Introduction
In 2020, colorectal cancer accounted for 10% of all newly diagnosed cancer cases globally, making it the third most diagnosed cancer worldwide [1]. Although 50%–70% of colorectal cancer patients undergo curative surgery, more than one-third of patients experience relapse or death [2-4]. Among patients with recurrence, approximately 75%–80% develop distant metastases, primarily in the liver, lungs, and peritoneum [4-6]. Oligometastasis, an intermediate stage between localized disease and widespread metastasis, has gained attention in treatment strategies [7]. Surgical resection of oligometastatic lesions has shown survival benefits in various cancers, including colorectal cancer [8-12]. However, for many patients, local therapies, such as radiofrequency ablation and stereotactic body radiotherapy (SBRT), are often preferred over surgery to avoid surgery-related morbidity [12,13]. Despite the promising results of SBRT, the outcomes for colorectal oligometastasis are generally less favorable compared to those observed in other primary cancers [12-16]. Given this challenge, further research is needed to improve the management of oligometastatic lesions in colorectal cancer. Moreover, due to limited and heterogeneous data and complex treatment considerations for these patients, understanding the effectiveness of SBRT and the factors influencing its outcomes is crucial. This study aimed to evaluate treatment outcomes and identify prognostic factors for survival in colorectal cancer patients with oligometastatic lesions treated with SBRT to optimize treatment strategies.
Materials and Methods
1. Study design and patient selection
This retrospective study analyzed patients with oligometastatic colorectal cancer who underwent SBRT for oligometastatic lesions at Kyungpook National University Chilgok Hospital between 2016 and 2022. A total of 141 treatment sessions involving 171 metastatic lesions were initially reviewed among 128 patients. Oligometastatic disease (OMD) was defined as the presence of five or fewer metastatic lesions, all amenable to local therapies, with the primary tumor under control. For patients repeatedly diagnosed with OMD, each OMD was considered as a separate case. After excluding patients who did not receive SBRT for all active oligometastatic lesions, those who had brain metastasis at the diagnosis of OMD, those who underwent both SBRT and other local therapies at the diagnosis of OMD, those with a biologically effective dose (BED) of <72 Gy10, and those with follow-up durations shorter than 6 months after SBRT, 84 cases involving 113 metastatic sites (88 lung, 19 liver, and 6 for lymph node) in 74 patients were included in the analysis. Computed tomography (CT) was the routine imaging modality, while magnetic resonance imaging (MRI) was typically performed when liver metastases were suspected. Positron emission tomography–computed tomography (PET-CT) was performed at the physician’s discretion. The Institutional Review Board approved this study, and the requirement for informed consent was waived owing to the retrospective nature of the study.
2. Radiotherapy
All patients underwent CT simulation in the supine position immobilized with Body Pro-Lok (CIVCO Inc., Coralville, IA, USA), with a slice thickness of 3 mm. For moving tumors, 4-dimensional (4D)-CT was performed to account for respiratory motion. The gross tumor volume (GTV) was contoured based on visible tumors, and the internal gross tumor volume (iGTV) was defined as the combination from each set of 4D-CT scans. A 5-mm margin in all directions was typically added to the iGTV to define the planning target volume (PTV). SBRT plans were generated with dynamic conformal arcs, static conformal beams, or intensity-modulated beams. The algorithms used to calculate dose distributions included the pencil beam algorithm, X-ray voxel Monte Carlo, the analytical anisotropic algorithm, and Acuros XB. The prescription dose was set to achieve at least 95% PTV coverage. Cone-beam CT was used for image guidance before each treatment. SBRT was performed using the VERO system (Mitsubishi Heavy Industries Ltd., Japan; BrainLab AG, Feldkirchen, Germany), VitalBeam (Varian Medical Systems, Palo Alto, CA, USA), and RapidArc (Varian Medical Systems). The BED was calculated using the following formula: BED = nd(1 + d/[α/β]), where n represents the number of fractions, d is the dose per fraction, and an α/β ratio of 10 was applied.
3. Follow-up
The post-SBRT follow-up consisted of blood tests, clinical evaluations, and imaging studies, including chest CT, abdominopelvic CT, and chest X-ray. Subsequent imaging intervals were tailored to individual patient needs, ranging from 2 to 6 months. At each follow-up visit, a thorough clinical assessment was conducted, including physical examinations and symptom evaluations. Additional diagnostic modalities, such as MRI and PET-CT, were performed as needed based on clinical indications or when specific patient factors warranted further investigation.
4. Study endpoint
Local failure was defined as the progression of the treated lesion within the PTV. Widespread failure was defined as the occurrence of six or more newly developed or recurrent metastatic lesions after the completion of SBRT.
The primary endpoint of this study was progression-free survival (PFS), defined as the period from the initiation of SBRT for oligometastasis to the first documented recurrence of any type. Additionally, prognostic factors influencing PFS were evaluated. Secondary endpoints included widespread failure-free survival (WSFFS), defined as the period from SBRT initiation to the development of widespread failure, and overall survival (OS), defined as the period from SBRT initiation to death from any cause, with their associated prognostic factors. For cases with multiple lesions treated using SBRT simultaneously or sequentially, the earliest start date of all SBRT treatments was used for the calculation.
Treatment-related toxicity was also assessed using the Common Terminology Criteria for Adverse Events version 5.0. Acute toxicity was defined as adverse events that occurred within the first 3 months following radiotherapy, while late toxicity was defined as events occurring beyond the 3-month post-treatment period.
5. Statistical analysis
Categorical variables are presented as frequencies (%) and were compared using Pearson’s chi-squared test or Fisher’s exact test. Survival outcomes were analyzed using the Kaplan-Meier method, with survival curves compared through the log-rank test to identify statistically significant differences between groups. Variables with a p-value <0.10 in the univariable Cox proportional hazards regression models were used to identify prognostic factors with multivariable Cox proportional hazards regression models with backward elimination. All statistical analyses were conducted with R Statistics version 4.4.2 (The R Foundation for Statistical Computing, Vienna, Austria). A p-value <0.05 was considered statistically significant.
Results
1. Characteristics of cases
This study included 84 cases with a median age of 71 years (range, 49 to 91). Of these 84 cases, 55 (65.5%) were male. Primary tumor sites were the colon in 39 cases (46.4%) and the rectum in 45 cases (53.6%). Most cases were stage III (41.7%) or IV (33.3%) at the time of the diagnosis. All tumors were adenocarcinoma. Fifty-eight cases (69.0%) had a single oligometastatic lesion. The lung was the most common metastatic site (73.8%), followed by the liver (20.2%). All patients were free of active disease, except for the lesion(s) treated with SBRT. The median SBRT dose for each lesion was 50 Gy (range, 36 to 60) delivered in a median number of 4 fractions (range, 3 to 10), with a median BED of 112.5 Gy10 (range, 72.0 to 180.0). The most common dose-fractionation regimens were 52 Gy in 4 fractions (BED 119.6 Gy10; 27 lesions, 23.9%), followed by 48 Gy in 4 fractions (BED 105.6 Gy10; 23 lesions, 20.4%), and 50 Gy in 4 fractions (BED 112.5 Gy10; 17 lesions, 15.0%). Detailed information on the patient, tumor, and treatment characteristics is summarized in Table 1 and Supplementary Table S1.
2. Survival outcomes and prognostic factors
The median follow-up duration was 32.2 months (range, 8.2 to 89.3 months). The 2-year PFS, WSFFS, and OS rates were 35.1%, 67.4%, and 80.8%, respectively (Fig. 1). Local failure was observed in 18 cases (21.4%).
The results of univariable analyses for PFS, WSFFS, and OS are summarized in Supplementary Table S2, where five variables with a p-value <0.10 were identified: age (>70 vs. ≤70 years), sex (female vs. male), oligometastatic status (repeat/induced vs. de novo), metastatic site (lung-confined vs. others), and PTV volume (≥17.6 vs. <17.6 cm3).
In multivariable analysis of PFS, oligometastatic status (hazard ratio [HR], 2.66; 95% confidence interval [CI], 1.40 to 5.04; p = 0.003) and PTV volume (HR, 1.99; 95% CI, 1.09 to 3.62; p = 0.025) were identified as significant prognostic factors (Table 2). When cases were categorized based on the number of adverse prognostic factors for PFS (repeat/induced oligometastasis, and larger PTV volume), having one (HR, 3.15; 95% CI, 1.11 to 8.98; p = 0.031) or two (HR, 5.14; 95% CI, 1.72 to 15.34; p = 0.003) adverse prognostic factors was significant adverse factors for PFS, compared to those with no adverse prognostic factors, in multivariable analysis adjusting for age, sex, metastatic site, and number of risk factors (Supplementary Table S3). Corresponding results for OS and WSFFS are shown in Table 2 and Supplementary Table S3.
For the purpose of risk stratification for OS and WSFFS, the number of risk factors (0 vs. 1 vs. 2) was used in the multivariable analyses. In addition, local failure was included as a covariate in the models for OS and WSFFS, as it was a significant factor in the univariable analyses (HR, 2.97; 95% CI, 1.55 to 5.68; p = 0.001 for OS and HR, 2.41; 95% CI, 1.17 to 4.98; p = 0.017 for WSFFS).
In the multivariable analysis that included age, sex, metastatic site, number of risk factors and local failure as covariates, older age (HR, 2.74; 95% CI, 1.32 to 5.72; p = 0.007), local failure (HR, 2.54; 95% CI, 1.27 to 5.09; p = 0.008), and having two adverse prognostic factors for PFS (HR, 3.39, 95% CI, 1.07 to 10.77; p = 0.044) were identified as poor prognostic factors for OS (Table 3). For WSFFS, female sex (HR, 2.04; 95% CI, 1.01 to 4.14; p = 0.047) and having two adverse prognostic factors for PFS (HR, 4.72; 95% CI, 1.04 to 21.39; p = 0.039) were identified as poor prognostic factors (Table 3). Survival curves for PFS, WSFFS, and OS stratified by the number of adverse prognostic factors for PFS are presented in Fig. 2.
3. Toxicities
Acute toxicity was observed in 10 out of 84 cases (11.9%), primarily presenting as fatigue and nausea, with no grade 3 or higher acute toxicities reported. Late toxicity occurred in 11 out of 84 cases (13.1%), with 10 cases classified as grade 1 or 2. One patient developed grade 3 late cardiac toxicity. No grade 4 or life-threatening late toxicities were observed.
Discussion and Conclusion
This study found that oligometastatic status and PTV volume were significantly associated with PFS after SBRT for OMD in colorectal cancer patients. The number of poor prognostic factors (repeat/induced OMD and larger PTV volume) was also associated with OS and WSFFS, suggesting a potential for stratifying patients to determine optimal treatment strategies.
In the current study, 2-year PFS, WSFFS, and OS rates were 35.1%, 67.4%, and 80.7%, respectively, which are consistent with previously reported findings. In previous studies, SBRT for various sites of oligometastatic colorectal cancer has been reported to achieve 2-year PFS rates ranging from 26.4% to 31.6% [17,18]. Widespread progression rates following SBRT for oligometastatic colorectal cancer have been reported to be around 35% at 2 years [18]. Colorectal patients with various oligometastatic sites treated with SBRT exhibit 2-year OS rates ranging from 76.1% to 79% [17,18].
Our study found that repeat/induced OMD and larger PTV volume (≥17.6 cm3) were associated with worse PFS outcomes (Table 2). Various prognostic factors for PFS after SBRT for oligometastatic colorectal cancer have been reported; some align with our findings, while others report different factors. Lee et al. [19] identified that oligoprogression (vs. oligometastasis), multiple lung lesions (vs. single), the presence of extrapulmonary metastatic lesions at presentation, and M1 disease at initial diagnosis were significantly associated with worse PFS after SBRT for pulmonary metastases from colorectal cancer. Agolli et al. [20] reported that metachronous OMD (vs. synchronous OMD) and complete response (vs. partial response/stable disease vs. disease progression) were positive prognostic factors for PFS in pulmonary oligometastatic colorectal cancer treated with SBRT. In the study by Sheikh et al. [18], PTV volume (> 17.5 vs. ≤17.5 cm3) was the sole prognostic factor for PFS after SBRT to multiple-site OMD. However, due to differences in patient cohorts and the prognostic factors considered across studies, further research is required to validate prognostic factors for PFS in oligometastatic colorectal cancer treated with SBRT.
Several studies identified prognostic factors for OS, including PTV or GTV volume, metastatic sites, SBRT dose, lines of previous systemic therapy, oligoprogression, etc. [17-19,21-24]. In the current study, older age (>70 years), the presence of local failure, and having two risk factors for PFS (both repeat/induced OMD and larger PTV volume) were significant adverse prognostic factors for OS after SBRT (Table 3). Widespread failure after local therapy for OMD is important, as it indicates systemic disease progression requiring systemic therapies [12,18]. Sheikh et al. [18] reported that a larger PTV volume (>17.5 cm3) and prior systemic therapy were associated with worse WSFFS after SBRT for oligometastatic colorectal cancer. In the current study, female sex and having two risk factors for PFS were significantly associated with worse WSFFS (Table 3).
These identified prognostic factors for OS and WSFFS may have important clinical implications in treatment decision-making. Patients with two risk factors for PFS may benefit from initiating or modifying chemotherapy in addition to SBRT, as they demonstrated significantly worse OS and WSFFS compared to those with no risk factors (Table 3). SBRT alone may be sufficient for patients with zero or one risk factor, allowing them to potentially defer chemotherapy or continue their current chemotherapeutic regimen. Although the BED of prescribed doses was not a significant factor for survival outcomes in this study, dose escalation may offer benefits in terms of local control and OS when applying SBRT to OMD. Consistent with our findings, local control has been reported to be correlated with better OS [22,25]. Several studies have demonstrated that a higher SBRT dose is associated with improved local control in oligometastatic colorectal cancer, which is known to have a lower local control rate after SBRT compared to other primary cancers [18,19,23,26-28]. Although local failure was not a statistically significant factor for WSFFS, its impact on widespread failure warrants further investigation, as widespread failure tended to occur more frequently in patients with local failure (11/18, 61.1% vs. 22/66, 33.3%; p = 0.062).
The limitations of our study include its single-institution, retrospective design, small patient cohort, and heterogeneity in prior disease status (e.g., oligometastatic vs. polymetastatic) and in prior treatments, including variations in primary tumor management, chemotherapeutic regimens, the number and cycles of chemotherapy, and local therapies for previously treated OMD. All of these factors may restrict the generalizability of our findings. Therefore, larger, multicenter prospective studies that take into account heterogeneity not captured in the current study are needed to identify more generalizable prognostic factors.
In conclusion, SBRT demonstrated favorable and safe clinical outcomes, supporting its role as an effective treatment option for oligometastatic colorectal cancer. Oligometastatic status and PTV volume were significantly associated with PFS. Additionally, risk stratification based on the number of poor prognostic factors contributed to a better understanding of survival outcomes, underscoring the necessity of a personalized approach to patient management. Further research is necessary to validate these findings and refine patient stratification for SBRT in colorectal cancer patients with OMD.
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