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Clinical Cancer Research 14, 2431, April 15, 2008. doi: 10.1158/1078-0432.CCR-07-4089
© 2008 American Association for Cancer Research
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Cancer Therapy: Clinical

Sunitinib for Treatment of Advanced Renal Cell Cancer: Primary Tumor Response

Astrid A.M. van der Veldt1, Martijn R. Meijerink2, Alfons J.M. van den Eertwegh1, Axel Bex3, Gijsbert de Gast4, John B.A.G. Haanen4 and Epie Boven1

Authors' Affiliations: Departments of 1 Medical Oncology and 2 Radiology, VU University medical center; and Departments of 3 Urology and 4 Medical Oncology, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands

Requests for reprints: Epie Boven, Department of Medical Oncology, VU University medical center, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands. Phone: 31-20-4444336; Fax: 31-20-4444355; E-mail: e.boven{at}vumc.nl.


   Abstract
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 Abstract
Patients and Methods
 Results
 Discussion
 References
 
Purpose: Nephrectomy before immunotherapy in patients with metastatic renal cell cancer (RCC) will improve patient outcome. In addition, the primary tumor is known to be refractory to cytokines. Sunitinib is now approved for treatment of advanced RCC, but its effect on the primary tumor has yet to be reported.

Experimental Design: All patients treated with sunitinib for advanced RCC without prior nephrectomy were reviewed and sequential computed tomography scans were evaluated for response in the primary tumor as well as metastases according to Response Evaluation Criteria in Solid Tumors. Volumes of primary tumors and central necrotic areas were measured with the perimeter method.

Results: Computed tomography scans were available for evaluation of response in 17 of 22 patients with a primary tumor in situ (1 patient with two primaries). According to Response Evaluation Criteria in Solid Tumors, 4 patients had a partial response, 12 had stable disease, and 1 had progressive disease. The one-dimensional longest diameter of the primary tumor correlated with the volumetric measurements both at baseline and at the time of evaluation of response. Excluding the patient with progressive disease, the median volume reduction was 31% associated with a median increase in the volume of necrosis of 39%. Three patients underwent nephrectomy and tumors showed extensive necrotic areas next to small fields of vital tumor cells.

Conclusions: Sunitinib can induce a significant reduction in volume of primary renal cell tumors. Further trials need to address the role of nephrectomy in advanced RCC patients on sunitinib treatment.

Until recently, cytokine therapy was the only treatment for metastatic renal cell cancer (mRCC), but less than 20% of patients benefit from a response (1). Responsiveness of the primary tumor to immunotherapy is very rare (2–4). For that reason, patients with synchronous metastases and a resectable primary tumor in situ will undergo a nephrectomy as part of a multimodality approach. This approach is largely supported by data from two randomized phase III clinical trials showing a longer overall survival in patients with nephrectomy followed by IFN-{alpha} versus patients on IFN-{alpha} alone (5–7). An additional feature in favor of nephrectomy is the rare phenomenon of spontaneous regression of metastases (8). It has also been argued that nephrectomy may improve the response to immunotherapy by reduction of immunosuppressive factors produced by the primary tumor.

There are several subtypes of renal cell cancer (RCC), of which ~75% contain clear cell carcinoma histology. At least 60% of these tumors is associated with inactivation of the von Hippel-Lindau tumor suppressor gene. This leads to elevated protein levels of hypoxia-inducible factor {alpha} and consequent overexpression of vascular endothelial growth factor and platelet-derived growth factor (9). These growth factors promote tumor angiogenesis, which likely contributes to the hypervascularity of RCC. Inhibitors of angiogenesis have proven efficacy in RCC, and among them is sunitinib (SU011248 or Sutent; Pfizer Pharmaceuticals Group). Sunitinib is an oral tyrosine kinase inhibitor of the vascular endothelial growth factor receptors, the platelet-derived growth factor receptors, flt-3, and c-Kit, and has been approved for the treatment of advanced RCC. In a randomized phase III clinical trial, sunitinib has shown an objective response rate of 31%, which was significantly higher than the 6% in patients that received IFN-{alpha} (10). The progression-free survival of the sunitinib treatment group was 11 months, whereas that of the IFN-{alpha} group was only 5 months (10). Based on current data available, sunitinib is now the preferred drug for first-line treatment of most mRCC patients (1).

Presently, there is little experience with the effects of sunitinib on the primary tumor in patients that present with mRCC. Therefore, we conducted a retrospective analysis of the drug-induced response in the primary tumor and also addressed the radiologic changes in contrast enhancement associated with the increase in central necrosis.


   Patients and Methods
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 Abstract
 Patients and Methods
Results
 Discussion
 References
 
Patients and treatment. Medical records were reviewed of patients treated with sunitinib for advanced RCC in two centers in the Netherlands (VU University medical center and the Netherlands Cancer Institute) from December 2005 to June 2007. Patients were selected that received sunitinib without prior nephrectomy. Most of the patients had been included in an expanded access program until September 2006, after which sunitinib was registered and available on doctor's prescription. Each participant signed an institutional review board–approved protocol-specific informed consent in accordance with national and institutional guidelines.

Sunitinib was administered orally at a dose of 50 mg daily, consisting of 4 wk of treatment followed by a 2-wk rest period in cycles of 6 wk. A dose reduction of sunitinib (to 37.5 mg and then to 25 mg) was allowed depending on the type and severity of adverse events. If patients had symptoms of progressive disease during the rest period, there was the possibility for continuous dosing of sunitinib at 37.5 mg/d.

Tumor response was assessed by computed tomography (CT) scans every two to three cycles of treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST; ref. 11). Tumor measurements were calculated separately for the response in the primary tumor and in the metastatic sites. Progression-free survival was the time between the first day of sunitinib and the date of progressive disease on the CT scan or clear clinical evidence of progressive disease. Survival was the time between the first day of treatment and the date of death or the date at which patients were last known to be alive. For progression-free survival and survival analysis, data collection was closed on November 1, 2007.

Image analysis. Portovenous phase CT scans of the abdomen were acquired ~70 s after i.v. injection of a low-osmolar nonionic contrast agent (Omnipaque or Ultravist 300). All series were reconstructed in 5-mm contiguous axial slices. Because volumetric measurements are considered as the reference standard for the assessment of the objective response, volumes of the primary tumors as visualized on CT scans were calculated using the perimeter method (12). Image viewing and manipulation were controlled with Centricity RA 600 version 6.1 software (GE Healthcare, Inc.), which allows the radiologist to draw perimeters around the regions of interest. The software then automatically calculates the area enclosed by the perimeter and the mean density of this area in Hounsefield units (HU).

An independent radiologist (M.R.M.) blinded to the patients' outcome examined the CT scan images. On each CT scan section in which the primary tumor was visible, the radiologist drew a line along the perimeter of the tumor to assess the area. The total volume (V) of the primary tumor was then calculated by summing the separate cross-sectional areas (A), multiplied by the section increment in millimeters (I), as follows: V = I(A1 + A2 + ...An), where n is the number of sections containing tumor and V is expressed in cubic centimeters. Primary tumors of RCC are known for central heterogeneity that is associated with intratumoral necrosis or hemorrhage on histologic assessment (13). Therefore, the volumetric measurements were repeated for the central hypodense nonenhancing part of the tumor. Nonenhancing areas at a density <40 HU were arbitrarily defined as most compatible with necrosis.

Statistical analysis. The total volume of the primary tumor, the volume of the hypodense nonenhancing part, and the volume of the solid part were calculated. The relation between volumetric measurements and the longest tumor diameter was assessed by Spearman correlation test. The Wilcoxon signed rank test was used to compare the tumor measurements at baseline and between 1.2 and 3.9 mo of sunitinib treatment. Two-tailed P < 0.05 was considered significant.


   Results
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 Abstract
 Patients and Methods
 Results
Discussion
 References
 
Patients and treatment response. Eighty-two patients with advanced RCC had been treated with sunitinib in the expanded access program, and an additional 13 patients received the drug on doctor's prescription following registration. Of these 95 patients, 22 patients had a primary tumor in situ. There were 17 males and 5 females, and the median age was 61 years (range, 48-77 years); 21 patients had clear cell carcinoma and 1 patient had non-clear cell carcinoma. According to the Memorial Sloan-Kettering Cancer Center criteria [based on the five risk factors: low Karnofsky performance status (<80%), high lactate dehydrogenase (>1.5 times the upper limit of normal), low serum hemoglobin, high corrected serum calcium (>10 mg/dL), and time from diagnosis to treatment <1 year; ref. 14], 16 patients were categorized into the intermediate-risk group and 6 patients into the poor-risk group. According to the prognostic criteria for vascular endothelial growth factor–targeted therapy by Choueiri et al. (ref. 15; based on the five risk factors: time from diagnosis to treatment <2 years, baseline platelet count >300 x 109/L, neutrophil count >4.5 x 109/L, corrected calcium <8.5 or >10 mg/dL, and initial Eastern Cooperative Oncology Group performance status >0), 1 patient had no adverse prognostic factor, 3 patients had 2, and 18 patients had >2 adverse prognostic factors. In 16 patients sunitinib was given as first-line treatment, and in 6 patients, as second-line treatment.

The primary decision not to perform a nephrectomy was based on a surgically unresectable primary tumor (n = 10), extensive metastatic burden defined as the sum of the diameter of the metastases exceeding the diameter of the primary tumor (n = 6), poor Memorial Sloan-Kettering Cancer Center prognosis (n = 2), solitary kidney (n = 2), high age (n = 1), and doctor's choice (n = 1).

At baseline, the median performance status according to Eastern Cooperative Oncology Group was 1 (range, 0-3). During sunitinib treatment, the physical condition of 8 of 22 patients improved remarkably. Three patients had an obvious deterioration of their performance status due to progressive disease. Four patients presented with symptoms related to the primary tumor consisting of flank pain and hematuria, which gradually disappeared in all of them. Four patients required a dose reduction to 37.5 mg/d because of adverse events and five switched to a continuous dosing schedule.

Four of 22 patients could not be evaluated for treatment response because of early termination of sunitinib due to progressive disease. In 18 patients, a follow-up CT scan was available. One of these 18 patients was excluded because he required embolization of the primary tumor within the first cycle due to extensive hematuria already present at the start of sunitinib. One patient had bilateral primary tumors. Summarized, 17 patients with 18 primary tumors were included in the image analyses.

According to RECIST, 4 of 17 patients reached a partial response, 12 had stable disease, and 1 had progressive disease (Table 1 ). Only in patient no. 15 the response of the primary tumor was not in line with the response of the metastases. Excluding the patient with progressive disease, RECIST calculations were analyzed for the primary tumor only, the metastases only, and the overall response, resulting in a median change of –12%, –28%, and –21%, respectively. Progression-free survival and survival of the individual patients are also depicted in Table 1.


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  		Table 1. Antitumor effects of sunitinib in patients with advanced RCC without prior nephrectomy

 
Imaging. The median volume of the 18 primary tumors was 208 cm3 at baseline. There was a high correlation between the volumetric measurements and the longest diameter of the primary tumors at baseline (Spearman's {rho} = 0.968, P = 1e–006; Fig. 1A ) and at the time of response evaluation (Spearman's {rho} = 0.956, P = 1e–006; Fig. 1B). At baseline, large tumors seemed to have larger necrotic areas; the necrotic volume correlated well with the tumor volume (Spearman's {rho} = 0.805, P = 5.51e–005). The patient with progressive disease was excluded from further analysis.


Figure 1
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  		Fig. 1. Relation between volumetric measurements and the size of the longest diameter of the primary RCC at baseline (A) and at first evaluation after the start of sunitinib (B).

 
During sunitinib treatment, the median density of the solid part decreased from 82 HU (range, 54-130 HU) to 66 HU (range, 49-116 HU; P = 0.028), whereas that of the hypodense nonenhancing, necrotic part was not altered. The changes in volumetric measurements of the primary tumor after 1.2 to 3.9 months of sunitinib are listed in Table 1. The volume of the primary tumor decreased in 13 of 17 patients (Fig. 2 ). In patients with partial response or stable disease (n = 16), the volume of the primary tumors (n = 17) significantly decreased with a median reduction of 31% (P = 0.001). The decrease of the volume of the solid part was also significant (median, 54%; P = 0.001). In contrast, a significant increase in the volume of the central necrosis was measured (median, 39%; P = 0.035). Changes in the volume of the solid part were significantly correlated with changes in the total volume of the primary tumor (Spearman's {rho} = 0.850, P = 1.52e–005) and changes in the necrotic volume (Spearman's {rho} = –0.645, P = 0.005).


Figure 2
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  		Fig. 2. Primary tumor of patient no. 6 at baseline (A) and after two cycles of sunitinib showing a decrease in size and an increase in necrosis (B). Perimeters were drawn around the tumor as well as around the necrotic part at baseline (C) and at the time of response (D). ROI, region of interest.

 
Follow-up CT scans were available to evaluate the long-term effects of sunitinib in seven patients with an initial decrease in the primary tumor volume. Although six of these patients had a further decrease in the primary tumor volume during continuation of sunitinib, the largest response was observed within the first 4 months (Fig. 3A ). During follow-up, the volume of the necrotic part remained more or less stable in most tumors (Fig. 3B), whereas the solid part decreased slightly further in six of eight tumors (Fig. 3C). Separate follow-up measurements of the longest diameter of the primary tumor and metastases during sunitinib treatment showed parallel decreases in size.


Figure 3
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  		Fig. 3. Follow-up measurements during sunitinib treatment in seven patients with a reduction in volume of the primary tumor. Colored lines belong to the same patients. One patient had bilateral primary tumors (light blue and dark blue lines).

 
Nephrectomy after sunitinib treatment. Three patients (nos. 9, 10, and 12) with mRCC had their kidney removed during sunitinib treatment. Initially, all presented with large right-sided primaries that seemed to be surgically unresectable because of suspected liver invasion. In patient no. 9, the primary tumor volume decreased by 46%. After 3 months on sunitinib, nephrectomy was carried out after discontinuation of the drug for 3 weeks. Patient no. 10 had 38% reduction of the primary tumor and underwent surgery after 11 months. Sunitinib was stopped 1 week before the operation. Patient no. 12 had 30% tumor volume reduction, and after 4 months surgery was done after withdrawal of sunitinib for only 2 days. Pathology revealed necrotic areas next to vital tumor cells (Fig. 4 ).


Figure 4
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  		Fig. 4. Pathology of a primary tumor of RCC (patient no. 12) after sunitinib treatment showing large necrotic areas (A) with preexistent blood vessels (B) next to vital tumor cells (C).

 
In the three patients there was no regrowth of disease in the treatment-free perioperative interval. No negative effects on hemostasis or wound healing were observed and the postoperative course was uneventful. After surgery, sunitinib was withheld in patient nos. 10 and 12 based on the excellent response in metastatic sites. Both patients presented with progressive disease 4 and 6 months after surgery, respectively. Patient no. 9 continued sunitinib after surgery until progressive disease, 6 months thereafter.


   Discussion
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 Abstract
 Patients and Methods
 Results
 Discussion
References
 
This is the first analysis on the effects of sunitinib on the primary tumor in 17 patients with advanced RCC expressed both according to RECIST and in volumetric measurements. Partial response or stable disease was measured in 16 of these patients. Thirteen patients had a volumetric reduction of the primary tumor of 18% to 64% associated with decrease of the longest diameter of 0% to 33%. The decrease in tumor volume was accompanied by an increase of central necrosis and a decrease of the vital solid part. In three patients with low metastatic tumor load, the primary tumor became surgically resectable. Apart from vital tumor cells, pathology showed extensive areas of necrosis. Our findings are of interest because outcome of advanced RCC patients without nephrectomy would have been poor in the cytokine era. Nowadays, when primary nephrectomy does not seem to be a valid option, patients may experience marked clinical benefit from sunitinib.

Primary tumors of RCC can grow to an enormous size as compared with their metastases, with longest diameters up to 20 cm (16). On sunitinib treatment, the longest diameter of the primary tumor shows a relatively smaller drop than that of the metastases (see Table 1). For this reason, large primary tumors will have an important effect on the overall objective response when these are included in RECIST measurements. Hence, the overall response may be underestimated because a relatively large reduction in primary tumor size is necessary to achieve a partial response as exemplified in patient nos. 12, 13, and 14. Therefore, it could be considered to exclude primary tumors in calculating the overall response according to RECIST.

Volumetric measurements, although cumbersome, may be preferred because tumor growth or shrinkage can be asymmetrical in one or even three dimensions. Fortunately, in our study, volumetric changes of the primary tumor of RCC showed a high correlation with the calculations according to RECIST. This indicates that the changes in size of the primary tumors can be considered symmetrical and that RECIST measurements reflect the response to sunitinib. Note that according to one-dimensional (RECIST), two-dimensional (WHO definition), and volumetric measurements, the response criteria are different and that a partial response is reached on a decrease in tumor size of 30%, 50%, and 65%, respectively (11).

Similar to findings in primary RCC, extensive necrosis can also be induced by sunitinib in hepatocellular carcinoma, reflected by a decrease in contrast enhancement on follow-up CT scans (17). Other tyrosine kinase inhibitors, such as sorafenib in RCC and imatinib in gastrointestinal stromal cell tumors, are known to cause early and extensive necrosis as well (18, 19). Treatment-induced necrosis is not part of standard criteria to assess tumor response. Because the necrotic part of primary tumors of RCC is often heterogeneous, very irregular, and asymmetrical, measuring necrosis by the longest diameter is difficult. Therefore, other methods to quantify necrosis are required. Here, we applied volumetric measurements and revealed an increase in necrosis in primaries. Another approach to include necrosis as part of tumor response has recently been described by Choi et al. (20, 21). In patients with gastrointestinal stromal cell tumors treated with imatinib, Choi response criteria (a ≥10% decrease in one-dimensional tumor size or a ≥15% decrease in tumor HU) seemed to be more accurate than RECIST and correlated significantly with time-to-tumor progression and disease-specific survival (20, 21). Faivre et al. (17) have also addressed the inadequacy of RECIST and used volumetric measurements for sunitinib-induced necrosis in hepatocellular carcinoma expressed as minor (<50%) and major (50%) posttreatment tumor necrosis. We show that RECIST criteria are well applicable to evaluate the response of metastases as well as of the primary RCC to sunitinib treatment. The increase in necrosis and the reduction of the solid part, however, might be a more consistent indicator for the extent of response. Note that increase of necrosis as well as tumor size would likely reflect progression of disease (patient no. 11). It remains to be investigated in mRCC treated with sunitinib whether other response criteria and functional imaging techniques will add to information already acquired by contrast-enhanced CT scans for measurements according to RECIST (22).

The pros and cons of cytoreductive nephrectomy in the presence of metastatic disease have long been a subject for debate (23–25). Historically, the nonresponsiveness of the primary tumor to cytokine therapy and the palliation of symptoms were arguments for a nephrectomy (2–4, 26). Increased perioperative and postoperative morbidity and mortality (27) in patients with incurable disease and a limited life expectancy were postulated as arguments against cytoreductive nephrectomy. Furthermore, surgery could lead to a potential delay or even cancellation of systemic therapy due to progression in metastatic sites, postoperative morbidity, or decreased performance status (25). The present responses of the primary tumor to sunitinib are very encouraging and put the role of a nephrectomy in a different light as compared with the guidelines in the cytokine era.

The observed responses in the primary tumor and the alleviation of symptoms on sunitinib treatment seem to have made the historical arguments for a nephrectomy defective reasoning. In our patients, sunitinib also improved the performance status in those with a response. Successful resection of the primary tumor directly invading adjacent organs and structures in three patients suggests that sunitinib may be used to improve surgical resectability in doubtful cases. Whether this is beneficial for patient outcome cannot be answered on the basis of these three cases. Prospective randomized phase III clinical trials in patients presenting with mRCC are warranted to define which patients treated with sunitinib will benefit from nephrectomy, to analyze whether nephrectomy has an effect on survival, and to determine the optimal timing of a nephrectomy (28). Such trials will lead to new guidelines on the role of nephrectomy in mRCC patients in the sunitinib era.


   Acknowledgments
 
We thank Dr. J. Berkhof for advice on statistics and Henk Mallo and Corinne Tillier for their help with patient care.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/ 3/07; revised 12/ 6/07; accepted 12/24/07.


   References
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 Abstract
 Patients and Methods
 Results
 Discussion
 References
 

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