SEARCH

SEARCH BY CITATION

Keywords:

  • MSKCC score;
  • outcome;
  • prognostic factor;
  • renal cell cancer;
  • sunitinib

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Study Type – Therapy (case series)

Level of Evidence 4

What's known on the subject? and What does the study add?

A randomized prospective phase III clinical trial for systemic treatment-naïve metastatic renal cell cancer (RCC) patients demonstrated the superiority of sunitinib over interferon with an acceptable safety profile. However, a commonly asked question is whether patients with RCC in clinical trials are representative of those with this disease being seen in ordinary clinical practice.

To our knowledge, this is the first report of sunitinib for the Japanese patients with metastatic RCC in ordinary clinical practice. The estimated median PFS and OS in this study were 9.3 and 32.2 months, respectively. The application of the MSKCC model distinctly separated OS curves (P < 0.001), suggesting that MSKCC prognostic factors might be still valid to predict survival in metastatic RCC in the era of molecular targeted therapy.

OBJECTIVES

  • • 
    To report the treatment efficacy and safety profile of sunitinib for patients with metastatic renal cell carcinoma (RCC) in ordinary clinical practice.
  • • 
    In addition, to investigate the prognostic clinicopathological factors in these patients.

PATIENTS AND METHODS

  • • 
    The present study consisted of native Japanese patients with metastatic RCC, comprising 29 pretreated and 34 systemic treatment-naïve patients.
  • • 
    Univariate and multivariate analyses were performed by the log-rank test and the Cox proportional hazards model, respectively.

RESULTS

  • • 
    Estimated median progression-free survival and overall survival (OS) were 9.3 months (95% confidence interval, CI, 5.0–13.7) and 32.2 months (95% CI, 24.4–40.0), respectively.
  • • 
    Among the patients pretreated before sunitinib, two patients were treated with initialized systemic therapy with sorafenib and the remaining 27 were initialized with interferon-α.
  • • 
    The OS from the initial systemic therapy of the patients in pretreated groups was 79.6 months (95% CI, 14.6–144.5).
  • • 
    The application of the Memorial Sloan-Kettering Cancer Center model distinctly separated the OS curves (P < 0.001).
  • • 
    The most common grade 3 adverse events were fatigue (53%), thrombocytopaenia (48%), hand-foot syndrome (16%), anaemia (20%), hypertension (10%) and leucopaenia (9%), although these events were manageable and reversible.

CONCLUSIONS

  • • 
    Sunitinib has a favourable efficacy/safety profile for Japanese metastatic RCC patients in clinical practice.
  • • 
    The estimated median OS was >2 years with acceptable tolerability.
  • • 
    The median OS from the initial systemic therapy of the pretreated patients was >6 years.
  • • 
    Memorial Sloan-Kettering Cancer Center prognostic factors still appear to be valid for predicting survival in metastatic RCC in the era of molecular targeted therapy.

Abbreviations
ECOG

Eastern Cooperative Oncology Group

Hb

haemoglobin

LDH

lactate dehydrogenase

MSKCC

Memorial Sloan-Kettering Cancer Center

ORR

objective response rate

OS

overall survival

PFS

progression-free survival

PS

performance status.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Sunitinib is an orally administered, multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1–3 and platelet-derived growth factor receptors α and β[1,2]. A randomized, prospective phase III clinical trial for systemic treatment-naïve metastatic RCC patients showed the superiority of sunitinib over interferon with respect to objective response rate (ORR) (31% vs 6%), progression-free survival (PFS) (11 vs 5 month) and overall survival (OS) (26.4 vs 21.8 months), with an acceptable safety profile [3,4]. These results indicate an improved prognosis in patients with RCC in the era of targeted therapy.

The first Japanese phase II study of single-agent sunitinib, which was conducted in 51 patients with metastatic RCC, also showed efficacy and tolerability comparable to that observed in Western patients [5]. In that study, the ORR was 52.0% in treatment-naïve patients, 53.8% among cytokine-pretreated patients and 52.9% in the overall population [5]. As a result of these findings, the multinational approvals of sunitinib for treatment of first- and second-line advanced RCC now include Japan.

However, a commonly asked question is whether patients with RCC in clinical trials are representative of those with this disease who are seen in ordinary clinical practice. Many patients with RCC do not meet the inclusion criteria, particularly those with a poorer prognosis. Patients with a poor performance status (PS), brain metastasis or other clinical parameters predicting shorter survival are often excluded from clinical trials. In the present study, we report the treatment efficacy and safety profile of sunitinib for patients with metastatic RCC in ordinary clinical practice. In addition, we also investigated the prognostic clinicopathological factors associated with OS in this population.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

PATIENT POPULATION

The present study consisted of native Japanese patients with metastatic RCC. The study group comprised 29 patients pretreated before sunitinib and 34 systemic treatment-naïve patients, who were all undergoing treatment at the Akita University Medical Center or the Cancer Institute Hospital, Japanese Foundation for Cancer Research, from March 2006 until January 2011. The patients included in the retrospective study were not consecutive. In this period, patients with metastatic renal cell cancer were treated by sunitinib or interferon-α as an initial treatment and sunitinib or sorafenib as a secondary treatment, fundamentally. All RCC patients were diagnosed on the basis of histological analysis of specimens obtained by radical nephrectomy or ultrasonographically-guided needle biopsy.

TREATMENT AND ASSESSMENT

Each patient signed a protocol-specific informed consent, approved by an institutional review board, in accordance with national and institutional guidelines. Sunitinib was administered orally at a dose of 50 mg daily, for 4 weeks followed by a 2-week rest period. Sunitinib was discontinued in the case of grade 3 or 4 toxicity and was re-administrated when toxicity was ≤grade 1. In the case of grade 3 non-haematological toxicity or grade 4 haematological toxicity, a dose reduction of sunitinib (to 37.5 mg and then to 25 mg) was allowed. The response was assessed by CT scans performed at least every two cycles of treatment, in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0 [6]. Safety and tolerability were assessed at regular intervals with adverse event monitoring using National Cancer Center Common Toxicity Criteria for Adverse Events, version 3.0, to document adverse events and classify severity; haematology and biochemistry; body weight; vital signs; and Eastern Cooperative Oncology Group (ECOG) PS.

STATISTICAL ANALYSIS

OS and PFS were measured from the initial administration of sunitinib until death from any cause, and from the date of initial administration of sunitinib until objective tumour progression or death, respectively. Time-to-event distributions were estimated using Kaplan–Meier curves. Univariate and multivariate analyses were performed by the log-rank test and the Cox proportional hazards model, respectively, aiming to assess the relationship between OS and the laboratory, as well as clinical variables. The laboratory variables included haemoglobin (Hb; male: <13 g/dL vs ≥13 g/dL; female: <11.5 g/dL vs ≥11.5 g/dL); neutrophil count (≤6600/µL vs >6600/µL); platelet count (≤4.5 × 105/µL vs >4.5 × 105/µL); corrected calcium (≤10 mg/dL vs >10 mg/dL) and lactate dehydrogenase (LDH; ≤1.5 × 230 IU/dL vs >1.5 × 230 IU/dL). The clinical variables included ECOG PS (≤1 vs >1); time from diagnosis of RCC to systemic therapy initiation (<12 months vs ≥12 months); time from diagnosis to sunitinib initiation (<12 months vs ≥12 months); history of nephrectomy (no vs yes); number of metastatic sites (1 vs ≥1); presence or absence of lung, bone, lymph node and brain metastasis (yes vs no); tumour grade (I, II vs III); clear cell histology (clear cell or no clear cell histology); and the presence or absence of sarcomatoid component (without sarcomatoid component vs with sarcomatoid component). The corrected serum calcium level was calculated using Payne's formula [7]. SPSS software was used for statistical analysis (SPSS for Windows, version 17.0, SPSS Inc., Chicago, IL, USA).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

PATIENT CHARACTERISTICS

The characteristics of the patients treated with sunitinib are shown in Table 1. Among the patients pretreated before sunitinib, two patients were initialized with systemic therapy with sorafenib because the approval of sorafenib had been given 3 months before that of sunitinib in Japan. The remaining 27 patients were initialized with interferon-α. The median (interquartile range) follow-up from the initial systemic therapy and sunitinib start was 17.3 (8.0–40.1) months and 7.7 (3.3–16.4) months, respectively. Overall, 19 (30%) patients showed a partial response and 32 (51%) patients showed stable disease longer than 3 months by RECIST criteria, indicating that 81% of the patients experienced a clinical benefit from sunitinib. Progression within 3 months was observed in 12 (19%) patients, and none experienced an early treatment failure before the initial assessment.

Table 1.  Patient characteristics
VariableValue
Age (years), median (range)62 (27–81)
Sex, n (%) 
 Male50 (79)
 Female13 (21)
Diagnosis to systemic therapy, n (%) 
 1 year16 (25)
 >1 year47 (75)
Diagnosis to sunitinib, n (%) 
 ≤1 year30 (48)
 >1 year33 (52)
Previous systemic therapy, n (%) 
 Yes29 (46)
 No34 (54)
Nephrectomy, n (%) 
 Done49 (78)
 None14 (22)
Number of metastatic sites, n (%) 
 131 (49)
 <132 (51)
Metastatic sites, n (%) 
 Lung43 (68)
 Liver16 (25)
 Bone19 (30)
 Lymph node24 (38)
 Brain5 (8)
Histological subtype, n (%) 
 Clear cell type51 (81)
 Papillary type6 (10)
 Chromophobe type2 (3)
 Others4 (6)

PFS AND OS

Estimated median PFS and OS were 9.3 months (95% CI, 5.0–13.7) and 32.2 months (95% CI, 24.4–40.0), respectively. Estimated 12-month PFS and 18-month OS rates were 47.8% and 53.7%, respectively. During follow-up, 28 (44%) patients died from RCC. In addition, we investigated the OS from the initial systemic therapy given to the patients in pretreated groups, and their median OS was 79.6 months (95% CI, 14.6–144.5).

PROGNOSTIC FACTORS ASSOCIATED WITH OS PERIOD

Finally, we investigated the prognostic factors associated with overall survival time. Univariate analysis showed that the various pretreatment factors were associated with worse OS (Table 2). All the factors in a Memorial Sloan-Kettering Cancer Center (MSKCC) score [8], which include ECOG PS >1 (P= 0.001), low Hb levels (P= 0.002), high corrected calcium levels (P= 0.008) and high LDH levels (P < 0.001), and ≤12 months between diagnosis and initial systemic therapy (P= 0.037), were associated with worse OS (Table 2). Multivariate analysis by a Cox proportional hazard model showed that low Hb and high LDH were independently associated with poorer OS among MSKCC scores (Table 3). In addition, brain metastasis and no history of nephrectomy were also associated with poorer OS.

Table 2.  Univariate analysis of factors associated with overall survival
CategoryNMedian OS95% CIP
  1. ECOG PS, Eastern Cooperative Oncology Group performance status; OS, overall survival; Dx, diagnosis; Tx, treatment; ULN, upper limit of normal range.

ECOG PS    
 0–15235.812.5–44.2 
 ≤2116.032.8–9.20.001
Haemoglobin    
 Normal26Not reached  
 Anaemia379.85.1–14.60.002
Calcium    
 >10 mg/dL5635.026.7–43.3 
 ≤10 mg/dL77.00.0–15.20.008
Lactate dehydrogenase    
 ≥1.5 × ULN5136.027.6–44.4 
 <1.5 × ULN122.30–8.2<0.001
Dx to systemic Tx    
 ≤1 year16Not reached  
 >1 year4712.53.2–21.80.037
Neutrophil count    
 ≥ULN5534.826.4–43.2 
 <ULN84.90–10.60.054
Platelet count    
 ≥ULN5933.925.8–42.1 
 <ULN43.41.9–4.80.051
Dx to sunitinib    
 ≤1 year3038.212.3–21.3 
 >1 year3310.66.5–14.70.106
Previous systemic therapy    
 Yes29Not reached  
 No3428.819.8–37.80.719
Nephrectomy    
 Done4936.127.4–44.7 
 None1410.35.8–15.10.039
Number of metastatic sites    
 13138.531.4–45.6 
 <1329.84.6–15.00.002
Lung metastasis    
 Yes4337.027.3–46.8 
 No2031.222.5–40.00.188
Liver metastasis    
 Yes167.04.0–9.9 
 No47Not reached 0.082
Bone metastasis    
 Yes1911.67.5–15.9 
 No4433.424.5–42.30.328
Lymph node metastasis    
 Yes2410.67.7–13.5 
 No3935.526.2–44.70.171
Brain metastasis    
 Yes56.40.0–13.1 
 No5835.327.2–43.40.001
Grade    
 1, 232Not reached  
 31910.38.2–12.30.158
Histology    
 Clear cell5133.324.9–41.8 
 Non-clear cell1216.92.9–17.60.961
Sarcomatoid    
 Without sarcomatoid5335.326.9–43.8 
 With sarcomatoid107.07.0–7.20.014
Table 3.  Multivariate analyses associated with poor survival
ParameterHazard ratio95% CIP
  1. LLN, lower limit of normal range; ULN, upper limit of normal range.

Laboratory data   
 Haemoglobin <LLN2.6581.064–7.5470.044
 Lactate dehydrogenase >1.5 × ULN2.6781.105–6.4900.029
Clinical data   
 Brain metastasis6.4992.277–18.5550.001
 No history of nephrectomy3.0861.287–7.4070.012

Because the patients included in the present study represent a mixture of treatment naïve and refractory RCC patients, we analyzed these two groups separately. The application of the MSKCC model (using PS, Hb, calcium, LDH and time from diagnosis to initiation of systemic therapy) to stratify patients into three risk groups for the treatment naïve patients (favourable: no risk factors, 12%, n= 4; intermediate: one or two risk factors, 59%, n= 20; poor: three to five risk factors, 29%, n= 10) distinctly separated the OS curves (Fig. 1A). On the other hand, the application of the MSKCC model for the treatment refractory patients [9] (using Hb, calcium and PS) to stratify patients into three risk groups (favourable: no risk factors, 13%, n= 12; intermediate: one risk factor, 62%, n= 13; poor: two or three risk factors, 25%, n= 4) also distinctly separated the OS curves (Fig. 1B).

image

Figure 1. Stratification of the overall survival for the patients with metastatic renal cell cancer by the respective Memorial Sloan-Kettering Cancer Center (MSKCC) risk scores. Stratification of the treatment naïve (A) and the treatment refractory (B) patients by MSKCC risk scores.

Download figure to PowerPoint

ADVERSE EFFECTS

All 63 patients experienced treatment-related adverse events, most of which were grade 1 or 2 in severity. The most common grade 3 or 4 adverse events were fatigue (53%), thrombocytopaenia (48%), hand-foot syndrome (16%), anaemia (20%), hypertension (10%) and leucopaenia (9%). Most of these adverse events were manageable and reversible. Although most patients were able to resume therapy after treatment modification, only two (3%) patients and one (1%) patient discontinued because of adverse fatigue and hand-foot syndrome events, respectively. In particular, the incidence of hypothyroidism (76%) was remarkable. Among these patients, levothyroxine had to be administered to maintain thyroid function in 37 (59%) patients.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

In the present study, we retrospectively analyzed the ORR, PFS, OS and prognostic factors in 63 native Japanese patients, suggesting that the results of the present study could reflect current clinical practice in metastatic RCC in our country. In this cohort, the ORR and clinical benefit (partial response plus stable disease >12 weeks) from sunitinib were 30% and 81%, respectively. These are somewhat lower than the results of a Japanese phase II study (52% and 78%) [5] but slightly better than the results from an expanded-access programme in Western countries (16% and 76%) [10]. The estimated median PFS and OS in the present study were 9.3 and 32.2 months, respectively. These are also somewhat lower than the results of the Japanese phase II study (12.2 and 33.1 months for treatment-naïve patients and 10.6 and 32.5 months for cytokine-refractory patients) but slightly better than the results from the expanded-access programme in Western countries (10.9 and 18.4 months) [5,10,11]. In addition, it should be noted that 42% of the patients in the present study were still on treatment, which may have resulted in an underestimation of the ORR, as suggested by a recent analysis showing a higher ORR after longer follow-up [3,12].

It is remarkable that the median OS from the initial systemic therapy of the pretreated patients was 79.6 months. In a phase III randomized clinical trial, sunitinib showed longer PFS and OS compared to interferon-α as a first-line therapy for patients with metastatic RCC [3,4]. Interestingly, the OS was not significantly different between the treatment naïve patients and pretreated patients in the present study (not reached and 24.2 months), in the expanded-access programme (18.4 and 18.1 months) [10] and in the Japanese phase II study (33.1 and 32.5 months, respectively [11]. These results suggest that sunitinib can give a favourable impact as a second-line therapy for patients refractory to cytokine therapy rather than for treatment-naïve patients.

All of the risk factors (ECOG PS >1, low Hb level, high corrected calcium level, high LDH level and ≤12 months between diagnosis and initial systemic therapy) were associated with worse OS in the MSKCC scores, which have been previously identified in patients treated with cytokines (Fig. 1A and Table 2) [8,9]. The application of the respect MSKCC models for the treatment naïve and refractory patients also distinctly separated the OS curves (Fig. 1). This is consistent with recent studies identifying patients who probably will benefit from tyrosine kinase inhibitors [12–15]. These results, as well as those obtained in the present study, indicate that MSKCC scores are associated with the behaviour of the disease rather than with specific forms of therapy. Therefore, MSKCC prognostic factors are still valid for predicting survival in metastatic RCC in the molecular targeted therapy era. However, the distribution of patients according to the MSKCC model is uneven: in the series from the present study, 13%, 62% and 25% of patients belonged to favourable, intermediate and poor risk groups, respectively. The disproportionately large number of patients in the intermediate group suggests that the outcome of this group may be somewhat heterogeneous. The prognostic significance of these factors remains to be verified in a larger study because the present study is only preliminary and has a small number of patients.

Apart from the MSKCC score, brain metastasis and no history of nephrectomy were also independently associated with poorer OS. The cumulative incidence of brain metastases is ≈10%, and these patients are considered to have a poor prognosis (median overall survival, 3–6 months) [16,17]. Although some studies have reported that sunitinib has activity against brain metastasis [18,19], and even against multiple brain lesions [19], there is insufficient information available about the activity of sunitinib for brain metastasis because most clinical trials have excluded patients with brain metastasis. Intracerebral haemorrhage in RCC patients with brain metastases should be considered as a cautious adverse effect to be treated with tyrosine kinase inhibitors, although the incidence of this remains to be reported. We consider radiotherapy as a primary treatment for patients with brain metastasis; thereafter, targeted therapies could be considered. However, in the present study, no patients suffered intracerebral haemorrhage.

Among the 49 patients who underwent nephrectomy, 22 patients did so as a cytoreductive strategy. Upfront cytoreductive nephrectomy, followed by systemic therapy, has been established as the standard care for metastatic RCC in the cytokine era [20,21]. Targeted agents, including sunitinib, have shown improved outcomes compared to cytokine therapy, transforming the treatment strategy of metastatic RCC. Although many studies focus on the role of cytoreductive nephrectomy in combination with targeted agents for patients with metastatic RCC, cytoreductive nephrectomy is still recommended at least for those patients with currently good PS.

All patients experienced treatment-related adverse events, most of which were grade 1 or 2 in severity, and most patients were able to resume therapy after treatment modification. In particular, the incidence of grade 3/4 haematological toxicities, including anaemia (20%), leucopaenia (9%) and thrombocytopaenia (48%), appears to be higher in the present study compared to the previous worldwide phase III clinical trial data [3,4], and also is consistent with the report from the Japanese phase II clinical trial [5,11].

In conclusion, sunitinib has a favourable efficacy/safety profile for Japanese metastatic RCC patients in clinical practice. The estimated median OS was >2 years with acceptable tolerability. In addition, it should be noted that the median OS from the initial systemic therapy of pretreated patients was >6 years. MSKCC prognostic factors appear to be still valid for predicting survival in metastatic RCC in the era of molecular targeted therapy.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

This work was partly supported by the Takeda Science Foundation, the Kobayashi Institute for Innovative Cancer Chemotherapy, and Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES
  • 1
    Hutson TE, Figlin RA. Novel therapeutics for metastatic renal cell carcinoma. Cancer 2009; 115: 23617
  • 2
    Christensen JG. A preclinical review of sunitinib, a multitargeted receptor tyrosine kinase inhibitor with anti-angiogenic and antitumour activities. Ann Oncol 2007; 18: x310
  • 3
    Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356: 11524
  • 4
    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 2009; 27: 358490
  • 5
    Uemura H, Shinohara N, Yuasa T et al. A phase II study of sunitinib in Japanese patients with metastatic renal cell carcinoma: insights into the treatment, efficacy and safety. Jpn J Clin Oncol 2010; 40: 194202
  • 6
    Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European organization for research and treatment of cancer, national cancer institute of the United States, national cancer institute of Canada. J Natl Cancer Inst 2000; 92: 2051
  • 7
    Payne RB, Little AJ, Williams RB, Milner JR. Interpretation of serum calcium in patients with abnormal serum proteins. Br Med J 1973; 4: 6436
  • 8
    Motzer RJ, Murphy BA, Bacik J, Russa P, Mazudmar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 2001; 20: 28996
  • 9
    Motzer RJ, Bacik J, Schwartz LH et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004; 22: 45463
  • 10
    Gore ME, Szczylik C, Porta C et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol 2009; 10: 75763
  • 11
    Tomita Y, Shinohara N, Yuasa T et al. Overall survival and updated results from a phase II study of sunitinib in Japanese patients with metastatic renal cell carcinoma. Jpn J Clin Oncol 2010; 40: 116672
  • 12
    Bamias A, Karadimou A, Lampaki S et al. Prognostic stratification of patients with advanced renal cell carcinoma treated with sunitinib: comparison with the Memorial Sloan-Kettering prognostic factors model. BMC Cancer 2010; 10: 45
  • 13
    Choueiri TK, Garcia JA, Elson P et al. Clinical factors associated with outcome in patients with metastatic clear-cell renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy. Cancer 2007; 110: 54350
  • 14
    Patil S, Figlin RA, Hutson TE et al. Prognostic factors for progression-free and overall survival with sunitinib targeted therapy and with cytokine as first-line therapy in patients with metastatic renal cell carcinoma. Ann Oncol 2011; 22: 295300
  • 15
    Heng DY, Xie W, Regan MM et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol 2009; 27: 57949
  • 16
    Schouten LJ, Rutten J, Huveneers HA, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 2002; 94: 2698705
  • 17
    Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol 2004; 22: 286572
  • 18
    Medioni J, Cojocarasu O, Belcaceres JL, Halimi P, Oudard S. Complete cerebral response with sunitinib for metastatic renal cell carcinoma. Ann Oncol 2007; 18: 12823
  • 19
    Zeng H, Li X, Yao J et al. Multifocal brain metastases in clear cell renal cell carcinoma with complete response to sunitinib. Urol Int 2009; 83: 4825
  • 20
    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 2001; 345: 16559
  • 21
    Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R. European Organisation for Research and Treatment of Cancer (EORTC) Genitourinary Group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 2001; 358: 96670