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chapter

50Treatment of AdvancedRenal Cell CarcinomaRamaprasad Srinivasan, MD, PhD l W. Marston Linehan, MD

Prognostic Factors

Surgical Management of Metastatic RenalCell Carcinoma

Immunologic Approaches in the Management of Advanced Clear Cell Renal Cell Carcinoma

Molecular Basis for Targeted Approachesin Clear Cell Renal Cell Carcinoma

Targeted Molecular Agents in Clear CellRenal Cell Carcinoma

Systemic Therapy for Non–Clear Cell Variants of Renal Cell Carcinoma

Renal cell carcinoma (RCC) is a term that includes a

variety of cancers arising in the kidney and com-

prises several histologically, biologically, and clini-

cally distinct entities (Linehan et al, 2007, 2009). An estimated

58,240 new cases o cancer arising in the kidney or renal pelvis

were diagnosed in 2010 in the United States (Jemal et al, 2010).

Approximately one third of all newly diagnosed RCC

patients present with synchronous metastatic disease

and an additional 20% to 40% of patients with clinically

localized disease at diagnosis will eventually develop

metastases (Skinner et al, 1971; Rabinovitch et al, 1994;

Bukowski, 1997). Metastatic RCC is almost always atal, with

10-year survival rates o less than 5% (Bukowski, 1997; Motzer

et al, 1999, 2000; Motzer and Russo, 2000; Négrier et al, 2002);

patients with metastatic disease account or the majority o deaths

(approximately 13,000 a year in the United States) related to RCC

(Jemal et al, 2010).

Advances in our understanding o the genetic and molecular

deects underlying the individual subtypes o RCC have led to the

development o novel agents designed to reverse or modulateaberrant pathways contributing to renal oncogenesis. These “tar-

geted” therapeutic strategies have largely supplanted other treat-

ment modalities in the initial management o metastatic clear cell

kidney cancer; however, surgery, irradiation, and cytokine therapy

remain appropriate choices in the management o selected patients

with advanced clear cell RCC. Although agents eective in clear

cell RCC are oten used in patients with other subtypes o RCC

there is scant evidence rom prospective studies demonstrating

beneft in non–clear cell RCC variants. More recently, elucidation

o aberrant oncogenic pathways in papillary, chromophobe, and

other variants o RCC has paved the way or evaluation o targeted

therapeutic approaches in these histologic subtypes (Linehan et al,

2009).

PROGNOSTIC FACTORSPatients with metastatic RCC generally have a poor prognos

with the majority succumbing to their disease. Ten-year surviv

in patients diagnosed with metastatic disease was estimated to b

less than 5% in the era o cytokine therapy and is unlikely

change signifcantly with the advent o targeted therapy. Howev

several clinical features such as a long time interva

between initial diagnosis and appearance of metastat

disease and presence of fewer sites of metastatic disea

have been observed to be associated with better outcom

Conversely, poor performance status and the presence o

lymph node and/or liver metastases are some facto

associated with shorter survival. Investigators at the Mem

rial Sloan-Kettering Cancer Center evaluated a variety o clinic

and laboratory parameters in 670 patients enrolled on vario

clinical trials o chemotherapy or immunotherapy in an eort

identiy those pretreatment actors that were able to best predi

outcome (Motzer et al, 1999). In a multivariate analysis,

poor performance status (Karnofsky score<

80), an elvated serum lactate dehydrogenase (LDH) level (>1

times upper limit of normal), a low hemoglobin (le

than the lower limit of normal), an elevated correcte

calcium concentration (>10 g/dL), and lack of pri

nephrectomy were independent predictors of a poo

outcome (Table 50–1). Patients could be stratied in

three distinct prognostic groups based on these ve poo

prognostic factors (Table 50–2). The overall survival (O

times in patients with no adverse factors (favorable-ris

group), one to two risk factors (intermediate-risk group

and more than three risk factors (poor-risk group) we

20 months, 10 months, and 4 months, respective

(Fig. 50–1) (Motzer et al, 1999). Subsequently, the same grou

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1476 SECTION XII  l Neoplasms of the Upper Urinary Tract

independent, external validation o the proposed model (Mekhai

et al, 2005). Similar prognostic schemes have also been proposed

by the Groupe Français d’Immunotherapie and by investigator

rom the University o Caliornia, Los Angeles (Tsui et al, 2000)

Validated prognostic models are used in clinical practice

to help make appropriate management decisions as wel

as in the design and interpretation of clinical trials

Modifcations o these prognostic schemes as well as identifcation

o reliable molecular markers are under investigation as suitable

predictors o response to and survival ater therapy with newe

targeted agents against vascular endothelial growth actor (VEGF

and mammalian target o rapamycin (mTOR) pathway compo

nents (Choueiri et al, 2007, 2008b; Motzer et al, 2008a).

SURGICAL MANAGEMENT OFMETASTATIC RENAL CELL CARCINOMA

Debulking or CytoreductiveNephrectomy in Patientswith Metastatic RCCThe role o cytoreductive nephrectomy preceding systemic therapy

has been extensively studied in the era o cytokine therapy. The

impetus or exploring this approach in metastatic RCC was pro

vided both by the perception that bulky tumors might inhibit key

components o the immune system critical or combating cancer

and by observations suggesting that removal o large primary

tumors may provide clinical beneft. To support this practice early

proponents o cytoreductive nephrectomy had cited (1) the rare

but well-described occurrence o spontaneous regression o meta

static lesions ater nephrectomy (Bloom, 1973; Middleton, 1980

Snow and Schellhammer, 1982; Marcus et al, 1993); (2) preclinica

data suggesting that large primary tumors may inhibit T-cell unc

tion (Kudoh et al, 1997; Bukowski et al, 1998; Ling et al, 1998

Uzzo et al, 1999a, 1999b); and (3) the inability o systemic agents

particularly cytokines, to induce meaningul responses in primary

renal tumors in most patients (Sella et al, 1993; Rackley et al

1994; Wagner et al, 1999). However, the risk o perioperative mor

bidity and mortality and the inability o a signifcant proportion

o patients undergoing nephrectomy to subsequently receive sys

temic therapy clearly underlined the need or unequivocal evi

dence o clinical beneft as well the ability to identiy patients

likely to beneft rom this approach.

 Nephrectomy as the sole therapeutic intervention in

the context of metastatic disease is unlikely to alter

outcome, as suggested by small retrospective analyses (DeKernion

et al, 1978). However, several retrospective studies have demon

strated the easibility o a combined modality approach in which

nephrectomy is ollowed by cytokine therapy, with some suggesting that this approach may avorably impact response and sur

vival. Investigators rom the National Cancer Institute (NCI

reported their experience in 195 patients undergoing nephrec

tomy ollowed by high-dose interleukin-2 (IL-2) therapy between

the years 1985 and 1996 (Walther et al, 1997b). An overall response

rate o 18% (including a complete response rate o 4%) ater IL-2

therapy was observed in this study. A notable fnding that emerged

rom this study was that although the majority o patients under

went successul resection o the primary tumor only 107/195

(55%) went on to receive IL-2 therapy. Rapid postoperative diseas

progression and perioperative surgical and medical morbidity were

the most common actors preventing delivery o systemic therapy

suggesting that careul patient selection may play an importan

identifed poor perormance status, high calcium level, low hemo-

globin value, elevated LDH level, and short time interval rom

initial diagnosis to treatment as actors that could best predict a

poor outcome in 463 patients receiving intereron-based therapy

in the frst-line setting (Motzer et al, 2002). This prognostic model

was ound to be predictive o survival in an independent data set

derived rom patients treated at the Cleveland Clinic and provides

Data from Motzer RJ, Mazumdar M, Bacik J, et al. Survival and prognostic

stratication of 670 patients with advanced renal cell carcinoma. J Clin Oncol1999;17:2530–40.

Table 50–1. 

Adverse Prognostic Factors in 670 Patients Treated with Chemotherapy or Immunotherapy at theMemorial Sloan-Kettering Cancer Center

Karnofsky performance score <80%Elevated lactate dehydrogenase (>1.5 times upper limit of normal)Low hemoglobin (<lower limit of normal)

Elevated corrected calcium (>10 mg/dL)Absence of prior nephrectomy

Data from Motzer RJ, Mazumdar M, Bacik J, et al. Survival and prognosticstratication of 670 patients with advanced renal cell carcinoma. J Clin Oncol

1999;17:2530–40.

Table 50–2. 

Risk Stratication Based on AdversePrognostic Factors in 670 Patients Treated

 with Chemotherapy or Immunotherapy atthe Memorial Sloan-Kettering Cancer Center

RISK GROUP

NO. OF ADVERSE

PROGNOSTIC FACTORS

MEDIAN OVERALL

SURVIVALGood 0 20 monthsIntermediate 1-2 10 monthsPoor 3-5 4 months

Figure 50–1. Survival analysis stratied according to risk group in670 patients treated with chemotherapy or immunotherapy at theMemorial Sloan-Kettering Cancer Center (n = 656; 14 patients

missing one or more of the ve risk factors were excluded). KPS,Karnofsky performance score; HGB, hemoglobin; LDH, lactatedehydrogenase. (From Motzer RJ, Mazumdar M, Bacik J, et al.Survival and prognostic stratication of 670 patients withadvanced renal cell carcinoma. J Clin Oncol 1999;17:2530–40.)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

   P  r  o  p  o  r   t   i  o  n

  s  u  r  v   i  v   i  n  g

0 risk factors (164 patients, 30 alive)

1 or 2 risk factors (348 patients, 23 alive)

3, 4, or 5 risk factors (144 patients, 1 alive)

Risk factors are no prior nephrectomyKPS <80low HGBhigh corrected calciumhigh LDH

Years following systemic therapy

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CHAPTER 50  l Treatment of Advanced Renal Cell Carcinoma 14

(all histologic subtypes were allowed); good perormance stat

(ECOG 0 or 1); presence o a resectable primary renal tumor; n

prior chemotherapy, irradiation, or immunotherapy; and adequa

organ unction. Although there were no signicant diffe

ences in the response rates to interferon observed in th

two study arms, OS was improved in the surgery plu

interferon arm (median 11.1 vs. 8.1 months for inte

feron alone,  P    =  .05) (Fig. 50–2). These data were similar

those rom a smaller EORTC trial (a total o 85 patients random

ized to intereron alone or intereron ater nephrectomy) that us

a similar design and reported a survival advantage avoring th

surgery plus intereron arm (median OS 17 vs. 7 months,  P  = .0

(Mickisch et al, 2001). A combined analysis o both trials reveal

data that were consistent with those reported in the individu

trials (Flanigan et al, 2004). These data support the use

cytoreductive nephrectomy in carefully selected patien

with metastatic RCC who are likely candidates for su

sequent cytokine therapy (data summarized in Table 50–3)

The impact of cytoreductive nephrectomy on outcom

in patients receiving VEGF or mTOR pathway inhibito

remains to be determined and is the subject of ongoin

trials. Similarly, although some patients with non–clear cell h

tologic subtypes o RCC were included in the aoremention

trials, the role o nephrectomy beore systemic therapy in the

patients is unclear.

Resection of MetastasesMost patients with metastatic RCC will not achieve a cure or lon

term disease remission with currently available systemic agent

role in the successul application o this combined modality

approach. The impact o patient and/or disease characteristics on

outcome is urther highlighted by a retrospective study. In Bennett

and associates’ (1995) series o 30 patients, which included several

patients with unavorable perormance status (Eastern Coopera-

tive Oncology Group [ECOG] 2) and multiple metastatic sites

including patients with brain or liver metastases, only 7 (23%)

were able to proceed with IL-2 ater nephrectomy. Conversely, in

a series that included only patients with avorable clinical/

prognostic actors (e.g., good perormance status, minimal comor-

bidity, no liver or brain metastases), the majority o patients were

able to proceed to systemic therapy ater nephrectomy, with high

response rates (35% to 40%) and OS (median 20 to 22 months)

ater cytokine-based treatment (Fallick et al, 1997; Figlin et al,

1997). Although these retrospective analyses and small

single-arm prospective studies conrmed the feasibility

of a tandem surgical/cytokine therapeutic approach,

their major contribution was in laying the foundation

for controlled, prospective studies to determine if out-

comes with cytokine therapy could be improved by prior

nephrectomy.

The most compelling evidence in support of cytoreduc-

tive nephrectomy is provided by two randomized phase

III studies conducted by the Southwest Oncology Group

(SWOG) and the European Organization for Research

and Treatment of Cancer (EORTC). The larger o the two

studies, SWOG trial 8949, randomized 241 patients with meta-

static RCC to receive intereron-α-2b either as initial therapy or

ater cytoreductive nephrectomy (Flanigan et al, 2001). Salient

eligibility criteria included a histologic diagnosis o kidney cancer

Figure 50–2. Actuarial survival among 241patients with metastatic renal cell carcinomarandomized to either interferon-α alone orinterferon-α after cytoreductive nephrectomy.(From Flanigan RC, Salmon SE, BlumensteinBA, et al. Nephrectomy followed by interferonalfa-2b compared with interferon alfa-2b alonefor metastatic renal-cell cancer. N Engl J Med2001;345:1655–59.)

100

80

60

40

20

0

0 24

No. at risk 

Interferon alone 121 21 4 0

Nephrectomy plus interferon 120 29 9 3

48 72

   S  u  r  v   i  v  a   l   (   %   )

Nephrectomy plus interferon

Interferon alone

Months

Table 50–3. 

Summary of Outcome in Randomized Studies of Interferon-α Alone or Interferon-α after CytoreductiveNephrectomy in Patients with Metastatic Kidney Cancer

STUDY

NO. OF ELIGIBLE PATIENTS RESPONSE RATE AFTER IFN (%) MEDIAN OVERALL SURVIVAL (MO

Total IFN Nx Plus IFN IFN Nx Plus IFN P  IFN Nx Plus IFN P 

Flanigan et al, 2001 241 121 120 3.6 3.3 NS 8.1 11.1 .05Mickisch et al, 2001 83 42 41 12 19 .38 7 17 .03Flanigan et al, 2004 331 163 161 5.7 6.9 .60 7.8 13.6 .002

IFN, interferon-α; Nx, cytoreductive nephrectomy.

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1478 SECTION XII  l Neoplasms of the Upper Urinary Tract

However, resection of limited metastatic disease has

been reported by several groups to be associated with

long disease-free intervals and OS. It should be empha-

sized that metastasectomy has not been evaluated sys-

tematically in a prospective, randomized fashion and

that the favorable outcome ascribed to resection of soli-

tary metastatic disease may reect patient selection bias,

inherent differences in tumor biology, and natural

history or other confounding factors.

Most studies detailing outcome ater metastasectomy are retro-

spective series. In most series, isolated pulmonary metastases were

the lesions most commonly amenable to resection with curative

intent. The OS o patients undergoing complete resection o 

limited metastatic disease is quite impressive, with reported

median 5-year survival rates o 35% to 50% in many series (Mid-

dleton, 1967; Skinner et al, 1971; Tolia and Whitmore, 1975;

O’Dea et al, 1978; Pogrebniak et al, 1992; Kierney et al, 1994;

Friedel et al, 1999; Murthy et al, 2005; Russo et al, 2007). The

larger o these studies have also attempted to identiy patients

most likely to beneft rom this approach. In a series o 278

patients with recurrent RCC treated at the Memorial Sloan-

Kettering Cancer Center, 211 were reported to have undergone

either complete (141 patients) or incomplete (70 patients) resec-

tion o recurrent tumor rom a variety o metastatic sites (Kavolius

et al, 1998). In this series, complete or “curative” resec-

tion was associated with a longer OS (44% 5-year

survival vs. 14% in patients undergoing incomplete

resection); multivariate analysis also identied the

presence of a solitary metastatic lesion, age younger

than 60 years, and a disease-free interval of more than

1 year as favorable prognostic indicators. In addition,

some studies have suggested that pulmonary metastases,

smaller tumor size (<4 cm in one series), and metachro-

nous lesions are predictors of better outcome after

metastasectomy (Friedel et al, 1999; Piltz et al, 2002; Murthy

et al, 2005). Although not supported by convincing evidence o 

survival beneft rom prospective studies, resection o isolated

metastatic lesions is a reasonable and widely employed practice

in selected RCC patients.

Palliative SurgeryCytoreductive nephrectomy can be performed with

palliative intent in patients with intractable pain, hema-

turia, constitutional symptoms, or a variety of paraneo-

plastic manifestations such as hypercalcemia, erythrocytosis,

secondary thrombocytosis, or hypertension. Symptoms such as

pain and laboratory abnormalities including hypercalcemia can

oten be eectively managed medically, whereas symptoms

such as hematuria may be amenable to alternative treatmentapproaches (e.g., angioembolization). Furthermore, resection of 

the primary renal tumor does not always result in clini-

cal benet; or instance, in one series, only a little over hal the

patients (7/12) with hypercalcemia experienced clinically mean-

ingul reductions in serum calcium levels (Walther et al, 1997a).

Cytoreductive nephrectomy with palliative intent is

therefore performed relatively infrequently but is appro-

priate in some patients.

Resection o metastases to alleviate pain or to orestall poten-

tially lie-threatening or debilitating complications is oten indi-

cated in a variety o situations. Patients who may beneft rom

noncurative resection o metastatic lesions include those with

solitary brain metastases, metastatic lesions in weight-bearing

Key Points: Cytoreductive Nephrectomyin Metastatic Renal Cell Carcinoma

l Two randomized studies have demonstrated improved sur-

vival in careully selected metastatic RCC patients undergo-

ing cytoreductive nephrectomy ollowed by cytokine

therapy (intereron-α) compared with those receiving cyto-

kine therapy alone.

l Several patient and/or disease characteristics appear to inu-

ence outcome; patients with poor perormance status,

comorbid medical conditions, rapidly progressive disease,

presence o brain metastases, and so on, are unlikely to

beneft rom this approach.

l The role o cytoreductive nephrectomy as a prelude to sys-

temic therapy with currently available novel targeted agents

is unclear and is the subject o ongoing clinical trials.

Key Points: Metastasectomy

l Resection o isolated metastatic lesions is appropriate in

selected patients.

l Several retrospective studies have suggested that patients

undergoing complete resection o isolated metastatic oci

may experience long disease-ree intervals, with median

overall survival rates o 35% to 50% in some reports.

l Several actors are associated with an improved outcome

ater metastasectomy, including complete resection, pres-

ence o solitary metastatic lesions, age younger than 60

years, smaller tumor size, presence o pulmonary metastases,

and development o metachronous metastatic disease.

l There are no prospective, randomized studies demonstrating

a avorable outcome with metastasectomy. It is thereore

possible that the avorable outcome ater resection o limited

metastatic disease may be a reection o patient selection

bias, dierences in tumor biology and natural history, or

other conounding actors not related to resection.

Key Points: Palliative Surgery

in Advanced Renal Cell Carcinomal In some patients with advanced RCC, cytoreductive nephrec-

tomy may help alleviate symptoms related to the primary

tumor (e.g., intractable pain, hematuria) or paraneoplastic

maniestations.

l However, nonsurgical options are oten eective in palliat-

ing symptoms associated with RCC; cytoreductive nephrec-

tomy is hence inrequently perormed with purely palliative

intent.

l Resection o metastatic lesions (oten in combination with

radiation or systemic therapy) is sometimes perormed or

relie o symptoms or to prevent lie-threatening or dis-

abling sequelae.

bones or joints, or vertebral metastatic lesions with impending

spinal cord or radicular compromise (Sundaresan et al, 1986; Kol

lender et al, 2000; Sheehan et al, 2003). Surgical resection is oten

combined with radiation and/or systemic therapy in many o the

aorementioned situations.

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