1. Comprehend current management of metastatic renal cell carcinoma.

2. Learn how functional imaging accompanied the development of anti-angiogenic therapies.

3. Understand how MRI is uniquely placed to answer the future challenges to guide patient management.

The large majority of kidney cancers are renal cell carcinomas (RCC), which when localised, can often be cured by surgery [1]. In contrast, in the 20-30% of metastatic (mRCC) patients, prognosis was much poorer until recently, explained by the limited therapeutic options for patients with mRCC, since it is resistant to conventional cytotoxic chemotherapy [2].

During the past 10 years, the introduction of therapies targeting tumour vessels (anti-angiogenic therapies), including VEGF (Vascular Endothelial Growth Factor) and mTOR (mammalian target of rapamycin) inhibitors, has radically changed the therapeutic arsenal for mRCC and considerably improved survival for patients with this disease. Median survival has thus increased from less than 1 year with the earlier standard immune therapy (IFN-α) to nearly 2 years with targeted anti-angiogenic therapy [3]. These new therapies however, brought new challenges to imagers for evaluation of tumour response. Despite an increase of clinical benefit in terms of progression-free and overall survival, many patients remained stable according to conventional response criteria such as RECIST. Many other biomarkers were proposed to follow-up patients under these drugs [4]. Imaging, including functional MRI, allows quantifying changes in tumour vessels, and was therefore a logical choice for the evaluation of anti-angiogenic therapies. In preclinical animal studies, MRI gave insight in biological mechanisms of efficacy, particularly to explore early response and the phenomenon of vascular normalization [5]. In human studies, several strategies were used to evaluate tumour response under therapy. Dynamic contrast-enhanced (DCE) imaging including ultrasound, CT and MRI quantified changes in perfusion. Parameters derived from DCE imaging were both prognostic and predictive of tumour response [6-8]. But MRI may also be used to quantify tumour burden, which was also showed to be an independent prognostic factor [9]. Indeed, images of whole-body diffusion MRI can be segmented to quantify total diffusion volume [10].

There remain many challenges for imaging in mRCC. Firstly, in anti-angiogenic therapies of mRCC, mechanisms of escape and progression are still poorly understood. In vivo imaging techniques can provide further insight on the underlying biology. Therapeutic management involves managing a succession of different anti-angiogenic drugs, and choosing the right time to change lines is essential to ensure maximal clinical benefit. Secondly, drug-related toxicities may lead to treatment discontinuation despite efficacy. There is no current biomarker allowing prediction or early detection of toxicities, and imaging may play an important role in this field. Finally, a new class of drugs is currently under clinical trial in mRCC (as in many other cancers): immunotherapy including anti-PD1 or PDL1 drugs [11]. A whole new field of research still has to be developed to describe and comprehend changes in tumours under these immunotherapies. In melanoma under ipilumab, a subset of patients have shown a flare effect with a drastic increase in tumour size, leading to the definition of new criteria of response (irRC or immune-related Response Criteria) [12]. MRI is ideally placed to explore these changes since it combines morphology and function, and explores several very different functions of tumours such as vascularisation, cellularity, hypoxia… Ancillary studies including multiparametric MRI should be proposed for future clinical trials.

1. Current treatment of metastatic renal cell carcinoma relies on anti-angiogenic drugs, used successively, to prolong patient survival.

2. Functional imaging accompanied anti-angiogenic drug development by helping elicit biological mechanisms, and developing biomarkers of tumour response.

3. Remaining challenges include understanding drug escape mechanisms and toxicities of anti-angiogenic drugs, as well as accompanying clinical trials using new immunotherapies