Survival impact of radiotherapy for patients with de novo metastatic rectal cancer

Harvey Yu-Li Su; Yun-Hsuan Lin; Ko-Chao Lee; Yueh-Ming Lin; Chun-Chieh Huang; Eng-Yen Huang; Tai-Jan Chiu; Shih-Yu Huang; Chia-Che Wu; Chang-Ting Lin; Ming-Chun Kuo; Kai-Lung Tsai

doi:10.3393/ac.2025.00605.0086

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Original Article Colorectal cancer Survival impact of radiotherapy for patients with de novo metastatic rectal cancer: Harvey Yu-Li Su^1,2,3,4,5, Yun-Hsuan Lin⁶, Ko-Chao Lee⁷, Yueh-Ming Lin⁷, Chun-Chieh Huang⁶, Eng-Yen Huang⁶, Tai-Jan Chiu³, Shih-Yu Huang³, Chia-Che Wu³, Chang-Ting Lin³, Ming-Chun Kuo³, Kai-Lung Tsai⁷; Annals of Coloproctology 2026;42(1):94-102.
DOI: https://doi.org/10.3393/ac.2025.00605.0086
Published online: February 26, 2026

¹Doctoral Program of Clinical and Experimental Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan

²School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan

³Division of Hematology Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan

⁴Genomic and Proteomic Core Laboratory, Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan

⁵Cancer Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan

⁶Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan

⁷Department of Colorectal Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan

Correspondence to: Kai-Lung Tsai, MD Department of Colorectal Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, No. 123, Dapi Rd, Niaosong District, Kaohsiung 833, Taiwan Email: kltsai@cgmh.org.tw

• Received: May 15, 2025 • Revised: August 28, 2025 • Accepted: September 15, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ARTICLE INFORMATION
REFERENCES

Abstract

Purpose
Metastatic rectal cancer (mRC) is a highly lethal and complex disease that demands a multidisciplinary treatment approach. However, the clinical effectiveness of radiotherapy (RT) for de novo mRC remains controversial and uncertain.
Methods
This retrospective cohort study examined medical records from Kaohsiung Chang Gung Memorial Hospital for patients with histologically confirmed de novo mRC diagnosed between January 2015 and December 2020. All patients received standard systemic therapy and radical surgery when feasible. The primary outcome, overall survival (OS), was assessed using the Kaplan-Meier method. Multivariable analysis was performed using a Cox regression model.
Results
Among 271 patients included in the analysis, 117 received RT and 154 did not. The median OS was significantly longer in the RT group compared with the non-RT group (27.8 months vs. 21.9 months; P=0.046). Multivariate analysis identified several independent predictors of OS: age ≥65 years (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.26–2.27; P=0.001), primary tumor resection (HR, 2.62; 95% CI, 1.90–3.61; P<0.001), M1b or M1c disease (HR, 1.97; 95% CI, 1.44–2.69; P<0.001), and receipt of RT (HR, 1.41; 95% CI, 1.02–1.94; P=0.036).
Conclusion
RT significantly improves OS in patients with mRC, underscoring its role in treatment strategies. These findings support its inclusion in therapeutic protocols and highlight the need for larger, multicenter trials to confirm and extend these results.
Keywords: Metastatic rectal cancer; Radiation; Tumor regression grade; Overall survival

INTRODUCTION

Colorectal cancer is the third most common cancer worldwide, with approximately 704,000 new cases diagnosed annually, and it remains the second leading cause of cancer-related mortality globally [1, 2]. The rectum is the most frequent site of colorectal cancer [3]. Preoperative short-course radiotherapy (RT) or chemoradiotherapy followed by total mesorectal excision is a well-established standard of care for stage II and III rectal cancer [4–6]. However, nearly 20% of patients present with metastatic disease at diagnosis, with the liver and lungs being the most frequent metastatic sites [7–9].

Advances in chemotherapy and the introduction of biologic agents, including anti–vascular endothelial growth factor (anti-VEGF) inhibitors and anti–epidermal growth factor receptor (anti-EGFR) inhibitors, have improved treatment outcomes for patients with metastatic rectal cancer (mRC) [10]. Despite these developments, approximately 80% of stage IV cases involve unresectable metastatic tumor burden. Over the past 2 decades, a multidisciplinary approach to rectal liver metastases has become increasingly established. Precision medicine has been critical in tailoring treatment sequences for individual patients, leading to improved survival [11]. Importantly, the 10-year recurrence-free survival rate has been reported at 20.6% [12, 13]. For patients with potentially operable mRC, current guidelines recommend upfront chemotherapy with or without preoperative chemoradiotherapy, followed by staged or synchronous resection of both the primary tumor and metastatic lesions [14, 15]. Prior studies also indicate that resection of the primary tumor in mRC is associated with better survival [16, 17]. Furthermore, the addition of RT may increase the likelihood of achieving curative resections (R0). Short-course RT delivered over one week (5 fractions of 5 Gy) combined with chemotherapy has demonstrated improved outcomes in terms of primary tumor resectability, prolonged disease-free survival, and acceptable toxicity [18, 19].

While surgery and chemotherapy are established treatment modalities for mRC, the precise role and indications for RT remain the subject of ongoing debate. RT can improve the resectability of primary rectal tumors and reduce the risk of locoregional recurrence, thereby prolonging progression-free survival [20]. Additionally, RT is used for palliative purposes, such as relieving pelvic pain, controlling bleeding, and improving quality of life [21].

The optimal treatment strategy and sequencing for patients with de novo mRC remain unresolved. In particular, the potential survival benefits of concurrent RT in this patient population are uncertain, especially when considered alongside systemic therapies. Clinical evidence supporting this approach is currently limited. Therefore, this study aimed to evaluate the effectiveness and safety of concurrent RT in patients diagnosed with de novo mRC.

METHODS

Ethics statement

This retrospective study was approved by the Institutional Review Board of the Chang Gung Medical Foundation (No. 202200942B0). The requirement for informed consent was waived due to use of deidentified data and the retrospective nature of the study. All procedures were conducted in accordance with the principles of the Declaration of Helsinki and complied with relevant institutional and national guidelines and regulations.

Patients and data processing

This retrospective cohort study was conducted using patient data from Kaohsiung Chang Gung Memorial Hospital. Patients with histologically confirmed de novo mRC between January 2015 and December 2020 were included in the analysis. De novo mRC was defined as rectal cancer with metastatic disease present at the time of initial diagnosis. Clinicopathological, therapeutic, and laboratory data were collected from electronic medical record systems and the hospital cancer registry. Database variables included age, sex, body weight, height, TNM status, primary tumor location and its distance from the anal verge, and carcinoembryonic antigen (CEA) levels at diagnosis.

Systemic treatment

All patients received standard chemotherapy for metastatic rectal cancer, consisting of either FOLFIRI (5-fluorouracil, leucovorin, and irinotecan) or FOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin), with the regimen determined by the treating clinicians. For eligible patients, targeted therapy with anti-VEGF agents (bevacizumab or its biosimilar) or anti-EGFR agents (cetuximab or panitumumab) was administered in combination with chemotherapy. The primary endpoint was overall survival (OS), defined as the time from diagnosis to death. Patients who demonstrated a favorable response to systemic chemotherapy, with or without RT, could undergo primary tumor resection at the discretion of the physician. For those who underwent radical surgery, the pathologic tumor regression score (TRS) was carefully assessed by experienced pathologists using the American Joint Committee on Cancer/College of American Pathologists (AJCC/CAP) tumor regression grading system [22].

Radiation therapy

The decision to administer RT was made by the surgeon or medical oncologist. The clinical target volume was delineated according to consensus guidelines, and an additional margin was applied to create the planning target volume. To ensure adequate coverage, 2 to 3 radiation portals were used, employing Cerrobend blocks or multileaf collimators. Radiotherapy regimens generally followed either a short-course protocol (25 Gy in 5 fractions of 5 Gy) or a long-course protocol (50.4 Gy in 28 fractions of 1.8 Gy). Detailed documentation was recorded for treatment duration, fractionation schedule, field coverage, and dose intensity. The choice between short-course and long-course regimens was made by the treating physician, taking into account patient preferences, comorbidities, overall health status, hospital accessibility, insurance coverage, and planned surgical procedures. At our institution, intensity-modulated radiation therapy (IMRT) was most frequently employed, although some patients received conventional 3D or 2D RT.

Statistical analysis

Statistical analyses were performed using IBM SPSS ver. 25.0 (IBM Corp) and R ver. 4.1.1 (R Foundation for Statistical Computing). Survival curve visualizations were generated using GraphPad Prism ver. 8.21 (GraphPad Software). Descriptive analyses of clinicopathological variables in the training and validation cohorts were conducted using the chi-square test for categorical variables and the t-test for continuous variables. OS rates were estimated with the Kaplan-Meier method, and intergroup differences were assessed using the log-rank test. Both univariate and multivariate analyses of prognostic factors were performed using Cox proportional hazards regression, with statistical significance defined as a P-value of <0.05.

RESULTS

Patient characteristics

In total, 271 eligible patients were included in the final analysis, consisting of 117 patients who received RT and 154 patients who did not (non-RT) (Fig. 1). The median age across all participants was 62 years (interquartile range [IQR], 53–68 years), and the median follow-up duration was 58.8 months. Of the total cohort, 204 patients (75.3%) were male, and 86 patients (31.7%) had a high body mass index (≥25 kg/m²). Comparative analysis showed that patients in the RT group were significantly younger (P=0.017) and more often male (P=0.002) than those in the non-RT group. The RT cohort also had a higher proportion of primary tumors located in the lower rectum (34.2% vs. 13.0%; P<0.001) and a greater proportion of patients presenting with M1a disease (61.5% vs. 46.1%; P=0.005). Detailed clinical characteristics and intergroup comparisons are summarized in Table 1.

All patients received standard systemic chemotherapy, and distribution between the groups was balanced. Utilization rates of key agents were similar: 5-fluorouracil (99.1% vs. 98.7%), irinotecan (89.7% vs. 81.8%), and oxaliplatin (56.4% vs. 59.7%). Likewise, administration of targeted therapies, including anti-VEGF and anti-EGFR agents, was evenly distributed across both groups.

Table 2 presents the distribution of RT regimens. Short-course RT was the predominant strategy, administered to 95 patients (81.2%), while 22 (18.8%) underwent long-course RT. Among the RT modalities, IMRT was the most frequently applied technique (54.7%), followed by volumetric-modulated arc therapy (16.2%) and 3D conformal radiation therapy (3D-CRT; 11.1%). Additionally, image-guided radiation therapy was incorporated with IMRT or 3D-CRT in 8.5% and 4.3% of cases, respectively.

Impact of RT for metastatic rectal cancer on OS and TRS

During the median follow-up period, 205 deaths were recorded. The median OS was 27.8 months for patients who received RT, compared with 21.9 months for those who did not. Kaplan-Meier survival analysis demonstrated a significant OS benefit in the RT group (log-rank P=0.046) (Fig. 2). Subgroup analysis, however, revealed no significant OS difference between patients treated with short-course versus long-course RT (log-rank P=0.630) (Fig. 3). Patients who received RT in combination with chemotherapy as part of a multimodal treatment approach experienced significantly higher rates of tumor and nodal downstaging (Table 3). Tumor downstaging and nodal downstaging rates in the RT group were 55.1% and 66.7%, respectively, both markedly higher than in the non-RT group (both P<0.001). When evaluating the TRS, the addition of RT significantly increased the proportion of patients achieving a favorable pathologic response (TRS 0–1), from 8.3% in the non-RT group to 28.1% in the RT group. Collectively, these results suggest that RT enhances local tumor control and contributes to improved OS (Fig. 4).

Univariate and multivariate analysis of OS

Univariate analysis identified several significant prognostic factors: age ≥65 years, primary tumor resection, CEA ≥10 ng/mL, and M1b or M1c disease. Patients aged ≥65 years had a median OS of 19.3 months, compared with 30.1 months for those younger than 65 years (P<0.001). Patients who underwent primary tumor resection had significantly better OS than those who did not (32.9 months vs. 16.4 months; P<0.001). Elevated CEA levels (≥10 ng/mL) were associated with worse OS (21.9 months vs. 28.5 months; P=0.001). In addition, patients with M1b or M1c disease had shorter OS compared with those with M1a (18.8 months vs. 33.5 months; P<0.001).

Multivariate analysis incorporated the significant variables identified in the univariate analysis (age ≥65 years, CEA ≥10 ng/mL, primary tumor resection, M1b or M1c disease, and RT). Independent prognostic factors for OS were confirmed as follows: age ≥65 years (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.26–2.27; P=0.001), primary tumor resection (HR, 2.62; 95% CI, 1.90–3.61; P<0.001), M1b or M1c disease (HR, 1.97; 95% CI, 1.44–2.69; P<0.001), and RT (HR, 1.41; 95% CI, 1.02–1.94; P=0.036) (Table 4).

DISCUSSION

The role of RT in the management of mRC has been the subject of considerable debate. Recent studies have highlighted the potential of RT to provide not only palliative benefits but also possible improvements in OS for patients with mRC [23–25]. In our study, RT was associated with a significant survival advantage, with the median OS extending to 27.8 months in the RT group compared with 21.9 months in the non-RT group. This benefit may reflect the contribution of RT in enhancing the resectability of primary rectal tumors, reducing the risk of locoregional failure, and thereby prolonging survival. Furthermore, RT has been employed for palliative purposes, relieving pelvic pain and controlling bleeding, both of which substantially improve the quality of life for patients with advanced disease.

Several prior studies support the survival benefit of adding RT to chemotherapy in mRC compared with chemotherapy alone. Wang et al. [24] reported that patients who received RT for the primary tumor had significantly longer survival than those who did not (20.07 months vs. 17.33 months; P=0.002). After applying inverse probability of treatment weighting, the benefit remained, with an HR of 0.62. Similarly, Hosseinali Khani et al. [26], using a Swedish registry, observed that patients with stage IV rectal cancer who did not undergo preoperative RT had worse OS than those who did (HR, 1.32; P<0.001). However, survival benefits have not been uniformly demonstrated. Zhou et al. [23], in an analysis of the SEER (Surveillance, Epidemiology, and End Results) registry, found that RT conferred survival advantages only in patients with unselected metastatic sites; after applying propensity score matching to adjust for confounders such as liver metastasis, the benefit was no longer significant. A recent meta-analysis pooling data from 8 studies evaluated the impact of RT on locoregional control and OS in mRC. The analysis showed that RT improved local recurrence-free survival compared with non-RT (risk ratio [RR], 1.15; 95% confidence interval [CI], 1.01–1.31; P=0.03). Moreover, the 5-year OS rate was significantly higher in the RT group (RR, 1.47; 95% CI, 1.14–1.89; P=0.003) [25]. Our findings align with this body of evidence, showing OS improvement from 21.9 to 27.8 months (P=0.046). Importantly, the survival benefit remained significant in multivariate analysis, underscoring the independent role of RT in the management of metastatic disease. Incorporating RT alongside systemic chemotherapy and surgery may thus be critical in developing optimal treatment strategies for mRC.

Although direct evidence that RT increases resection rates is limited, some studies have investigated the feasibility of curative surgery following RT in patients with metastatic rectal cancer. A multicenter study evaluating short-course RT combined with systemic therapy and resection/ablation in clinical practice found that, among 50 patients who received RT, 36 (72.0%) underwent curative surgery, achieving 2-year recurrence-free survival and OS rates of 64% and 80%, respectively [27, 28]. Another study assessed a protocol involving neoadjuvant chemotherapy and RT, followed by local treatment of all tumor sites and subsequent adjuvant chemotherapy in stage IV rectal cancer with potentially resectable metastases. Of 75 patients, 64 (85.3%) proceeded to curative surgery. These findings suggest that, in select patients, RT may facilitate curative resection, although additional studies are needed to validate and expand on these results.

Our study demonstrated that primary tumor resection (PTR) is a strong independent prognostic factor for OS in mRC, consistent across both univariate and multivariate analyses. These findings align with previous reports. In a pooled analysis of the TRIBE and TRIBE2 studies, Fanotto et al. [29] showed that patients who underwent PTR had longer OS compared with those who did not undergo surgery (26.6 months vs. 22.5 months; P<0.001). Similarly, another study of mCRC patients treated with bevacizumab-based chemotherapy reported significantly better median OS in the PTR group than in the non-PTR group (22.5 months vs. 17.8 months; P<0.01) [30]. A recent meta-analysis including 2,805 patients further confirmed a significant OS advantage for PTR, with a difference of 6.76 months (P<0.0001) [31]. Nevertheless, most of these studies were retrospective, and prospective trials have shown less clear benefits. The CAIRO4 study demonstrated that upfront PTR prior to systemic chemotherapy did not improve survival in patients without obstructive symptoms (20.1 months vs. 18.3 months; P=0.32) [32]. Similarly, the pivotal JCOG1007 trial, which examined PTR followed by chemotherapy in unresectable mCRC, found no OS improvement compared with chemotherapy alone (25.9 months vs. 26.7 months; P=0.69) [33]. The discrepancy may partly reflect study design differences: in our study, PTR was performed not upfront but after systemic treatment in selected patients. Consequently, those who underwent radical surgery were likely to have responded well to chemotherapy, introducing a potential selection bias that could contribute to the observed survival benefit.

The prognostic role of elevated CEA levels in mCRC has been widely studied, particularly in relation to OS. High CEA is consistently associated with greater tumor burden, liver metastasis, and poorer survival outcomes [34]. In patients who undergo radical tumor resection or metastasectomy, CEA may also serve as a marker of minimal residual disease and predict recurrence [35]. In our analysis, CEA ≥10 ng/mL was significantly associated with OS in univariate analysis (P=0.001); however, the association was no longer significant in multivariate analysis (P=0.323). This may be related to the relatively low CEA cutoff value applied. Evidence suggests that higher CEA thresholds yield stronger prognostic utility. For example, Prager et al. [36] reported that a cutoff of 26.8 ng/mL effectively discriminated OS in mCRC. Similarly, other studies have shown that progressively higher CEA levels correspond with shorter OS [37]. These findings suggest that applying higher CEA cutoffs may enhance its predictive power for OS in mRC.

This study has several limitations. First, its retrospective, single-center design may introduce selection bias and restrict generalizability. The imbalance in baseline characteristics between treatment groups could also contribute to population bias. Although multivariate analyses were performed to adjust for confounders, the relatively small sample size limited the use of propensity score matching, which could more effectively balance baseline characteristics. Second, because of the retrospective design, we were unable to report acute or chronic RT-related toxicities, and thus this study does not address the short- or long-term safety of RT in frail stage IV patients. Future prospective, multicenter randomized controlled trials are essential to validate these findings, particularly in asymptomatic patients, and should incorporate comprehensive quality-of-life assessments. Such studies would provide more robust evidence to guide optimal treatment strategies.

Conclusions

This study demonstrates that integrating RT into the standard treatment regimen for patients with de novo metastatic rectal cancer significantly improves OS. These results support the critical role of RT in enhancing patient outcomes and highlight the urgent need for larger, multicenter trials to confirm these findings and refine treatment strategies.

ARTICLE INFORMATION

Conflict of interest

No potential conflict of interest relevant to this article was reported.

Funding

The study was supported by grants from Chang Gung Memorial Hospital (No. CORPG8L0621, No. CORPG8M0601, No. CORPG8M0602).

Acknowledgments

The authors thank the Genomic and Proteomic Core Laboratory, Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital for the technical supports.

Author contributions

Conceptualization: HYLS, KLT; Data curation: YHL, KCL, YML, CCW, CCH, MCK; Formal analysis: YHL, KCL, CTL; Funding acquisition: HYLS; Investigation: TJC; Methodology: CCH, EYH; Project administration: YML, CCH; Visualization: CTL, MCK; Writing–original draft: HYLS , SYH; Writing–review & editing: all authors. All authors read and approved the final manuscript.

Fig. 1.

Flowchart of the patient enrollment in the study. mRC, metastatic rectal cancer; RT, radiotherapy.

Fig. 2.

Kaplan-Meier analysis of overall survival (OS) in patients with de novo metastatic rectal cancer stratified according to whether they received radiotherapy (RT).

Fig. 3.

Kaplan-Meier plots for overall survival in patients with metastatic rectal cancer receiving short- or long-course radiotherapy (RT).

Fig. 4.

Tumor regression score (TRS) distribution by treatment group (with or without radiotherapy [RT]). TRS was classified as follow: 0, complete response (no viable cancer cells); 1, moderate response (small clusters or single cancer cells remaining); 2, minimal response (residual cancer with predominant fibrosis); and 3, poor response (minimal or no tumor kill, extensive residual cancer).

Table 1.

Comparison of clinical characteristics and treatment outcomes between patients with and without RT (n=271)

Characteristic	Non-RT group (n=154)	RT group (n=117)	P-value
Age (yr)	63 (54.7–70)	60 (51–67)	0.017
<65	86 (55.8)	76 (65.0)	0.082
≥65	68 (44.2)	41 (35.0)
Sex			0.002
Female	49 (31.8)	18 (15.4)
Male	105 (68.2)	99 (84.6)
Body mass index (kg/m²)	22.4 (20.5–25.6)	24.0 (21.8–26.1)	0.572
Tumor size (cm)	5.0 (4.0–6.5)	5.25 (4.17–7.0)	0.267
Primary tumor location			<0.001
Low	20 (13.0)	40 (34.2)
Middle	57 (37.0)	49 (41.9)
Upper	62 (40.3)	24 (20.5)
NA	15 (9.7)	4 (3.4)
Primary tumor resection			0.204
Yes	103 (66.9)	69 (59.0)
No	51 (33.1)	48 (41.0)
Clinical T category			0.076
T1–T2	19 (12.3)	9 (7.7)
T3	69 (44.8)	40 (34.2)
T4	62 (40.3)	67 (57.3)
Unknown	4 (2.6)	1 (0.8)
Clinical N category			0.011
N0	24 (15.6)	11 (9.4)
N1	61 (39.6)	35 (29.9)
N2	65 (42.2)	69 (59.0)
Unknown	4 (2.6)	2 (1.7)
M category			0.005
M1a	71 (46.1)	72 (61.5)
M1b	67 (43.5)	42 (35.9)
M1c	16 (10.4)	3 (2.6)
Tumor grade			0.658
Low	61 (39.6)	40 (34.2)
High	6 (3.9)	5 (4.3)
Unknown	87 (56.5)	72 (61.5)
CEA^a
>Normal range	106/143 (74.1)	74/104 (71.2)	0.664
≥ 10 ng/mL	89/143 (62.2)	53/104 (51.0)	0.090
Systemic treatment
5-Fluorouracil	152 (98.7)	116 (99.1)	0.242
Irinotecan	126 (81.8)	105 (89.7)	0.084
Oxaliplatin	92 (59.7)	66 (56.4)	0.620
Anti-VEGF	91 (59.1)	77 (65.8)	0.312
Anti-EGFR	51 (33.1)	39 (33.3)	0.995

Values are presented as median (interquartile range) or number (%).

RT, radiotherapy; NA, not applicable; CEA, carcinoembryonic antigen; VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor.

^aPatients with missing CEA data were excluded.

Table 2.

Distribution of RT course and modality (n=117)

Variable	No. of patients (%)
RT course
Short course	95 (81.2)
Long course	22 (18.8)
RT modality
2D RT	5 (4.3)
3D-CRT	13 (11.1)
IMRT	64 (54.7)
2D RT and IMRT	1 (0.9)
VMAT	19 (16.2)
3D-CRT with IGRT	5 (4.3)
IMRT with IGRT	10 (8.5)

RT, radiotherapy; 3D-CRT, 3D conformal radiation therapy; IMRT, intensity-modulated radiation therapy; VMAT, volumetric-modulated arc therapy; IGRT, image-guided radiation therapy.

Table 3.

Impact of RT on T and N categories in patients with primary tumor resection (n=172)

Variable	Non-RT group (n=103)	RT group (n=69)	P-value
T category			<0.001
No change	85 (82.5)	31 (44.9)
Downstage	18 (17.5)	38 (55.1)
N category			<0.001
No change	82 (79.6)	23 (33.3)
Downstage	21 (20.4)	46 (66.7)

Values are presented as number (%). T or N downstaging indicates that the pathologic T or N category after treatment is lower than the initial clinical T or N category.

RT, radiotherapy.

Table 4.

Univariate and multivariate analysis of OS in patients with metastatic rectal cancer

Characteristic	Median OS (mo)	Univariate analysis		Multivariate analysis
Characteristic	Median OS (mo)	HR (95% CI)	P-value	HR (95% CI)	P-value
Age (yr)			<0.001^*		0.001^*
<65	30.1	1		1
≥65	19.3	1.78 (1.35–2.36)		1.69 (1.26–2.27)
Sex			0.819
Female	27.8	1
Male	24.4	1.04 (0.75–1.43)
Body mass index (kg/m²)			0.874
<25	25.0	1
≥25	25.2	0.98 (0.72–1.32)
Tumor size (cm)			0.251
<5	30.3	1
≥5	21.9	1.21 (0.87–1.67)
T category			0.485
T1–T2	24.4	1
T3–T4	25.7	1.19 (0.73–1.93)
N category			0.737
N0–N1	25.2	1
N2	25.9	0.95 (0.72–1.26)
Primary tumor resection			<0.001^*		<0.001^*
Yes	32.9	1		1
No	16.4	2.64 (1.99–3.52)		2.62 (1.90–3.61)
CEA (ng/mL)			0.001^*		0.323
<10	28.5	1		1
≥10	21.9	1.63 (1.20–2.21)		1.17 (0.86–1.61)
M category			<0.001^*		<0.001^*
M1a	33.5	1		1
M1b or M1c	18.8	2.41 (1.81–3.20)		1.97 (1.44–2.69)
Anti-VEGF			0.571
Yes	25.9	1
No	22.2	0.92 (0.68–1.23)
Anti-EGFR			0.136
Yes	30.3	1
No	20.9	1.25 (0.93–1.68)
Radiotherapy			0.046^*		0.036^*
Yes	27.8	1		1
No	21.9	1.33 (1.00–1.77)		1.41 (1.02–1.94)

OS, overall survival; HR, hazard ratio; CI, confidence interval; CEA, carcinoembryonic antigen; VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor.

*P<0.05.

REFERENCES

1. Morgan E, Arnold M, Gini A, Lorenzoni V, Cabasag CJ, Laversanne M, et al. Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut 2023;72:338–44. Article PubMed
2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209–49. Article PubMed PDF
3. Li Y, Feng Y, Dai W, Li Q, Cai S, Peng J. Prognostic effect of tumor sidedness in colorectal cancer: a SEER-based analysis. Clin Colorectal Cancer 2019;18:e104–16. Article PubMed
4. Shin SJ, Yoon HI, Kim NK, Lee KY, Min BS, Ahn JB, et al. Upfront systemic chemotherapy and preoperative short-course radiotherapy with delayed surgery for locally advanced rectal cancer with distant metastases. Radiat Oncol 2011;6:99.Article PubMed PMC PDF
5. Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CA, Putter H, Kranenbarg EM, et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:29–42. Article PubMed
6. van Gijn W, Marijnen CA, Nagtegaal ID, Kranenbarg EM, Putter H, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol 2011;12:575–82. Article PubMed
7. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7–30. Article PubMed PDF
8. Mitry E, Guiu B, Cosconea S, Jooste V, Faivre J, Bouvier AM. Epidemiology, management and prognosis of colorectal cancer with lung metastases: a 30-year population-based study. Gut 2010;59:1383–8. Article PubMed
9. Leporrier J, Maurel J, Chiche L, Bara S, Segol P, Launoy G. A population-based study of the incidence, management and prognosis of hepatic metastases from colorectal cancer. Br J Surg 2006;93:465–74. Article PubMed PDF
10. Hernandez Dominguez O, Yilmaz S, Steele SR. Stage IV colorectal cancer management and treatment. J Clin Med 2023;12:2072.Article PubMed PMC
11. Ciardiello F, Ciardiello D, Martini G, Napolitano S, Tabernero J, Cervantes A. Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin 2022;72:372–401. Article PubMed PDF
12. Moslim MA, Bastawrous AL, Jeyarajah DR. Neoadjuvant pelvic radiotherapy in the management of rectal cancer with synchronous liver metastases: is it worth it? J Gastrointest Surg 2021;25:2411–22. Article PubMed PDF
13. Creasy JM, Sadot E, Koerkamp BG, Chou JF, Gonen M, Kemeny NE, et al. Actual 10-year survival after hepatic resection of colorectal liver metastases: what factors preclude cure? Surgery 2018;163:1238–44. Article PubMed PMC
14. Yoon HI, Koom WS, Kim TH, Ahn JB, Jung M, Kim TI, et al. Upfront systemic chemotherapy and short-course radiotherapy with delayed surgery for locally advanced rectal cancer with distant metastases: outcomes, compliance, and favorable prognostic factors. PLoS One 2016;11:e0161475. Article PubMed PMC
15. van Dijk TH, Tamas K, Beukema JC, Beets GL, Gelderblom AJ, de Jong KP, et al. Evaluation of short-course radiotherapy followed by neoadjuvant bevacizumab, capecitabine, and oxaliplatin and subsequent radical surgical treatment in primary stage IV rectal cancer. Ann Oncol 2013;24:1762–9. Article PubMed
16. Xu H, Xia Z, Jia X, Chen K, Li D, Dai Y, et al. Primary tumor resection is associated with improved survival in stage IV colorectal cancer: an instrumental variable analysis. Sci Rep 2015;5:16516.Article PubMed PMC PDF
17. Manyam BV, Mallick IH, Abdel-Wahab MM, Reddy CA, Remzi FH, Kalady MF, et al. The impact of preoperative radiation therapy on locoregional recurrence in patients with stage IV rectal cancer treated with definitive surgical resection and contemporary chemotherapy. J Gastrointest Surg 2015;19:1676–83. Article PubMed PDF
18. Cambray M, González-Viguera J, Macià M, Losa F, Soler G, Frago R, et al. Short-course radiotherapy in stage IV rectal cancer with resectable disease. Clin Transl Oncol 2021;23:2482–8. Article PubMed PDF
19. Kim KH, Shin SJ, Cho MS, Ahn JB, Jung M, Kim TI, et al. A phase II study of preoperative mFOLFOX6 with short-course radiotherapy in patients with locally advanced rectal cancer and liver-only metastasis. Radiother Oncol 2016;118:369–74. Article PubMed
20. Yin TC, Chen PJ, Yeh YS, Li CC, Chen YC, Su WC, et al. Efficacy of concurrent radiotherapy in patients with locally advanced rectal cancer and synchronous metastasis receiving systemic therapy. Front Oncol 2023;13:1099168.Article PubMed PMC
21. Cameron MG, Kersten C, Vistad I, Fosså S, Guren MG. Palliative pelvic radiotherapy of symptomatic incurable rectal cancer: a systematic review. Acta Oncol 2014;53:164–73. Article PubMed PMC
22. Chen HY, Feng LL, Li M, Ju HQ, Ding Y, Lan M, et al. College of American Pathologists tumor regression grading system for long-term outcome in patients with locally advanced rectal cancer. Oncologist 2021;26:e780–93. Article PubMed PMC PDF
23. Zhou Y, Wang D, Tan F, Zhou Z, Zhao L, Güngör C, et al. The survival impact of radiotherapy on synchronous metastatic rectal cancer: metastatic site can serve for radiotherapy-decision. J Cancer 2022;13:2171–8. Article PubMed PMC
24. Wang G, Wang W, Jin H, Dong H, Chen W, Li X, et al. The effect of primary tumor radiotherapy in patients with unresectable stage IV rectal or rectosigmoid cancer: a propensity score matching analysis for survival. Radiat Oncol 2020;15:126.Article PubMed PMC PDF
25. Agas RA, Co LB, Jacinto JC, Yu KK, Sogono PG, Bacorro WR, et al. Neoadjuvant radiotherapy versus no radiotherapy for stage IV rectal cancer: a systematic review and meta-analysis. J Gastrointest Cancer 2018;49:389–401. Article PubMed PDF
26. Hosseinali Khani M, Påhlman L, Smedh K. Treatment strategies for patients with stage IV rectal cancer: a report from the Swedish Rectal Cancer Registry. Eur J Cancer 2012;48:1616–23. Article PubMed
27. Li R, Wang Q, Zhang B, Yuan Y, Xie W, Huang X, et al. Neoadjuvant chemotherapy and radiotherapy followed by resection/ablation in stage IV rectal cancer patients with potentially resectable metastases. BMC Cancer 2021;21:1333.Article PubMed PMC PDF
28. Kok EN, Havenga K, Tanis PJ, de Wilt JH, Hagendoorn J, Peters FP, et al. Multicentre study of short-course radiotherapy, systemic therapy and resection/ablation for stage IV rectal cancer. Br J Surg 2020;107:537–45. Article PubMed PDF
29. Fanotto V, Rossini D, Casagrande M, Bergamo F, Spagnoletti A, Santini D, et al. Primary tumor resection in synchronous metastatic colorectal cancer patients treated with upfront chemotherapy plus bevacizumab: a pooled analysis of TRIBE and TRIBE2 studies. Cancers (Basel) 2023;15:5451.Article PubMed PMC
30. Wang Z, Liang L, Yu Y, Wang Y, Zhuang R, Chen Y, et al. Primary tumour resection could improve the survival of unresectable metastatic colorectal cancer patients receiving bevacizumab-containing chemotherapy. Cell Physiol Biochem 2016;39:1239–46. Article PubMed PDF
31. Shu Y, Xu L, Yang W, Xu X, Zheng S. Asymptomatic primary tumor resection in metastatic colorectal cancer: a systematic review and meta-analysis. Front Oncol 2022;12:836404.Article PubMed PMC
32. van der Kruijssen DE, Elias SG, van de Ven PM, van Rooijen KL, Lam-Boer J', Mol L, et al. Upfront resection versus no resection of the primary tumor in patients with synchronous metastatic colorectal cancer: the randomized phase III CAIRO4 study conducted by the Dutch Colorectal Cancer Group and the Danish Colorectal Cancer Group. Ann Oncol 2024;35:769–79. Article PubMed
33. Kanemitsu Y, Shitara K, Mizusawa J, Hamaguchi T, Shida D, Komori K, et al. Primary tumor resection plus chemotherapy versus chemotherapy alone for colorectal cancer patients with asymptomatic, synchronous unresectable metastases (JCOG1007; iPACS): a randomized clinical trial. J Clin Oncol 2021;39:1098–107. Article PubMed PMC
34. Lee JH, Lee SW. The roles of carcinoembryonic antigen in liver metastasis and therapeutic approaches. Gastroenterol Res Pract 2017;2017:7521987.Article PubMed PMC PDF
35. Saito G, Sadahiro S, Kamata H, Miyakita H, Okada K, Tanaka A, et al. Monitoring of serum carcinoembryonic antigen levels after curative resection of colon cancer: cutoff values determined according to preoperative levels enhance the diagnostic accuracy for recurrence. Oncology 2017;92:276–82. Article PubMed PMC PDF
36. Prager GW, Braemswig KH, Martel A, Unseld M, Heinze G, Brodowicz T, et al. Baseline carcinoembryonic antigen (CEA) serum levels predict bevacizumab-based treatment response in metastatic colorectal cancer. Cancer Sci 2014;105:996–1001. Article PubMed PMC PDF
37. Xie H, Wei L, Wang Q, Tang S, Gan J. Grading carcinoembryonic antigen levels can enhance the effectiveness of prognostic stratification in patients with colorectal cancer: a single-centre retrospective study. BMJ Open 2024;14:e084219. Article PubMed PMC

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Survival impact of radiotherapy for patients with de novo metastatic rectal cancer

Ann Coloproctol. 2026;42(1):94-102. Published online February 26, 2026

DOI: https://doi.org/10.3393/ac.2025.00605.0086

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Survival impact of radiotherapy for patients with de novo metastatic rectal cancer

Fig. 1. Flowchart of the patient enrollment in the study. mRC, metastatic rectal cancer; RT, radiotherapy.

Fig. 2. Kaplan-Meier analysis of overall survival (OS) in patients with de novo metastatic rectal cancer stratified according to whether they received radiotherapy (RT).

Fig. 3. Kaplan-Meier plots for overall survival in patients with metastatic rectal cancer receiving short- or long-course radiotherapy (RT).

Fig. 4. Tumor regression score (TRS) distribution by treatment group (with or without radiotherapy [RT]). TRS was classified as follow: 0, complete response (no viable cancer cells); 1, moderate response (small clusters or single cancer cells remaining); 2, minimal response (residual cancer with predominant fibrosis); and 3, poor response (minimal or no tumor kill, extensive residual cancer).

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Survival impact of radiotherapy for patients with de novo metastatic rectal cancer

Characteristic	Non-RT group (n=154)	RT group (n=117)	P-value
Age (yr)	63 (54.7–70)	60 (51–67)	0.017
<65	86 (55.8)	76 (65.0)	0.082
≥65	68 (44.2)	41 (35.0)
Sex			0.002
Female	49 (31.8)	18 (15.4)
Male	105 (68.2)	99 (84.6)
Body mass index (kg/m²)	22.4 (20.5–25.6)	24.0 (21.8–26.1)	0.572
Tumor size (cm)	5.0 (4.0–6.5)	5.25 (4.17–7.0)	0.267
Primary tumor location			<0.001
Low	20 (13.0)	40 (34.2)
Middle	57 (37.0)	49 (41.9)
Upper	62 (40.3)	24 (20.5)
NA	15 (9.7)	4 (3.4)
Primary tumor resection			0.204
Yes	103 (66.9)	69 (59.0)
No	51 (33.1)	48 (41.0)
Clinical T category			0.076
T1–T2	19 (12.3)	9 (7.7)
T3	69 (44.8)	40 (34.2)
T4	62 (40.3)	67 (57.3)
Unknown	4 (2.6)	1 (0.8)
Clinical N category			0.011
N0	24 (15.6)	11 (9.4)
N1	61 (39.6)	35 (29.9)
N2	65 (42.2)	69 (59.0)
Unknown	4 (2.6)	2 (1.7)
M category			0.005
M1a	71 (46.1)	72 (61.5)
M1b	67 (43.5)	42 (35.9)
M1c	16 (10.4)	3 (2.6)
Tumor grade			0.658
Low	61 (39.6)	40 (34.2)
High	6 (3.9)	5 (4.3)
Unknown	87 (56.5)	72 (61.5)
CEA^a
>Normal range	106/143 (74.1)	74/104 (71.2)	0.664
≥ 10 ng/mL	89/143 (62.2)	53/104 (51.0)	0.090
Systemic treatment
5-Fluorouracil	152 (98.7)	116 (99.1)	0.242
Irinotecan	126 (81.8)	105 (89.7)	0.084
Oxaliplatin	92 (59.7)	66 (56.4)	0.620
Anti-VEGF	91 (59.1)	77 (65.8)	0.312
Anti-EGFR	51 (33.1)	39 (33.3)	0.995

Variable	No. of patients (%)
RT course
Short course	95 (81.2)
Long course	22 (18.8)
RT modality
2D RT	5 (4.3)
3D-CRT	13 (11.1)
IMRT	64 (54.7)
2D RT and IMRT	1 (0.9)
VMAT	19 (16.2)
3D-CRT with IGRT	5 (4.3)
IMRT with IGRT	10 (8.5)

Variable	Non-RT group (n=103)	RT group (n=69)	P-value
T category			<0.001
No change	85 (82.5)	31 (44.9)
Downstage	18 (17.5)	38 (55.1)
N category			<0.001
No change	82 (79.6)	23 (33.3)
Downstage	21 (20.4)	46 (66.7)

Characteristic	Median OS (mo)	Univariate analysis		Multivariate analysis
Characteristic	Median OS (mo)	HR (95% CI)	P-value	HR (95% CI)	P-value
Age (yr)			<0.001^*		0.001^*
<65	30.1	1		1
≥65	19.3	1.78 (1.35–2.36)		1.69 (1.26–2.27)
Sex			0.819
Female	27.8	1
Male	24.4	1.04 (0.75–1.43)
Body mass index (kg/m²)			0.874
<25	25.0	1
≥25	25.2	0.98 (0.72–1.32)
Tumor size (cm)			0.251
<5	30.3	1
≥5	21.9	1.21 (0.87–1.67)
T category			0.485
T1–T2	24.4	1
T3–T4	25.7	1.19 (0.73–1.93)
N category			0.737
N0–N1	25.2	1
N2	25.9	0.95 (0.72–1.26)
Primary tumor resection			<0.001^*		<0.001^*
Yes	32.9	1		1
No	16.4	2.64 (1.99–3.52)		2.62 (1.90–3.61)
CEA (ng/mL)			0.001^*		0.323
<10	28.5	1		1
≥10	21.9	1.63 (1.20–2.21)		1.17 (0.86–1.61)
M category			<0.001^*		<0.001^*
M1a	33.5	1		1
M1b or M1c	18.8	2.41 (1.81–3.20)		1.97 (1.44–2.69)
Anti-VEGF			0.571
Yes	25.9	1
No	22.2	0.92 (0.68–1.23)
Anti-EGFR			0.136
Yes	30.3	1
No	20.9	1.25 (0.93–1.68)
Radiotherapy			0.046^*		0.036^*
Yes	27.8	1		1
No	21.9	1.33 (1.00–1.77)		1.41 (1.02–1.94)

Table 1. Comparison of clinical characteristics and treatment outcomes between patients with and without RT (n=271)

Values are presented as median (interquartile range) or number (%).

RT, radiotherapy; NA, not applicable; CEA, carcinoembryonic antigen; VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor.

^aPatients with missing CEA data were excluded.

Table 2. Distribution of RT course and modality (n=117)

RT, radiotherapy; 3D-CRT, 3D conformal radiation therapy; IMRT, intensity-modulated radiation therapy; VMAT, volumetric-modulated arc therapy; IGRT, image-guided radiation therapy.

Table 3. Impact of RT on T and N categories in patients with primary tumor resection (n=172)

Values are presented as number (%). T or N downstaging indicates that the pathologic T or N category after treatment is lower than the initial clinical T or N category.

RT, radiotherapy.

Table 4. Univariate and multivariate analysis of OS in patients with metastatic rectal cancer

OS, overall survival; HR, hazard ratio; CI, confidence interval; CEA, carcinoembryonic antigen; VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor.