cytoreductive nephrectomy (when and why)

Cytoreductive NephrectomyWHEN AND WHY

Dr. Ahmad Kharrouby

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).

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).

Introduction

Prior to the introduction of VEGF-targeted agents, systemic treatment options for mRCC were limited to : Cytokines :

IL-2 IFN-α

Introduction

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

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).

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.

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

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).

Prognostic factors

Risk Stratification

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

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

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).

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

Introduction

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

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).


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).


There are no results from randomized controlled trials that demonstrate that CN is beneficial in the era of targeted therapy.


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)


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).


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.


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)


These data are nonrandomized and retrospective, but provide valuable outcome data for patients without 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


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.


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).


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.


These studies therefore suggest, despite their retrospective flaws, that CN is beneficial in a major subset of patients.

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 2016101. ClinicalTrials.gov. Clinical Trial to Assess the Importance of Nephrectomy (CARMENA). http://clinicaltrials.gov/ct2/show/NCT00930033


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).


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).


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.


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.

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.

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.

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).


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).


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).

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).


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.


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).


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).


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)

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).


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)

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.

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

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 [email protected]

http://www.medscape.com/viewarticle/766630

mailto:[email protected]

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cytoreductive nephrectomy (when and why)

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