Platinum Priority – Kidney Cancer
Editorial by Brant A. Inman and Daniel J. George on pp.16–17 of this issue
Primary Tumor Response to Targeted Agents in Patients with
Metastatic Renal Cell Carcinoma
E. Jason Abela, Stephen H. Culpb,1, Nizar M. Tannirc, Surena F. Matinb, Pheroze Tambolid,
Eric Jonaschc, Christopher G. Woodb,*
aDepartment of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
bDepartment of Urology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
cDepartment of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
dDepartment of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
E U R OP E A N UR O L O G Y 5 9 ( 2 0 1 1 ) 1 0– 1 5
available at www.sciencedirect.com
journal homepage: www.europeanurology.com
Accepted September 27, 2010
Published online ahead of
print on October 16, 2010
Renal cell carcinoma
Primary tumor response
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Background: The recent development of multiple targeted agents for metastatic
renal cell carcinoma (mRCC) has changed the treatment paradigm; hence the
benefit and optimal timing of cytoreductive nephrectomy is being reevaluated.
Objective: To determine primary tumor response to treatment with targeted
agents in patients with mRCC.
Design, setting, and participants: We reviewed the clinical and radiographic data
2009 without prior systemic treatment who received targeted therapy with their
primary tumor in situ.
Measurements: Two independent reviewers measured the diameter of primary
and metastatic tumors at baseline and subsequent scans, using Response Evalua-
tion Criteria Solid Tumors (RECIST) v.1.1 to assess disease response.
Results and limitations: We identified 168 consecutive patients with a median 15
mo of follow-up and a median maximum tumor diameter of 9.6 cm. Median
maximum primarytumor response was?7.1% (interquartilerange: ?14.0 to?0.1).
with <10% decrease in primary tumor within in the first 60 d, median maximum
response was ?7.2% at 154 d versus ?24.5% maximum response at 174.5 d for
18 patients with ?10% decrease in primary tumor during the initial 60 d.
Conclusions: Decrease in primary tumor diameter >30% while on targeted therapy
for mRCC is rare, with most patients demonstrating minimal or no decrease in
primary tumor diameter. Early response predicts a better overall primary tumor
# 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Department of Urology – Unit 1373, The University of Texas M.D. Anderson
Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Tel. +1 713 563 7463;
Fax: +1 713 792 3474.
E-mail address: firstname.lastname@example.org (C.G. Wood).
0302-2838/$ – see back matter # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2010.09.034
The development of multiple new agents targeting vascu-
lar endothelial growth factor or cellular growth pathways
has transformed the treatment of patients with metastatic
and increased survival compared to immunotherapy,
targeted therapy has become the standard first-line
systemic therapy for the majority of new mRCC patients
. In the immunotherapy era, upfront cytoreductive
nephrectomy became standard for selected mRCC patients
after improved overall survival was demonstrated in two
randomized trials versus interferon-a alone [2,3]. Follow-
ing this accepted paradigm, the majority of patients in the
initial phase 3 clinical trials of targeted agents for mRCC
also underwent nephrectomy prior to receiving targeted
therapy [4–9], and cytoreductive nephrectomy before
systemic therapy continues to be a standard treatment
for selected patients. However, the optimal timing of
surgery is unknown, and the availability of improved
systemic therapy has prompted a reevaluation of the
role and timing of cytoreductive nephrectomy in mRCC
Recently, several groups have reported success with
targeted agents in patients with the primary tumor in situ,
indicating that presurgical targeted therapy may have a role
in the treatment of mRCC [10–15]. However, there are no
large randomized trials of presurgical targeted therapy;
thus, it is difficult to know what type of response is typical
and when is the best time to perform nephrectomy in a
patient responding to therapy. The objective of our study
was to evaluate the primary tumor response in mRCC
patients treated with targeted therapy, to describe the
median response, and to evaluate when this response
2. Material and methods
Upon internal review board approval, we retrospectively reviewed the
medical records of all treatment-naı ¨ve mRCC patients from November 1,
2004, to December 31, 2009, who had an intact primary kidney tumor
and were undergoing therapy for mRCC with targeted agents, as detailed
in Table 1. The choice of targeted agent was at the discretion of the
treating medical oncologist. Patients were considered eligible if images
from baseline and at least one follow-up abdominal contrast-enhanced
computed tomography (CT) or magnetic resonance imaging (MRI) scan
were available for review. Of 212 consecutive patients identified, 27
were excluded for lack of imaging, and 17 patients were excluded
because of enrollment in active clinical trials at the time of analysis.
Follow-up was calculated using the Kaplan-Meier method.
2.2. Assessment of treatment response
To assess response to targeted therapy, two independent reviewers
measured the diameter of primary and metastatic tumors at baseline and
CriteriaSolid Tumors(RECIST) v.1.1 . To evaluate the response in sites
other than the primary tumor, we divided the patients into two groups:
patients who had clinical benefit from treatment (stabledisease or partial
response [PR] in metastatic sites) and patients who did not benefit from
treatment (progressive disease in metastatic sites).
Pathologic data (histologic subtype, Fuhrman grade, and presence of
sarcomatoid dedifferentiation) were obtained from primary tumor
biopsy unless the patient had undergone subsequent cytoreductive
nephrectomy, in which case data were collected from pathologic
analysis of the surgical specimen.
2.3. Statistical analysis
Linear regression was used to determine the association between
changes in primary tumor size and metastatic disease. Logistic
regression was used to calculate an odds ratio (OR) corresponding to
Table 1 – Distribution of targeted agents, with dosage used and percentage change in primary tumor diameter while on treatment
DrugNo. (%) Median percentage
Median time between
imaging in days (IQR)
50 mg PO daily 4 wk on/2 wk off
10 mg/kg IV every 14 d
Bevacizumab plus erlotinib:
Bevacizumab 10 mg/kg IV every 14 d + erlotinib
150 mg PO daily
400 mg PO twice daily
25 mg IV every week
Bevacizumab plus chemotherapy:
Bevacizumab 10 mg/kg IV every 14 d
Gemcitabine 1200 mg/m2IV every 2 wk
Capcitabine 1.5 g twice daily for 21 of 28 d
150 mg PO daily
800 mg PO daily
?10.2 (?21.1 to ?2.8) 105 (76–201)
25 (15)0.1 (?4.2 to 4.6)55 (54–56)
?10.1 (?17.1 to ?6.0)54.5 (54–56)
?6.0 (?12.3 to 0.4) 90 (61.5–124)
?4.0 (?8.6 to ?0.5)56 (52–84)
?6.1 (?11.9 to ?0.7)58 (43–118)
?5.1 (?9 to ?1.3)51.5 (41–62)
?11.1 (–) 48 (–)
IQR = interquartile range; PO = oral; IV = intravenous.
EUROPEAN UROLOGY 59 (2011) 10– 15
metastatic disease sites. For all analyses, Stata v.10.1 (StataCorp, College
Station, TX, USA) was used.
We identified 168 patients (Table 2) who met the inclusion
of 15 mo (interquartile range [IQR]: 7.9–32.2). At initial
evaluation, clinical rationale to defer upfront cytoreductive
nephrectomy included widespread metastatic disease in 52
patients (30%), enrollment in a clinical trial in 46 patients
(27%), brain metastasis, non–clear cell or sarcomatoid
dedifferentiation on biopsy in 30 patients (18%), physician
or patient preference in 17 patients (10%), poor perfor-
mance status (PS)/comorbidities in 16 patients (10%), and
primary tumor considered unresectable in 7 patients (4%).
The median maximum tumor diameter at baseline was
9.6 cm (IQR: 6.0–20.2). Median change in primary tumor
size with each therapy is listed in Table 1, and the overall
median maximum change in primary tumor diameter was
?7.1% (IQR: ?14.0 to ?0.1) at a median time of 62 d (IQR:
54–118). The median change in primary diameter was
?6.5 mm (IQR: ?12.6 to ?0.02). Adverse events attributed
to targeted therapy are shown in Table 3, and reduction of
drug dosage was required in 26 patients (16%).
When considering metastatic disease sites, 99 patients
(59%) had a PR or stable disease, and 69 patients (41%) had
progressive disease during treatment. Primary tumor
response ?10% was associated with PR or stable disease
in metastatic sites (p = 0.005). After controlling for time on
therapy, patients with ?10% decrease in primary tumor
diameter within 60 d of beginning therapy were 2.25 times
more likely to have stable disease or PR to therapy (OR:
2.39; 95% confidence interval, 1.14–5.02; p = 0.022) in the
metastatic disease sites.
Table 2 – Patient and disease characteristics
Age, yr, median (range; %)
Tumor diameter, cm, median (range; %)
Gender, No. (%)
59.1 (18.3–79.8; 52.8–65.1)
9.6 (1.8–22.1; 6.9–11.6)
Race, No. (%)
BMI, median (IQR)27.9 (24.7–31.0)
ECOG PS, No. (%)
Metastatic sites, No. (%)
Side, No. (%)
Clinical T stage, No. (%)
Local symptoms, No. (%)
Metastatic symptoms, No. (%)
Systemic symptoms, No. (%)
Histologic subtype, No. (%)
Unknown (RCC NOS)
present in specimen, No. (%)
Fuhrman grade, No. (%)
BMI = body mass index; IQR = interquartile range; ECOG = Eastern
Cooperative Oncology Group; PS = performance status; RCC = renal cell
carcinoma; NOS = not otherwise specified.
Fig. 1 – Waterfall plot showing primary tumor maximum overall response
to treatment with targeted agents. Bold lines indicate partial response
and progressive disease, as defined by Response Evaluation Criteria Solid
Table 3 – Adverse events associated with treatment
Stomatitis or mouth ulceration
*All complications were grade 2 or greater according to Common
Terminology Criteria for Adverse Events v.4.0.
E U RO P E A N U R O L O G Y 59 ( 2 0 1 1 ) 1 0 – 1 5
Fifty-five patients (33%) underwent delayed cytoreduc-
tive nephrectomy at a median of 75 d from treatment to
either bevacizumab (n = 21 [39%]) or bevacizumab and
erlotinib (n = 23 [43%]). For patients not undergoing cyto-
reductive nephrectomy, a total of 23 patients (14%) contin-
study,themajorityofwhom(n = 17[74%])weretreatedwith
sunitinib. In the remaining patients, reasons for discontinu-
of disease in 64 patients (38%), unable to tolerate side effects
(n = 11 [7%]), worsening PS (n = 3 [2%]), worsening comorbid
conditions (n = 5 [3%]), surgery for metastatic disease (n = 4
original therapy (n = 3 [2%]).
Sixty-one patients (36%) did not undergo cytoreductive
nephrectomy after the initial course of therapy or discon-
tinued the first-line treatment because of progression.
Primary targeted therapy was extended in these patients,
and multiple abdominal CT or MRI studies were available
for analysis (median of four imaging studies [IQR: 3–5]).
Median time between treatment initiation and final
imaging was 216 d, and sunitinib was the most commonly
used agent (77%). The median maximum percentage change
in primary tumor diameter was ?11.5% (IQR: ?21.8 to
?4.3), which occurred at a median of 160 d (IQR: 86–225)
after treatment initiation. For 43 patients (70%) with <10%
reduction in the diameter of the primary tumor within the
first 60 d, the median maximum response was ?7.2% (IQR:
?12.8 to ?1.7) and occurred at a median of 154 d (IQR: 86–
218). In 18 patients (30%) with ?10% reduction in primary
tumor diameter within the first 60 d, the median maximum
at a median time of 174.5 d (IQR: 83–278). Among these 18
patients, 15 (83%) were treated with sunitinib, and 3 (16%)
were treated with sorafenib. There was no significant
difference between the times to maximum response
between the two groups.
At baseline abdominal imaging evaluation, 44 patients
(26%) had evidence of a tumor thrombus: 23 patients (52%)
had thrombus confined to the renal vein, and 21 patients
(48%) had thrombus extending into the inferior vena cava
(IVC). In two patients, the thrombus was initially within the
IVC <2 cm and decreased in height to just inside the renal
vein on follow-up. In another patient, the thrombus
decreased from within the IVC initially just above the
hepatic veins to below the hepatic veins within the IVC
(>2 cm within IVC). In one patient, IVC thrombus pro-
gressed from below the hepatic veins to above the
diaphragm while on therapy.
Because the majority of the mRCC patients in phase 3
clinical trials with targeted agents had upfront nephrec-
tomy [4–9], high-quality data demonstrating consistent
treatment response in the primary tumor of mRCC is
comparatively scarce. Recent reports have described the
approach of treatment with targeted therapy prior to
surgery [11–15] and have demonstrated that dramatic
responses are possible (Fig. 2). In a presurgical phase 2 trial,
Fig. 2 – Primary tumor responding to therapy with sunitinib. Before therapy (left), the large primary tumor and lymphadenopathy would make
cytoreductive nephrectomy difficult and possibly dangerous. After therapy (right), the response in the primary tumor and lymph nodes enabled this
patient to undergo laparoscopic nephrectomy.
Fig. 3 – Primary tumor response to a targeted agent according to the
amount of response. Most patients show minimal response or tumor
stability during treatment.
EUROPEAN UROLOGY 59 (2011) 10– 15
Jonasch et al reported that although none of the 45 patients
achieved a PR by RECIST criteria (ie, at least 30% decrease in
diameter) in the primary tumor after 8 wk of bevacizumab
treatment, there were 23 patients whose primary tumor
diameter decreased >10% . In a similar study with
sorafenib, Cowey et al reported only 7% PR, but 40% of
patients had >10% decrease in primary tumor size .
Finally, two retrospective series of 17 and 19 patients,
respectively, with in situ primary tumors treated with
sunitinib reported PR rates of 12% and 16%, respectively, in
the primary tumor [12,13]. In the current study with 168
patients, we found a low overall rate of primary tumor PR of
6%, with >90% of patients achieving a minor response or
complete responses were seen in the primary tumor.
Although even the minimal levels of primary tumor
response to targeted therapy that we observed in the
current study are considerably better than the reported
responses with immunotherapy [17,18], primary mRCC
tumors do not seem to respond as well as RCC metastatic
sites. For example, sunitinib has been reported to produce
in phase 3 clinical trials  compared to rates of 10–16% for
the primary tumor [12,13].
Performing cytoreductive nephrectomy in patients with
large tumors or advanced-stage disease is technically
difficult, and resection of adjacent organs is not uncommon,
with subsequent increased morbidity . For these
patients, the benefit of size reduction prior to surgery is
obvious. However, achieving a PR is an arbitrary goal for the
purposes of surgical planning, because the amount of tumor
downsizing necessary to facilitate surgery is different for
each patient and among surgeons. For most patients with
large tumors, the 6.5-mm median decrease in diameter is
not significant. However, because there is no universally
accepteddefinition ofan ‘‘unresectable’’ tumor,it is difficult
to evaluate whether tumors become ‘‘resectable’’ after
therapy, with the rarity of dramatic PT responses. At high-
volume centers in which complex surgeries are performed
by experienced surgeons, occasional responses elicited by
targeted agents have intensified the debate over when to be
more aggressive surgically and when to defer surgery.
With >95% of patients having stable disease or a
response in their primary tumor (Fig. 3), it is rare that
tumors progress and make surgery not feasible. This low
level of isolated primary tumor progression has been
demonstrated in prior studies , and early reports of
surgery after targeted therapy suggest minimal or no
increase in major complications using a presurgical
RCC is known to invade vascular structures and produce
venous tumor thrombi that may extend from the renal vein
into the IVC and eventually into the right side of the heart,
requiring complex surgery, with sternotomy and cardio-
pulmonary bypass in some patients. Given the apparent
rarity of thrombus downstaging while on targeted therapy
and risk of thrombus extension, surgical resection should
remain the gold standard for the majority of patients with
IVC thrombus outside of a clinical trial.
Choosing the optimal time to perform nephrectomy can
be difficult in patients responding to systemic therapy. In
our experience, the median time to maximum primary
tumor response was between 5 and 6 mo of therapy,
regardless of the amount of response. Most importantly, the
response to therapy in the first 60 d was predictive of the
maximum overall response. Patients with ?10% decrease in
tumor diameter in first 60 treatment days had significantly
better median overall response: 24.5% versus 7.2%. These
findings are important to clinicians considering presurgical
therapy in complex cases and may help guide investigators
To our knowledge, the current study represents the
largest series reporting primary tumor response in mRCC
patients treated with targeted agents, but there are several
limitations. Along with the inherent bias of a retrospective
study, there is likely a selection for patients with higher-
volume disease and more comorbidities compared to
clinical trials with low-risk patients. However, we believe
that patients with large tumors and bulky metastatic
disease represent the population of patients who may
benefit most from presurgical therapy. We acknowledge
that the cohort of patients with multiple scans is a highly
selected group for response to therapy because most
patients are taken off treatment with disease progression.
Nevertheless, this cohort of ‘‘responding patients’’ is most
appropriate for evaluating the optimal timing of surgery.
Finally, the criticisms of the adequacy of RECIST to assess
response to targeted agents [21–23] are not relevant to our
study, given that absolute size reduction is a goal in
Primary tumor response to targeted agents is highly
variable (Fig. 4), with dramatic responses being rare. In
the absence of evidence from randomized trials demon-
strating a survival benefit for presurgical or nonsurgical
treatment with targeted agents, we do not advocate
changing the current paradigm of upfront cytoreductive
nephrectomy prior tosystemic therapyfor selected patients
Fig. 4 – Box plot demonstrating variable primary tumor response to
different targeted agents. The shaded box represents the 25th and 75th
percentiles, with the ends of lines demonstrating two standard
deviations and outliers shown as dots for each type of therapy.
E U RO P E A N U R O L O G Y 59 ( 2 0 1 1 ) 1 0 – 1 5
outside of clinical trials. Presurgical therapy should be
investigated in patients with unresectable, locally advanced
tumors, serious comorbidities, or high-volume metastatic
disease for whom upfront cytoreductive nephrectomy is
rarely recommended [19,24]. Large randomized trials are in
progress to answer the important questions of what is the
optimal timing of cytoreductive nephrectomy and whether
cytoreductive nephrectomy improves survival in mRCC
patients treated with targeted agents. However, these trials
and it is critical that we evaluate current data from patients
treated with the primary tumor in place to guide therapy
and future research.
Author contributions: Christopher G. Wood had full access to all the data
in the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Abel, Culp, Wood.
Acquisition of data: Abel, Culp.
Analysis and interpretation of data: Abel, Culp.
Drafting of the manuscript: Abel, Culp, Tannir, Matin, Tamboli, Jonasch,
Critical revision of the manuscript for important intellectual content: Abel,
Culp, Tannir, Matin, Jonasch, Wood.
Statistical analysis: Abel, Culp, Wood.
Obtaining funding: None.
Administrative, technical, or material support: Wood.
Supervision: Abel, Culp, Tannir, Matin, Tamboli, Jonasch, Wood.
Other (specify): None.
Financial disclosures: I certify that all conflicts of interest, including
affiliation, grants orfunding,consultancies,honoraria,stockownership or
are the following: Eric Jonasch is a Genentech consultant and provides
expert testimony; Christopher G. Wood is a consultant for Pfizer
and Ethicon. This study was presented at the ASCO Genitourinary
Cancer Symposium and at the American Urological Association Annual
Funding/Support and role of the sponsor: None.
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