Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma:
`Is It Still Imperative in the Era of Targeted Therapy?
`Allan J. Pantuck, Arie S. Belldegrun, and Robert A. Figlin
`
`Abstract
`
`In the era before cytokine therapy, controversy existed about the need for cytoreductive nephrec-
`tomy in treating patients with metastatic renal cell carcinoma. In 1978, Dekernion showed that
`nephrectomy alone had no effect on survival. During this period, removal of the malignant kidney
`was confined to palliative therapy in some settings of metastatic RCC, such as pain related to the
`kidney mass, intractable hematuria, erythrocytosis, uncontrolled hypertension, or poorly con-
`trolled hypercalcemia.When interleukin-2 was approved by the Food and Drug Administration in
`1992, the role of nephrectomy was reexamined. After a decade of controversy, two randomized
`controlled studies established that cytoreductive surgery has a role in properly selected patients
`and offers a survival advantage when done before cytokine therapy. Unfortunately, the mecha-
`nisms underlying this benefit remain poorly understood. Immunotherapy may work best when
`there is a small volume of cancer present, and removing a large primary tumor may prevent the
`seeding of additional metastases. Data have also suggested that primary tumors were capable of
`producing immunosuppressive compounds that might decrease the efficacy of immunotherapy.
`Another hypothesis suggested that removing the kidney altered the acid/base status of the
`patient to such an extent that the growth of the tumor was hindered. With the emergence
`in 2006 of two targeted agents for advanced renal cell carcinoma, the role of cytoreductive
`nephrectomy has reemerged as a source of controversy. Although evidence-based medical prac-
`tice suggests a role for nephrectomy before the use of targeted agents, the arguments for and
`against this practice will be weighed.
`
`More than 200,000 new cases of kidney cancer are diagnosed
`annually and more than 100,000 deaths occur from this disease
`each year worldwide, with the highest incidence in North
`America, Europe, and Australia (1). Renal cell carcinoma (RCC)
`accounts for 3% of all adult malignancies and is steadily
`increasing at a rate of f2.5% per year across population groups
`(2). Kidney cancer
`is the most
`lethal of
`the urologic
`malignancies with more than 40% of patients dying of their
`cancer (3). Approximately 20% to 30% of patients present with
`metastatic disease and 20% to 40% of patients undergoing
`nephrectomy for clinically localized RCC will develop metas-
`tases (4). Although it has been more than 35 years since the
`radical nephrectomy was standardized by the work of Robson
`
`Authors’Affiliation: Departments of Urology and Medicine, David Geffen School
`of Medicine at University of California at Los Angeles, Los Angeles, California
`Received 8/2/06; accepted 10/12/06.
`Presented at the Second Cambridge Conference on Innovations and Challenges in
`Renal Cancer, March 24-25, 2006, Cambridge, Massachusetts.
`Requests for reprints: Allan J. Pantuck, Department of Urology, David Geffen
`School of Medicine at University of California at Los Angeles, 10833 Le Conte
`Avenue, Los Angeles, CA 90095-1738; E-mail: apantuck@mednet.ucla.edu, or
`Arie S. Belldegrun, Division of Urologic Oncology, David Geffen School of
`Medicine at University of California at Los Angeles, Los Angeles, CA 90095, or
`Robert A. Figlin, Departments of Medicine and Urology, David Geffen School of
`Medicine at University of California at Los Angeles, 2333 Peter Ueberroth Building,
`Los Angeles, CA 90095.
`F 2007 American Association for Cancer Research.
`doi:10.1158/1078-0432.CCR-06-1916
`
`and colleagues (5), the management of both localized and
`metastatic RCC has changed dramatically in the last 20 years,
`predicated on major advancements in renal imaging, surgical
`techniques, and the development of effective therapies for
`advanced disease, which have resulted in improved survival of a
`select group of patients and an overall change in the natural
`history of the disease (6).
`Patients with metastatic RCC face a poor prognosis, with a
`historical median survival of 6 to 10 months and a 2-year
`survival of 10% to 20% (7); however, subsets of patients with
`advanced disease have shown improvements in survival. This
`improved outlook for some patients with advanced and
`metastatic RCC through the 1990s and up to the present time
`are related to the introduction of
`immunotherapeutic
`approaches and a better understanding of the role and timing
`of cytoreductive nephrectomy (8 – 10). In 1978, Dekernion
`et al. (11) showed that nephrectomy alone had a minimal effect
`on survival in patients with metastatic RCC, a widely held
`position in the era before the emergence of treatment with
`biological response modifiers.
`
`The Era of Cytokine Therapy
`
`Historically, the principle behind cytoreductive nephrectomy
`as a treatment
`for metastatic RCC was based on the
`immunologic phenomenon of ‘‘spontaneous’’ regression of
`metastasis after nephrectomy. However, in a review of 474
`
`www.aacrjournals.org
`clincancerres.aacrjournals.org Downloaded from
`
`
`
`693s
`Clin Cancer Res 2007;13(2 Suppl) January 15, 2007
`on August 3, 2017. © 2007 American Association for Cancer
`Research.
`
`NOVARTIS EXHIBIT 2068
`Breckenridge v. Novartis, IPR 2017-01592
`Page 1 of 5
`
`

`

`patients with metastatic disease who underwent nephrectomy
`alone, only 4 (0.8%) experienced spontaneous regression of
`their metastatic disease (12). More recently, Marcus et al. (13)
`reported that of 91 patients, 4 (4.4%) with lung metastases only
`had complete regression of all metastatic disease after neph-
`rectomy. Widely accepted historical indications for nephrecto-
`my for metastatic RCC have been to improve quality of life.
`Removal of the malignant kidney may be of palliative benefit in
`some settings of metastatic RCC and is appropriate when the
`patient is having pain related to the kidney mass, intractable
`hematuria, erythrocytosis, uncontrolled hypertension, or per-
`sistent hypercalcemia that does not respond to pharmacologic
`agents (14). 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 metastatic RCC 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 (11), cytoreductive
`surgery was proposed to have a role when done in conjunction
`with cytokine therapy. More than a decade was required to
`resolve this question for most investigators. A number of early
`studies on prognostic factors in RCC suggested that undergoing
`nephrectomy was associated with improved survival (15, 16).
`Potential disadvantages 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. (17) reported on a series of 30 patients with metastatic
`RCC 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 ne-
`phrectomy. These studies led to a reevaluation of eligibility
`criteria and stricter criteria for determining whether cytoreduc-
`tive nephrectomy was appropriate for a given patient (18).
`Overall, these retrospective single-institution studies showed
`favorable response rates of 18% to 39%, with a median overall
`survival of 12 to 20.5 months (19 – 22). One such study from
`University of California at Los Angeles of 203 metastatic RCC
`patients treated with various combinations of IL-2 immuno-
`therapy regimens with and without adjunctive nephrectomy
`attempted to delineate the specific benefit
`that adjunctive
`nephrectomy can provide and to determine the factors that
`maximize the effects of
`immunotherapy (23). The study
`reported an overall 3-year survival rate of 31%, with the
`highest survival rates in patients treated by cytoreductive
`nephrectomy followed by immunotherapy, and found that
`the worst outcomes were achieved in those patients undergoing
`immunotherapy with their primary tumor in place (3-year
`survival rate, 4%). These results were later expanded to an
`evaluation of 335 patients, which showed 1- and 2-year sur-
`vival rates of 29% and 4% for patients treated with IL-2 and
`their primary tumor in place and 67% and 44% for patients
`receiving any kind of immunotherapy after adjunctive nephrec-
`tomy (24).
`
`The best evidence for performing cytoreductive nephrectomy
`before cytokine therapy came from two prospective random-
`ized clinical trials, Southwest Oncology Group (SWOG) 8949
`and European Organization for Research and Treatment of
`Cancer (EORTC) 30947 (9, 10), which revealed a survival
`benefit for nephrectomy followed by IFN-a compared with
`IFN-a alone (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. (8) did a
`combined analysis of these two trials, which yielded a median
`survival of 13.6 months for nephrectomy plus IFN-a versus
`7.8 months for IFN-a alone. Cytoreductive nephrectomy
`seemed to improve overall survival in patients with metastatic
`RCC treated with IFN-a independent of patient performance
`status, site of metastases, and presence of measurable disease.
`A retrospective study recently reported by Han et al. (25)
`showed that patients with more than one metastatic site had a
`lower response rate to adjuvant immunotherapy after nephrec-
`tomy of the primary tumor and a significantly shorter survival
`than patients with a single metastatic site. Although the
`observed survival benefit in the SWOG and EORTC Genitouri-
`nary Group studies was independent of the location of meta-
`static sites, neither trial stratified the number of metastatic sites
`or overall tumor burden, and therefore this question remains
`unresolved.
`Investigators at University of California at Los Angeles
`supplemented the SWOG findings with retrospective data to
`address the relative efficacy of IFN-a versus IL-2 after cyto-
`reductive nephrectomy using a comparable population treated
`with IL-2 from the University of California at Los Angeles
`Kidney Cancer Database, which conatins the records of more
`than 450 metastatic RCC patients treated with immunotherapy
`(26). Using the eligibility criteria for the SWOG 8949 study, 89
`patients treated with IL-2-based regimens after nephrectomy
`were identified. Survival of these patients was analyzed and
`compared with the survival of 120 patients in the SWOG
`surgery arm. Median survival of
`the patients treated with
`nephrectomy plus IL-2 was 16.7 months, which was twice that
`of the IFN-a only SWOG arm, and 4 months (30%) greater
`than the nephrectomy plus IFN-a SWOG arm. At 5 years, the
`survival rate was 19.6% for patients who received IL-2
`compared with 10% for those who received IFN-a.
`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 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
`(10, 27).
`None of these explanations has been satisfactorily examined.
`A provocative study arose from SWOG 8949 that examined the
`role of postoperative azotemia resulting from cytoreductive
`nephrectomy in enhancing survival, with the interesting
`hypothesis that it is the removal of the kidney and not the
`removal of the tumor that should be credited (28). It has been
`
`Clin Cancer Res 2007;13(2 Suppl) January 15, 2007
`Downloaded from
`on August 3, 2017. © 2007 American Association for Cancerclincancerres.aacrjournals.org
`
`694s
`www.aacrjournals.org
`
`Research.
`
`NOVARTIS EXHIBIT 2068
`Breckenridge v. Novartis, IPR 2017-01592
`Page 2 of 5
`
`

`

`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
`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).
`
`The Era of Targeted Therapy
`
`The approval of two new targeted agents for metastatic RCC
`by the U.S. Food and Drug Administration (FDA) in 2005-2006
`marks the beginning of a new era in the management of RCC.
`Sorafenib (BAY 439006) is orally bioavailable and was
`developed initially for its inhibitory effects on Raf-1, but
`further activity was shown against additional receptor tyrosine
`kinases in both the tumor cell and tumor vasculature, including
`vascular endothelial growth factor receptor 2, platelet-derived
`growth factor receptor, FLT-3, and c-KIT. With its approval on
`December 20, 2005 by the Food and Drug Administration,
`sorafenib became the first Food and Drug Administration –
`approved treatment for advanced RCC in more than a decade.
`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 support-
`ive 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; ref. 29). Sunitinib malate is
`another oral multikinase inhibitor that targets the phosphor-
`ylase activity of several receptor tyrosine kinases, including the
`vascular endothelial growth factor receptor, platelet-derived
`growth factor receptor, KIT, and FLT-3 tyrosine kinases.
`Approval of sunitinib for the treatment of advanced RCC was
`based on the results of a pair of single-arm, multicenter studies.
`The first study enrolled 106 patients in whom prior cytokine
`therapy had failed. The trial was designed to investigate the
`objective response rate of sunitinib therapy. The second study
`used a similar design to trial 1, treating 63 RCC patients in
`whom cytokine therapy failed. Data indicate that sunitinib
`induces a partial response, stable disease, and progressive
`disease in 15 (24%), 29 (46%), and 19 (30%) patients,
`respectively (30).
`In January 2006,
`the Food and Drug
`Administration granted accelerated approval for sunitinib in
`the treatment of patients with advanced RCC. In contrast to its
`approval for gastrointestinal stromal tumors, which was based
`on the ability of sunitinib to delay the growth of tumors, this
`approval was based on the partial response rate of sunitinib
`and its duration of response.
`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. These questions are legitimate.
`
`Is Cytoreductive Nephrectomy Still Imperative?
`
`Two main camps are forming: evidence-based literalists who
`see the proven benefits of these agents to be shown only in the
`setting of postnephrectomy patients and medical nephrecto-
`mists who 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
`(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). 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
`
`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 era of
`molecularly targeted therapy has just begun and will continue
`to play an important role in the management of advanced RCC
`for the foreseeable future. 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. The initiation of a
`phase 3 study to compare the survival of patients treated by
`nephrectomy plus targeted therapy with the survival of patients
`treated by targeted therapy alone, with nephrectomy reserved
`for clinical indications, should be considered to answer these
`questions. Until evidence from such a study becomes available
`to guide physicians, and without evidence to the contrary,
`cytoreductive nephrectomy should be considered to have
`shown a survival benefit and should be used in appropriately
`selected patients with metastatic RCC receiving postsurgical
`systemic therapies.
`
`Open Discussion
`
`Dr. Atkins: Could removing the primary kidney tumor
`affect the efficacy of antiangiogenic therapy?
`Dr. Pantuck: The primary may be making angiogenic
`factors, but just as easily the primary tumor often makes
`antiangiogenic factors that can inhibit metastases.
`Dr. Rini:
`In terms of a randomized trial, we have a therapy,
`debulking nephrectomy, which, in two prospective randomized
`trials in a combined analysis, has a 5-month survival advantage.
`I would have a hard time randomizing patients to an arm that
`does not include that therapy.
`Dr. Figlin:
`I am puzzled why the targeted therapy-only arm
`in the absence of nephrectomy would be ethically unaccept-
`able. If these agents are working systemically, and you have
`removed from that patient population people who require a
`
`www.aacrjournals.org
`clincancerres.aacrjournals.org Downloaded from
`
`
`
`695s
`Clin Cancer Res 2007;13(2 Suppl) January 15, 2007
`on August 3, 2017. © 2007 American Association for Cancer
`Research.
`
`NOVARTIS EXHIBIT 2068
`Breckenridge v. Novartis, IPR 2017-01592
`Page 3 of 5
`
`

`

`nephrectomy for palliative purposes, why do the prior trials
`dictate the need for surgery in the new era of targeted agents?
`Dr. Sosman:
`If we had endless numbers of patients,
`it
`would be a good experiment to examine the role of nephrec-
`tomy. However, we have limited patients, plus I do not think
`a phase 3 study is reasonable. A phase 2 study would be
`preferable.
`Dr. Pantuck: There is no question that some patients will
`do better in terms of performance status and quality of life
`when they have large tumors that are symptomatic and causing
`problems. I am not arguing that nephrectomy in that setting
`does not provide a benefit.
`Dr. Rini:
`In somebody with a small primary, we could make
`the argument
`that debulking nephrectomy may not be
`beneficial. Appropriately selected patients is key.
`Dr. Pantuck: A phase 2 study is obviously easier to do than
`a phase 3 study because it is one arm and requires fewer
`patients. My hesitation is that nobody will believe it because
`it is not randomized and controlled.
`Dr. Flaherty: Some of the patients I have treated with
`sorafenib the longest have not had a prior nephrectomy,
`because their primary tumors constitute about 80% of their
`target lesion volume. For these patients to achieve a response or
`progress by Response Evaluation Criteria in Solid Tumors
`criteria is hard. They do not change as much in terms of their
`target tumor volume compared with patients who just have
`lung nodules. The best way to wreck a response rate or to
`artificially prolong progression-free survival
`is to include
`patients who have not had prior nephrectomy because those
`
`patients had a big target lesion that contributes to 80% of their
`measurement.
`Dr. Rini: You would have to look at the measurements both
`with and without the primary.
`Dr. Flaherty: That would be more meaningful.
`Dr. Atkins: The argument in immunotherapy was always
`that the primary tumor somehow influenced the response of
`the metastatic disease to immunotherapy, not that it influenced
`the measurements. We are unsure whether that paradigm
`applies to targeted therapy. I think a phase 2 study in selected
`patients with relatively small tumor burden in primary tumor
`compared with metastatic disease burden who are not being
`considered as candidates for immunotherapy should be per-
`formed. We could ascertain the effect of therapy on the meta-
`stases and the primary tumor and see whether they are similar.
`Dr. Kaelin:
`I think it would be a complete waste of time and
`money to do a one-arm phase 2 study. What are you looking
`for? I know it is feasible to treat the patients without doing the
`nephrectomy. Also, there is no biologically compelling reason
`that the response rate will be different between the primary site
`and metastases.
`Dr. Atkins: The question is not
`‘‘Does this prolong
`survival?’’ but ‘‘Does the primary tumor respond and does it
`respond in the same way as the metastatic lesions?’’
`Dr. Wood: But it’s not just a question of shrinking the
`tumor; it’s a question of the biology of the tumor.
`Dr. Pantuck:
`I’m also not concerned about shrinking the
`primary tumor. The question is can you match the efficacy in
`terms of disease-free progression.
`
`References
`1. Parkin DM, Bray F, Ferlay J, Pisani P. Global
`cancer statistics, 2002. CA Cancer J Clin 2005;55:
`74 ^ 108.
`2. Chow WH, Devesa SS, Warren JL, Fraumeni JF, Jr.
`Rising incidence of renal cell cancer in the United
`States. JAMA 1999;281:1628 ^ 31.
`3. Jemal A, Murray T, Ward E, et al. Cancer statistics,
`2005. CA Cancer J Clin 2005;55:10 ^ 30.
`4. Lam JS, Shvarts O, Leppert JT, Figlin RA, Belldegrun
`AS. Renal cell carcinoma 2005: new frontiers in stag-
`ing, prognostication and targeted molecular therapy.
`J Urol 2005;173:1853 ^ 62.
`5. Robson CJ, Churchill BM, AndersonW.The results of
`radical nephrectomy for renal cell carcinoma. J Urol
`1969;101:297 ^ 301.
`6. Pantuck AJ, Zisman A, Belldegrun AS. The changing
`natural history of renal cell carcinoma. J Urol 2001;
`166:1611 ^ 23.
`7. Medical Research Council Renal Cancer Collabora-
`tors. Interferon-a and survival in metastatic renal car-
`cinoma: early results of a randomised controlled trial.
`Lancet 1999;353:14 ^ 7.
`8. 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.
`9. Flanigan RC, Salmon SE, Blumenstein BA, et al. Ne-
`phrectomy followed by interferon a-2b compared
`with interferon a-2b alone for metastatic renal-cell
`cancer. N Engl J Med 2001;345:1655 ^ 9.
`10. Mickisch GH, Garin A, van Poppel H, de Prijck L,
`Sylvester R. Radical nephrectomy plus interferon-a-
`based immunotherapy compared with interferon a
`alone in metastatic renal-cell carcinoma: a randomised
`trial. Lancet 2001;358:966 ^ 70.
`11. Dekernion JB, Ramming KP, Smith RB. The natural
`history of metastatic renal cell carcinoma: a computer
`analysis. J Urol 1978;120:148 ^ 52.
`
`12. Montie JE, Stewart BH, Straffon RA, Banowsky LH,
`Hewitt CB, Montague DK. The role of adjunctive ne-
`phrectomy in patients with metastatic renal cell carci-
`noma. J Urol 1977;117:272 ^ 5.
`13. Marcus SG, Choyke PL, Reiter R, et al. Regression
`of metastatic renal cell carcinoma after cytoreductive
`nephrectomy. J Urol 1993;150:463 ^ 6.
`14. Walther MM, Patel B, Choyke PL, et al. Hypercalce-
`mia in patients with metastatic renal cell carcinoma:
`effect of nephrectomy and metabolic evaluation.
`J Urol 1997;158:733 ^ 9.
`15. 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.
`16. 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.
`17. Bennett RT, Lerner SE,Taub HC, et al. Cytoreductive
`surgery for stage IV renal cell carcinoma. J Urol 1995;
`154:32 ^ 4.
`18. Fallick ML, McDermott DF, LaRock D, et al. Ne-
`phrectomy before interleukin-2 therapy for patients
`with metastatic renal cell carcinoma. J Urol 1997;158:
`1691 ^ 5.
`19. 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 ^ 84.
`20. Franklin JR, Figlin R, Rauch J, Gitlitz B, Belldegrun
`A. Cytoreductive surgery in the management of meta-
`static renal cell carcinoma: the UCLA experience.
`Semin Urol Oncol 1996;14:230 ^ 6.
`21. Guinan P, Stuhldreher D, Frank W, Rubenstein M.
`Report of 337 patients with renal cell carcinoma em-
`phasizing 110 with stage IV disease and review of the
`literature. J Surg Oncol 1997;64:295 ^ 8.
`
`22. 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.
`23. Figlin R, Gitlitz B, Franklin J, et al. Interleukin-2-
`based immunotherapy for the treatment of metastatic
`renal cell carcinoma: an analysis of 203 consecutively
`treated patients. Cancer J Sci Am 1997;3:S92 ^ 7.
`24. Belldegrun A, Shvarts O, Figlin RA. Expanding the
`indications for surgery and adjuvant interleukin-2-
`based immunotherapy in patients with advanced renal
`cell carcinoma. Cancer J Sci Am 2000;6:S88 ^ 92.
`25. Han KR, Pantuck AJ, Bui MH, et al. Number of
`metastatic sites rather than location dictates overall
`survival of patients with node-negative metastatic re-
`nal cell carcinoma. Urology 2003;61:314 ^ 9.
`26. Pantuck AJ, Belldegrun AS, Figlin RA. Nephrecto-
`my and interleukin-2 for metastatic renal-cell carcino-
`ma. N Engl J Med 2001;345:1711 ^ 2.
`27. Wunderlich H, SteinerT, Kosmehl H, et al. Increased
`transforming growth factor h-1plasma level in patients
`with renal cell carcinoma: a tumor-specific marker?
`Urol Int 1998;60:205 ^ 7.
`28. Gatenby RA. The possible role of postoperative
`azotemia in enhanced survival of patients with meta-
`static renal cancer after cytoreductive nephrectomy.
`Cancer Res 2002;62:5218 ^ 22.
`29. Escudier B, Szczylik C, Eisen T, 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.
`30. Motzer RJ, Michaelson MD, Redman BG, et al.
`Activity of SU11248, a multitargeted inhibitor of vas-
`cular endothelial growth factor receptor and platelet-
`derived growth factor receptor, in patients with
`metastatic renal cell carcinoma. J Clin Oncol 2005;
`24:16 ^ 24.
`
`Clin Cancer Res 2007;13(2 Suppl) January 15, 2007
`Downloaded from on August 3, 2017. © 2007 American Association for Cancerclincancerres.aacrjournals.org
`
`
`696s
`www.aacrjournals.org
`
`Research.
`
`NOVARTIS EXHIBIT 2068
`Breckenridge v. Novartis, IPR 2017-01592
`Page 4 of 5
`
`

`

`Clinical Cancer Research
`
`AAG:!...D American Association
`:;-n,. for Cancer Research
`
`Cytoreductive Nephrectomy for Metastatic Renal Cell
`Carcinoma: Is It Still Imperative in the Era of Targeted
`Therapy?
` 
`Allan J. Pantuck, Arie S. Belldegrun and Robert A. Figlin
`Clin Cancer Res  
`
`2007;13:693s-696s.
`
` 
` 
` 
` 
`
` 
` 
`
`Updated version
` 
`
`
`
`Access the most recent version of this article at:
` http://clincancerres.aacrjournals.org/content/13/2/693s
` 
`
`Cited articles
` 
`Citing articles
` 
`
`This article cites 27 articles, 2 of which you can access for free at:
` http://clincancerres.aacrjournals.org/content/13/2/693s.full#ref-list-1
`
` 
`This article has been cited by 1 HighWire-hosted articles. Access the articles at:
`
` http://clincancerres.aacrjournals.org/content/13/2/693s.full#related-urls
` 
`
`E-mail alerts
` 
`Reprints and
`Subscriptions
` 
`Permissions
` 
`
`Sign up to receive free email-alerts
`
` related to this article or journal.
`
`To order reprints of this article or to subscribe to the journal, contact the AACR Publications
`.
`pubs@aacr.org
`Department at
` 
`To request permission to re-use all or part of this article, contact the AACR Publications
`.
`permissions@aacr.org
`Department at
` 
`
`Downloaded from
`
`clincancerres.aacrjournals.org
`
`on August 3, 2017. © 2007 American Association for Cancer
`Research.
`
`NOVARTIS EXHIBIT 2068
`Breckenridge v. Novartis, IPR 2017-01592
`Page 5 of 5
`
`