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2019 SUO Annual Meeting

SUO 2019: Overview of Challenges in Adjuvant Renal Cell Carcinoma Trials

Washington, DC (UroToday.com) To start the SUO-CTC session on trial updates, Dr. Naomi Haas provided an overview of the challenges seen in adjuvant renal cell carcinoma (RCC) trials. Dr. Haas notes that in 2017 there was a consensus meeting of RCC experts at the FDA White Oak campus to identify challenges and to make recommendations for adjuvant RCC trials.1 She notes that historically only 4% of adult cancer patients currently participate in clinical trials, due in part to the stringent eligibility criteria, which sometimes do not represent the “real world” patients.

Focusing on disease characteristics, Dr. Haas highlighted that most metastatic and adjuvant clinical trials are restricted to clear cell RCC. Non-clear cell RCC is very heterogeneous but increasingly defined by pathways that are responsive to available agents. Thus, non-clear cell RCC patients can be included in trials in an independent cohort. Furthermore, we know that high-risk patients (pT3-4, N+, microscopic R1) have the most to gain from adjuvant therapy, thus we should be prioritizing these patients in clinical trials.

In a recent collaborative effort, Correa et al. validated currently used recurrence prediction models for RCC by using prospective data from the ASSURE adjuvant trial.2 Eight RCC recurrence models (UISS, SSIGN, Leibovich, Kattan, MSKCC, Yaycioglu, Karakiewicz, and Cindolo) were selected on the basis of their use in clinical practice and clinical trial designs. These models, along with the TNM staging system, were validated using 1,647 patients with resected localized high-grade or locally advanced disease (≥ pT1b grade 3 and 4/pTanyN1M0) from the ASSURE cohort.3 Prospective validation of predictive and prognostic models for localized RCC showed a substantial decrease in each of the predictive abilities of the model compared with their original and externally validated discriminatory estimates. Among the models, the SSIGN score performed best (0.688, 95% CI 0.686-0.689), and the UISS model performed worst (0.556, 95% CI 0.555-0.557). Compared with the 2002 TNM staging system (C-index, 0.60), most models only marginally outperformed standard staging. Importantly, all models, including TNM, demonstrated statistically significant variability in their predictive ability over time and were most useful within the first 2 years after diagnosis.

Looking at patient characteristics, many patients with resected RCC have impaired renal function, however many of the drugs used are not metabolized by the kidney and these patients should be included. The timing of adjuvant therapy has been suggested to be 4-16 weeks for enrollment, as most patients have recovered from surgery by 30 days, but some may need extra time for recovery.

Several points have been made for criteria for radiology eligibility:

  • Attempt to be more inclusive of radiographic features
  • Protocols need to be explicit in defining what is acceptable for baseline pulmonary nodules, lymph nodes, etc – longer eligibility period (16 weeks) could allow follow-up of suspicious lesions
  • Non-malignant lymph nodes vary in size depending on location
  • Use of CT scans with IV contrast or non-contrast CT chest and MRI with gadolinium of the abdomen and pelvis
  • 3rd generation gadolinium agents do not cause systemic sclerosis and are safe even in patients with low GFRs
  • Chest x-ray and ultrasounds are insufficient to determine disease, which is not recommended

Research biopsies also have important implications for patients. ASCO recently released a research statement4 noting that the ASCO framework assumes that the ethical considerations surrounding research biopsies are different for optional biopsies, where patients are free to enroll in a trial but decline research biopsies, and mandatory biopsies, where trial participation is dependent on consent to one or more nontherapeutic procedures. 

A summary of the adjuvant RCC consensus guidelines are as follows:1

  • Non-clear cell patients can be included in an independent cohort.
  • High-risk patients gain the greatest advantage from adjuvant therapy.
  • Agents not secreted by the kidney should not exclude patients with renal insufficiency.
  • Therapy should begin 4-16 weeks post-op.
  • Both partial and radical nephrectomy should be eligible.
  • R1 soft tissue or vascular margins should be included.
  • All suspicious lymph nodes should be resected.
  • CT imaging with IV contrast is preferred; non-contrast CT chest and MRI abdomen and pelvis with gadolinium are allowed for renal insufficiency.
  • Biopsy for possible malignancy recurrence is preferred.
  • Uniform approach for indeterminant radiographic findings and definition of radiographic recurrence must be defined at trial entry.
  • Uniform approach for establishing the date of recurrence should be included in any trial design.
  • Patient perspectives on placebo, unblinding, and research biopsies are important in conducting a trial.

Presented by: Naomi B. Haas, MD, Director, Prostate and Kidney Cancer Program, Associate Professor of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 20th Annual Meeting of the Society of Urologic Oncology (SUO), December 4 - 6, 2019, Washington, DC  

References:

  1. Agrawal S, Haas NB, Bagheri M, et al. Eligibility and radiologic assessment for adjuvant clinical trials in kidney cancer. JAMA Oncol 2019 Nov 21 [Epub ahead of print].
  2. Correa AF, Jegede O, Haas NB, et al. Predicting Renal Cancer Recurrence: Defining Limitations of Existing Prognostic Models with Prospective Trial-Based Validation. J Clin Oncol 2019;37(23):2062-2071.
  3. Haas NB, Manola J, Uzzo RG, 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):2008-2016.
  4. Levit LA, Peppercorn JM, Tam AL, et al. Ethical Framework for Including Research Biopsies in Oncology Clinical Trials: American Society of Clinical Oncology Research Statement. J Clin Oncol 2019;37(26):2368-2377.