Stereotactic Ablative Body Radiotherapy in Patients in Oligometastatic Cancers: A UroToday Journal Club - Christopher Wallis & Zachary Klaassen
February 4, 2021
Christopher J.D. Wallis, MD, Ph.D., Instructor in Urology, Vanderbilt University Medical Center, Nashville, Tennessee
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center
Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club. I'm Chris Wallis, a Fellow in Urological Oncology at Vanderbilt. And with me today is Zach Klaassen, an Assistant Professor in the Division of Urology at MCG. And today we're discussing a recently published article assessing stereotactic ablative body radiotherapy in patients with oligometastatic cancer, a prospective registry-based, single-arm, observational, evaluation study. This here is the citation for this publication in Lancet Oncology. And so by way of background, approximately one-quarter, 1% of the people in Western nations, the authors highlight about 140,000 patients in England, are diagnosed with metastatic cancer each year. And traditionally treatment for patients with these metastatic solid-organ cancers is systemic therapy with overall palliative rather than curative intent. And typically this is chemotherapy, although, sometimes targeted therapies are used.
Oligometastatic disease is a sub-classification of patients with metastatic disease based on their burden. And it exists in a continuum between localized disease and widely metastatic disease. And so this sample comes from prostate cancer, discussing widely metastatic castrate-resistant disease, but this may be applied to nearly any solid-organ malignancy. And patients with oligometastatic disease have a more favorable prognosis than those with widespread metastatic disease. And this has raised consideration as to whether the treatment of either the local tumor and/or metastatic sites in patients following oligometastatic disease may be beneficial.
And so these treatment approaches may be taken locally, and that can be surgically or radiation-based, and again, metastatic-directed, and again, either surgically or with radiation approaches. And SABR is a form of external beam radiotherapy in which a high dose per fraction is used, and a relatively low number of fractions are utilized. And preliminary data has suggested that the use of SABR may confer disease control of metastasis, which in turn may delay the need for systemic therapy and spare patients the toxicity associated with the systemic treatments.
And so a Phase II randomized data have come from the SABR-COMET trial, looking at the role of SBRT or SABR in patients with all oligometastatic disease compared to the control arm who received their systemic therapy is as indicated.
And this showed that patients who received SABR to oligometastatic sites had improved overall survival, as well as progression-free survival. In the context of the NHS system, there are concerns raised that these small Phase II results may lack generalizability, and this is potentially particularly true in the context of SABR, which requires specialist equipment and training. And so as a result, the NHS provided funding for SABR in the context of extracranial metastases for a prospective clinical effectiveness and safety study.
And so these authors designed a prospective registry-based, single-arm observational study in 17 commissioned NHS radiotherapy centers, with prior historical data indicating that approximately 500 eligible patients should be anticipated each year. The authors included patients with any solid-organ cancer who had three or fewer sites of metachronous extracranial metastases, except in the context of colorectal cancer, in which liver metastases were not counted against this number with a maximum of two of these sites of spinal disease. Patients had to be eligible for SABR but deemed unsuitable for surgical resections and metastases. And the maximum metastasis size allowed was 6 centimeters, although 5 centimeters was the maximum for liver or lung disease.
Patients prior to enrollment in this prospective cohort were screened using a combination of PET-CT, whole-body MRI, CT, or bone scan as appropriate based on the patient's disease. And brain imaging was performed in those who had cancers with known CNS predilections. Patients were excluded if they had evidence of brain metastases, spinal cord compression, or had had prior radiotherapy to the metastatic sites.
In terms of treatment prior to enrollment, patients discontinue their systemic therapy. And so if this was chemotherapy, a requirement was for at least four weeks off therapy prior to SABR. And for those on target therapies, at least two weeks off therapy was required before SABR was initiated. And the treatment was given according to the UK SABR Consortium Guidelines, with treatment plans depending on the size and location of disease with those constraints prioritized above dosage on the basis of toxicity considerations.
Utilized doses ranged from 24 to 60 Gray in between 3 to 8 fractions. And all sites involved across 17 centers participated in an accreditation program, including test cases to ensure the quality and generalizability of the treatment administered.
Following treatment, patients were seen every three months for two years as part of the study protocol and then defaulted to routine clinical follow-up thereafter. And at each visit, patients were assessed for their response to treatment as well as adverse events.
The primary outcome assessed was overall survival, and secondarily, the authors considered median OS local control, time to local or distant progression, safety, and health-related quality of life.
At this point in time, I'm going to pass it over to Dr. Klaassen to discuss the results and implications of this study.
Zachary Klaassen: Thanks, Chris. So as you can see here, these are the panels for the baseline clinical and procedural characteristics. On the left side, you can see that there's a wide range of age included in this study, with the majority of patients being 60 to 69, or 70 to 79 years of age. The median age overall was 69 years. And the majority of patients, about two-thirds were male.
In terms of the performance status, the majority of these patients had excellent performance status: 71.1% with a performance status of 0. On the bottom left panel, you can see that the breakdown by disease site most commonly included in this trial was prostate cancer, 28.6%. The second was colorectal cancer at 27.9%. And the third was renal cancer at 10.1%. If you look at the middle panel, this is the looking at the site of first treated metastases. Most commonly was the lymph nodes at 31.3%, followed by the lung at 29.3%. And then in a distant third was bone metastasis at 12%. In terms of the number of metastases for the patients, the majority of patients had one metastatic site at 75.6%, 19.6% had two locations in metastasis, and 4.8% had three metastases.
And then moving over to the right panel, you can see the type of previous systemic therapy. The majority of patients at 53.5% had chemotherapy, followed by 30.9% of the patients had hormonal therapy. The type of post-SABR systemic therapy was most commonly chemotherapy at 38.4%, followed by immunotherapy at 34.7%. And in terms of the number of SABR fractions used, the majority of patients at 55.9% used 3 fractions, followed by 33.1% receiving 5, and 10.5% receiving 8.
This is the Kaplan-Meier analysis of the overall survival. In the total cohort, you can see the curve on the slide here. The median follow-up was 13 months, with an interquartile range of 6 to 23 months. The overall survival rate at 1 year was 92.3%, with a 95% confidence interval of 90.5 to 93.9%. And the OS rate at 2 years was 79.2% with a 95% confidence interval of 76.0 to 82.1%.
This next slide looks at the overall survival estimates at 1 and 2 years after the start of SABR broken down by disease site. And so to quickly summarize, you can see here of interest to the UroToday group, prostate cancer was not available at 1 year, but at 2 years was 94.6%. In terms of renal cancer, 1 year was 95.3%, and 2 years was 82.4%. The historically bad malignancies included lung cancer with a 2-year overall survival rate of 65.4%, and melanoma at 60.5% 2-survival.
This curve here shows the local control via the Kaplan-Meier method: 19.9% of patients had local progression, and the local control rate at 1 year was 86.9%, with a 95% competence interval of 84.6 to 88.9%. The 2-year local control rate was 72.3%, with a 95% confidence interval of 68.7, 75.6%.
These final results slide is the treatment-related adverse events. As you can see in this table, there were very few Grade 4 adverse-related events. In terms of Grade 3, 2% of patients had fatigue. And subsequently, the rest of these were just almost anecdotal in terms of their adverse event rate at less than 1% Grade 3.
Several discussion points from this SABR study from the NHS. Patients with metachronous extracranial oligometastases treated with SABR in a real-world setting achieve a high rate of 1 and 2-year overall survival rates, with low rates of severe toxicity. Compared with most systemic treatments delivered 6 months to patients with metastatic disease, SABR is a non-invasive outpatient treatment that has minimal toxicity and excellent local control, as well as being acceptable in terms of convenience and societal costs. And perhaps most importantly, prior to this study, SABR for oligometastases was not funded by the NHS. But as of March 2020, SABR became available as a treatment option for patients with oligometastatic disease based on the criteria set forth in this study.
So in conclusion, in patients with extracranial oligometastatic cancer, SABR was associate with high overall survival and low toxicity. And these findings complement evidence from the randomized Phase II SABR-COMET trial and represent real-world high-level evidence supporting SABR in this cohort. And most importantly, there's a Phase III RCT underway, and we'll look forward to seeing the results of that study in the near future.
Thank you for your attention to this UroToday Journal Club.