MDACC 2018: Debate: Adjuvant Therapy for Locally Advanced Renal Cell Carcinoma: Is it Ready for Prime Time?

Houston, TX (UroToday.com) Jose A. Karam, MD opened the debate by emphasizing the importance of patient selection for adjuvant therapy.  Those that would most benefit from adjuvant therapy are those that are at high risk of recurrence.  This can be defined by scoring systems such as the UCLA Integrated Staging System (UISS)1 and Leibovich score2. Dr. Karam referenced a useful online resource provided by Fox Chase to assist physcians in identifying those at high risk of recurrence:

There have been three trials demonstrating no advantage to adjuvant therapy (sorafenib, axitinib, or pazopanib) in terms of disease-free survival (DFS) and overall survival (OS): (ASSURE 3, ARISER 4, PROTECT 5 , ATLAS6).  It was noted that ATLAS was stopped early due to a preplanned analysis demonstrating no significant difference in DFS.  The only study demonstrating DFS benefit with adjuvant therapy is the S-TRAC trial 7.  This trial showed a DFS at 3 and 5 years, but no benefit in OS.  Although, it should be noted that OS was not a primary endpoint.  A post hoc analysis was performed for those with high-risk clear cell RCC and again, there was a DFS, but not an OS8

However, there are several caveats to consider in the negative trials.  For example, in the ASSURE trial, there were low-risk patients included in trial whereas, in the S-TRAC trial, there were no low-risk patients included.  Additionally, the ASSURE trial allowed dose reductions where the S-TRAC trial did not allow dose reductions.  Other differences among the studies were primary endpoints (ARISER: DFS and OS, ASSURE: DFS, S-TRAC: DFS, PROTECT: DFS), histological subtypes included (ARISER-clear cell: 97%, ASSURE-clear cell: ~80%, S-TRAC-clear cell: ~100%, PROTECT-clear cell: ~100%).   Importantly, the recurrence risk of the patients included the study varied widely (view slide).  Additionally, as mentioned prior, it is important to consider that some studies allowed dose reductions (see slide) and that the study locations were different. So why was the S-TRAC study the only one that had a positive result for DFS?  It included patients with the right histology (clear cell), the right risk group (high risk), the right drug (sunitinib), at the right dose and duration. There are several ongoing trials for immunotherapy, however, results will not be available for 3-5 years.   Dr. Karam concluded that the options he gives his high-risk patients are surveillance, sunitinib for 1 year or enrollment in a trial with immunotherapy.

UroToday MDACC Management of Locally Advanced Renal Cell Carcinoma Risk

UroToday MDACC Management of Locally Advanced Renal Cell Carcinoma
Dr. Jeffrey J. Tomaszewski, MD, Assistant Professor of Urologic Oncology at MD Anderson Cancer Center at Cooper in Camden, New Jersey took the stand against adjuvant therapy.  One compelling animal study showed that sunitinib accelerated metastasis in a mouse xenograft model9.  The mechanism behind this acceleration was hypothesized to be from hypoxia-driven epithelial to mesenchymal transition.  Additionally, perhaps it is not surprising that adjuvant therapy may not have a role in RCC as VEGF-targeted adjuvant therapy has failed in multiple other cancers including colon cancer, triple negative breast cancer, non-small cell lung cancer, and melanoma. There is also evidence of overtreatment.  In the S-TRAC trial, 10 patients need to be treated for 1 patient to have a DFS.  In the ASSURE trial, 136 patients would need to be treated for 1 patient to have a DFS. Additionally, the results in the studies may not be clinically applicable as many required dose reductions.   In the S-TRAC trial, the only positive result was DFS and until there is data to support that treatment delays symptomatic progression, DFS advantage alone does not justify sunitinib in the adjuvant setting.  For these reasons, perhaps adjuvant therapy is not ready for routine use.


Presented by: Jose A. Karam, MD, Associate Professor of Urologic Oncology at MD Anderson Cancer Center in Houston, TX

Written by Dr. Amy H. Lim, MD, PhD, Urologic Oncology Fellow and Ashish M. Kamat, MD, (@UroDocAsh), Professor, Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX at the 13th Update on the Management of Genitourinary Malignancies, The University of Texas (MDACC - MD Anderson Cancer Center) November 9-10, 2018, Dan L. Duncan Building, Houston, TX

References:
1. Lam JS, Shvarts O, Leppert JT, Pantuck AJ, Figlin RA, Belldegrun AS. Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognostic nomogram and risk group stratification system. J Urol. 2005;174(2):466-72; discussion 72; quiz 801.
2. Leibovich BC, Blute ML, Cheville JC, Lohse CM, Frank I, Kwon ED, et al. Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer. 2003;97(7):1663-71.
3. Haas NB, Manola J, Uzzo RG, Flaherty KT, Wood CG, Kane C, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016;387(10032):2008-16.
4. Chamie K, Donin NM, Klöpfer P, Bevan P, Fall B, Wilhelm O, et al. Adjuvant Weekly Girentuximab Following Nephrectomy for High-Risk Renal Cell Carcinoma: The ARISER Randomized Clinical Trial. JAMA Oncol. 2017;3(7):913-20.
5. Motzer RJ, Haas NB, Donskov F, Gross-Goupil M, Varlamov S, Kopyltsov E, et al. Randomized Phase III Trial of Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma. J Clin Oncol. 2017;35(35):3916-23.
6. Gross-Goupil M, Kwon TG, Eto M, Ye D, Miyake H, Seo SI, et al. Axitinib Versus Placebo as an Adjuvant Treatment for Renal Cell Carcinoma: Results From the Phase III, Randomized ATLAS Trial. Ann Oncol. 2018.
7. Ravaud A, Motzer RJ, Pandha HS, George DJ, Pantuck AJ, Patel A, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med. 2016;375(23):2246-54.
8. Motzer RJ, Ravaud A, Patard JJ, Pandha HS, George DJ, Patel A, et al. Adjuvant Sunitinib for High-risk Renal Cell Carcinoma After Nephrectomy: Subgroup Analyses and Updated Overall Survival Results. Eur Urol. 2018;73(1):62-8.
9. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009;15(3):232-9.
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