastases The majority of patients (37 of 54) in this study had unilateral pulmonary metastases. In patients with complete resection, there was no difference in postthoracotomy survival between patients who had unilateral metastases (5-year survival 40.3%) versus patients with bilateral localization of the metastasis (40.4%; p = 0.93). 4.4. Number of metastases The mean number of nodules resected was 2.7 2.9 (range 1 to 19). The survival of the 22 patients with solitary metastases was 54.7% at 5 years (median survival 71.6 months). Five-year survival rate for the 32 patients with multiple metastases was 29.8% (median survival 32.7 months). This difference in survival was not significant (p = 0.07). However, the classification in solitary metastasis, 2 6 metastases and more than six metastases showed with 5-year survival rates of 54.7%, 32.0% and 0% significant differences (p = 0.02). 4.5. Resectability The overall survival of the 54 patients who underwent complete resection (R0) of the pulmonary metastases was 39.9% with a median survival of 46.5 months. None of the patients with incomplete resection (R1 and R2) survived more than four years. Three-year survival rate of the patients with incomplete resection was 22%, the median survival 13.3 months. These differences were significant (p = 0.0006). 4.6. Multivariate analysis Relative risks of death and multivariate analysis were calculated on all 64 patients. When considered separately, metachronous versus synchronous, number of metastases (solitary, 2 6 and >6 metastases) and resectability were significant prognostic variables; localization (uni- vs. bilateral) and age (not shown) were not significant. The relative risks of death for each variable are adjusted for all variables of interest: age, synchronous vs. metachronous, number of metastases (solitary vs. multiple), localization and resectability (Table 2). The best prognosis was observed for metachronous metastases, single metastases and curative resectability. Patients with incomplete resections had clearly the worst prognosis. Table 2 Multivariate Cox regression analysis of potential risk factors for pulmonary metastasectomy in patients with advanced RCC 4.7. Staging of the international registry of lung metastases The International registry of lung metastases performed a prognostic grouping that used three parameters of prognostic significance: resectability, DFI and number of metastases. We staged our patients in according to these four prognostic groups: Group I: resectable, no risk factors (DFI 36 months and single metastasis); Group II: resectable, one risk factor (DFI < 36 months or multiple metastases); Group III: resectable, two risk factors (DFI < 36 months and multiple metastases) and Group IV unresectable (Fig. 1). The 5-year survival rates were 52.5% (median survival 75.2 months), 48.2% (59.0 months), 21.5% (35.0 months) and 0% (13.3 months) for group I, II, III and IV, respectively. The differences between the groups were highly significant (p = 0.0003). 5. Discussion Hazard ratio 95% CI p Age 60 years >60 years 0.06 0.5 1.7 0.8 DFI Metachronous Synchronous 7.8 1.5 11.5 0.005 Location Unilateral Bilateral 1.2 0.72 3.4 0.25 Number Solitary Multiple 5.4 0.16 0.83 0.02 R-status R0 R1/R2 11.1 0.1 0.5 0.001 Barney and Churchill in 1939 were the first to demonstrate the value of resecting a pulmonary metastases in a patient with RCC [4]. Since than metastasectomy of lung metastases from RCC represents the best treatment in selected cases, especially in patients with limited RCC and good performance status. Recent advances in immunochemotherapy have led to response rates as high as 20% with concomitant improvements in cancer specific survival. The present study was conducted to describe criteria for selecting patients with isolated pulmonary metastases. The aim was to identify patients who would benefit from metastasectomy or who should be treated with immunochemotherapy.

80 H.S. Hofmann et al. / European Urology 48 (2005) 77 82 Fig. 1. Kaplan-Meier plots of survival for RCC patients with pulmonary metastases. Overall survival predicted by risk groups of the International registry of lung metastases. Overall 5-year survival in our series was 33% and 39.9% for complete resection, respectively. Similar results for surgery were observed in the literature, with 5-year survival rates ranging from 36 to 54% for complete resection. The most important and multivariate significant prognostic factor influencing survival is resectability. Patients with incomplete resection had with a 3-year survival rate of 22% and a median survival of 13.3 months a 11.1-fold evaluated relative risk in correlation to patients with complete resection. Median survival with untreated metastatic RCC is 10 months [1]. Atzpodien has reported overall 5-year survival of 16% with a median survival of 20 months for 425 patients with metastatic RCC treated with subcutaneous IL-2/INF-alpha2A therapy [5]. Patients with metastatic RCC limited to the lung fared significantly better than patients who had evidence of disease in multiple organs [6]. Thus, preoperative diagnostic assessment must analyze the curative resectability of the metastases, because patients with residual tumor tissue or bulky disease did not benefit from operation. This confirms data from other studies, who also detected significant worse survival for patients with incomplete resection of metastases [7,8]. The second multivariate significant risk factor is the time between treatment of primary RCC and occurrence of pulmonary metastases, but only in the criteria of synchronous versus metachronous metastases. Patients with synchronous metastases have a very short survival after metastasectomy and the relative risk in correlation to patients with metachronous metastases is 7.8 higher. Synchronous metastasizing is also a significant risk factor in patients treated only with combined immunochemotherapy [9]. May et al. reported a relative risk of 1.81 for patients with synchronous different organ metastases in RCC in correlation to metachronous occurrence. The median survival after nephrectomy of node-negative RCC and immunotherapy for patients with only synchronous lung metastases is 31 months. This is nearly twice as long as our median survival (15.3 months). Nevertheless, that the results of May et al. only include RCC patients with a very good prognostic factor tumor negative lymph nodes at the time of diagnosis, this outcome implicates, that patients with synchronous metastases may profit from immunochemotherapy in correlation to surgery. In the group of completely resected patients the DFI, which had a cut-off of 36 months, is not a significant prognostic factor. Recent reports [8], 10) appear to support our results, in other metastasectomy studies DFI is a prognostic parameter and varied largely between one to four years [11 13]. Univariate analysis of our data shows that the number of resected metastases is relevant for survival of complete resected patients. The best prognosis have patients with solitary metastasis, therefore many reports [10,11] as well as the International Registry of Lung Metastases [14] limit their staging to patients with solitary versus multiple metastases. However, the results of this study is the finding that worse prognosis is combined with more than 6 metastases. We only found one immunotherapy study that investigate the correlation of the number of lung metastases in RCC patients and survival [6]. Han et al. identified 9 of 120 patients with lung metastases who had only a solitary lesion in the lung. These 9 patients had a 5-year survival rate of 67%, which was significant in correlation to patients with two or more metastases. The overall response rate for immunotherapy after nephrectomy in the study of Han et al. was very high (44%) for patients with lung metastases, which may be connected with the fact that only favorable risk groups (primary tumor without node infiltration, lung metastases) were recruited. Most study groups report more modest response rates for immunotherapy with IL-2, IFN-a and 5-FU [15]. The role of metastasectomy in combination with immunotherapy as neoadjuvant or adjuvant therapy is discussed controversially. Kim and Louie reviewed 399 patients with metastatic RCC who received IL-2 with or without lymphokine-activated killer cell immunotherapy [16]. Eleven patients underwent surgical resection of the residual tumor in the lung, kidney, retroperitoneum, or pelvis, and were rendered surgically free of disease after immunotherapy and remained alive without recurrence after a median follow up of 21 months. Progrebniak et al. reported

H.S. Hofmann et al. / European Urology 48 (2005) 77 82 81 about 23 patients who underwent resection of pulmonary metastases of RCC of whom 18 had previously received interleukin immunotherapies [17]. Patients who underwent complete resection of the metastatic disease had a mean survival of 49 months. Walther et al. describe their experiences of adjuvant immunotherapy after pulmonary metastasectomy. All 93 patients received palliative tumornephrectomy, 32% an additional resection of the lung metastases [18]. But only 40% of the surgically treated patients could receive immunotherapy because of fast tumor progression. Summarizing the present data of combined therapy from the early 90 s no conclusions can be drawn and newer studies are lacking. 6. Conclusions In RCC the results of lung metastatic surgery are increasingly recognized because of the obvious failure of systematic therapeutic approaches. On the basis of our data we can recommend pulmonary metastasectomy in RCC patients who have technical resectable metastases with as much as possible positive prognostic factors (metachronous metastases with long DFI, solitary up to 6 metastases) and a good functional status. In patients with unresectable metastases or several bad prognostic factors (synchronous metastases or short DFI, more than 6 metastases) immunotherapy should be the preferred treatment. References [1] Dekernion JB, Ramming KP, Smith RB. The natural history of metastatic renal cell carcinoma: a computer analysis. J Urol 1978;120:148 52. [2] Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med 1996;335:865 75. [3] Heinzer H, Huland E, Huland H. Treatment of metastatic renal cell carcinoma. Value of immunotherapy compared with surgery of metastases. Urologe A 2000;39:356 61. [4] Barney JD, Churchill EJ. Adenocarcinoma of the kidney with metastases to the lung: cured nephrectomy and lobectomy. J Urol 1939;42:269 76. [5] Atzpodien J, Royston P, Wandert T, Reitz M. Metastatic renal carcinoma comprehensive prognostic system. Br J Cancer 2003;88:348 53. [6] Han KR, Pantuck AJ, Bui MH, et al. Number of metastatic sites rather than location dictates overall survival of patients with node-negative metastatic renal cell carcinoma. Urology 2003;61:314 9. [7] Pfannschmidt J, Hoffmann H, Muley T, et al. Prognostic factors for survival after pulmonary resection of metastatic renal cell carcinoma. Ann Thorac Surg 2002;74:1653 7. [8] Piltz S, Meimarakis G, Wichmann MW, et al. Long-term results after pulmonary resection of renal cell carcinoma metastases. Ann Thorac Surg 2002;73:1082 7. [9] May M, Helke C, Bock M, Hoschke B. Impact of immunochemotherapy on survival of patients with metastatic renal cell carcinoma A retrospective study comparing interferon-alpha-2a/vinblastine versus interferon-alpha-2a/interleukin-2/5-fluorouracil. Urologe A 2004;43: 1111 9. [10] Fourquier P, Regnard JF, Rea S, Levi JF, Levasseur P. Lung metastases of renal cell carcinoma: results of surgical resection. Eur J Cardiothorac Surg 1997;11:17 21. [11] Cerfolio RJ, Allen MS, Deschamps C, et al. Pulmonary resection of metastatic renal cell carcinoma. Ann Thorac Surg 1994;57:339 44. [12] Kavolius JP, Mastorakos DP, Pavlovich C, et al. Resection of metastatic renal cell carcinoma. J Clin Oncol 1998;16:2261 6. [13] Friedel G, Hurtgen M, Penzenstadler M, Kyriss T, Toomes H. Resection of pulmonary metastases from renal cell carcinoma. Anticancer Res 1999;19:1593 6. [14] Friedel G, Pastorino U, Buyse M, et al. Resection of lung metastases: long-term results and prognostic analysis based on 5206 cases the International Registry of Lung Metastases. Zentralbl Chir 1999;124:96 103. [15] Brinkmann OA, Roigas J, Hertle L. Systemic immunotherapy of metastatic renal cell carcinoma and long-term outcome. Urologe A 2002;41:231 8. [16] Kim B, Louie AC. Surgical resection following interleukin 2 therapy for metastatic renal cell carcinoma prolongs remission. Arch Surg 1992;127:1343 9. [17] Pogrebniak HW, Haas G, Linehan WM, Rosenberg SA, Pass HI. Renal cell carcinoma: resection of solitary and multiple metastases. Ann Thorac Surg 1992;54:33 8. [18] Walther MM, Alexander RB, Weiss GH, et al. Cytoreductive surgery prior to interleukin-2-based therapy in patients with metastatic renal cell carcinoma. Urology 1993;42:250 7 discussion 257 258. Editorial Comment Allan J. Pantuck, Los Angeles, CA, USA apantuck@mednet.ucla.edu Approximately 30% to 50% of patients with RCC will eventually develop metastatic disease. Patients with metastatic RCC generally face a poor prognosis, however subsets of patients with advanced disease display a heterogeneous prognosis and outcome with some patients experiencing prolonged survival. Immunotherapy can be expected to produce objective responses in only 10 to 20% of metastatic RCC patients, of which only 5 10% will be complete responders. The role of surgery in metastatic RCC is becoming clearer, and the optimal management of many patients will involve a combined approach with surgery and systemic immunotherapy. Clinical situations in which surgery is potentially appropriate for patients with metastatic RCC include: excision of solitary or multiple metastases, excision of locally recurrent disease, resection of a residual mass after systemic therapy, and palliation. Despite the recent interest in algorithms to predict RCC recurrence and survival, the literature provides little guidance to the clinician faced with the management of these patients,

82 H.S. Hofmann et al. / European Urology 48 (2005) 77 82 and selection criteria are not well defined. Hofmann et al. [1] help fill this gap in the literature. Previously, several series have suggested a potential benefit for complete surgical resection of all tumor burden, including removal of both the primary renal mass as well as metastatic deposits in carefully selected patients with minimal volume metastatic disease. Surgical removal of solitary metastasis was widely accepted as potentially effective by the mid-1970s after several groups reported five-year overall survival rates of 29% to 35% [2 4]. It is possible that these rates may in fact may be better or worse depending on other clinical and/or pathologic factors such as performance status, site of metastasis, interval after nephrectomy, and whether the metastasis is completely resected. Hofmann et al. contribute significantly to the literature by describing the outcome of 64 patients undergoing pulmonary resection of metastatic RCC, making it the largest such series to date. It should be emphasized that it took nearly 30 years to accumulate this experience and noted that these 64 patients represent a carefully selected group. Only patients who had disease that was judged to be potentially curative by surgical means and no evidence of extrapulmonary metastases were treated with this aggressive approach. In this population 5-year survival was 33.4%, and median survival was 39.2 months. More importantly, they were able to further stratify the patients into prognostic groups whose 5 year survival ranged from 0% to 52%. Factors which predicted for a better survival included ability to perform a complete resection, disease free interval greater than 36 months, and limited number of metastases. Overall, the data supports the notion that metastasectomy is a viable treatment option for carefully selected patients, and that this approach can by tailored to individual patients using standard eligibility criteria. References [1] Hofmann, et al. Prognostic factors and survival after pulmonary resection of metastatic renal cell carcinoma. Eur Urol 2005. [2] O dea MJ, Zincke H, Utz DC, Bernatz PE. The treatment of renal cell carcinoma with solitary metastasis. J Urol 1978;120:540 2. [3] Dreicer R, Galbraith SS, Davis CS, See WA. Surgical resection of metastatic renal cell carcinoma: The University of Iowa experience. Urol Oncol 1997;3:99 101. [4] Kavolius JP, Mastorakos DP, Pavlovich C, Russo P, Burt ME, Brady MS. Resection of metastatic renal cell carcinoma. J Clin Oncol 1998;16:2261 6.