ReviewTo predict progression-free survival and overall survival in metastatic renal cancer treated with sorafenib: Pilot study using dynamic contrast-enhanced Doppler ultrasound☆
Introduction
Sorafenib (BAY43-9006) was originally identified through its inhibitory effects on Raf-1 (c-Raf IC 50 = 2 nM.), a serine/threonine kinase and member of the Raf/MEK/ERK signalling pathway.1 Addition, biochemical and cellular mechanistic assays demonstrated further activity against B-Raf (B-raf wild type IC50 = 25 nM, B-raf mutant = 38 nM) and several receptor tyrosine kinases, including VEGFR-2, PDGFR, Fit-3 and c-KIT2.2 Sorafenib significantly inhibited neovascularisation in breast and colon xenograft models, and showed potent dose-dependent tumour regression in various xenograft models1 including two human colon cancers, pancreatic and human breast cancer.2
Different phase I and II studies have demonstrated the efficacy of this new agent in refractory solid tumours.3, 4, 5 Ahmad and colleagues in a series of 41 patients with renal cell carcinoma (RCC) demonstrated stable disease in 30% and tumour shrinkage of >25% in 40%.6
The activity of sorafenib in renal cell carcinoma (RCC) has been demonstrated in a phase II trial with disease control in 70% of 202 patients at 12 weeks.33 A double-blind randomised phase III study was initiated in November 2003 in RCC comparing sorafenib, 400 mg bid or a matching placebo (orally) in patients who had failed first-line treatment, and 905 patients had been enrolled. Highly significant improvement in PFS has recently been reported.34
Solid tumour survival and distant dissemination largely depend on two angiogenic growth factors, bFGF and VEGF, which have been shown to differentially activate Raf. Targeted delivery of a mutant form of Raf-1 to tumour blood vessels inhibited angiogenesis and was also shown to lead to regression of established tumours.7 Doppler ultrasonography (DCE-US) is the technique usually used at our institute to assess the size and echostructure of abdominal tumours as well as tumour neovascularisation.35 DCE-US imaging of tumour vascularisation could therefore be an excellent tool for predicting the efficacy of antiangiogenic drugs such as sorafenib in the clinic.
Morphological and functional imaging modalities such as contrast-enhanced magnetic resonance imaging (MRI), computed tomography (CT scan) or positron emission tomography (PET scan) must be used to evaluate tumour response to antiangiogenic treatment. Both morphological and functional data are provided by Doppler ultrasonography (DCE-US) with contrast agent injection.8 The size of tumours can be accurately measured and the percentage of contrast uptake, a yardstick of tumour vascularity, can be evaluated with this technique.9
The objective of this study was to evaluate whether DCE-US using perfusion software (Vascular Recognition Imaging) and contrast agent, could be used to correlate changes in tumour vasculature with tumour response, progression-free survival (PFS) and overall survival (OS).
We thus compared the changes from baseline in patterns of tumour vascularisation detected during treatment, in an attempt to predict clinical outcomes.
Section snippets
Patients
Thirty patients, 12 women and 18 men (mean age: 56.2 ± 8.7 SD) with ultrasonographically evaluable metastatic RCC were enrolled in this parallel study during the above-mentioned large phase III study. Examinations were performed at baseline, and after 3 and 6 weeks on sorafenib or a placebo in patients with tumour targets that were accessible to DCE-US. Specialised sonographers were blinded to treatment group assignment. Metastatic RCC were in the liver (patients [pts] n = 8), homolateral adrenal
Results
Thirty patients were enrolled and a total of 85 examinations were performed: 30 at baseline, 28 at 3 weeks (two patients had stopped the treatment before 3 weeks) and 27 at 6 weeks (one patient had stopped the treatment before 6 weeks). Among the 27 patients who were fully assessable, nine were treated with sorafenib and 18 received the placebo. The difference in PFS between these two groups of patients (median: 18 weeks placebo group and 40 sorafenib group) was statistically significant (p = 0.04) (
Discussion
The results of this study demonstrate the value of evaluating tumour vascularity with DCE-US with perfusion software (VRI) and contrast agent injection.
Since 1999, high-frequency Doppler ultrasonography has been capable of detecting neovascularisation in animal tumour models10, 11 and in human tumours.12, 13 Contrast-enhanced ultrasonography has been used to optimise the detection of angiogenesis.14 This technique has benefited from major technological improvements such as digitisation and
Conclusion
DCE-US is a new simple noninvasive imaging technique allowing accurate evaluation of tumour vascularisation. Overall, the combination of a decrease in contrast uptake exceeding 10% with stability or a decrease in tumour volume significantly predicted PFS and OS in this population of RCC patients. In addition, these criteria seem capable of selecting patients who will benefit from treatment with sorafenib. Imaging approaches such as DCE-US may advance the identification of new predictors of
Conflict of interest statement
None declared.
Acknowledgement
The authors are grateful to Lorna Saint Ange for editing.
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This work was presented at the ASCO and ECCO meetings in 2005.