Ultrasound in the Assessment of Tumor Response in the Age of Targeted and Immuno-Oncology Therapies. Back to the Future

In Oncology, ultrasound has been long considered among the least convincing imaging techniques to evaluate response to chemoteraphy. The inter-operator variability, reduced panoramic view, and the impossibility of providing information about lung and bones were justified reasons for considering computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) as superior techniques compared to ultrasound imaging (US). But should we accept this message as unequivocal and true for every possible clinical setting in Oncology and most importantly even for any future scenario? Most likely not. Inspite of the above mentioned limitations, US techniques have become able to provide additional informations that are complementary to those provided by other techniques. Our readers could undoubtedly think that this merit belongs to the technological development of that the ultrasound techniques have experienced in recent years, including contrast enhanced ultrasound and sonoelastography [1] [2] [3]. However, while this thought is undoubtedly correct, this paradigm shift is in addition derived from the parallel progress in the development of new anticancer drugs. The conventional cytotoxic regimens, whose efficacy is measured according to the extent of tumour shrinkage, have become flanked or replaced by targeted therapies that achieve disease stabilisation with a reduced rate of objective responses. Most often, this effect mirrors a reduction in intratumoral microvascular blood flow. Different clinical trials have evaluated the possibility of correlating CEUS parameters and clinical response to these new agents. Indeed, a correlation was demonstrated for patients with renal cell carcinoma (RCC) treated with sunitinib [4] and sorafenib [5] [6], for patients with hepatocellular carcinoma (HCC) treated with bevacizumab [7] and sorafenib [8], and for patients with liver metastases from neuroendocrine tumours [9]. In the case of HCC, CEUS obtained using vascular endothelial growth factor receptor-2 (VEGFR-2) targeted microbubbles was also explored in a murine model, resulting in a potential imaging modality to discriminate sorafenib responders and non-responders [10].

• Reference

• 1 Dietrich CF, Lorentzen T, Appelbaum L. et al. EFSUMB Guidelines on Interventional Ultrasound (INVUS), Part III – Abdominal Treatment Procedures (Short Version). Ultraschall in Med 2016; 37: 27-45 . doi: 10.1055/s-0035-1553965. Epub 2016 Feb 12
• 2 Sidhu PS, Cantisani V, Dietrich CF. et al. The EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound (CEUS) in Non-Hepatic Applications: Update 2017 (Short Version). Ultraschall in Med 2018; 39: 154-180 . doi: 10.1055/s-0044-101254. Epub 2018 Mar 6
• 3 Dietrich CF, Bamber J, Berzigotti A. et al. EFSUMB Guidelines and Recommendations on the Clinical Use of Liver Ultrasound Elastography, Update 2017 (Short Version). Ultraschall in Med 2017; 38: 377-394 . doi: 10.1055/s-0043-103955. Epub 2017 Apr 13
• 4 Lassau N, Koscielny S, Albiges L. et al. Metastatic renal cell carcinoma treated with sunitinib: early evaluation of treatment response using dynamic contrast-enhanced ultrasonography. Clin Cancer Res 2010; 16: 1216-1225
• 5 Lamuraglia M, Escudier B, Chami L. et al. To predict progression-free survival and overall survival in metastatic renal cancer treated with sorafenib: pilot study using dynamic contrast-enhanced Doppler ultrasound. Eur J Cancer 2006; 42: 2472-2479
• 6 Escudier B, Lassau N, Angevin E. et al. Phase I trial of sorafenib in combination with IFN alpha-2a in patients with unresectable and/or metastatic renal cell carcinoma or malignant melanoma. Clin Cancer Res 2007; 13: 1801-1809
• 7 Lassau N, Koscielny S, Chami L. et al. Advanced hepatocellular carcinoma: early evaluation of response to bevacizumab therapy at dynamic contrast-enhanced US with quantification--preliminary results. Radiology 2011; 258: 291-300
• 8 Zocco MA, Garcovich M, Lupascu A. et al. Early prediction of response to sorafenib in patients with advanced hepatocellular carcinoma: the role of dynamic contrast enhanced ultrasound. J Hepatol 2013; 59: 1014-1021
• 9 Lin X, Chen J, Xu M. et al. Application of Parametric Contrast-Enhanced Ultrasound for Early Treatment Response Evaluation in Metastatic Hepatic Neuroendocrine Neoplasm (abstract 189 (I8)). ENETs annual conference 2017 https://www.enets.org/application-of-parametric-contrast-enhanced-ultrasound-for-early-treatment-response-evaluation-in-metastatic-hepatic-neuroendocrine-neoplasm.html
• 10 Baron Toaldo M, Salvatore V, Marinelli S. et al. Use of VEGFR-2 Targeted Ultrasound Contrast Agent for the Early Evaluation of Response to Sorafenib in a Mouse Model of Hepatocellular Carcinoma. Mol Imaging Biol 2015; 17: 29-37
• 11 Kim SH, Lee YJ, Kim YJ. et al. Contrast-Enhanced Ultrasound for Early Prediction of Response of Breast Cancer to Neoadjuvant Chemotherapy. Ultraschall in Med 2019; 40: 194-204
• 12 Wei X, Li Y, Zhang S. et al. Ultrasound Targeted Apoptosis Imaging in Monitoring Early Tumor Response of Trastuzumab in a Murine Tumor Xenograft Model of Her-2–Positive Breast Cancer. Transl Oncol 2014; 7: 284-291
• 13 Di Cosimo S, Campbell C, Azim HA. et al. The use of breast imaging for predicting response to neoadjuvant lapatinib, trastuzumab and their combination in HER2-positive breast cancer: Results from Neo-ALTTO.
• 14 Bargellini I, Scionti A, Mismas V. et al. Identification of responders to sorafenib in hepatocellular carcinoma: is tumor volume measurement the way forward?. Oncology 2014; 86: 191-198
• 15 Choi YR, Kim JH, Park SJ. et al. Therapeutic response assessment using 3D ultrasound for hepatic metastasis from colorectal cancer: Application of a personalized, 3D-printed tumor model using CT images. PloS One 2017; 12: e0182596