Adjuvant therapy in renal cell carcinoma-past, present, and future

Abstract

To date, no effective adjuvant treatment for renal cell carcinoma (RCC) has been described, but research in this area is important since the 5-year relapse rate for intermediate- and high-risk early-stage RCC is 30%-40%. Metastatic RCC can be treated successfully with immune therapy and targeted therapy. Adjuvant trials with immune therapy have been conducted, but they reported no benefit in disease-free survival, and clinical trials with targeted agents have not yet reported results. Further advances in our understanding of the molecular pathogenesis of RCC will identify additional potential targets for adjuvant treatment trials. Future challenges will consequently include target identification, as well as trial design to answer multiple trial questions concurrently, comprehensively, and economically. We review the past efforts, summarize the current adjuvant clinical trial landscape, and consider the challenges in adjuvant trials for RCC. Additionally, we identify potential future adjuvant trial treatments and propose an alternative design for future adjuvant clinical trials.

Figure 1

Timeline for licensed therapies for metastatic RCC and correlating adjuvant clinical trials. Immune therapies preceded targeted anti-angiogenesis therapies both in terms of approval for treatment of metastatic disease and in research for adjuvant benefit. Adjuvant trials with immune therapy were not successful and those with targeted agents are not completed yet. FDA, US Food and Drug Administration; IFN, interferon; IL-2, interleukin 2; mTOR, mammalian target of rapamycin; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor. Adapted with permission of Future Medicine Ltd.

Figure 2

Important molecular pathways and drug targets in RCC. Inactive VHL leads to increased concentrations of HIF-alpha subunits. The PI3K/mTOR pathway also increases expression of HIF-alpha subunits. The resulting transcriptional stimulation of the HIF response element HRE and the rise in VEGF production stimulates endothelial growth and increased vascular supply to the tumor. Targeted therapies inhibit a variety of molecules along the involved signaling cascades in both tumor and endothelial cells. VHL,Von Hippel Lindau; HIF, hypoxia-induced factor; HRE, HIF response element; VEGF, vascular endothelial growth factor; mTOR, mammalian target of rapamycin; MAPK, mitogen-activated protein kinase. Adapted with permission of Future Medicine Ltd.

Figure 3

Schematic comparison of traditional and MAMS trial design. Testing three experimental treatments with traditional trial design requires more time and more control arm enrollment than MAMS trial design. Separate analysis and design of phase II and phase III trials makes the traditional trial design process also less efficient in terms of cost and administrative effort. Additional points of analysis allow for early termination of non-effective experimental treatments in MAMS trials. MAMS, multi-arm multi-stage; C, control/placebo arm; D, drug/experimental arm; P, point of primary analysis; S, point of secondary analyses. Adapted with permission of Future Medicine Ltd.