# Oligometastatic Disease: SBRT and the SABR-COMET Paradigm

## Introduction

The oligometastatic state represents a biologically distinct condition that lies between localized cancer and widespread metastatic disease. In this state, patients have a limited number of metastatic lesions that are potentially amenable to local ablative therapies. This concept was first proposed by Hellman and Weichselbaum in 1995 and has since been validated by randomized clinical trials. These trials have demonstrated that stereotactic ablative radiotherapy (SABR or SBRT) directed at all metastatic sites can improve both progression-free survival and overall survival in selected patients.

## Defining Oligometastatic Disease

### Historical Definition

Oligometastatic disease is generally defined as the presence of one to five metastatic lesions involving one to three organs. However, there is no universally accepted maximum number of metastases; some clinical trials permit up to five lesions, while others allow as many as ten.

### ESTRO-EORTC Consensus Classification

The European Society for Radiotherapy and Oncology (ESTRO) and the European Organisation for Research and Treatment of Cancer (EORTC) have proposed a consensus classification to better characterize oligometastatic disease. This classification includes several subtypes: synchronous oligometastatic disease, where metastases are present at the time of initial diagnosis; metachronous oligometastatic disease, where metastases appear after treatment of the primary tumor; oligoprogressive disease, characterized by progression at limited sites while other disease remains controlled on systemic therapy; oligopersistent disease, where residual disease persists at limited sites following systemic therapy; and oligorecurrent disease, which refers to limited recurrence after prior definitive treatment.

### Biologic Basis

Oligometastatic disease may reflect tumors with inherently limited metastatic capacity. These tumors often exhibit distinct molecular profiles, including fewer driver mutations and less genomic complexity compared to widely metastatic cancers. In select patients, eradication of all metastatic deposits through local therapies may be curative. Additionally, circulating tumor DNA (ctDNA) dynamics are emerging as a tool to help identify patients with true oligometastatic disease who are most likely to benefit from local ablative treatments.

## Landmark Trials

### SABR-COMET (Phase II)

The SABR-COMET trial enrolled 99 patients with controlled primary tumors and one to five metastatic lesions at any site. Patients were randomized in a 2:1 ratio to receive SABR to all metastatic sites plus standard of care versus standard of care alone. The primary endpoint was overall survival. The trial demonstrated a remarkable improvement in 5-year overall survival, with 42.3% in the SABR arm compared to 17.7% in the control arm. Progression-free survival at five years was also improved (17.3% vs. 3.2%). However, treatment-related mortality occurred in three patients (4.5%) in the SABR group. This was the first randomized trial to show an overall survival benefit for SABR in oligometastatic disease.

### SABR-COMET-3 and SABR-COMET-10

Building on the initial results, the SABR-COMET-3 trial is a phase III study focusing on patients with one to three metastases and has completed accrual. The SABR-COMET-10 trial, also phase III, is ongoing and includes patients with four to ten metastases. These studies aim to provide definitive evidence supporting the use of SABR in the oligometastatic setting.

### NRG BR002

The NRG BR002 trial specifically addressed oligometastatic breast cancer, comparing SABR or surgery to all metastases versus standard systemic therapy. Unlike SABR-COMET, this trial did not demonstrate a progression-free survival or overall survival benefit, highlighting that not all cancer histologies may derive equal benefit from local ablative therapies.

### ORIOLE Trial

The ORIOLE trial investigated oligometastatic prostate cancer patients with one to three metastases, randomizing them to SABR versus observation. SABR significantly improved six-month progression-free survival (81% vs. 39%) and identified immune correlates associated with response to SABR, suggesting a potential immunomodulatory effect.

### STOMP Trial

The STOMP trial enrolled patients with oligorecurrent prostate cancer (one to three metastases detected by choline PET) and compared metastasis-directed therapy (either SBRT or surgery) to surveillance. The median androgen deprivation therapy (ADT)-free survival was longer in the metastasis-directed therapy group (21 months) compared to surveillance (13 months), supporting the use of local therapy to delay systemic treatment initiation.

| Trial | Population | Comparison | Primary Endpoint | Key Result |
|---|---|---|---|---|
| SABR-COMET (Phase II) | 1–5 mets, any histology | SABR + SOC vs. SOC | OS | 5-yr OS: 42.3% vs. 17.7% |
| SABR-COMET-3 (Phase III) | 1–3 mets | SABR + SOC vs. SOC | OS | Completed accrual; results pending |
| SABR-COMET-10 (Phase III) | 4–10 mets | SABR + SOC vs. SOC | OS | Ongoing |
| NRG BR002 | Oligomet breast cancer | SABR/surgery vs. SOC | PFS/OS | Negative (no benefit) |
| ORIOLE | 1–3 mets, prostate | SABR vs. observation | 6-mo PFS | 81% vs. 39% |
| STOMP | 1–3 mets, prostate (oligorecurrent) | MDT vs. surveillance | ADT-free survival | 21 mo vs. 13 mo |

![Forest plot summarizing overall survival outcomes from major randomized trials of SBRT for oligometastatic disease](images/oligomet-trial-outcomes.jpg)

## Patient Selection

### Favorable Characteristics

Patients most likely to benefit from SABR for oligometastatic disease typically present with metachronous oligometastases, meaning a longer disease-free interval after initial treatment. A controlled primary tumor and good performance status (ECOG 0-1) are important favorable factors. The strongest evidence supports treating patients with one to three metastases. Favorable primary tumor histologies include prostate, colorectal, non-small cell lung cancer (NSCLC), and breast cancer. Additionally, all metastatic sites should be amenable to local ablative therapy.

### Unfavorable Characteristics

Conversely, patients with synchronous widespread disease that has been reduced to an oligometastatic state by systemic therapy (oligopersistent disease), rapidly progressive disease despite systemic therapy, poor performance status, or histologies with limited supporting data such as pancreatic or gastric cancers are less likely to benefit. An uncontrolled primary tumor also portends a worse prognosis.

### Biomarker-Guided Selection

Emerging strategies for patient selection include monitoring ctDNA clearance after systemic therapy, which may identify those most likely to benefit from SABR. Molecular profiling targeting genes associated with metastatic capacity and advanced imaging with novel PET tracers such as PSMA for prostate cancer or FAPI may improve staging accuracy. Prospective validation of these biomarker-guided approaches is ongoing.

## SBRT Technique for Oligometastatic Sites

### Dose and Fractionation

SBRT dose prescriptions are site-specific and follow established guidelines. For lung metastases, peripheral lesions typically receive 48-54 Gy in 3-4 fractions, while central lesions are treated with 50-60 Gy in 5 fractions. Liver metastases are treated with 45-60 Gy over 3-5 fractions. Spine metastases receive either a single fraction of 16-24 Gy or 24-30 Gy in 3 fractions. Adrenal metastases are treated with 36-48 Gy in 3 fractions, and lymph node metastases receive 24-45 Gy in 3-5 fractions. A biologically effective dose (BED10) greater than 100 Gy is associated with optimal local control across these sites.

### Treatment Planning Principles

High-quality immobilization and motion management tailored to the anatomic site are essential for precise delivery. Image guidance using cone-beam CT (CBCT) or kilovoltage imaging is performed at each fraction to ensure accuracy. Treatment plans aim for conformal dose distributions with rapid dose fall-off to spare organs at risk (OARs). Plan evaluation includes metrics such as conformity index and gradient index to optimize treatment quality.

## Integration with Systemic Therapy

### Sequencing

SABR can be administered before, during, or after systemic therapy depending on the clinical scenario. Concurrent immunotherapy may enhance the abscopal effect, an immune-mediated response outside the irradiated field (discussed further in Lecture 75). Typically, treatment breaks in systemic therapy for SABR last one to two weeks.

### Oligoprogressive Disease

In cases of oligoprogressive disease, SABR is directed at the progressing metastatic sites while continuing systemic therapy that controls the majority of disease. This approach allows patients to remain on effective systemic regimens longer and is particularly relevant in EGFR or ALK-mutant NSCLC and hormone-sensitive prostate cancer. It is an emerging strategy to extend the duration of targeted therapies.

![Schematic illustrating the integration of SBRT with systemic therapy across the oligometastatic disease continuum](images/oligomet-treatment-integration.jpg)

## Surveillance After SABR

After SABR, patients undergo cross-sectional imaging with CT or PET/CT every three to four months for the first two years, followed by imaging every six months thereafter. Where available, ctDNA monitoring can provide early detection of recurrence. New oligometastatic lesions identified during surveillance may be treated with additional SABR, a strategy known as repeat oligometastatic-directed therapy. However, the development of polymetastatic disease necessitates a change in systemic therapy.

![Follow-up imaging protocol and decision algorithm after SBRT for oligometastatic disease showing response assessment](images/oligomet-surveillance.jpg)

## Key Clinical Pearls

The SABR-COMET trial established a new treatment paradigm by demonstrating a significant overall survival benefit for SABR in oligometastatic disease, with 42% versus 18% survival at five years. Oligometastatic disease is a biologically distinct state, making careful patient selection critical to achieving favorable outcomes. The most favorable scenario involves metachronous oligometastatic disease with a long disease-free interval and a controlled primary tumor. Site-specific SBRT doses targeting a biologically effective dose (BED10) greater than 100 Gy optimize local control. Additionally, oligoprogressive disease is an emerging indication for SABR, enabling continuation of effective systemic therapy.

## References

1. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET Phase II randomized trial. *J Clin Oncol*. 2020;38(25):2830-2838.  
2. Hellman S, Weichselbaum RR. Oligometastases. *J Clin Oncol*. 1995;13(1):8-10.  
3. Phillips R, Shi WY, Deek M, et al. Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: the ORIOLE phase 2 randomized clinical trial. *JAMA Oncol*. 2020;6(5):650-659.  
4. Guckenberger M, Lievens Y, Bouma AB, et al. Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation. *Lancet Oncol*. 2020;21(1):e18-e28.