Key Points
Question
What is the rate of toxic effects from stereotactic ablative body radiotherapy?
Finding
In this population-based phase 2 nonrandomized clinical trial of 381 patients with oligometastatic or oligoprogressive disease that was designed to capture toxic effects prospectively as the primary end point, the rates of grades 2, 3, 4, and 5 toxic effects were 14.2%, 4.2%, 0%, and 0.3%, respectively.
Meaning
The trial results suggest that stereotactic ablative body radiotherapy has acceptable rates of toxic effects, and this potentially supports enrollment in phase 3 randomized efficacy trials.
Abstract
Importance
After the publication of the landmark SABR-COMET trial, concerns arose regarding high-grade toxic effects of treatment with stereotactic ablative body radiotherapy (SABR) for oligometastases.
Objective
To document toxic effects of treatment with SABR in a large cohort from a population-based, provincial cancer program.
Design, Setting, and Participants
From November 2016 to July 2020, 381 patients across all 6 cancer centers in British Columbia were treated in this single-arm, phase 2 trial of treatment with SABR for patients with oligometastatic or oligoprogressive disease. During this period, patients were only eligible to receive treatment with SABR in these settings in trials within British Columbia; therefore, this analysis is population based, with resultant minimal selection bias compared with previously published SABR series.
Interventions
Stereotactic ablative body radiotherapy to up to 5 metastases.
Main Outcomes and Measures
Rate of grade 2, 3, 4, and 5 toxic effects associated with SABR.
Findings
Among 381 participants (122 women [32%]), the mean (SD; range) age was 68 (11.1; 30-97) years, and the median (range) follow-up was 25 (1-54) months. The most common histological findings were prostate cancer (123 [32%]), colorectal cancer (63 [17%]), breast cancer (42 [11%]), and lung cancer (33 [9%]). The number of SABR-treated sites were 1 (263 [69%]), 2 (82 [22%]), and 3 or more (36 [10%]). The most common sites of SABR were lung (188 [34%]), nonspine bone (136 [25%]), spine (85 [16%]), lymph nodes (78 [14%]), liver (29 [5%]), and adrenal (15 [3%]). Rates of grade 2, 3, 4, and 5 toxic effects associated with SABR (based on the highest-grade toxic effect per patient) were 14.2%; (95% CI, 10.7%-17.7%), 4.2% (95% CI, 2.2%-6.2%), 0%, and 0.3% (95% CI, 0%-0.8%), respectively. The cumulative incidence of grade 2 or higher toxic effects associated with SABR at year 2 by Kaplan-Meier analysis was 8%, and for grade 3 or higher, 4%.
Conclusions and Relevance
This single-arm, phase 2 clinical trial found that the incidence of grade 3 or higher SABR toxic effects in this population-based study was less than 5%. Furthermore, the rates of grade 2 or higher toxic effects (18.6%) were lower than previously published for SABR-COMET (29%). These results suggest that SABR treatment for oligometastases has acceptable rates of toxic effects and potentially support further enrollment in randomized phase 3 clinical trials.
Trial Registration
ClinicalTrials.gov Identifier: NCT02933242
This nonrandomized clinical trial examines toxic effects of treatment with stereotactic ablative radiotherapy in a large cohort from a Canadian population-based, provincial cancer program.
Introduction
Stereotactic ablative radiotherapy (SABR) is a technique that delivers very large hypofractionated doses of highly conformal radiotherapy (RT) to tumor targets with the aid of onboard imaging; it was originally developed and used in the curative setting for lung cancer.1,2 Oligometastases refer to a state of disease in which cancer has spread beyond the primary site but is not yet widely metastatic, often defined as 1 to 3 or 5 metastases.3 More recently, SABR has been tested for use in the oligometastatic setting, most prominently in the landmark randomized phase 2 SABR-COMET trial, which demonstrated a promising survival advantage to SABR but a concerning rate of high-grade toxic effects (28.8% for grade 2 or higher, 4.5% for grade 5).4,5
British Columbia (BC), Canada, participated in the SABR-COMET trial, and as a provincially coordinated program across 6 cancer centers, decided to limit the use of SABR in the oligometastatic setting to clinical trials while awaiting results from SABR-COMET and subsequent phase 3 trials to maintain standardized technique and monitor rates of late toxic effects.6 This protocol was developed while SABR-COMET was ongoing in anticipation of a high demand for SABR in the province between SABR-COMET closure and phase 3 trials opening, with a goal to expand the ability to offer SABR in a safe, ethical, consistent, and provincially coordinated manner.7
Without preliminary results available or phase 3 data in support of SABR in the oligometastatic setting, there was a strong local consensus that it was critical to open a phase 2 trial to assess the adverse effects and quality of life on a population scale. The primary objective of this study was to determine the rate of late toxic effects. We planned a priori to continue the study until we opened phase 3 trials that assessed SABR in the oligometastatic setting; therefore, the sample size was increased from the originally published protocol.
Methods
Study Design
In BC, RT is provincially coordinated with a common RT planning software infrastructure. This enables radiation oncologists and physicists to peer review contours and plans at other centers. All 6 BC cancer centers participated in this investigator-initiated, open-label, phase 2 nonrandomized clinical trial in which all participants provided written informed consent to receive treatment with experimental SABR for all sites of persistent or progressing metastatic disease. This study was approved by the joint University of British Columbia and BC Cancer Research Ethics Board. The study methods were published, including the patient eligibility criteria, doses, and organ at risk (OAR) constraints.7 In brief, adult patients with a histologically confirmed cancer, Eastern Cooperative Oncology Group score of 0 to 2, life expectancy of more than 6 months, metastatic disease on imaging, and primary tumor treated radically or controlled by prior palliative RT or systemic therapy were eligible if there were a maximum of 5 metastases (either 5 in total for oligometastatic disease or 5 not controlled in the oligoprogressive setting).6 Brain metastases were allowed to be treated off trial using stereotactic radiosurgery before enrollment and were not captured. Patients with brain metastases only with no other site of disease were excluded. Systemic therapy had to be discontinued for at least 2 weeks before and 1 week after treatment with SABR. Pre-enrollment imaging requirements included (1) brain computed tomography (CT) or magnetic resonance imaging (MRI) (for tumor sites with propensity for brain metastasis), (2) positron emission tomography (PET) CT in evidence-based indications or CT of the neck/chest/abdomen/pelvis and a bone scan if no PET-CT was performed, and (3) an MRI of the spine that was an additional requirement for patients with vertebral or paraspinal metastases.
Procedures
The RT planning details, including dose and fractionation prescription and OAR constraints, are in the published protocol7 (eTables 1 and 2 in Supplement 1). The OAR dose constraints were prioritized vs covering the tumor targets (volume of the planning target volume receiving 100% of the prescription dose aimed to equal at least 95%). However, volume was allowed to be as low as 50% to spare nearby critical OARs without being excluded from study enrollment. The trial mandated a tumor board review with respect to eligibility and peer review of target and OAR contours by a separate radiation oncologist through a provincially coordinated rota system before final enrolment.
Outcomes
The primary end points were toxic effects assessed by the National Cancer Institute Common Toxicity Criteria version 4 (presented in this article) and quality of life measured via patient reported outcomes (to be presented in the future). A reasonable level of toxic effects associated with SABR was defined a priori with the following end points: less than 5% grade 5 toxic effects, less than 10% grade 4 toxic effects, and less than 25% grade 3 toxic effects.
Prespecified secondary outcomes included progression-free survival, time from SABR treatment to disease progression at any site or death, overall survival, lesion control rate, time to initiating or resuming systemic therapy, and the number of treatment cycles of further chemotherapy/systemic therapy. Toxic effects were calculated based on patients who actually initiated treatment with SABR (ie, patients enrolled in the study but who did not initiate the course of SABR were excluded).
We prospectively collected National Cancer Institute Common Toxicity Criteria. Each toxic effect was classified as not associated with, unlikely associated with, possibly associated with, probably associated with, or definitely associated with SABR. Those rated as possibly, probably, or definitely associated were included in the analysis. A toxic effects review committee reviewed all grade 3 or greater toxic effects after trial completion, and, by majority vote, recategorized grade and potential association with SABR, as necessary. Several members reviewed all deaths. This committee comprised radiation oncologists and medical physicists from all 6 BC cancer centers, including coinvestigators and radiation oncologists not involved with the trial. The principal investigator was present at the review meetings, but did not participate in discussions of causality and grade.
Statistical Analysis
As previously published, the original sample size was set at 200, which was estimated to give a 95% confidence that the grade 4 or greater toxic effects were less 5% if there were 4 or fewer events.7 However, as planned a priori, we submitted a research ethics board amendment to double the sample size while waiting for phase 3 trials to open, which allowed us to continue to administer treatment with SABR in a safe and ethical manner while also improving the confidence limits of the toxic effect assessments. In addition, it enabled the potential for future subanalyses by body site treated, such as lymph node metastases, since they were not included in the SABR-COMET trial.7 An accrual of 50 patients with lymph node metastases was anticipated with the increased sample size to 400 (based on the fact we accrued 20 with the first 150 patients at time of protocol amendment), and that the proposed sample size increase would be associated with a 95% confidence that the true rate of grade 4 greater toxic effects was less than 10% if the rate of grade 4 events continued at the same pace. At the interim analysis, we did not examine the toxic effects data. Rather, only the demographic characteristics and the sites of SABR were examined. Therefore, the type 1 error was not spent. Statistical analyses were conducted using SPSS (version 14.0; IBM), and statistical significance was set at .05.
Results
From June 2016 to November 2020, 381 patients were enrolled at all 6 BC cancer centers (Figure 1). Median (range) follow-up at the time of analysis was 25 (1-54) months. Median overall survival was not reached, and in depth survival analysis will be presented in the future. The mean (SD; range) age was 68 (11.1; 30-97) years. Table 1 presents the remainder of the patient characteristics. Of the 263 patients with a single metastasis treated with SABR, 214 of 263 (81%) had oligometastatic disease, and 49 of 263 (19%) had oligoprogressive disease.
Figure 1. Study Profile.
CT indicates computed tomography; SABR, stereotactic ablative body radiotherapy; sim, simulation.
Table 1. Patient Characteristics.
| Characteristic | No./total No. (%) |
|---|---|
| Sex | |
| Female | 122/381 (32) |
| Male | 259/381 (68) |
| Site of primary cancer | |
| Prostate | 123/381 (32) |
| Colorectal | 63/381 (17) |
| Breast | 42/381 (11) |
| Lung | 33/381 (9) |
| Kidney | 34/381 (9) |
| Other | 86/381 (23) |
| Site of metastases treated with SABR on trial | |
| Lung | 188/548 (34) |
| Nonspine bone | 136/548 (25) |
| Spine | 85/548 (16) |
| Lymph node | 78/548 (14) |
| Liver | 29/548 (5) |
| Adrenal | 15/548 (3) |
| Others | 17/548 (3) |
| No. of metastatic sites treated with SABR on trial | |
| 1 | 263/381 (69) |
| 2 | 82/381 (22) |
| 3 | 26/381 (7) |
| 4-5 | 10/381 (3) |
| Oligometastatic or oligoprogressive disease | |
| Oligometastatic | 318/381 (83) |
| Oligoprogressive | 63/381 (17) |
Abbreviation: SABR, stereotactic ablative radiotherapy.
Toxic Effects
The grades 2, 3, 4, and 5 cumulative toxic effects associated with SABR (based on the highest grade toxic effects per patient) were 14.2% (95% CI, 10.7%-17.7%), 4.2% (95% CI, 2.2%-6.2%), 0%, and 0.3% (95% CI, 0%-0.8%), respectively. The grade 2 or greater toxic effects were 18.6% (95% CI, 14.7%-22.5%). Table 2 presents the toxic effects by Common Terminology Criteria for Adverse Events version 4 category. There were no gastrointestinal fistula or gastric hemorrhage toxic effects. Table 3 presents the cumulative incidence of toxic effects by site, while eTable 3 in Supplement 1 presents the grade 3 or greater cumulative incidence of toxic effects by site. eTable 4 in Supplement 1 presents the grade 2 or greater and 3 or greater incidence for toxic effects during years 1 to 5, respectively. There were 10.3% grade 3 or higher toxic effects for SABR to liver metastases, and 6.7% for SABR to adrenal metastases. It was less than 5% for the other sites. Cumulative incidence of grade 2 or higher toxic effects by Kaplan-Meier analysis at 2 years was 8%, and at 4 years was 23%. Cumulative incidence of grade 3 or higher toxic effects at 2 years was 4%, and at 4 years was 6% (Figure 2). Cumulative incidence of toxic effects increased over time until year 3, after which it stabilized. eFigure 1 in Supplement 1 presents the cumulative prevalence from year 0 to 2 and 0 to 5. eFigure 2 in Supplement 1 is a swimmer plot for when grade 3 or higher toxic effects developed and when they resolved. Patient-reported quality of life will be assessed in a future article.
Table 2. Toxic Effects Associated With SABR by CTCAE Category per Patient.
| Characteristic | Grade, No./total No. (%) | ||||
|---|---|---|---|---|---|
| ≥2 | 2 | 3 | 4 | 5 | |
| Pain | 25/381 (7) | 20/381 (5) | 5/381 (1) | 0 | 0 |
| Diarrhea | 4/381 (1) | 3/381 (1) | 1/381 (0.3) | 0 | 0 |
| Constipation | 2/381 (1) | 2/381 (1) | 0 | 0 | 0 |
| Pneumonitis | 5/381 (1) | 5/381 (1) | 0 | 0 | 0 |
| Fracture | |||||
| Rib | 5/381 (1) | 5/381 (1) | 0 | 0 | 0 |
| Spine | 7/381 (2) | 3/381 (1) | 4/381 (1) | 0 | 0 |
| Neuropathy | 6/381 (2) | 6/381 (2) | 0 | 0 | 0 |
| Other | 39/381 (10) | 28/381 (7) | 10/381 (3) | 0 | 1/381 (0.3) |
Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events; SABR, stereotactic ablative radiotherapy.
Table 3. Grade 2 or Higher Toxic Effects per Patient Associated With SABR by Site Treated With SABR.
| Characteristic | No./total No. (%) | |||||
|---|---|---|---|---|---|---|
| Lung | Bone | Spine | Lymph node | Liver (n = 29) | Adrenal (n = 15) | |
| Pain | 3/188 (2) | 13/136 (10) | 4/85 (5) | 1/78 (1) | 4/29 (14) | 0 |
| Diarrhea | 0 | 2/136 (1) | 1/85 (1) | 1/78 (1) | 0 | 0 |
| Constipation | 0 | 0 | 0 | 0 | 0 | 2/15 (13) |
| Pneumonitis | 4/188 (2) | 1/136 (1) | 1/85 (1) | 0 | 0 | 0 |
| Fracture | ||||||
| Rib | 2/188 (1) | 3/136 (2) | 0 | 0 | 1/29 (3) | 0 |
| Spine | 0 | 0 | 7/85 (8) | 0 | 0 | 0 |
| Neuropathy | 2/188 (1) | 0 | 2/85 (2) | 2/78 (3) | 0 | 0 |
| Other | 9/188 (5) | 12/136 (9) | 3/85 (4) | 7/78 (9)a | 3/29 (10)b | 4/15 (27)c |
| Total, per patient | 16/188 (9) | 22/136 (16) | 16/85 (19) | 10/78 (13) | 6/29 (21) | 4/15 (27) |
Abbreviation: SABR, stereotactic ablative radiotherapy.
Ascites, hydronephrosis, abdominal aortic aneurysm, esophagitis, proctitis, and arm fibrosis.
Nausea and vomiting, bile duct stenosis, jaundice, and death.
Adrenal insufficiency, fatigue, bloating, shortness of breath, and nausea.
Figure 2. Cumulative Incidence of Grade 2 or Higher and Grade 3 or Higher Toxic Effects.
Kaplan-Meier plot of the cumulative incidence of grade 2 or higher toxic effects (A) and grade 3 or higher toxic effects (B). Median time to toxic effects was not reached.
The grade 2 or higher cumulative toxic effects associated with SABR were 18.2% (95% CI, 14.0%-22.5%) in patients with oligometastatic disease and 20.6% (95% CI, 10.0%-30.6%) in patients with oligoprogressive disease. This was not statistically significantly different between the 2 groups using the χ2 test (2 sided): it was 16.7% (95% CI, 12.2%-21.2%) in patients receiving treatment with SABR for a single metastasis and 22.9% (95% CI, 15.3%-30.5%) in patients receiving treatment with SABR for multiple metastases. This was not statistically significantly different between the 2 groups using the χ2 test (2 sided).
For 1 patient with grade 5 toxic effects at the time of analysis, the committee was evenly split on whether the death was unlikely, possibly, or probably associated with SABR (vs disease progression); therefore, it was averaged to possibly associated. The patient had metastatic colon cancer to the liver and was treated with SABR (54 Gy/3) for 2 segment VIII liver metastases, including 1 near the right hepatobiliary tract. There was a 125% hotspot on the right hepatobiliary tract. VBED1072 Gy for the central hepatobiliary tract (as defined by Toesca et al8) is 66 cc, VBED1066 Gy is 69 cc, and DmeanBED10 is 42.7 Gy. The patient had biliary stenosis 15 months after treatment with SABR, requiring endoscopic retrograde cholangiopancreatography and biliary drain, and then developed ascending cholangitis and fungemia. The patient eventually died of recurrent biliary infections associated with the biliary drain, which was confirmed after review by an independent infectious diseases physician. Imaging results also showed progression of disease as an alternative explanation for the biliary stenosis, the subsequent biliary drain, and death.
Discussion
This relatively large, population-based, phase 2 nonrandomized clinical trial demonstrated a low rate of high-grade toxic effects, which was lower than the a priori cutoffs. The finding of a cumulative incidence of grade 3 to 5 toxic effects less than 5% suggests that SABR in the oligometastatic setting is safe. However, the single grade 5 toxic effects that was possibly associated with SABR serves as a reminder of the potential toxic effects of this ablative treatment and the need to proceed cautiously and with sufficient level 1 evidence, particularly for patients with abdominal metastases.
The results show a lower rate of toxic effects than the landmark SABR-COMET randomized phase 2 clinical trial,4,5,6 but the results are similar to rates of grade 3 or higher toxic effects compared with other nonrandomized studies.9,10,11,12 In 2021, the National Health Service in England published a large, prospective, observational, registry-based, single-arm study that documented a similar rate of toxic effects. However, this registry study was primarily designed to provide access to SABR within the National Health Service, and the authors stated that they “adopted a pragmatic approach to adverse event reporting that may have missed treatment associated with toxic effects because of a potential lack of site monitoring...[and] the Kaplan-Meier analysis assume no event unless an event was recorded…potentially lead[ing] to detection bias because events cannot account for patients lost to follow-up, for instance due to disease progression.”12 In contrast, with the primary objective of this SABR-5 study being to document toxic effects, we implemented several measures to ensure that toxic effects were accurately captured. First, we prospectively collected toxic effects as the primary outcome at all 6 BC cancer centers through a centralized electronic records system. Second, we developed a toxic effects review committee that reviewed all grade 3 or higher toxic effects events and recategorized grade and potential association with SABR when necessary. Multiple physicians reviewed all deaths.
The result of the toxic effects review committee was the recategorization of a grade 5 event from not associated to possibly associated with SABR, as described in the Results. This highlights that other series of SABR toxic effects that do not place a primary emphasis on toxic effects or have a toxic effects review committee may underreport toxic effects. It is also possible that our review errs on the side of overattributing toxic effects to SABR rather than disease progression. This further highlights the need for phase 3 randomized clinical trials to assess causality of SABR to toxic effects.
Liver and adrenal SABR had greater than 5% grade 3 or higher toxic effects (3 of 29 [10.3%] and 1 of 15 [6.7%], respectively). This is in context of low number of participants for these sites. We plan to update the analysis at 4 years median follow-up and would examine if these higher rates of grade 3 or more toxic effects persist. Overall, we recommend caution when planning treatment with SABR for liver and adrenal targets. In 1 patient with grade 5 toxic effects that were associated with the liver being treated with SABR, the hotspot was in the hepatobiliary tract. There is emerging evidence around predictors for central hepatobiliary tract toxic effects, including biliary stricture requiring intervention and infection, with dose constraints proposed: for liver metastases, VBED1072 Gy less than 21 cc, and VBED1066 Gy less than 24 Gy; and for primary liver cancer, VBED1040 Gy less than 37 cc, and VBED1030 Gy less than 45 cc.8,13
We hypothesize that the relatively low rates of toxic effects are associated with 2 main factors. First, as outlined in the protocol (Supplement 2), and similar to the SABR-COMET, SABR-COMET-3, and SABR-COMET-10 trials, the priority for planning was to respect the OAR constraints vs target coverage. Second, we believe the provincially coordinated individual peer review of OARs and targets was associated with high-quality and safe RT plans. Anecdotally, radiation oncologists who had less SABR experience had relatively frequent changes in their OARs after peer review, although unfortunately we did not collect robust data on the peer review process.
Compared with SABR-COMET,7 this study’s inclusion criteria were mostly similar. The difference was the large number of participants (381 vs 99), which increased the statistical power. Another difference was the inclusion of oligoprogressive disease (within up to 5 progressive lesions) in this study. While this had an association with the survival outcome, toxic effects of SABR were not significantly different.
Strengths and Limitations
The results of this nonrandomized clinical trial should be considered in the context of their strengths and limitations. Treatment with SABR was delivered to multiple sites in patients with broad histological findings; therefore, the rate of toxic effects may not be generalized to specific histological findings or SABR locations. As a nonrandomized study, we were unable to determine what proportion of toxic effects described were associated with the SABR intervention vs as a part of the natural history of the metastatic disease or from non-SABR oncological treatments. The single grade 5 event is a good example of this, and the toxic effects review committee was split on their interpretation of whether the event was not associated, possibly associated, or probably associated with SABR for the liver. However, in a jurisdiction where SABR for oligometastases was limited to enrollment in this trial, this is a relatively unique population-based analysis relatively free from selection bias. Unlike the British observational registry study, which admits to a pragmatic approach to adverse events that likely missed adverse events,12 the current study’s primary objective was measuring toxic effects, and we had a robust approach. Therefore, to our knowledge, we believe this is the most comprehensive analysis of SABR toxic effects in the setting of oligometastatic disease.
Conclusions
The results of this nonrandomized clinical trial, as defined a priori, suggest that SABR for oligometastatic disease was relatively safe in this provincially coordinated population-based phase 2 trial with rates of grade 2 or higher, 3 or higher, 4 or higher, and 5 or higher of less than 20%, less than 5%, less than 0.5%, and less than 0.5%, respectively, if they are treated as per the protocol on this study. These results are encouraging that in a program with rigorous peer review, quality assurance, and prioritization of meeting OAR constraints vs tumor target coverage, SABR is associated with acceptable rates of toxic effects. Ultimately, these results support further enrollment in randomized phase 3 clinical trials.14,15
eTable 1. Dose fractionation of SABR
eTable 2. Organs at risk constraints for SABR
eTable 3. Grade 3+ toxicity by site treated with SABR
eTable 4. Incidence per year of grade 2+ and 3+ toxicity
eFigure 1. Prevalence at year 2 and 5
eFigure 2. Swimmer plot of grade 3+ toxicity
Trial protocol
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. Dose fractionation of SABR
eTable 2. Organs at risk constraints for SABR
eTable 3. Grade 3+ toxicity by site treated with SABR
eTable 4. Incidence per year of grade 2+ and 3+ toxicity
eFigure 1. Prevalence at year 2 and 5
eFigure 2. Swimmer plot of grade 3+ toxicity
Trial protocol