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Year : 2013  |  Volume : 40  |  Issue : 2  |  Page : 64-67

Cytoreductive nephrectomy for metastatic renal cell carcinoma

Department of Urology, KLES Kidney Foundation, KLE University's JN Medical College, Belgaum, Karnataka, India

Date of Web Publication23-Jul-2013

Correspondence Address:
Rajendra B Nerli
Department of Urology, KLES Kidney Foundation, KLE University's JN Medical College, Belgaum 590 010, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0974-5009.115472

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Renal cell carcinoma is the most lethal urologic malignancy. Up to 30% of patients with kidney cancer have metastatic disease and 30% of those treated for local or locally advanced disease progress to metastases. Radical nephrectomy is the standard treatment for the management of nondisseminated kidney cancer, but the role of cytoreductive nephrectomy in patients with metastatic disease is controversial.

Keywords: Cytoreductive nephrectomy, prognosis, renal cell carcinoma

How to cite this article:
Nerli RB. Cytoreductive nephrectomy for metastatic renal cell carcinoma. J Sci Soc 2013;40:64-7

How to cite this URL:
Nerli RB. Cytoreductive nephrectomy for metastatic renal cell carcinoma. J Sci Soc [serial online] 2013 [cited 2021 Jul 26];40:64-7. Available from: https://www.jscisociety.com/text.asp?2013/40/2/64/115472

  Introduction Top

Renal cell carcinoma (RCC) accounts for 2%-3% of all adult malignant neoplasms and is the most lethal of all the common urologic cancers. In contrast to the 20% mortality rates associated with prostate and bladder carcinomas, 30%-40% of patients with RCC die of their cancer. [1],[2] Approximately 54,000 new diagnoses of RCC are made each year in the United States, and 13,000 patients die of this disease. [3] Approximately one third of all newly diagnosed RCC patients present with synchronous metastatic disease and an additional 20%-40% of patients with clinically localized disease at diagnosis eventually develop metastases. [4] Patients with metastatic RCC (mRCC), which is almost always fatal, face a poor prognosis, with a historical median survival of 6-10 months and a 2-year survival of 10%-20%. [5] However, several clinical features such as a long time interval between initial diagnosis and the appearance of metastatic disease and the presence of fewer sites of metastatic disease have been observed to be associated with a better outcome. Conversely, poor performance status and the presence of lymph nodes and/or liver metastases are some factors associated with shorter survival.

In a multivariate analysis, a poor performance status (Karnofsky score <80%), an elevated serum lactate dehydrogenase (LDH) level (>1.5 times upper limit of normal), low hemoglobin (less than the lower limit of normal), an elevated corrected calcium concentration (>10 g/dL), and lack of prior nephrectomy were independent predictors of a poor outcome [Table 1].Patients could be stratified into three distinct prognostic groups based on these five poor prognostic factors [Table 2]. [6] The overall survival (OS) times in patients with no adverse factors (favorable-risk group), one to two risk factors (intermediate-risk group), and more than three risk factors (poor-risk group) were 20 months, 10 months, and 4 months, respectively. [6]
Table 1: Adverse prognostic factors in 670 patients treated with Chemotherapy or immunotherapy at the Memorial Sloan-Kettering cancer center

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Table 2: Risk stratification based on adverse prognostic factors in 670 patients treated with chemotherapy or immunotherapy at the memorial Sloan-Kettering cancer center

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Motzer et al., [7] identified poor performance status, high calcium level, low hemoglobin value, elevated LDH level, and short time interval from initial diagnosis to treatment as factors that could best predict a poor outcome in 463 patients receiving interferon-based therapy in the first-line setting. Validated prognostic models are used in clinical practice to help make appropriate management decisions as well as in the design and interpretation of clinical trials.

  Debulking or Cytoreductive Nephrectomy in Patients with mRCC Top

In 1978, Dekernion et al., [8] showed that nephrectomy alone had a minimal effect on survival in patients with mRCC, a widely held position in the era before the emergence of treatment with biological response modifiers. Historically, the principle behind cytoreductive nephrectomy as a treatment for mRCC was based on the immunologic phenomenon of "spontaneous" regression of metastasis after nephrectomy. However, in a review of 474 patients with metastatic disease who underwent nephrectomy alone, only 4 (0.8%) experienced spontaneous regression of their metastatic disease. [9] More recently, Marcus et al., [10] reported that of 91 patients, 4 (4.4%) with lung metastases only had complete regression of all metastatic disease after nephrectomy. Historically, indications for nephrectomy for mRCC have been to improve quality of life. The removal of the malignant kidney may be of palliative benefit in some settings of mRCC and is appropriate when the patient is having pain related to the kidney mass, intractable hematuria, erythrocytosis, uncontrolled hypertension, or persistent hypercalcemia that does not respond to pharmacologic agents. [11] Surgery may also be directed at metastases to control local symptoms, which include the relief of spinal cord compression and fixation of fractures. Although nephrectomy alone for mRCC was widely discredited, with the emergence of modern immunotherapy in the 1980s and 1990s, the role of nephrectomy and the relative efficacy of initial biological response modifier treatment versus nephrectomy reemerged as a source of controversy.

Although nephrectomy alone clearly offered no curative benefit in the setting of metastatic disease, [8] cytoreductive surgery was proposed to have a role when done in conjunction with cytokine therapy. It took more than a decade to resolve this question for most investigators. Several early studies on prognostic factors in RCC suggested that undergoing nephrectomy was associated with improved survival. [6],[12] However, this was also associated with potential disadvantages which included perioperative morbidity and mortality, as well as delay in starting systemic therapy.

Consistent with these concerns, other early studies suggested that a significant percentage of patients were noted to have disease progression that prevented them from receiving immunotherapy after undergoing surgery. For example, Bennett et al., [13] reported on a series of 30 patients with mRCC who underwent nephrectomy in preparation for systemic therapy. Of these patients, 77% had disease progression or surgery-related morbidity or mortality that prevented the subsequent administration of interleukin-2 (IL-2) after nephrectomy [Figure 1] and [Figure 2]. These studies led to a reevaluation of eligibility criteria and stricter criteria for determining whether cytoreductive nephrectomy was appropriate for a given patient. [14] Overall, these retrospective single-institution studies showed favorable response rates of 18%-39%, with a median overall survival of 12-20.5 months. [12],[15],[16],[17]
Figure 1: CT scan axial view showing the right-sided renal cell carcinoma with hepatic metastasis

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Figure 2: (a) CT scan coronal view showing the right-sided renal cell carcinoma. (b) CT scan showing the right-sided renal cell carcinoma with hepatic metastases. (c) Operative specimen of the right kidney

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The best evidence for performing cytoreductive nephrectomy before cytokine therapy came from two prospective randomized clinical trials, Southwest Oncology Group (SWOG) 8949 [18] and European Organization for Research and Treatment of Cancer (EORTC) 30947, [19] which revealed a survival benefit for nephrectomy followed by IFN-compared with IFN-alone (a median survival of 11.1 and 8.1 months, respectively, in the SWOG trial, and 17 and 7 months, respectively, in the EORTC trial). Flanigan et al., [20] did a combined analysis of these two trials, which yielded a median survival of 13.6 months for nephrectomy plus IFN-versus 7.8 months for IFN-α alone. Cytoreductive nephrectomy seemed to improve the overall survival in patients with mRCC treated with IFN-independent of the patient performance status, site of metastases, and presence of measurable disease. The mechanisms involved that underlie the survival benefit of cytoreductive nephrectomy are still not clearly understood. A number of hypotheses are generally offered, ranging from the simplistic notion that removal of a symptomatic local tumor may improve performance status and therefore improve prognosis, that reduction in tumor burden itself may enhance the potential of an immune-mediated response to systemic treatment, that removal of the tumor actually benefits the patient as a surrogate for the removal of a source of growth factors, immunosuppressant cytokines, and other molecules that underlie paraneoplastic symptoms such as cachexia, and that nephrectomy removes a source of future additional metastases. [19],[21]

Studies which arose from SWOG 8949 examined the role of postoperative azotemia in enhancing survival. It has been long known that many tumors acidify their peritumoral microenvironment as a means of overcoming the negative effects of the intracellular acidosis that results from tumor cell hypoxia and increased glycolytic metabolism. Mathematical models based on graded systemic metabolic acidosis associated with mild renal failure (there was a 20% increase in blood urea nitrogen and creatinine in the SWOG patients) suggest that unilateral nephrectomy may alter the dynamics of the tumor-host interface and further acidify the tumor pH sufficiently to exceed the tolerance of tumor cells, slowing or reversing tumor growth and invasion. In this interesting report, which looked at the surgical arm of the SWOG study, patients experiencing a postoperative increase in blood urea nitrogen and creatinine had a significantly improved survival (17 versus 4 months) compared with those who did not (P = 0.0007).

  Cytoreductive Nephrectomy in the Era of Targeted Therapy Top

Sorafenib became the first Food and Drug Administration (FDA)-approved treatment for advanced RCC. This approval was based on the demonstration of improved progression-free survival in a large, multinational, randomized, double-blind, placebo-controlled phase 3 study and a supportive phase 2 study. The median progression-free survival was 167 days in the sorafenib group versus 84 days in the placebo control group (hazard ratio, 0.44; 95% confidence interval, 0.35-0.55; log-rank P < 0.000001). [22] In January 2006, FDA granted accelerated approval for sunitinib in the treatment of patients with advanced RCC. [23]

With these dramatic advances in the treatment of advanced RCC, the questions surrounding the necessity and benefit of nephrectomy before targeted therapies have reemerged as clinically relevant controversies. There are clinicians who believe that benefits of these agents are shown only in the setting of postnephrectomy patients while others believe that the new agents obviate the need for nephrectomy. The former point to the sunitinib phase 2 studies, in which 100% of patients were treated after progression with cytokine therapy and 97% of patients' previous treatment included cytoreductive nephrectomy (CN; 100% of patients treated in the larger of the two phase 2 studies). Similarly, in the sorafenib phase 3 study, 82% of patients were treated after progression with cytokine therapy, including IL-2 (44%) and an IFN (68%), and 94% of patients' previous treatment included cytoreductive nephrectomy. The latter point to radiographs from the sorafenib and sunitinib studies, which show notable reductions in the size of metastatic and primary lesions (in select cases). There are currently several phase 2 studies being conducted to evaluate the ideal timing of CN. [24] Unfortunately, at present, there is no valid basis on which one can deduce the relative contribution cytoreductive nephrectomy makes to the benefits shown for these new targeted agents.

  Conclusions Top

Before the availability of effective systemic treatment for advanced RCC, nephrectomy did not contribute to patient survival, and surgery was confined to the realm of palliative therapy. With the introduction of immune-based agents, nephrectomy was shown to improve survival when done before cytokine therapy in wisely selected patients. The valid clinical question of whether to remove the primary tumor before targeted therapy is one that, at present, has no answer and will become increasingly common, affecting thousands of patients. Until evidence from such a study becomes available to guide physicians, and without evidence in contrast, cytoreductive nephrectomy should be considered to have shown a survival benefit and should be used in appropriately selected patients with mRCC receiving postsurgical systemic therapies.

  References Top

1.Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer J Clin 1999;49:8-31.  Back to cited text no. 1
2.Pantuck AJ, Zisman A, Belldegrun AS. The changing natural history of renal cell carcinoma. J Urol 2001;166:1611-23.  Back to cited text no. 2
3.Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300.  Back to cited text no. 3
4.Lam JS, Shvarts O, Lepper JT, Figlin RA, Belldegrun AS. Renal cell carcinoma 2005: New frontiers in staging, prognostication and targeted molecular therapy. J Urol 2005;173:1853-62.  Back to cited text no. 4
5.Medical Research Council Renal Cancer Collaborators. Interferon- and survival in metastatic renal carcinoma: Early results of a randomized controlled trial. Lancet 1999;353:14-7.  Back to cited text no. 5
6.Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999;17:2530-40.  Back to cited text no. 6
7.Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 2002;20:289-96.  Back to cited text no. 7
8.Dekernion JB, Ramming KP, Smith RB. The natural history of metastatic renal cell carcinoma: A computer analysis. J Urol 1978;120:148-52.  Back to cited text no. 8
9.Montie JE, Stewart BH, Straffon RA, Banowsky LH, Hewitt CB, Montague DK. The role of adjunctive nephrectomy in patients with metastatic renal cell carcinoma. J Urol 1977;117:272-5.  Back to cited text no. 9
10.Marcus SG, Choyke PL, Reiter R, Jaffe GS, Alexander RB, Linehan WM, et al. Regression of metastatic renal cell carcinoma after cytoreductive nephrectomy. J Urol 1993;150:463-66.  Back to cited text no. 10
11.Walther MM, Patel B, Choyke PL, Lubensky IA, Vocke CD, Harris C, et al. Hypercalcemia in patients with metastatic renal cell carcinoma: Effect of nephrectomy and metabolic evaluation. J Urol 1997;158:733-9.  Back to cited text no. 11
12.Neves RJ, Zincke H, Taylor WF. Metastatic renal cell cancer and radical nephrectomy: Identification of prognostic factors and patient survival. J Urol 1988;139:1173-6.  Back to cited text no. 12
13.Bennett RT, Lerner SE, Taub HC, Dutcher JP, Fleischmann J. Cytoreductive surgery for stage IV renal cell carcinoma. J Urol 1995;154:32-4.  Back to cited text no. 13
14.Fallick ML, McDermott DF, LaRock D, Long JP, Atkins MB. Nephrectomy before interleukin-2 therapy for patients with metastatic renal cell carcinoma. J Urol 1997;158:1691-5.  Back to cited text no. 14
15.Franklin JR, Figlin R, Rauch J, Gitlitz B, Belldegrun A. Cytoreductive surgery in the management of metastatic renal cell carcinoma: The UCLA experience. Semin Urol Oncol 1996;14:230-6.  Back to cited text no. 15
16.Guinan P, Stuhldreher D, Frank W, Rubenstein M. Report of 337 patients with renal cell carcinoma emphasizing 110 with stage IV disease and review of the literature. J Surg Oncol 1997;64:295-8.  Back to cited text no. 16
17.Citterio G, Di Lucca G, Scaglietti U, Gilberti S, Baldini M, Rugarli C. Reduction of brain metastasis following immunotherapy with interleukin-2 for stage IV renal cell cancer. Acta Oncol 1997;36:228-30.  Back to cited text no. 17
18.Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, et al. Nephrectomy followed by interferon a-2b compared with interferon-2b alone for metastatic renal-cell cancer. N Engl J Med 2001;345:1655-9.  Back to cited text no. 18
19.Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R. Radical nephrectomy plus interferon-based immunotherapy compared with interferon alone in metastatic renal-cell carcinoma: A randomised trial. Lancet 2001;358:966-70.  Back to cited text no. 19
20.Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED. Cytoreductive nephrectomy in patients with metastatic renal cancer: A combined analysis. J Urol 2004;171:1071-6.  Back to cited text no. 20
21.Wunderlich H, Steiner T, Kosmehl H, Junker U, Reinhold D, Reichelt O, et al. Increased transforming growth factor-1 plasma level in patients with renal cell carcinoma: A tumor-specific marker? Urol Int 1998;60:205-7.  Back to cited text no. 21
22.Escudier B, Szczylik C, Eisen T, Stadler WM, Schwartz B, Shan M, et al. Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). J Clin Oncol 2005;23:LBA4510.  Back to cited text no. 22
23.Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2005;24:16-24.  Back to cited text no. 23
24.Jonasch E. Presurgical therapy in metastatic renal cell carcinoma. Expert Rev Anticancer Ther 2007;7:73-8.  Back to cited text no. 24


  [Figure 1], [Figure 2]

  [Table 1], [Table 2]

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