Sequential Radiotherapy May Facilitate Deferral of Systemic Therapy Initiation in Oligometastatic Renal Cell Carcinoma, Journal Club - Christopher Wallis & Zachary Klaassen

January 19, 2022

Zachary Klaassen and Christopher Wallis discuss a publication entitled, “Definitive Radiotherapy in lieu of Systemic Therapy for Oligometastatic Renal Cell Carcinoma: A single-arm, Single-center, Feasibility, Phase Two Trial”. In this study, the feasibility and efficacy of radiotherapy was tested to defer systemic therapy for patients with oligometastatic renal cell carcinoma. Dr. Wallis speaks to advanced renal cell carcinoma and available treatment approaches. They also discuss the need for a larger randomized trial to further assess definitive radiotherapy for oligometastatic renal cell carcinoma patients.


Christopher J.D. Wallis, MD, Ph.D., Assistant Professor in the Division of Urology at the University of Toronto.

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center

Read the Full Video Transcript

Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club discussion. Today, we are discussing our recent publication entitled, Definitive radiotherapy in lieu of systemic therapy for oligometastatic renal cell carcinoma: A single-arm, single-center, feasibility, phase two trial.  I'm Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto. With me today is Zach Klaassen, Assistant Professor in the Division of Urology at the Medical College of Georgia.

Shown here, is the citation for this recent publication, in Lancet Oncology, led by Dr. Tang and Dr. Tannir.

The field of advanced renal cell carcinoma has rapidly evolved over the last few years. While this figure only goes to 2019, even further advances have been seen in the last 18 months. And in general, these trials have focused on optimizing the combination systemic therapy approach with the use of combined immune checkpoint blockade, or immune check blockade with targeted therapies.

However, we know that advanced renal cell carcinoma is clinically heterogeneous. While some patients present with widespread metastatic disease and have rapid progression, others may have few metastases and these may progress with a relatively indolent clinical course. There are translational data suggesting that genetic differences between the patients and tumors, may underpin these disparate clinical courses.

Therefore, when we consider treatment approaches for advanced renal cell carcinoma, we need to consider the context of the underlying biology. Systemic therapy with modern doublet approaches has a median progression-free survival that ranges somewhere between 11 and 24 months. Additionally, these drugs are costly and have high rates of severe toxicity.  To the right of the screen, we are highlighting just an example from the CLEAR trial, but you can see here, that grade three events are present in 82 to 83% of patients. So this is not insignificant toxicity for the vast majority of patients receiving this therapy.  Additionally, these clinical trials have focused on patients with rapid clinical trajectories, and more severe disease burdens, who are likely to respond best to systemic approaches.

However, among patients with clinically indolent advanced renal cell carcinoma and oligometastatic disease presentation, definitive local control may delay or eliminate the need for systemic therapy with the associated toxicity and cost. Radiotherapy may be an ideal approach for this local control, as it is relatively non-invasive, low cost, and maybe repeatedly applied.

However, to date, radiotherapy in advanced renal cell carcinoma has been relatively underexplored on the basis of two rationales. Number one, there is historical data that have suggested the radioresistance of RCC tumor clones. And additionally, older trial data, which suggested a high rate of radiation-related death. However, we know from trials outside the RCC space, that there may be both progression-free and overall survival benefits for the use of radiotherapy in patients with oligometastatic disease.

Thus, in this study, the authors sought to test whether definitive radiotherapy, in lieu of systemic therapy, was feasible for treating patients with oligometastatic renal cell carcinoma and whether this would extend progression-free survival and defer systemic therapy.

This was the MD Anderson Cancer Center Renal Cell Carcinoma Oligometastasis Trial, a single-arm, single-center, phase two study. Patients were included if they were 18 years or older and had histologically confirmed renal cell carcinoma with up to five sites of metastases. Patients had to have adequate performance status, adequate marrow/liver function, and be a candidate for radiotherapy to all sites of disease.  Patients were excluded if they had systemic therapy for metastatic renal cell carcinoma, or they were allowed to be included if they had a single line of therapy, as long as that was stopped at least one month prior. Patients were further excluded if they were pregnant, had comorbidities that precluded the safe provision of radiotherapy, if they had known psychiatric or substance use disorders or had evidence of diffused metastatic disease.

The authors assessed patient prognosis according to standard IMDC criteria, and they performed a staging within six weeks of enrollment using CT of the chest/abdomen/pelvis, a PET scan, as well an MRI of the abdomen.  All sites of disease were targeted with stereotactic body radiotherapy, except where this was deemed unsafe. And in that case, definitive hypofractionated radiation was used instead.  Repeated treatments were allowed for restricted disease progression.

Patients were followed until death or the initiation of systemic therapy. While treatment decisions were based on the treating oncologist's discretion, the trial guidelines suggested that systemic therapy be initiated where there is evidence of progression in three or more metastatic lesions, where radiotherapy toxicity precluded further radiotherapy, where there was a local progression, or in the case of patient or doctor preference.  Patients were evaluated every 12 weeks for the first year, and then every 18 weeks thereafter. At these intervals, patients received restaging images which were assessed using RECIST criteria, laboratory investigations, and clinical evaluation for adverse events.  In addition, a biopsy was performed both at baseline and at three months, following radiotherapy where feasible.

The co-primary endpoints were the feasibility of definitive radiotherapy, defined as all planned radiotherapy being delivered with less than seven days of unplanned treatment delay. The second co-primary endpoint was progression-free survival.  Secondary endpoints included estimation of median relative change in Ki-67 labeling, 12-month overall survival, 12-month freedom from new lesion development, and safety and systemic therapy-free survival.  Exploratory endpoints included immunohistochemical staining of pre and post-radiotherapy biopsy samples for a number of markers relevant to assess the efficacy of radiation.

The authors planned to accrue 30 patients over 20 months with an anticipated progression-free survival of 24 months, and a minimum six-month follow-up window. This would allow the assessment of a one-year progression-free survival of 71% with an expected confidence interval of 56% to 100%.  The authors used the Kaplan–Meier technique to assess progression-free survival, overall survival, time to a new lesion, and systemic therapy-free survival.  For progression-free survival and time to new lesions, patients were censored with the initiation of systemic therapy. The authors use the Wilcoxon ranked sum test to compare the proportions of marker positive cells.

In post hoc analyses, the authors further sought to estimate time to disease progression that was not salvageable by radiotherapy. And to do so, they adjusted systemic therapy-free survival using censoring of systemic therapy initiated at the provider's choice, rather than for specific oncology indications.  Second, they assessed the best radiographic response and the proportion of patients who had local disease progression within the radiotherapy treated field.

At this point in time, I'm going to hand it over to Zach to walk us through the results.

Zachary Klaassen: Thanks, Chris. So this trial looked at 45 patients for eligibility, and ultimately enrolled and consented to 30 patients. Among these 30 patients, 17 patients received one round of definitive radiotherapy, 13 received two rounds of definitive radiotherapy, and all 30 were included in the intention-to-treat and the safety analyses.

This is table one baseline patient characteristics. The median age of these patients was 65 years, 80% were male, 67% were white, and the time from nephrectomy to metastases was just over four years. In terms of time from metastases to registration, 5.5 months, and a previous nephrectomy was performed in all of these patients.  In terms of IMDC risk score, 47% of patients had no risk factors, and 40% had one risk factor.  In previous therapies, systemic therapy was used in 30% of patients, additional surgery in 30%, definitive radiotherapy in 7%, and cryoablation in 3%.

This table looks at the radiation treatment characteristics, divided by the first round of radiotherapy and the second round of radiotherapy. And for both the first and second rounds, the lung was the most common site of utilization, encompassing two-thirds of patients in the first round, and six out of 13 patients in the second round.  In terms of the number of sites treated, most commonly, was just one site in two-thirds of patients in the first round, and 77% of patients in the second round.  The most common radiation fractionation was 50 Gy per four fractions, including 16 out of 30 patients in the first round, and eight out of 13 in the second round.

This is the Kaplan–Meier plot for progression-free survival. On the left, the median follow-up in this cohort was 17.5 months, with an interquartile range of 13.2 to 24.6 months, with a one-year progression-free survival rate of 64%.  The median progression-free survival was 22.7 months with a 95% confidence interval of 10.4 months, to not reached.  The 12-month freedom from new lesion development probability in this cohort of 30 patients was 67%.

This is the Kaplan–Meier plot for systemic therapy-free survival. The one-year systemic therapy-free survival probability was 82%. And the median systemic therapy-free survival was not reached in this cohort of patients.

This is a swimmer plot of patient baseline and treatment characteristics, toxicity, and outcomes. As you can see here on the left with the arrows, indicating continuing to be on trial. The majority of patients are still on trial. And the authors defined adjusted systemic therapy-free survival, as the estimated time until disease progression, not salvageable by radiotherapy, with a one-year rate of 86%.

This table looks at the adverse events among these 30 patients. As you can see here, this is well tolerated with only one grade four hyperglycemia, one grade three muscle weakness and pain, and three grade two patients experiencing pain.

So several discussion points from this important phase two trial. This trial supports sequential radiotherapy as an alternative to systemic therapy for oligometastatic renal cell carcinoma. This is based on a median progression-free survival of 22.7 months with no patients dying as of yet. The frequency of grade three or higher adverse events was modest. And the median systemic therapy-free survival was not reached at the time of the data cutoff.  This supports the previous studies that have shown that SBRT can produce local control rates of greater than 90% in renal cell carcinoma.  So in addition to the local effects of radiotherapy in controlling the metastatic sites, another potential mechanism for increased efficacy is a radiotherapy-induced immune stimulation, which may control disease dissemination, or halt the progression of microscopic disease.

So in conclusion, this is the first prospective trial of serial definitive local therapy as a single modality to treat oligometastatic renal cell carcinoma.  Additionally, these results suggest that sequential radiotherapy to defer systemic therapy is a feasible strategy, with encouraging progression-free survival and overall survival data, among these patients with low-volume metachronous oligometastatic RCC who have undergone a previous nephrectomy.

Based on the small sample size of 30 patients, future larger randomized trials are important to investigate the risk and benefits of SBRT monotherapy. And if the current results are confirmed, they would validate this treatment approach for select patients with metastatic RCC.

We thank you very much for your attention, and we hope you enjoyed this Journal Club discussion of this important phase two trial.