Bone metastases affect prognosis but not effectiveness of third-line targeted therapies in patients with metastatic renal cell carcinoma

Abstract

Introduction: Treatment of metastatic renal cell carcinoma (mRCC) has improved with the use of targeted therapies, but bone metastases continue to be negative prognostic factor. Methods: Patients with mRCC treated with everolimus (EV) or sorafenib (SO) after two previous lines of targeted therapies were included in the analysis. Overall survival (OS) and progressionfree survival (PFS) were assessed based on the presence of bone metastases and type of therapy; they were also adjusted based on prognostic criteria. Results: Of the 233 patients with mRCC, 76 had bone metastases. Of the 233 patients, EV and SO were administered in 143 and 90 patients, respectively. Median OS was 10.4 months in patients with BMs and 17.4 months in patients without bone metastases (p = 0.002). EV decreased the risk of death by 18% compared to SO (adjusted hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.74-0.91; p < 0.001), with comparable effects in patients with or without bone metastases. In the same manner, EV decreased the risk of progression by 12% compared to SO (adjusted HR 0.88, 95% CI 0.82-0.96; p = 0.002), but this difference was not significant in patients without bone metastases. The major limitations of the study are its retrospective nature, the heterogeneity of the methods to detect bone metastases, and the lack of data about patients treated with bisphosphonates. Conclusions: The relative benefit of targeted therapies in mRCC is not affected by the presence of bone metastases, but patients without bone metastases have longer response to therapy and overall survival. IntroductionThe skeleton is commonly affected by metastatic cancer. Genitourinary tumours, such as prostate and renal cell carcinoma (RCC), are particularly likely to spread to the bone. This represents the first and the fourth causes of bone metastases at post-mortem examination, with an incidence rate of 70% and 35% of cases, respectively.1 In renal cancer, bone metastases represent the second most common site of distant metastatic spread (after lung).2 Generally, the most frequent sites are pelvis, spine and ribs.3-6 Skeletal involvement in RCC is an aggressive, lytic process causing significant morbidity from skeletal-related events (SREs).3 In mRCC, SREs have been related to decreased functional independence, loss of autonomy and decreased quality of life compared with bone metastases from other tumours. During the last decade some targeted therapies have been approved for mRCC; 8 these can be classified as follows: (1) inhibitors of the vascular endothelial growth factor (VEGF) (i.e., bevacizumab in combination with interferon) or its receptor (VEGFR) (i.e., sorafenib, sunitinib, pazopanib, axitinib), and (2) mTOR inhibitors (mTORi) (i.e., temsirolimus and everolimus).Current guidelines recommend VEGF/VEGFR inhibitors as first-line therapy and temsirolimus in poor-risk patients, while there is no univocal indication for mTOR or VEGFR inhibitors as subsequent lines.9-12 Given the increasing incidence of RCC, improvements in overall surviv...

Radiological Response Heterogeneity Is of Prognostic Significance in Metastatic Renal Cell Carcinoma Treated with Vascular Endothelial Growth Factor-targeted Therapy

“…In addition, treatment response at week 8 by disease site was not prognostic for survival. This is in contrast to previous studies which have shown that bone and liver metastases are adverse independent prognostic factors for OS in metastatic RCC [16][17][18]. This correlates with findings from patients treated with cytokines where liver and bone metastases have been included as adverse factors in a prognostic model [19].…”

Third-line treatment in metastatic renal cell carcinoma and bone metastases

“…Iacovelli and colleagues have published an important analysis examining the role of bone metastases in prognosis and prediction of efficacy in the third-line setting. 1 This work confirms previous publications that bone metastases in mRCC are associated with a poorer overall survival. 2 However, the search for predictive markers that can help determine which agent is more efficacious for a particular patient remains elusive.…”

“…Finally, because axitinib is relatively new and not included in these studies, it is unknown how this newer VEGF inhibitor would compare. 1 Bone metastases are often difficult to treat in mRCC. Their response to targeted therapy is less satisfactory compared to other sites, such as lung metastases.…”

Targeted therapies for previously treated advanced or metastatic renal cell carcinoma: systematic review and network meta-analysis

“…Five of these studies have been excluded from this review because of the update of the scope excluding sunitinib as it is not recommended at second line in the most up-to-date ESMO guidance for RCC 12. Five new studies, one RCT and four retrospective chart reviews were identified in the update and extension searches (including terms for lenvatinib with everolimus) run in January 2018, making a total of 12 included studies 13–15 19 20 27–33…”

“…Twelve studies (n=5144) met the inclusion criteria (table 1): five RCTs (one double-blind28 and four open-label13 15 20 28) and seven observational studies19 27 29–33 (retrospective cohort studies). Sample sizes varied from 101 (HOPE 205)15 to 821 (CheckMate 025)14 participants.…”