Chen L, Song HC, Meng FZ, Zhang SY, An ZY, Ling XY, Zhang C, Zhu XC, Wang JZ, Song RP, Liu LX. Impact of textbook outcome after hepatectomy for colorectal metastases on salvage curative-intent treatment at recurrence. World J Gastrointest Oncol 2026; 18(7): 120704 [DOI: 10.4251/wjgo.v18.i7.120704]
Corresponding Author of This Article
Lian-Xin Liu, PhD, Dean, FACS, FRCS, Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, No. 17 Lujiang Road, Hefei 230001, Anhui Province, China. liulx@ustc.edu.cn
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Oncology
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Chen L, Song HC, Meng FZ, Zhang SY, An ZY, Ling XY, Zhang C, Zhu XC, Wang JZ, Song RP, Liu LX. Impact of textbook outcome after hepatectomy for colorectal metastases on salvage curative-intent treatment at recurrence. World J Gastrointest Oncol 2026; 18(7): 120704 [DOI: 10.4251/wjgo.v18.i7.120704]
Long Chen, Hua-Chuan Song, Fan-Zheng Meng, Shen-Yu Zhang, Ze-Yang An, Xin-Yu Ling, Can Zhang, Xing-Chun Zhu, Ji-Zhou Wang, Rui-Peng Song, Lian-Xin Liu, Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
Long Chen, Hua-Chuan Song, Fan-Zheng Meng, Shen-Yu Zhang, Ze-Yang An, Xin-Yu Ling, Can Zhang, Xing-Chun Zhu, Ji-Zhou Wang, Rui-Peng Song, Lian-Xin Liu, Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei 230001, Anhui Province, China
Long Chen, Hua-Chuan Song, Fan-Zheng Meng, Shen-Yu Zhang, Ze-Yang An, Xin-Yu Ling, Can Zhang, Xing-Chun Zhu, Ji-Zhou Wang, Rui-Peng Song, Lian-Xin Liu, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei 230001, Anhui Province, China
Co-corresponding authors: Rui-Peng Song and Lian-Xin Liu.
Author contributions: Chen L, Song HC, and Meng FZ designed the research study; Zhang SY, An ZY, Ling XY, Zhang C, and Zhu XC performed the research and collected the data; Chen L and Song HC analyzed and interpreted data, and they contributed equally to this manuscript as co-first authors; Chen L wrote the manuscript; Song RP and Liu LX contributed equally to this manuscript as co-corresponding authors; Wang JZ, Song RP, and Liu LX revised and proofed the manuscript. All authors have read and approved the final manuscript.
Supported by Scientific Research Project of Anhui Provincial Department of Education, No. 2024AH030058; Joint Fund Project of USTC, No. YD9110002083; and Joint Fund for Medical Artificial Intelligence, No. MAI2023Q034.
Institutional review board statement: The study was reviewed and approved by the First Affiliated Hospital of University of Science and Technology of China Institutional Review Board (approval No. 2025-RE-429).
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymous clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Data sharing statement: All data and materials are available from the corresponding author.
Corresponding author: Lian-Xin Liu, PhD, Dean, FACS, FRCS, Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, No. 17 Lujiang Road, Hefei 230001, Anhui Province, China. liulx@ustc.edu.cn
Received: March 9, 2026 Revised: March 31, 2026 Accepted: April 24, 2026 Published online: July 15, 2026 Processing time: 129 Days and 2.2 Hours
Abstract
BACKGROUND
Colorectal cancer is a leading cause of cancer-related mortality worldwide, with the liver being the most common site of distant metastasis. Hepatectomy is the gold standard for colorectal liver metastases (CRLM). However, up to 70% of patients experience recurrence within 5 years, for whom salvage curative-intent treatment (SCT) provides a second chance for cure. Textbook outcome (TO) is a composite metric that captures the ideal perioperative course and is associated with improved long-term survival. However, whether achieving TO influences eligibility for SCT upon recurrence remains unexplored.
AIM
To investigate whether achieving TO following initial hepatectomy for CRLM is an independent predictor of a patient’s eligibility for SCT upon intrahepatic recurrence.
METHODS
This multicenter, retrospective cohort study was conducted at two tertiary referral centers in China. We enrolled patients with CRLM who underwent hepatectomy from February 2017 to March 2025 and subsequently developed intrahepatic recurrence. The primary exposure was TO, defined as a composite metric comprising R0 resection, absence of major complications, no prolonged postoperative length of stay, no readmission within 90 days, and no mortality within 90 days. Univariable and multivariable logistic regression analyses evaluated the impact of TO on receiving SCT. Furthermore, to rigorously account for immortal time bias, subsequent survival outcomes were assessed utilizing a 12-month landmark analysis and time-dependent Cox proportional hazards models. A directed acyclic graph was constructed to identify potential confounders and guide variable selection for multivariable models.
RESULTS
TO was achieved in 69.1% (141/204) of patients. The TO group had a higher rate of SCT upon recurrence than the non-TO group (47.5% vs 14.3%, P < 0.001). TO was identified as an independent predictor of receiving SCT (odds ratio: 3.54, 95% confidence interval: 1.52-8.25, P = 0.003). Median overall survival (OS) was significantly longer in the TO group (not reached at a median follow-up of 39.3 months) compared with the non-TO group (35.2 months; P < 0.001). To adjust for immortal time bias, a 12-month landmark analysis confirmed the survival advantage of SCT (median residual OS: Not reached vs 32.8 months; P < 0.001). Furthermore, multivariable time-dependent Cox analysis verified SCT as an independent prognostic factor for improved OS (hazard ratio: 0.50, 95% confidence interval: 0.26-0.94, P = 0.031).
CONCLUSION
Achieving TO is a robust independent predictor of eligibility for SCT upon recurrence.
Core Tip: Following hepatectomy for colorectal liver metastases, the quality of the index surgery determines more than just short-term recovery. This study suggests that achieving a textbook outcome is the strongest independent predictor of eligibility for salvage curative-intent treatment upon intrahepatic recurrence. By preserving physiological reserve, textbook outcome helps maintain the critical therapeutic window for life-prolonging repeat interventions.
Citation: Chen L, Song HC, Meng FZ, Zhang SY, An ZY, Ling XY, Zhang C, Zhu XC, Wang JZ, Song RP, Liu LX. Impact of textbook outcome after hepatectomy for colorectal metastases on salvage curative-intent treatment at recurrence. World J Gastrointest Oncol 2026; 18(7): 120704
Colorectal cancer ranks among the leading causes of cancer-related mortality worldwide, with the liver being the most common site of distant metastasis[1]. Liver metastasis represents the predominant cause of death in these patients[2,3]. Historically, the prognosis for untreated colorectal liver metastases (CRLM) was dismal, with a median survival of merely 6.9 months and a 5-year survival rate below 5%[4]. Today, hepatectomy remains the gold standard for achieving long-term survival and potential cure. Patients undergoing successful resection can achieve a median overall survival (OS) of 35-60 months, with 5-year survival rates ranging from 40% to 57%[5-9].
However, despite this survival benefit, recurrence occurs in up to 70% of patients within 5 years after surgery and remains the primary cause of treatment failure[10]. Intrahepatic recurrence is the most frequent pattern of failure. For these patients, achieving a second cure is possible; the literature indicates that salvage curative-intent treatment (SCT) - including repeat hepatectomy and ablation therapy - offers survival outcomes comparable to primary resection, provided that the lesions are technically treatable and the patient’s liver function remains adequate[11-13]. Consequently, the critical clinical question has shifted from solely “how to prevent recurrence” to “how to optimize the host for the management of recurrence”.
In recent years, textbook outcome (TO) has emerged as a rigorous, patient-centered composite metric to evaluate the quality of surgical care. Unlike conventional metrics that rely on isolated parameters such as mortality or complication rates, TO captures the ideal perioperative course in an all-or-none fashion[14-16]. Growing evidence suggests that achieving a TO after hepatectomy is significantly associated with improved long-term survival, establishing it not merely as a quality benchmark but also as an independent prognostic indicator[17-19]. However, while the link between TO and OS is well documented, the specific mechanism driving this survival benefit remains unclear. Specifically, the impact of the quality of the index surgery on the feasibility of subsequent salvage treatment upon recurrence has not been explored.
We hypothesize that a successful index hepatectomy - defined by achieving TO - leaves a favorable physiological and anatomical legacy. This may preserve the patient’s functional reserve and minimize intra-abdominal adhesions, thereby maximizing the opportunity for salvage curative-intent therapies if recurrence occurs. To test this hypothesis, we conducted a multicenter retrospective cohort study to investigate the association between achieving TO at the primary resection and the likelihood of receiving salvage treatment upon subsequent intrahepatic recurrence.
MATERIALS AND METHODS
Patient and treatment
This multicenter retrospective study enrolled consecutive patients with pathologically confirmed CRLM who underwent hepatectomy at The First Affiliated Hospital of USTC and Anhui Provincial Cancer Hospital (February 2017 to March 2025) and subsequently developed intrahepatic recurrence. A total of 451 patients underwent curative-intent hepatectomy for CRLM at the two participating centers. Among these, 252 patients (55.9%) developed postoperative recurrence. Of these, 204 patients (81.0% of those with recurrence, 45.2% of the overall surgical cohort) presented with intrahepatic recurrence and constituted the final study cohort. Exclusion criteria included extrahepatic metastases, palliative resection, or incomplete follow-up data. The study was approved by the Institutional Ethics Committee (approval No. 2025-RE-429) and adhered to the Declaration of Helsinki (2024 revision). The requirement for informed consent was waived. Reporting followed the STROBE guidelines.
Definition and data collection
TO: The TO, a composite quality metric derived from prior studies and expert consensus, was employed to evaluate perioperative outcomes following hepatectomy for CRLM. This multidimensional indicator incorporates five key parameters: (1) Major postoperative complications (Clavien-Dindo grade ≥ III)[20]; (2) Unplanned 90-day readmission; (3) 90-day mortality; (4) Prolonged postoperative hospitalization [> 11 days, exceeding the 75th percentile of the cohort’s length of stay (LOS)][21]; and (5) Resection margin status[14,15,19,22-24]. Margin positivity was defined as either R1 resection or R2 resection[25]. Achievement of TO required the simultaneous fulfillment of all criteria: Absence of major complications, no prolonged hospitalization, no 90-day readmission, no 90-day mortality, and an R0 resection margin. Patients failing to meet any single criterion were classified as non-TO. Prolonged postoperative hospitalization was defined as a LOS exceeding 11 days, which corresponded to the 75th percentile of the entire cohort’s LOS[23]. To test the robustness of our findings and to address potential concerns regarding cohort-dependent definitions, we performed sensitivity analyses using alternative LOS thresholds at the 50th percentile (> 8 days) and 90th percentile (> 18 days). The components of our TO definition were selected based on a review of the literature and expert consensus[14,15].
SCT: SCT was defined as any local-regional intervention aimed at achieving complete tumor clearance in patients with intrahepatic recurrence (with or without concurrent extrahepatic disease). This included: (1) Repeat hepatectomy, considered the gold standard for resectable recurrence with the goal of achieving R0 resection; (2) Thermal ablation, including radiofrequency ablation and microwave ablation, applied for small (< 3 cm) or deep-seated lesions unsuitable for repeat hepatectomy; and (3) Combined resection and ablation, a hybrid approach for patients with multifocal or complex recurrence patterns. At both participating centers, all decisions regarding SCT were made by a multidisciplinary tumor board consisting of hepatobiliary surgeons, medical oncologists, radiologists, interventional radiologists, and pathologists. The multidisciplinary tumor board evaluated anatomical resectability (based on imaging), liver function reserve (Child-Pugh score, indocyanine green clearance), and performance status before recommending SCT. Patient preferences were also considered after thorough discussion of risks and benefits.
Follow-up
All patients were followed up according to a standardized institutional protocol. Surveillance visits included physical examination, measurement of serum carcinoembryonic antigen and carbohydrate antigen 19-9 levels, and computed tomography or magnetic resonance imaging of the chest, abdomen, and pelvis. These assessments were performed quarterly (every 3 months) for the first 2 years after surgery and semiannually (every 6 months) thereafter. The data cutoff date for the final follow-up analysis was June 2025.
Statistical analysis
Data analysis was performed using R version 4.4.2 (http://www.R-project.org). Descriptive statistics included mean ± SD, median with interquartile range, and n (%). Continuous variables were compared using t-test or Mann-Whitney U test, while categorical variables were assessed using the χ2 test or Fisher’s exact test. Univariable and multivariable logistic regression models were fitted to identify predictors of receiving SCT.
Survival outcomes were evaluated using the Kaplan-Meier method with the log-rank test and Cox proportional hazards models. Furthermore, to strictly account for the potential immortal time bias associated with the receipt of SCT - as patients must survive long enough to experience recurrence and receive subsequent therapies - two rigorous statistical approaches were additionally employed. First, a landmark analysis was conducted for the Kaplan-Meier survival estimates, setting the landmark time at 12 months post-hepatectomy to exclude early mortality or censored cases. Second, for the multivariable survival analysis, SCT was modeled as a time-dependent covariate (using the counting process format) in the Cox proportional hazards regression to evaluate its true prognostic effect. Variables with P < 0.10 in the univariable analysis were entered into the multivariable models. Statistical significance was defined as a two-sided P < 0.05.
RESULTS
Patient characteristics
Among the 252 patients with postoperative recurrence, 204 met the inclusion criteria (Figure 1). Analysis of the recurrence patterns (Supplementary Table 1) revealed that non-TO patients had significantly higher rates of combined intra- and extrahepatic recurrence (24, 30.0% vs 25, 14.5%, P = 0.008) and early recurrence (54, 67.5% vs 66, 38.4%), while late recurrence was more frequent in the TO group (60, 34.9% vs 16, 20.0%). Notably, the rate of repeat hepatectomy for recurrence was substantially higher in the TO group (49, 28.5% vs 2, 2.5%, P < 0.001). We compared baseline characteristics between the 204 included patients and the 48 excluded patients, both subgroups derived from the same population of 252 patients with recurrence. As shown in Supplementary Table 2, baseline characteristics between the included (n = 204) and excluded (n = 48) patients were generally comparable, except for a higher proportion of low-grade tumors and metachronous presentation in the excluded group (both P < 0.05).
Figure 1 Study flow chart.
CRLM: Colorectal liver metastases; TO: Textbook outcome.
In the final cohort (n = 204), TO was achieved in 141 patients (69.1%). As shown in Table 1, patients in the TO group presented with smaller tumors (P = 0.003) and required less invasive surgery, as evidenced by a higher laparoscopic approach rate (P < 0.001), a lower major hepatectomy rate (P = 0.018), and a lower simultaneous resection rate (P < 0.001). Additionally, patients in the TO group were more likely to have received neoadjuvant therapy (P = 0.005) and more likely to present with metachronous metastases (P = 0.012).
Table 1 Demographics and baseline characteristics, n (%)/mean ± SD/median (interquartile range).
Compared with the non-TO group, patients achieving TO demonstrated superior perioperative outcomes, characterized by shorter operative duration (182 minutes vs 240 minutes; P < 0.001), less blood loss (100 mL vs 200 mL; P < 0.001), and lower transfusion requirements (6, 4.3% vs 14, 22.2%; P < 0.001). Accordingly, the median postoperative LOS was significantly reduced in the TO group (7 days vs 14 days; P < 0.001).
Table 2 and Figure 2 delineate the specific reasons for failing to achieve TO. In the non-TO group, major complications were the predominant driver of failure (49.2%, 31/63), followed by unplanned 90-day readmission (22.2%, 14/63). Incomplete tumor clearance (R1/R2 margin) and 90-day mortality occurred in 6.4% and 1.6% of non-TO cases, respectively. Multivariable analysis identified laparoscopic approach, nonsimultaneous resection, and body mass index ≥ 24 kg/m2 as independent predictors of achieving TO (Supplementary Table 3).
The median time to recurrence was significantly longer in the TO group than in the non-TO group (7.5 months vs 3.3 months; P < 0.001). Non-TO patients were more likely to present with disseminated disease (intra- and extrahepatic recurrence: 23, 36.5% vs 24, 17.0%; P = 0.002). Consequently, the rate of SCT was substantially higher among patients who had achieved TO at the index surgery (47.5% vs 14.3%; P < 0.001) (Table 3).
Table 3 General characteristics of postoperative recurrence, n (%)/median (interquartile range).
On univariable analysis, the laparoscopic approach (P = 0.005), simultaneous resection (P = 0.034), major hepatectomy (P = 0.029), and TO (P < 0.001) were identified as significant predictors of undergoing SCT. Multivariable regression confirmed that TO was the only independent predictor associated with the receipt of SCT (odds ratio: 3.54, 95% confidence interval: 1.52-8.25; P = 0.003) (Table 4). Across all three percentile-based definitions (50th, 75th, and 90th), TO remained a statistically significant independent predictor of receiving SCT (all P < 0.05). These consistent findings demonstrate that the association between TO and SCT eligibility is robust and not an artifact of a specific cohort-dependent threshold (Supplementary Table 4).
Table 4 Effect of risk factors on salvage curative-intent treatment by univariable and multivariable analysis.
During a median follow-up of 39.3 months, 71 patients (34.8%) died. The median OS for the entire cohort was 70.9 months (95% confidence interval: 48.7-not reached). It is important to note that because only 34.8% of patients experienced the event of death during follow-up, the median OS was extrapolated beyond the observed follow-up period using the Kaplan-Meier estimator, which is appropriate when the survival curve does not cross the 50% threshold. When stratified by TO status, patients in the non-TO group had significantly shorter median OS compared with the TO group (35.2 months vs not reached; P < 0.001) (Figure 3A). To adjust for immortal time bias, a landmark analysis at 12 months post-hepatectomy was performed. After excluding 25 patients who died or were censored before the landmark time, the survival advantage of the SCT group remained highly significant. From the 12-month landmark, the median OS was 32.8 months for the non-SCT group and not reached for the SCT group (P < 0.001) (Figure 3B). Sensitivity analyses utilizing 6-month and 18-month landmarks yielded consistent results, reaffirming the robustness of this survival benefit (Supplementary Table 5).
Figure 3 Survival analysis.
A: Overall survival rates after hepatectomy for colorectal liver metastases classified according to textbook outcome and non-textbook outcome; B: Kaplan-Meier estimates of overall survival stratified by the receipt of salvage curative-intent treatment, using a 12-month landmark analysis to account for immortal time bias. TO: Textbook outcome; SCT: Salvage curative-intent treatment.
Univariable and multivariable cox regression analysis
Univariable Cox regression analysis identified major hepatectomy, neoadjuvant therapy, simultaneous resection, TO, and SCT as significant prognostic factors for OS (all P < 0.05). In the subsequent multivariable Cox regression, we modeled SCT as a time-dependent covariate to eliminate immortal time bias. The results confirmed that both adjuvant therapy (hazard ratio: 0.58, 95% confidence interval: 0.33-1.01, P = 0.053) and the receipt of SCT (hazard ratio: 0.50, 95% confidence interval: 0.26-0.94, P = 0.031) independently predicted improved OS (Table 5). Finally, the proportional hazards assumption was verified for all models using Schoenfeld residuals global tests (all P > 0.05) (Supplementary Table 6).
Table 5 Univariable and multivariable cox regression analyses of factors associated with overall survival.
This study represents the first investigation into the association between achieving TO following initial hepatectomy and the subsequent management of intrahepatic recurrence in patients with CRLM. The central finding of our analysis is that TO serves as the sole independent predictor of receiving SCT. Historically, research on TO has largely been confined to its use as a composite metric for perioperative quality or its correlation with long-term survival. Our findings offer a potential mechanistic framework that warrants further investigation. Our findings show an association between TO and later SCT eligibility. One hypothesis, needing more study, is that TO may preserve physiological and anatomical reserve, though we didn’t directly test this mechanism here.
Before interpreting our results, it is important to emphasize that all findings are associational. To guide our analysis and visualize potential confounding, we constructed a directed acyclic graph (Supplementary Figure 1). The directed acyclic graph illustrates that baseline patient and tumor characteristics (e.g., tumor burden, performance status, neoadjuvant response) may confound the associations among TO, SCT, and OS. While we adjusted for these measured confounders in multivariable models, residual confounding from unmeasured factors - such as tumor biology (e.g., RAS mutation status) or systemic inflammatory response - cannot be excluded. When we propose potential mechanisms (e.g., preservation of physiological reserve or minimization of adhesions), these are hypotheses generated from our associational findings and should be tested in future mechanistic or prospective studies.
Conventionally, the quality of hepatobiliary surgery has been benchmarked against isolated metrics, such as morbidity, mortality, and LOS[26-28]. Although each outcome metric provides valuable insights into patient prognosis, a single parameter fails to capture the multidimensional complexity of the patient’s recovery trajectory[21]. Furthermore, as perioperative safety has improved in specialized centers, outcome indicators like mortality now exhibit very low event rates. This lack of statistical variation limits their discriminatory power to distinguish between good and excellent performance[29,30]. Against this backdrop, TO has emerged as a superior composite measure. By aggregating the most desirable short-term outcomes into a single “all-or-none” metric, TO reflects the ideal surgical journey[15-19,21]. This indicator has been evaluated across various surgical fields, with results demonstrating its feasibility and effectiveness as a parameter for assessing the quality of surgical care and identifying inter-hospital variations[14-19,21].
TO elucidate the determinants of an ideal surgical course, the cohort was stratified based on TO attainment. Comparative analysis of baseline characteristics revealed that patients achieving TO were more likely to have undergone minimally invasive surgery or minor hepatectomy, and to present with metachronous metastases, smaller tumor burden, and a history of neoadjuvant therapy. In the subsequent multivariable analysis, a laparoscopic approach and non-simultaneous resection (staged or metachronous procedures) were identified as independent predictors of achieving TO, alongside body mass index categories (Supplementary Table 3). These findings corroborate contemporary literature, which consistently associates minimally invasive techniques and reduced surgical complexity with superior composite outcomes[14,16,18,31,32]. Although a laparoscopic approach and non-simultaneous resection predicted SCT univariably, they lost independent significance after adjusting for TO. This collinearity occurs because both factors strongly predict achieving TO. Clinically, this suggests a mediation pathway: Less invasive techniques facilitate TO, which comprehensively preserves the functional reserve necessary for salvage therapies. Consequently, TO supersedes isolated surgical variables as a holistic predictor of long-term therapeutic trajectories.
Currently, research on TO primarily focuses on its relationship with short-term prognosis and long-term survival[9-15,31]. For instance, Lanari et al[33] recently reported a significant correlation between achieving TO and prolonged OS (P = 0.01). Similarly, Dawood et al[34] demonstrated that TO achievement was associated with improved odds of 5-year OS (odds ratio: 1.22, 95% confidence interval: 1.20-1.24) and 5-year disease-free survival (odds ratio: 1.26, 95% confidence interval: 1.16-1.37). Our findings corroborate these reports, reinforcing the utility of TO as a robust prognostic marker. However, our study extends this knowledge by identifying a potential mechanism for this survival advantage: The preservation of eligibility for salvage treatment.
Surgical resection remains the cornerstone of curative therapy for CRLM; however, the disease course is often characterized by recurrence[27,35-38]. In this setting, the goal shifts to SCT. Decisions regarding repeat intervention are complex and must be driven by a multidisciplinary team, weighing anatomical feasibility against physiological reserve.
Repeat hepatectomy is the preferred modality when technically feasible, with safety profiles now matching those of primary resections in expert centers[12,13]. Conversely, for small (< 3 cm) or deep-seated tumors where re-resection entails high morbidity, ablation techniques offer a parenchymal-sparing solution[39]. Dupré et al[40] compared the efficacy of repeat hepatectomy vs radiofrequency ablation for recurrent CRLM after primary hepatectomy and found no statistically significant difference in median OS, which was 33 months in both groups. Additionally, hybrid approaches combining resection and ablation have expanded the limits of resectability for complex recurrence patterns[41,42]. The survival advantage conferred by these salvage treatments is well-established. However, eligibility for such aggressive therapy is not random. It is heavily contingent upon the patient’s recovery from the initial operation. This reinforces our central hypothesis: TO at the primary resection minimizes adhesion formation and preserves functional status, thereby maintaining the “therapeutic window” for successful salvage treatment upon recurrence.
Despite the curative potential of hepatectomy, postoperative recurrence remains the major obstacle to long-term survival in CRLM. Crucially, our rigorous sensitivity analyses - incorporating both landmark modeling and time-dependent Cox regression - confirm that the substantial survival advantage conferred by SCT is a genuine therapeutic benefit, rather than a statistical artifact driven by immortal time bias. Consequently, the ability to undergo SCT is a critical determinant of prognosis. However, the factors governing a patient’s eligibility for these rescue therapies have historically been underappreciated. Recent evidence suggests that the quality of the index surgery exerts a profound legacy effect. Surgical resection remains the preferred and most effective therapeutic option, aiming to achieve R0 resection[43,44]. Sakai et al[45] demonstrated that achieving an initial R0 resection is significantly associated with a higher likelihood of repeat resection for recurrence, highlighting the importance of initial oncological clearance.
Beyond technical factors, the biological impact of surgical quality is pivotal. Tanaka et al[46] elucidated that major complications trigger a severe systemic inflammatory response. This inflammatory surge suppresses cell-mediated immunity, creating a permissive microenvironment for the outgrowth of residual micrometastases. Clinically, this manifests as early and aggressive recurrence, which often renders patients ineligible for salvage therapy due to multifocal or disseminated disease. Complications prolong recovery time, leading to sarcopenia, malnutrition, and decreased physical performance status. Consequently, when recurrence occurs, patients may be unable to tolerate major surgeries such as hepatectomy[47].
In this context, LOS serves as a valuable composite surrogate for the patient’s recovery trajectory. Rather than a mere administrative metric, prolonged hospitalization comprehensively reflects the cumulative burden of surgical trauma, infection, and delayed functional recovery. By incorporating LOS, TO is associated with the identification of patients who appear to have preserved immunological and physical fitness, which could correlate with a maintained window of opportunity for future curative interventions[46,48]. We acknowledge that the definition of prolonged LOS remains heterogeneous across studies. To address this concern, we performed sensitivity analyses using alternative percentile thresholds (50th and 90th). Importantly, TO remained a robust independent predictor of receiving SCT across all definitions, confirming that our findings are not artifact of a specific cohort-dependent cutoff. Nevertheless, the lack of a globally standardized LOS cutoff continues to limit direct comparisons across studies from different healthcare systems, where discharge practices vary substantially. Future international collaborative efforts are warranted to establish a clinically meaningful and universally applicable LOS threshold for inclusion in the TO definition for liver surgery.
Currently, predicting therapeutic trajectories for recurrent CRLM relies heavily on isolated perioperative metrics, such as margin status or complication rates. However, clinical experience dictates that determining eligibility for SCT is a nuanced, multidimensional process. It depends not only on the anatomical pattern of recurrence but also on the patient’s systemic condition, functional liver reserve, and physiological tolerance. A patient may achieve a technical R0 resection at the index surgery yet suffer from major complications and a protracted recovery. Such a course often leads to sustained physical deconditioning, effectively precluding the patient from undergoing repeat hepatectomy upon recurrence despite anatomically resectable disease. Consequently, reliance on any single parameter fails to capture the cumulative physiological toll of the initial surgery. As a composite metric, TO better reflects the preservation of the patient’s long-term therapeutic potential.
In the present cohort of 204 patients with recurrent disease, 141 (69.1%) achieved TO at the index operation. Notably, nearly half of these TO patients (47.5%) successfully underwent SCT upon recurrence. We hypothesize that the attainment of TO - specifically through the avoidance of major complications and the preservation of hepatic parenchymal function - serves to safeguard the patient’s physiological reserve. It is plausible that minimizing surgical insult and avoiding major complications is associated with better preservation of physical performance status, which in turn could influence SCT eligibility. Nevertheless, our study did not directly measure performance status or inflammatory markers, and this interpretation should be considered hypothesis-generating. Consequently, when recurrence occurs, these patients may retain the functional resilience required to tolerate subsequent aggressive interventions, such as repeat hepatectomy or thermal ablation.
The median OS of 70.9 months in our cohort is consistent with contemporary series of CRLM patients undergoing hepatectomy, where 5-year survival rates of 40%-57% are reported[5-9]. The fact that median OS exceeded the median follow-up reflects both the favorable prognosis of patients selected for hepatectomy and the relatively short follow-up period relative to the long natural history of the disease. Our multivariable Cox regression analysis further identified the timely initiation of adjuvant therapy as an independent prognostic factor for OS. This underscores a critical logistical advantage of TO: An uncomplicated recovery - free from prolonged hospitalization or readmission - ensures that patients adhere to the optimal oncological timeline, preserving the therapeutic window for systemic treatment. Beyond these logistical benefits, we hypothesize that TO may serve as a surrogate marker for favorable tumor biology. Patients who achieve TO often present with controllable tumor burden (facilitating R0 resection) and may have demonstrated favorable responses to neoadjuvant therapy. Such patients are likely to exhibit less aggressive phenotypes. Consequently, even when recurrence occurs, it tends to manifest in patterns that are more biologically amenable to salvage local interventions, consistent with the higher salvage rates observed in our TO cohort.
We recognize that the association between TO and receipt of SCT may be influenced by baseline patient and tumor characteristics. In our cohort, patients who achieved TO were more likely to present with smaller tumors, metachronous metastases, and a history of neoadjuvant therapy, and they underwent less extensive surgery. These factors are themselves favorable prognostic indicators and may select for patients with inherently less aggressive tumor biology and preserved physiological reserve. Therefore, while TO serves as a strong predictor of SCT eligibility, it should be interpreted as a composite marker that integrates both perioperative quality and favorable baseline characteristics, rather than as an isolated causal factor.
This study has several limitations that merit consideration. First, despite the implementation of multivariable adjustment, the retrospective cohort design introduces inherent selection bias. As observed in our baseline characteristics, patients who achieved TO differed significantly from those who did not. While our models accounted for these factors, residual confounding cannot be entirely excluded, particularly regarding the nuanced multidisciplinary decision-making processes for salvage therapies. Second, regarding external validity, this study was conducted at two high-volume tertiary referral centers in China. The surgical expertise, perioperative management protocols, and aggressive approaches to salvage treatments at these specialized institutions may differ from those in non-tertiary or Western settings, potentially limiting the generalizability of our findings. Third, our analysis is constrained by the presence of unmeasured confounders. Crucial clinical parameters such as Eastern Cooperative Oncology Group performance status, objective frailty indices, sarcopenia assessments, and detailed quality of life metrics were not consistently recorded in our database. These variables significantly influence both the perioperative recovery trajectory (TO) and the eligibility for SCT. Fourth, while TO is widely adopted as a comprehensive benchmark for surgical quality, the heterogeneity of its definitions in contemporary literature - such as variations in the inclusion and thresholds of LOS - can complicate direct cross-study comparisons and inter-institutional benchmarking. Furthermore, the relatively limited sample size may restrict the statistical power of subgroup analyses regarding specific recurrence patterns. Finally, while we have proposed several potential mechanisms underlying the observed association - including that avoidance of major complications may mitigate systemic inflammatory responses, and that an uncomplicated primary surgery may result in fewer intra-abdominal adhesions to technically facilitate repeat hepatectomy - these explanations remain hypothesis-generating. We lacked objective data (e.g., inflammatory markers or standardized intraoperative grading of adhesions during the second surgery) to empirically test these pathways. Consequently, our findings warrant external validation through larger-scale, prospective multicenter trials to definitively establish the predictive value of TO for eligibility for curative-intent treatment upon recurrence. Future studies incorporating objective assessments of these mechanistic parameters are needed to establish the causal pathways linking surgical quality to long-term oncological outcomes.
CONCLUSION
In summary, achieving TO following hepatectomy for CRLM is a robust predictor of eligibility for SCT should recurrence occur. Beyond serving as a short-term quality metric, TO is a strong predictor of preserved physiological reserve and anatomical integrity, which correlates with patients remaining candidates for the long-term continuum of care. These associations warrant further investigation. Therefore, improving perioperative quality to maximize TO rates is critical, as it may help secure the possibility of life-prolonging interventions in the future.
ACKNOWLEDGEMENTS
Thanks to all authors for their efforts in this work.
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Creativity or innovation: Grade B, Grade B, Grade B
Scientific significance: Grade B, Grade B, Grade B
P-Reviewer: Ghannam WM, MD, Professor, Egypt; Isik A, MD, PhD, Academic Fellow, Consultant, Professor, United States S-Editor: Hu XY L-Editor: A P-Editor: Wang CH
