Cytoreductive nephrectomy for advanced renal cell carcinoma, when to do it and why. Indications and benefits.

1. Cytoreductive
Nephrectomy
WHEN AND WHY
Dr. Ahmad Kharrouby

2. Introduction
 Renal cell carcinoma (RCC) accounts for only 3% of all adult malignancies
 60,000 new cases of kidney cancer and 26,000 deaths each year in the EU
alone
1. Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and mortality in Europe in 2006. Ann. Oncol. 18(3), 581–592
(2007).

3. Introduction
 Metastatic disease is present in up to 30% of patients at the time of diagnosis.
 Metastatic RCC (mRCC) is one of the most chemotherapy-resistant
malignancies, and is associated with a poor prognosis
1. Flanigan RC, Yonover PM. The role of radical nephrectomy in metastatic renal cell carcinoma. Semin. Urol. Oncol. 19(2), 98–102 (2001).

4. Introduction
 Prior to the introduction of VEGF-targeted agents, systemic treatment options
for mRCC were limited to :
 Cytokines :
 IL-2
 IFN-α

5. Introduction
 Cytoreductive nephrectomy (CN) was and still a part of a
multimodality treatment for patients with:
 Synchronous metastatic disease
 A good performance status (PS)

6. Introduction
 The rationale of CN for mRCC was based mainly
on evidence from two 2001 similar randomized
trials:
 1-The Southwest Oncology Group (SWOG) trial 8949 patients
 2-The European Organization for the Research and Treatment of Cancer (EORTC) trial 30947
patients
 Performance score of 0–1 were prospectively randomized to CN followed by IFN-α versus IFN-α without
surgery.
1. Flanigan RC, Salmon SE, Blumenstein BA et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for
metastatic renal-cell cancer. N. Engl. J. Med. 345(23), 1655–1659 (2001).
2. Mickisch GH, Garin A, Van Poppel H, de Prijck L, Sylvester R. Radical nephrectomy plus interferon-alfa-based immunotherapy compared
with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet358(9286), 966–970 (2001).

7. Introduction
 In both studies, a statistically significant improvement in overall survival (OS)
was documented for CN prior to IFN-α therapy.
 The benefit in OS was limited and did not exceed 6 months in a combined
analysis.

8. Introduction
 Based on these two studies
 CN should not be used indiscriminately.
 Patients should be selected for surgery along certain prognostic risk factors
 PS has been established as one of the most important factors

9. Introduction
 The Memorial Sloan–Kettering Cancer Center (MSKCC) risk score is the most
commonly used.
1. Motzer RJ, Bukowski RM, Figlin RA et al. Prognostic nomogram for sunitinib in patients with metastatic renal cell carcinoma. Cancer 113(7), 1552–1558
(2008).

10. Prognostic factors

11. Risk Stratification

13. Introduction
 With the rare exception of a few patients with solitary metastasis, CN alone
cannot achieve cure
 Is generally viewed as part of a multimodality management that combines
 Surgery
 Systemic therapy

14. Introduction
 The introduction of drugs that target angiogenesis has improved treatment of
mRCC.
 Currently approved agents include:
 Receptor tyrosine kinase inhibitors (TKIs)
 VEGF-antibodies
 mTOR inhibitors

15. Introduction
 The increased activity of targeted therapy, both in terms of outcome and
response at metastatic sites and the primary tumor, renewed the
controversy about the role of CN
1. Pantuck AJ, Belldegrun AS, Figlin RA. Cytoreductive nephrectomy for metastatic renal cell carcinoma: is it still imperative in the era of
targeted therapy? Clin. Cancer Res. 13(2 Pt 2), 693s–696s (2007).

16. Introduction
 To simplify the this contoversy, 3 practice concepts are
present currently, but none is fully proven as the
standard.
 The classic CN followed by immunotherapy
 Immunotherapy alone without nephrectomy
 Pretreatment immunotheraphy to CN
 In other words the same concepts that initially came
with cytokine and IFN treatments and the standards
established by SWOG and EORTC trials

17. Introduction
 The discussion regarding CN surgery had been rather dogmatic.
 Yes or no
 When and why

18. Clinical Evidence of a
Benefit From CN
 The strongest evidence for a survival benefit following CN stems from the two
randomized Phase III studies (SWOG and EORTC) as mentoned before.
1. 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. 171(3), 1071–1076 (2004).

19. Clinical Evidence of a
Benefit From CN
 Sunitinib was registered in the USA and Europe in 2007 for the treatment of
mRCC and became the approved first-line therapy for all patients, including
patients with primary tumors in situ.
 The OS was prolonged with sunitinib compared to interferons (median: 26.4 vs
21.8 months)
 The same regimen of sunitinib leads to responses in the primary tumor at a
rate previously unseen with cytokine treatment.
1. Motzer RJ, Hutson TE, Tomczak P et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with
metastatic renal cell carcinoma. J. Clin. Oncol. 27(22), 3584–3590 (2009).
2. van der Veldt AA, Meijerink MR, van den Eertwegh AJ et al. Sunitinib for treatment of advanced renal cell cancer: primary tumor
response. Clin. Cancer Res. 14(8), 2431–2436 (2008).

20. Clinical Evidence of a
Benefit From CN
 There are no results from randomized controlled trials that demonstrate that
CN is beneficial in the era of targeted therapy.

21. Clinical Evidence of a
Benefit From CN
 The benefit of sunitinib and other targeted agents has largely been
demonstrated in a nephrectomized patient population.
1. Crispen PL, Blute ML. Role of cytoreductive nephrectomy in the era of targeted therapy for renal cell carcinoma.Curr. Urol. Rep. 13(1), 38–46 (2011)

22. Clinical Evidence of a
Benefit From CN
 Therefore the prolonged survival largely apply to patients with without the
primary tumor in situ.
 Whether:
 Synchronous
 Metachronous
1. Crispen PL, Blute ML. Role of cytoreductive nephrectomy in the era of targeted therapy for renal cell carcinoma.Curr. Urol. Rep. 13(1), 38–46 (2011).

23. Clinical Evidence of a
Benefit From CN
 It is unknown if similar survival could be achieved without CN.
 Retrospective data suggest that survival with targeted therapy alone (without
nephrectomy) can be prolonged in patients with good prognostic risk factors.

24. Clinical Evidence of a
Benefit From CN
 In a recent series including 188 patients received only targeted theraphy, and
with no or few risk factors.
 Median OS of 30.3 month
 While those with moderate risk factors had a median OS of 10.4 months
Richey SL, Culp SH, Jonasch E et al. Outcome of patients with metastatic renal cell carcinoma treated with targeted therapy without cytoreductive
nephrectomy. Ann. Oncol. 22(5), 1048–1053 (2011)

25. Clinical Evidence of a
Benefit From CN
 These data are nonrandomized and retrospective, but provide valuable
outcome data for patients without CN.

26. Clinical Evidence of a
Benefit From CN
 None of the published Phase III trials in the era of
targeted therapy provide information :
 Had a previous radical nephrectomy for locally confined
disease and developed metastasis later (metachronus)
 Had an upfront CN for synchronous mRCC

27. Clinical Evidence of a
Benefit From CN
 However, until further Phase III level evidence becomes
available, CN is currently regarded as standard of care for
patients with low metastatic burden and a good PS.

28. Clinical Evidence of a
Benefit From CN
 Multiple retrospective series report an advantage for patients undergoing
CN.
 An analysis from the Surveillance, Epidemiology, and End Results (SEER)
database from 1988 to 2004 identified 5372 patients with primary mRCC of
whom 2447 (44.5%) underwent CN.
 The no-surgery group had a 2.5-fold increased rate of overall and cancer-
specific mortality.
1. Zini L, Capitanio U, Perrotte P et al. Population-based assessment of survival after cytoreductive nephrectomy versus no surgery in patients with metastatic renal cell
carcinoma. Urology 73(2), 342–346 (2009).

29. Clinical Evidence of a
Benefit From CN
 A smaller retrospective population-based
study from Canada reported a similar
association of improved OS in patients who
had a CN prior to TKI treatment, which was
independent of other prognostic factors.
 Recently, a Dutch population-based study
observed a 50% reduction in mortality if CN
was performed prior to systemic therapy.
1. Warren M, Venner PM, North S et al. A population-based study examining the effect of tyrosine kinase inhibitors on survival in metastatic renal cell carcinoma in Alberta and the role of
nephrectomy prior to treatment. Can. Urol. Assoc. J. 3(4), 281–289 (2001).
2. Aben KK, Heskamp S, Janssen-Heijnen ML et al. Better survival in patients with metastasised kidney cancer after nephrectomy: a population-based study in the Netherlands. Eur. J.
Cancer 47(13), 2023–2032 (2011).
•• Retrospective population-based analysis on survival following CN. Demonstrates improved survival across all risk scores.

30. Clinical Evidence of a
Benefit From CN
 These studies therefore suggest, despite their retrospective flaws, that CN is
beneficial in a major subset of patients.

31. Clinical Evidence of a
Benefit From CN
 The role of CN is now being investigated in the
CARMENA trial, which has been recruiting patients
in Europe since 2009.
 Patients with biopsy-proven clear cell mRCC
(Eastern Cooperative Oncology Group PS 0 or 1),
without prior systemic therapy or surgical
interventions, are being randomized to either
 CN followed by sunitinib
 Sunitinib alone
 The primary end point is OS, with a noninferiority
design aiming at inclusion of 576 patients
 The estimated completion date is 2016
101. ClinicalTrials.gov. Clinical Trial to Assess the Importance of Nephrectomy (CARMENA). http://clinicaltrials.gov/ct2/show/NCT00930033

33. Clinical Evidence of a
Benefit From CN
 An initially resectable primary tumor may progress to
unresectability or cause symptoms.
 Progression of the primary tumor under targeted
therapy has been observed.
 In a retrospective study of 19 patients with advanced
RCC and the primary tumor in situ who received
presurgical sunitinib, nine patients (47%) had
progressive disease in the primary tumor.
1. Thomas AA, Rini BI, Lane BR et al. Response of the primary tumor to neoadjuvant sunitinib in patients with advanced renal cell carcinoma. J. Urol. 181(2),
518–523 (2009).

34. Clinical Evidence of a
Benefit From CN
 On the other hand, there have been reports of patients treated with a
combination of VEGF-targeted therapy and surgery being rendered disease-
free, with complete remissions for months in which they were taken off
treatment.
1. Thomas AA, Rini BI, Lane BR et al. Response of the primary tumor to neoadjuvant sunitinib in patients with advanced renal cell carcinoma. J. Urol. 181(2), 518–
523 (2009).

35. Clinical Evidence of a
Benefit From CN
 In a recent series, 36 patients were taken off treatment for a median of 7
months (range: 1–31 months), with 33% of patients recurrence-free at a
median follow-up of 12 months.
1. Johannsen M, Staehler M, Ohlmann CH et al. Outcome of treatment discontinuation in patients with metastatic renal cell carcinoma and no evidence of disease
following targeted therapy with or without metastasectomy. Ann. Oncol. 22(3), 657–663 (2011).
•• Retrospective analysis on outcome following cessation of targeted therapy in patients with complete response. Demonstrates the importance of surgery in this
setting.

36. Clinical Evidence of a
Benefit From CN
 Unlike IL-2, cure following TKI therapy has yet to be reported with any
consistency;
 Treatment cessation has resulted in 'drug holidays' for months in those
patients, which would not be an option if the primary tumor was left in situ.

37. Translational Research Supporting a
Rationale for CN in the Era of Targeted
Therapy
 Despite the improvement in survival following CN in combination with IFN-
α, the mechanism is still not fully understood and several factors have been
proposed.

38. Translational Research Supporting
a Rationale for CN in the Era of
Targeted Therapy
 Surgical removal of tumor burden may effectively interrupt the negative
influence of the tumor microenvironment such as immune suppression, and
production of VEGF and other growth factors.

39. Selecting Patients for CN
 Proper patient selection for surgery is paramount.
 It has been observed that up to 31% of patients never receive systemic therapy
following CN.
1.Kutikov A, Uzzo RG, Caraway A et al. Use of systemic therapy and factors affecting survival for patients undergoing cytoreductive nephrectomy. BJU
Int. 106(2), 218–223 (2010).

40. Selecting Patients for CN
 Of the various reasons for not receiving systemic therapy,
 postoperative death was reported in eight out of 141 patients (5.6%
of all patients).
 The risk of death after surgery correlated with the number
of
 metastatic sites
 symptoms at presentation
 poor PS
 high tumor grade
 presence of sarcomatoid features
Kutikov A, Uzzo RG, Caraway A et al. Use of systemic therapy and factors affecting survival for patients undergoing cytoreductive
nephrectomy. BJU Int. 106(2), 218–223 (2010).

41. Selecting Patients for CN
 In a retrospective analysis, Out of 65 patients
identified who underwent CN, 28% experienced
delayed systemic therapy.
 Reasons for delay were related to surgery, with
high-grade complications in 33%.
1. O'Malley RL, Brewer KA, Hayn MH et al. Impact of cytoreductive nephrectomy on eligibility for systemic treatment and effects on survival: are surgical
complications or disease related factors responsible? Urology 78(3), 595–600 (2011).

43. Symptomatic Primary Tumors
 Nephrectomy for symptomatic primary tumors is logical for palliation,
especially if the tumor is not infiltrating into adjacent structures.
 However, symptomatic primary tumors are often large masses, with
involvement of adjacent structures.
 In the pre-VEGF-targeted therapy era, the experience with CN in 23 patients
with contiguous organ involvement (stage T4 Nx M1) was evaluated at the MD
Anderson Cancer Center (TX, USA) for outcome and morbidity.
1. Kassouf W, Sanchez-Ortiz R, Tamboli P et al. Cytoreductive nephrectomy for T4NxM1 renal cell carcinoma: the M.D. Anderson Cancer Center
experience. Urology 69(5), 835–838 (2007).

44. Symptomatic Primary Tumors
 Of the seven patients with local symptoms, five experienced postoperative
palliation.
 OS was short (median: 7.1 months) for those receiving cytokine-based
systemic therapy.

45. Symptomatic Primary Tumors
 As mentioned before, risk of surgical side effects is increased in this group of
patients and may have delayed the onset of systemic therapy.
1. Abdollah F, Sun M, Thuret R et al. Mortality and morbidity after cytoreductive nephrectomy for metastatic renal cell carcinoma: a population-based
study. Ann. Surg. Oncol. 18(10), 2988–2996 (2011).

46. Symptomatic Primary Tumors
 In the era of the current more effective therapy there is a chance to downsize
tumors
 A better approach may therefore be to start with targeted therapy and
reconsider surgery in cases of substantial size reduction
1. Bex A, van der Veldt AA, Blank C et al. Neoadjuvant sunitinib for surgically complex advanced renal cell cancer of doubtful resectability: initial experience with
downsizing to reconsider cytoreductive surgery. World J. Urol. 27(4), 533–539 (2009).

47. Symptomatic Primary Tumors
 For those with more severe local symptoms, evidence from multiple
series suggests that radiological arterial embolization may be a safe
and tolerable alternative to CN to palliate local symptoms
 The low morbidity and shorter hospital stay may allow for rapid onset
of targeted therapy
Maxwell NJ, Saleem Amer N, Rogers E, Kiely D, Sweeney P, Brady AP. Renal artery embolisation in the palliative treatment of renal carcinoma. Br. J. Radiol. 80(950),
96–102 (2007)

48. Pretreatment Strategies
 Approximately 20% of patients with mRCC are refractory to first-line therapy
and progress rapidly.
 It is unlikely that these patients will benefit from upfront CN.
 This has lead to the third trending treatment concept of pretreatment for three
month with sunitinib, to be followed by CN in case of response
1. Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N. Engl. J. Med. 356(2), 115–124 (2007).

49. Pretreatment Strategies
 A prospective, randomized EORTC trial has opened in The
Netherlands, Belgium, Italy, the UK and Canada, comparing immediate
versus deferred CN in patients with synchronous mRCC (EORTC 30073;
SURTIME)

50. Pretreatment Strategies

51. Two-Years View
 Within the next 2 years, the CARMENA and the EORTC 30073 SURTIME trial are
expected to have completed accrual
 Both trials have the potential to define the role and sequence of CN in general,
and identify proper candidates for CN individually.

52. Conclusion
 Despite the lack of randomized controlled trials, there is sufficient evidence to
support the hypothesis that a major subgroup of mRCC patients benefits from
CN in combination with the approved current first-line therapy.
 As with drug therapy, the decision to perform CN should not be a 'one size fits
all' approach, and patients should be carefully selected instead.
 In the absence of predictive biomarkers, presurgical targeted therapy to select
out nonresponders seems a promising step in this direction

53. Main source
 Selecting Patients for Cytoreductive Nephrectomy in Advanced Renal Cell
Carcinoma
 Who and When
 Authors and Disclosures
 Axel Bex*1 and Tom Powles2
1The Netherlands Cancer Institute, Division of Surgical Oncology, Department of Urology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
2Barts Cancer Institute, Experimental Cancer Medicine Centre, Queen Mary, University of London (QMUL), Mile End Road, London E1 4NS, UK
Financial & competing interests disclosure
A Bex and T Powles have been involved in the advisory boards of Pfizer, GlaxoSmithKline, Novartis and Bayer. The authors have no other relevant affiliations or financial
involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those
disclosed.
No writing assistance was utilized in the production of this manuscript.
*Author for correspondence
Tel.: +31 20 512 2553 Fax: +31 20 512 2554 a.bex@nki.nl
 http://www.medscape.com/viewarticle/766630

54. Thank You