Following the introduction, Dr. Flanigan began his presentation of advanced renal cancer. In the same vein as prior lecturers, he chose a topic that paralleled his career, providing insight into the opportunities he had along his long career, as well as advice to up and coming urologic oncologists.
Advanced renal cancer continues to be a difficult disease process with limited treatment options. With 5-year survival <10% and median survival approximately 12 months, there are over 135,000 cases of advanced kidney cancer deaths worldwide, which a likely underestimation. Unfortunately, locally advanced RCC also has a poor prognosis, with high rates of recurrence (50-85%), even despite complete resection of all visible disease. The Motzer criteria, one of many prognostic indicators, is often used to help risk stratify patients for treatment, but also provides important prognostic data.
Kidney cancer, as we know from the work by the NIH and Dr. Linehan, is a very diverse umbrella term. While primarily referring to clear cell histology RCC (ccRCC), Dr. Flanigan reminded the group that there are many histologies of RCC, and significant work is needed to better understand the less common ones.
He then paid tribute to his mentors in residency at Case Western University, his chairman and chief residents. In particular, one chief resident, Dr. Jean deKernion (4th SUO president), helped generate his interest in “palliative nephrectomy”, which at that time was purely palliative for patients with symptomatic large volume primary disease. However, in writing on these patients, he noted that some patients did quite well – a small subset. This helped initiate his interest in the field. These mentors are also the ones that encouraged him, as was common at the time, to be dual certified in both general surgery and urology – hence leading to a more diverse career, including kidney transplantation. He briefly then reviewed his career at both University of Kentucky followed by his time at Loyola.
There were a few sentinel events that helped guide his career. The first was becoming the Chair of the renal subdivision of the SWOG GU group (under mentorship of SWOG GU chair Dr. Crawford). The second was formation of the LAK-Cell Extramural working group / Cytokine working group.
The first led to his ability to start and run the landmark SWOG 8949 study evaluating IFN-alpha +/- nephrectomy in the setting of mRCC with 241 patients, which found a modest benefit to patients undergoing “cytoreductive nephrectomy,” particularly patients with good performance status.1 This was validated in a subsequent EORTC trial, and more recent population level data confirms its overall and cancer specific survival benefit (in the cytokine era).
However, the big question now is whether that benefit still exists in the targeted therapy era. With improved survival outcomes, is cytoreductive nephrectomy still needed? If so, what is the timing of systemic therapy relative to nephrectomy? Smaller series and clinical trials seemed to support the continued role of cytoreductive nephrectomy, but there was often conflicting reports and somewhat complicated by heavy selection for better survival outcomes.
With regards to his other sentinel event, he joined Dr. Rosenberg in the LAK-cell extramural working group on the heels of promising data and response to LAK-cell therapy – unfortunately, while this didn’t end up being successful, this did lead to his involvement with the Cytokine working group. He briefly reviewed their experience with IL-2, which remains to this day, the only therapy associated with CR and durable response in the setting of mRCC. The 7% of patients who have CR have median survival exceeding 80 months on the original trial. However, while it fell by the wayside for some time, it has regained interest – while utilized on better selected patients now leading to better overall response rates, CR rates are similar at 7%. IL-2 is much better tolerated now however, so he strongly recommended consideration for any patient with ECOG PS 0-1 with mRCC.
He briefly reviewed the subsequent development of targeted therapy and now immune checkpoint blockage for RCC. But as with all the other malignancies, the question now becomes sequencing of the systemic therapies. To help do that, we must be critical of the specific patient population in each of the clinical trials and see which one best matches our patient. Unfortunately, non-clear cell RCC is a grab-bag of many different histologies, and trials are lacking in this space – there have been some Phase II clinical trial efforts to look at everolimus (ESPN and ASPEN), but both had numerical but not statistically significant benefit compared to sunitinib. SWOG 1500 is a new clinical trial for metastatic or locally advanced Papillary RCC.
Lastly, he addressed the . While two well-known clinical trials (ASSURE and S-TRAC) had conflicting results regarding the benefit of adjuvant therapy in locally advanced, completely resected RCC, he believes the positive PFS in S-TRAC should be taken with grain of salt, as there was no OS benefit – he made a point to state FDA approval for adjuvant indication was given too early, and in the absence of OS benefit, there is limited utility. He encouraged a focus on the neoadjuvant approach. Particularly for smaller tumors, it may allow for nephron sparing surgery rather than nephrectomy. After briefly reviewing the early results of axinitib and pazopanib in the neoadjuvant setting, he concluded this segment by saying neoadjuvant therapy has a lot of promise, but we need better patient selection.
At this point, he provided the following take-home messages for the audience, with a focus on urologists early in their career:
1. Urologic surgeons should continue to be active in the development of new surgical techniques and systemic agents
2. Younger urologists should look for clinical and research mentors and role models
3. Continue to challenge the “accepted” truths and find ways to investigate them
4. Look for research collaborators in basic, translational or clinical research
5. They should be persistent but also malleable in their research efforts – sometimes things change!
6. Continue to participate in organizations that help organize clinical trials, especially those designing new Level 1 evidence
We thank Dr. Flanigan for his work and his long career.
1. Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, Caton JR Jr, Munshi N, Crawford ED. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001 Dec 6;345(23):1655-9.
Presented by: Robert C. Flanigan, MD, FACS, Professor Department Chairperson, Urology Loyola University, Illinois
Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, twitter: @tchandra_uromd at the 18th Annual Meeting of the Society of Urologic Oncology, November 20-December 1, 2017 – Washington, DC