The Changing Therapeutic Landscape of Metastatic Renal Cancer

Abstract

The practising clinician treating a patient with metastatic clear cell renal cell carcinoma (CCRCC) faces a difficult task of choosing the most appropriate therapeutic regimen in a rapidly developing field with recommendations derived from clinical trials. NCCN guidelines for kidney cancer initiated a major shift in risk categorization and now include emerging treatments in the neoadjuvant setting. Updates of European Association of Urology clinical guidelines also include immune checkpoint inhibition as the first-line treatment. Randomized trials have demonstrated a survival benefit for ipilimumab and nivolumab combination in the intermediate and poor-risk group, while pembrolizumab plus axitinib combination is recommended not only for unfavorable disease but also for patients who fit the favorable risk category. Currently vascular endothelial growth factor (VEGF) targeted therapy based on tyrosine kinase inhibitors (TKI), sunitinib and pazopanib is the alternative regimen for patients who cannot tolerate immune checkpoint inhibitors (ICI). Cabozantinib remains a valid alternative option for the intermediate and high-risk group. For previously treated patients with TKI with progression, nivolumab, cabozantinib, axitinib, or the combination of ipilimumab and nivolumab appear the most plausible alternatives. For patients previously treated with ICI, any VEGF-targeted therapy, not previously used in combination with ICI therapy, seems to be a valid option, although the strength of this recommendation is weak. The indication for cytoreductive nephrectomy (CN) is also changing. Neoadjuvant systemic therapy does not add perioperative morbidity and can help identify non-responders, avoiding unnecessary surgery. However, the role of CN should be investigated under the light of new immunotherapeutic interventions. Also, markers of response to ICI need to be identified before the optimal selection of therapy could be determined for a particular patient.

Cell Motility and Cancer

“…Also, tumor-associated fibroblasts increase local tumor aggressiveness favoring the development of metastases, as it has been reported in different tumors [63][64][65]. Cell migration due to chemotaxis can also be observed in processes related to tumor development, as it has been demonstrated with T-cells serving as the basis for the recently developed immune therapies [66]. In this sense, the PD-1/PD-L1 axis blockage is a promising therapeutic tool that is being successfully used in several types of malignant tumors, including kidney [67], breast [68], lung [69] and bladder [70] cancers, as well as malignant melanoma [71].…”

<p>Prognostic Value and Potential Biological Functions of CLDN8 in Patients with Clear Cell Renal Cell Carcinoma</p>

“…Further, the treatment of metastatic ccRCC is one of the thorniest problems in urology. 17,19 The emergence of bioinformatics has contributed to addressing the above issues. As a reliable established bioinformatics tool, TCGA database is an invaluable resource that provides the foundation for the development of diagnostic and therapeutic methods for ccRCC.…”

Axitinib as a third or further line of treatment in renal cancer. A single institution experience

“…Antioangiogenetic agents [5][6][7][8][9] along with mTOR inhibitors [10,11] or their combination [12] and immune checkpoint inhibitors [13], led to the regulatory approval of 10 different agents for metastatic RCC patients the last 12 years resulting in a significant increase of overall survival of RCC patients [14,15]. Available treatments have not only increased survival of patients, but also improved their quality of life and performance status allowing more lines of therapy [16]. The latter also correlates with improved survival [16].…”