Prognostic effect of surgical margin in patients undergoing hepatectomy for colorectal liver metastasis
Katsunori Sakamoto
, Yoichiro Uchida, Kentaro Kadono, Hidenobu Kojima, Asahi Sato, Takashi Ito, Takamichi Ishii, Etsuro Hatano
Keywords: Colorectal liver metastasis (CRLM); surgical margin; recurrence
Submitted Mar 29, 2025. Accepted for publication May 08, 2025. Published online May 26, 2025.
doi: 10.21037/hbsn-2025-192
Surgical margin is an important prognosticator in patients undergoing hepatectomy for colorectal liver metastases (CRLM) (1). However, the incidence of cut-end recurrence is relatively low, approximately 5–20%, even in patients with pathologically positive (R1) resection (1). Therefore, cut-end recurrence is not an underlying cause of poor prognosis in patients with narrow surgical margin, but it is thought to reflect tumor progression and biology (1,2). In a recent single-center, large-scale retrospective study, Perrin et al. showed that patients with a narrow surgical margin after hepatectomy for CRLM experienced more aggressive recurrences that were less amenable to salvage (2). Narrow surgical margin resulted from an aggressive tumor background; this is because the study showed that the positive and <1 mm margin groups included patients with a significantly higher proportion of multiple tumors, larger tumors, and higher tumor markers.
Perrin et al. classified surgical margin as positive (0 mm), <1.0, 1.0–9.9, and ≥10 mm (2). This classification allowed for clear stratification of recurrence-free survival. However, in clinical practice, especially in cases of multiple CRLM, the surgical margin can often be within 1.0–9.9 mm. In fact, the number of patients included in the 1.0–9.9 mm group was higher compared with the positive and <1 mm groups (n=882, 158, and 101). Since 2010, several reports have categorized subcentimeter surgical margins in detail (3-8) (Table 1). Several studies suggested an acceptable subcentimeter cut-off value for surgical margins that showed better prognosis (6-8). In contrast, a similar number of previous reports stated that the subcentimeter margin does not have a significant effect on prognosis (3-5). The latest study evaluating the prognostic effect of subcentimeter margins was published in 2018 (8); therefore, it is necessary to reconsider a study on the effect of subcentimeter margins on prognosis.
Table 1
| Study | Published year | Period | Follow-up period (median) | Margin | Prognosis | P value | |
|---|---|---|---|---|---|---|---|
| Index | Value | ||||||
| Studies evaluating subcentimeter margin | |||||||
| Muratore et al. (3) | 2010 | 1999–2007 | 56.5 months | <1 mm (n=55) | – | – | – |
| 1–2 mm (n=42) | 5-year OS | Approximately 23% | 0.714 | ||||
| 3–5 mm (n=81) | Approximately 24% | ||||||
| 6–10 mm (n=52) | Approximately 29% | ||||||
| >10 mm (n=84) | 45.9% | – | |||||
| Lordan et al. (4) | 2010 | 1996–2006 | NR | <1 mm (n=6) | 3-year OS | 50.3% | NS |
| 1–3 mm | 62.8% | ||||||
| >3 mm, <5 mm | 61.7% | ||||||
| ≥5 mm, <10 mm | 60.4% | ||||||
| ≥10 mm | 70.1% | ||||||
| Postriganova et al. (5) |
2014 | 1998–2012 | 31 months | 0 mm | Recurrence rate | 47.1% | 0.316 |
| >0 mm, <1 mm | 56.3% | ||||||
| ≥1 mm, <3 mm | 35.5% | ||||||
| ≥3 mm, <10 mm | 50.9% | ||||||
| ≥10 mm | 47.2% | ||||||
| Angelsen et al. (6) | 2014 | 1998–2010 | NR | <1 mm (n=48) | Recurrence rate | 81.3% | – |
| 1–4 mm (n=77) | 81.8% | ||||||
| 5–9 mm (n=46) | 65.2% | ||||||
| ≥10 mm (n=71) | 60.5% | ||||||
| Hamady et al. (7) | 2014 | 1987–2010 | 33 months | <1 mm (n=663) | 3-year DFS | 34% | <0.001 |
| 1–4.9 mm (n=852) | 42% | ||||||
| 5–9.9 mm (n=439) | 40% | ||||||
| ≥10 mm (n=761) | 42% | ||||||
| Memeo et al. (8) | 2018 | 2006–2013 | NR | 0 mm (NR) | 5-year OS | 58% | 0.0001 |
| 1–5 mm (NR) | 76% | ||||||
| >5 mm (NR) | 80% | ||||||
| Perrin et al. (2) | 2025 | 1991–2012 | 8.62 years | Positive (n=158) | RFS (HR) | 2.09 | <0.001 |
| <1 mm (n=101) | 1.63 | ||||||
| 1.0–9.9 mm (n=882) | 1.26 | ||||||
| ≥10 mm (n=635) | Ref. | ||||||
| Studies evaluating submilimeter margin vs. 0 mm margin | |||||||
| Are et al. (9) | 2007 | 1991–2003 | 42 months | Involved (n=112) | 5-year OS | 26% | Ref. |
| <1 mm (n=138) | 29% | 0.59 | |||||
| ≥1 mm (n=769) | 35–45% | 0.07– <0.01 | |||||
| Sadot et al. (10) | 2015 | 1992–2012 | NR | 0 mm (n=245) | 5-year OS | 24% | Ref. |
| 0.1–0.9 mm (n=160) | 26% | <0.05 | |||||
| ≥1 mm (n=1,956) | 46–48% | <0.05 | |||||
| Östrand et al. (11) | 2024 | 2009–2013 | 5.4 years | 0 mm (n=68) | 5-year OS | 32.8% | 0.00012 |
| 0.1–0.9 mm (n=65) | 41.5% | ||||||
| ≥1 mm (n=621) | 56.2% | ||||||
DFS, disease-free survival; HR, hazard ratio; NR, not reported; NS, not significant; OS, overall survival; RFS, recurrence-free survival.
In contrast, there are several recent reports regarding the association between narrower surgical margins, such as 1 mm or submillimeter margins and prognosis (1). The majority of the reports concluded that 1 mm was the minimum acceptable surgical margin to achieve a better prognosis compared with 0 mm or submillimeter margins (1). Therefore, nowadays, in patients who cannot obtain a sufficient surgical margin (≥10 mm) to preserve future liver remnant, hepatectomy with a 1 mm surgical margin can often be performed (1). Meanwhile, several studies reported that even a submillimeter surgical margin showed a better prognosis compared with a 0 mm surgical margin (Table 1) (9-11). de Haas et al. reported that even a 0 mm surgical margin resection has a positive prognostic effect in the current era of effective chemotherapy (12).
The association between surgical margin width and detailed recurrence patterns, including multiple sites and local recurrences, has not been sufficiently reported previously (Table 2). Previous major meta-analyses evaluating the association between surgical margin and survival did not include data on the incidence of local recurrence (15,16). Perrin et al. reported that surgical margin recurrence was significantly more frequent in the positive and <1 mm groups compared with that of the ≥1 mm group, and both liver recurrence without surgical margin and multiple site recurrence were more frequently observed in the positive and <1 mm groups (2). This result implies that at least part of the observed R1 effect may not be etiological, but rather reflect its role as a surrogate marker. Additionally, salvage therapy for any recurrence site, including the liver, was less frequently performed for the positive and <1 mm groups compared with that of the ≥1 mm group. To our knowledge, there are no previous reports that evaluated the association between surgical margin width and the incidence of salvage hepatectomy.
Table 2
| Study | Published year | Study period | Follow-up period | Surgical margin width |
Total recurrence | Margin recurrence† | Multiple site recurrence† | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Outcome | P value | Outcome | P value | Outcome | P value | |||||||
| Truant et al. (13) | 2015 | 2000–2010 | Mean, 43 months | <1 mm (n=59) | 76.3% | 0.101 | 5.6% | 0.025 | 20.6% | 0.465 | ||
| ≥1 mm (n=214) | 65.0% | 16.9% | 22.0% | |||||||||
| Sakai et al. (14) | 2021 | 2001–2016 | NR | <1 mm (n=55) | 80.0% | NR | 14.5% | NR | 30.9% | NR | ||
| ≥1 mm (n=174) | 71.3% | 2.3% | 17.2% | |||||||||
| Perrin et al. (2) | 2025 | 1991–2012 | Median, 8.62 years | Positive (n=158) | 76% | NR | 23% | NR | 20% | 0.003 | ||
| <1 mm (n=101) | 73% | 30% | 21% | |||||||||
| 1.0–9.9 mm (n=882) | 62% | 16% | 12% | |||||||||
| ≥10 mm (n=635) | 51% | 15% | 12% | |||||||||
†, total patient number, including no recurrence. NR, not reported.
The recurrence patterns of 1.0–9.9 and ≥10 mm in the study by Perrin et al. showed similar patterns. However, a surgical margin of ≥1 mm might not be sufficient for CRLM resection because recurrence-free survival rate was better in the ≥10 mm group than that in the 1.0–9.9 mm group. Therefore, a recurrence pattern with more detailed data, such as the number and size of tumors in intrahepatic recurrences with remnant liver volume or relationship with major vessels, which disallowed repeat hepatectomy, should be evaluated. Additionally, Perrin et al. did not report overall survival (OS) rate. However, recurrence-free survival is an inadequate surrogate endpoint for OS for the studies of resected CRLM (17). Because salvage surgery for recurrence is relatively frequent among patients with colorectal metastasis, OS should also be assessed to evaluate the clinical effect of CRLM treatment. The Fine-Gray subdistribution hazard models using three competing risks were adopted in this study. This approach is rarely applied in CRLM studies, and the application of this method adds methodological rigor, thereby serving as a model for future studies in this space.
The study by Perrin et al. suggests a definition for R1 resection. Two primary definitions for R1 resection have been reported: 0 and <1 mm (2,13,14,18). Perrin et al. (2) reported that any local recurrence was similar between the positive and <1 mm groups (14% vs. 19%). Therefore, they implied that defining R1 as <1 mm is reasonable, as previously reported (18).
Perrin et al. included no data about genomic profiles, such as BRAF and KRAS status, though they indicated it in their study limitation. Several reports have evaluated the association between KRAS status and surgical margin with prognosis (19,20). Given that the study period in the study by Perrin et al. was relatively old (1991–2012), genomic profiles might not be fully evaluated. Therefore, further studies are warranted to evaluate the prognostic effect of surgical margin status in the recent era of genomic evaluation. Similarly, the chemotherapy regimens might have varied and not been sufficiently evaluated (2). As perioperative chemotherapy has been advancing and might have a strong prognostic effect on minimizing surgical margin width (12), further studies are warranted. Furthermore, they did not present more detailed data about the surgical margin by evaluating whole resection surfaces. The clinical effect of tumor surgical margins in areas close to major vessels (R1-vascular) differs from that in areas distant from major vessels [R1-parenchyma (R1-par)] (21). R1-par, which is considered as technical failure, should be avoided because it shows a high recurrence rate (21). R1-vascular resection should be avoided whenever possible, but considered in multiple bilateral CRLM with intraoperative ultrasonography (IOUS)-guided parenchymal-sparing hepatectomy (21). In any other cases, and in those patients with low intrahepatic tumor burden, R1-par and R1-vascular hepatectomy should be considered as a technical mistake. In such a case, the risk of local recurrence is very high close to patients with R2 resection.
Surgical margin is affected by the surgeon’s skill, surgical devices, such as ultrasonic dissectors, and the relationship with major vessels or adjacent organs. Given that liver parenchyma is easily crushed and removed by compression or suction using surgical devices, margin width in millimeters is easily changed. Therefore, detailed information about surgical devices used should be described in studies evaluating surgical margin width for hepatectomy for CRLM. Furthermore, pathological assessment, such as determining which area of the tumor represents the true surgical margin, can be difficult to detect. Ultimately, the surgeon’s discretion is paramount during radical CRLM resection. Thus, in cases of multiple lesions where the surgical margin width may be small in preoperative simulation using preoperative imaging, hepatectomy by an expert surgeon is desirable because high-advanced preoperative planning and precise surgical techniques that consider surrounding blood vessels are required. In addition, parenchymal-sparing hepatectomy becomes standard procedure for CRLM treatment, Nevertheless, surgical margin may have less survival effect compared with tumor burden, tumor marker values, genetic profile, chemotherapy response, and characteristics of primary tumors (8-11,15). Hazard ratios of tumor burden, tumor marker, and perioperative chemotherapy showed higher values than that of surgical margin (8-11,15). Therefore, the surgical margin width should be comprehensively determined for each patient.
Recently, minimally invasive approaches have been rapidly expanding, even during liver surgery. Given that tumor palpation by tactile sensation becomes increasingly difficult in robotic approaches, followed by laparoscopic approaches, a visually-focused surgery is necessary. However, to maximize the visual effect, a high-skill technique to maintain a dry operative field is demanded. Although high-resolution image quality, three-dimensional visualization, and fluorescent imaging may provide strong assistance, the effect of surgical margin width on prognosis in minimally invasive surgery should be further studied. Furthermore, optimal surgical margin during hepatectomy for CRLM should be determined by artificial intelligence systems in the near future. Finally, based on the previous study, although the extent of the surgical margin width was largely determined by the tumor condition, hepatectomy should be performed while ensuring the widest surgical margin possible.
Acknowledgments
We would like to thank Editage (www.editage.jp) for English language editing.
Footnote
Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article has undergone external peer review.
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