RAS mutation nomograms to predict prognosis after radiofrequency ablation of recurrent colorectal liver metastases

doi:10.21203/rs.3.rs-3605934/v1

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RAS mutation nomograms to predict prognosis after radiofrequency ablation of recurrent colorectal liver metastases

https://doi.org/10.21203/rs.3.rs-3605934/v1

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Objectives: This study was conducted to develop nomograms for predicting repeat intrahepatic recurrence (rIHR) and overall survival (OS) after radiofrequency ablation (RFA) treatment in patients with recurrent colorectal liver metastases (CLMs) after hepatectomy based on RAS mutation and clinicopathologic features.

Methods: A total of 160 consecutive patients with recurrent CLMs after hepatectomy who were treated with ultrasound-guided percutaneous RFA from 2012 to 2022 were retrospectively included. Potential prognostic factors associated with rIHR and OS after RFA, identified by the competing-risks model and Cox proportional hazard model, respectively, were used to construct nomograms. The performance of each nomogram was evaluated by Harrell’s C-index and calibration curve with bootstrapping.

Results: The 1-, 2-, and 3-year rIHR rates after RFA were 59%, 69%, and 74%, respectively. The 1-, 3- and 5-year OS rates were 96.2%, 66.7%, and 47.0%, respectively. Four predictive factors, RAS mutation, interval from hepatectomy to intrahepatic recurrence, carcinoembryonic antigen (CEA) level at ablation, and ablation margin, were incorporated in the rIHR nomogram with a C-index of 0.694. Five predictive factors, RAS mutation, largest CLM at hepatectomy, CEA level at ablation, extrahepatic disease, and ablation margin, were incorporated intothe OS nomogram with a C-index of 0.743. The calibration curves presented good agreement between thenomograms and actual observations.

Conclusions: The established nomograms can predict the individual risk of rIHR and OS after RFA for recurrent CLMs and contribute to better individualized management.

Advances in knowledge: This study highlights the predictive value of RAS mutation for rIHR and OS after RFA of recurrent CLMs.

radiofrequency ablation

colorectal cancer liver metastases

nomogram

recurrence

RAS mutation

Colorectal cancer (CRC) is the second leading cause of cancer death worldwide,¹ with up to 50% of patients eventually developing liver metastases.² Hepatectomy is the standard management for resectable colorectal liver metastases (CLMs), and the 5-year overall survival (OS) rate of postoperative patients can reach 40–60%.³ However, recurrence rates exceed 50% within two years after hepatectomy, and the principle site of recurrence is the liver.⁴ Repeat hepatectomy in selected patients may be a reasonable therapeutic strategy to achieve long-term survival, but it is challenging owing to postsurgical adhesions and limited liver reserve.⁵ Radiofrequency ablation (RFA) is widely used as an alternative treatment for small recurrent CLMs.⁶ Unfortunately, only 25% of patients with recurrent CLMs achieve long-term intrahepatic recurrence-free survival after RFA.⁷ Therefore, there is a clear need to obtain better prognostic information before RFA to facilitate individualized clinical management.

A nomogram is a visual model for statistical predictions that combines independent factors and can help clinicians and patients in shared decision-making and inform the probability of recurrence and survival. However, to our knowledge, no nomograms have been specifically designed for recurrent CLM patients treated with RFA. Furthermore, RAS mutation is used to predict response to targeted therapies and is increasingly considered a novel predictor for prognosis after CLM ablation.⁸ Therefore, more accurate prognostication may potentially be achieved by inclusion of this genetic biomarker in nomograms. This study was designed to develop nomograms that incorporate RAS mutation for the prediction of repeat intrahepatic recurrence (rIHR) and OS after RFA for recurrent CLMs.

Subjects

Between January 2012 and January 2022, a total of 219 consecutive patients underwent ultrasound-guided percutaneous RFA for recurrent CLMs after hepatectomy at our hospital. Of these, 59 patients were excluded for the following reasons: 1. RAS mutation data were not available (n = 37); 2. no resection of the primary tumour was performed (n = 1); 3. residual unablated tumour after RFA was not retreated with an additional session of RFA (n = 11); and 4. patients were lost to follow-up (n = 10). After these exclusions, 160 patients were included in the analysis. Liver metastases were diagnosed based on radiologic findings of contrast-enhanced computed tomography (CT) and/or magnetic resonance imaging (MRI) in the context of a clinical history of metastatic CRC. In general, RFA was recommended for recurrent CLM patients with limited liver reserve and/or deeply located tumours requiring major hepatectomy.

Radiofrequency ablation procedure

All RFA procedures were performed under general anaesthesia using real-time ultrasound (US) or contrast-enhanced ultrasound (CEUS) guidance by a radiologist team with more than 10 years of experience in US-guided interventions. The RFA equipment used in this study included a CelonLab system (Olympus, Germany), Valleylab system (Tyco Healthcare, North Haven, CT), RITA 1500X system (AngioDynamics, Latham, NY) or LDRF-120S RFA system (LeadElectron, Mianyang, China). The US guidance devices included the Aloka ultrasound systems (Alokaa-10, Tokyo, Japan) or GE systems (E9, GE, United States). All ablations were performed with the intent to completely cover the tumour plus a safety margin of at least 5 mm in all directions. CEUS was performed immediately after RFA to assess the completeness of the ablation. If residual unablated tumour was present, additional RFA was performed during the same session. Perioperative chemotherapy was prescribed following consensus among the multidisciplinary team.

Imaging follow-up

Contrast-enhanced CT/MRI was performed 1 month after RFA and every 3 months thereafter in the next 2 years. If no recurrence was detected, the period between imaging sessions could be extended to every 6 months. The last follow-up was completed in December 2022. Technical effectiveness was defined as complete tumour ablation demonstrated by imaging at the 1-month follow-up after RFA. When a residual unablated tumour was detected, a secondary RFA session was performed. The presence of new enhancement lesions within or adjacent to the complete ablation zone was defined as local tumour progression (LTP). Newly enhanced lesions in the liver outside the ablation zone were considered intrahepatic distant recurrence (IDR). Intrahepatic recurrence included LTP and IDR.

Ablation margins and RAS gene analysis

One month after RFA, ablation margins were evaluated by two radiologists with more than 5 years of experience, as previously described.⁹ Using a PACS workstation, pre- and post-RFA contrast-enhanced CT/MR images were displayed side by side to measure the distances from the tumour boundary to the selected anatomic landmarks on the three orthogonal planes. The margin at each landmark was calculated by subtracting the post-RFA distance from the pre-RFA distance; the smallest value was recorded as the ablation margin. In the case of multiple tumours, the smallest ablation margin was recorded as the ablation margin. Genomic DNA was extracted from primary tumour or CLM tissue samples and subjected to either next-generation sequencing or polymerase chain reaction to screen for mutations in KRAS/NRAS (RAS) codons 12, 13, and 61.

Candidate predictor variables

The candidate predictors included age at ablation; sex; primary tumour characteristics (American Joint Committee on Cancer (AJCC) T category, node-positive primary tumour, and location (right colon, left colon, or rectum)); initial CLM diagnosis (synchronous or metachronous); RAS mutation; characteristics of hepatectomy (largest tumour size (≤ 3 cm or > 3 cm), number, concurrent RFA at the time of hepatectomy, margin status (R0, defined as a pathologically negative margin ≥ 1 mm, or R1)); interval from hepatectomy to intrahepatic recurrence (≤ 12 months or > 12 months); and characteristics of RFA treatment (extrahepatic disease at ablation, carcinoembryonic antigen (CEA) level at ablation (≤ 5 ng/ml or > 5 ng/ml), preablation chemotherapy (none, cytotoxic, or cytotoxic + biological agent), largest tumour size (≤ 3 cm or > 3 cm), number, ablation margin (< 5 mm or ≥ 5 mm), and receipt of postablation chemotherapy). For patients with multiple hepatectomies, data from the last operation were assessed. Tumour size and number at hepatectomy were based on pathological results from resection specimens.

Statistical analysis

Categorical variables are presented as frequencies (percentages), and continuous variables are presented as medians (IQRs). Time to rIHR was calculated from the time of RFA to the first radiologic evidence of LTP or IDR, whichever occurred first. Death that occurred before rIHR was classified as a competing risk. The cumulative incidence function (CIF) was used to estimate the cumulative rate of rIHR. OS was measured from the time of RFA to patient death or last follow-up. The Kaplan‒Meier method was used to estimate OS. A competing-risks (Fine-Gray) model and a Cox proportional hazard model were constructed to determine the independent predictors of rIHR and OS after RFA, respectively. Factors with a P value < 0.10 in univariable analyses were assessed in multivariable analyses using backwards selection according to the Akaike information criterion. Nomograms were developed based on the results of multivariable analysis to predict rIHR and OS rates. Discrimination of the nomograms was evaluated using Harrell’s C-index. The calibration of the nomograms was performed using calibration curves with bootstraps of 1000 resamples. All patients were classified into low-risk and high-risk groups according to the median of the total score predicted by the nomogram. The rIHR rates of each group were estimated by the CIF method and compared by Gray's test. The OS rates of each group were estimated by the Kaplan‒Meier method and compared by a log-rank test. Statistical analyses were performed using R 4.2.2 (http://www.r-project.org). P values < 0.05 were considered significant.

Patient characteristics

Baseline characteristics are presented in Table 1. The cohort comprised a total of 160 patients treated in 171 sessions for 258 lesions. The median age was 59 years, and 31.2% of the patients were female. A total of 151 patients (94.4%) had undergone one round of hepatectomy, and the other 9 patients had undergone two rounds of hepatectomy. At the time of RFA, 37 (23.1%) patients had extrahepatic disease, including lung only (n = 28), lung and lymph nodes (mediastinal, abdominal, both mediastinal and abdominal) (n = 4), abdominal lymph nodes (n = 3), and bone (n = 2).

Table 1

Characteristics of the patients
Characteristic	Patients (n = 160)
Age at ablation (years)	59 (54–64)
Sex
Male	110 (68.8)
Female	50 (31.2)
Primary tumour site
Left colon	79 (49.4)
Right colon	19 (11.9)
Rectum	62 (38.8)
Primary T stage
T1-3	126 (78.8)
T4	34 (21.2)
Nodal metastases
No	52 (32.5)
Yes	108 (67.5)
RAS mutation status
Wild type	93 (58.1)
Mutant	67 (41.9)
No. of previous hepatectomy
Single	151 (94.4)
Two	9 (5.6)
Initial CLM diagnosis
Synchronous	116 (72.5)
Metachronous	44 (27.5)
Factors associated with hepatectomy of CLM
Number of tumours	4 (2–6)
Size of largest CLM (cm)	2.2 (1.5–3.3)
Type of procedure
Resection	116 (72.5)
Resection and RFA	44 (27.5)
Resection margin
R0	113 (70.6)
R1	47 (29.4)
Factors associated with RFA of recurrent CLM
Interval from hepatectomy to intrahepatic recurrence (months)	6 (3–10)
Number of tumours	1 (1–2)
Size of largest CLM (cm)	1.8 (1.4–2.4)
CEA level at ablation (ng/ml)	5.36 (3.16–9.90)
Extrahepatic disease at ablation	37 (23.1)
Preablation chemotherapy
No	99 (61.9)
Cytotoxic chemo	13 (8.1)
Cytotoxic chemo + biological agent	48 (30.0)
Postablation chemotherapy	66 (41.2)
Ablation margin
<5mm	67 (41.9)
≥5mm	93 (58.1)
Values were shown as n (%), or median (IQR)
RFA, radiofrequency ablation; CLM, colorectal liver metastases; CEA, carcinoembryonic antigen

At a median follow-up of 39 months (range 8-126 months) after RFA, 113 patients (70.6%) experienced rIHR after RFA, including 87 patients with IDR as the initial recurrence, 19 patients with LTP as the initial recurrence, and 7 patients with synchronous IDR and LTP. Death occurred in 56 (35.0%) patients. The 1-, 2-, and 3-year rIHR rates after RFA were 59%, 69%, and 74%, respectively. The median OS after RFA was 53 months, and the 1-, 3- and 5-year OS rates were 96.2%, 66.7%, and 47.0%, respectively. Through the end of 2022, 33 of 258 (12.8%) treated tumours showed evidence of LTP, and 101 of 160 (63.1%) patients showed evidence of IDR.

Prognostic factors of rIHR and OS after RFA for recurrent CLMs

Univariable analysis identified five factors that significantly affected rIHR after RFA: primary tumour location, RAS mutation, interval from hepatectomy to intrahepatic recurrence, CEA level at ablation, and ablation margin. Multivariable competing-risks regression analysis showed that primary tumour location was not an independent prognostic factor for rIHR, but RAS mutation (subdistribution hazard ratio [SHR], 1.92; 95% CI, 1.32–2.79), interval from hepatectomy to intrahepatic recurrence ≤ 12 months (SHR, 2.07; 95% CI, 1.24–3.44), CEA level at ablation > 5 ng/ml (SHR, 1.55; 95% CI, 1.06–2.28) and ablation margin < 5 mm (SHR, 1.91; 95% CI, 1.30–2.80) were independently associated with higher rIHR after RFA (Table 2).

Table 2

Univariable and multivariable analyses of risk factors for rIHR and OS after RFA
	rIHR				OS
Variable	Univariable		Multivariable		Univariable		Multivariable
	SHR (95% CI)	P-value	SHR (95% CI)	P-value	HR (95% CI)	P-value	HR (95% CI)	P-value
Age (≤ 60 as ref.)
> 60	0.84 (0.58–1.21)	0.345			1.43 (0.85–2.43)	0.182
Gender (female as ref.)
Male	0.77 (0.51–1.16)	0.212			0.68 (0.40–1.15)	0.152
Primary tumour site (left colon as ref.)
Right colon	1.82 (0.92–3.60)	0.085			1.57 (0.67–3.68)	0.298
Rectum	1.50 (1.03–2.20)	0.036			1.36 (0.77–2.40)	0.294
Primary T stage (T1-3 as ref.)
T4	1.19 (0.76–1.87)	0.440			0.84 (0.43–1.63)	0.604
Nodal metastases (no as ref.)
Yes	1.09 (0.76–1.56)	0.656			1.44 (0.81–2.55)	0.217
RAS mutation status (wild type as ref.)
Mutant	2.24 (1.53–3.29)	< 0.001	1.92 (1.32–2.79)	< 0.001	3.13 (1.82–5.38)	< 0.001	2.24 (1.27–3.95)	0.005
Initial CLM diagnosis (metachronous as ref.)
Synchronous	1.04 (0.69–1.55)	0.866			0.88 (0.50–1.55)	0.667
No. of previous hepatectomy (one as ref.)
Two	1.44 (0.78–2.63)	0.243			1.78 (0.76–4.17)	0.182
Factors associated with hepatectomy of CLM
No. of CLM (solitary as ref.)
Multiple	1.27 (0.77–2.09)	0.343			0.64 (0.35–1.20)	0.162
Size of largest CLM (≤ 3 cm as ref.)
> 3 cm	1.20 (0.79–1.82)	0.398			1.76 (1.02–3.03)	0.042	2.26 (1.28–3.98)	0.005
Type of procedure (resection as ref.)
Resection and RFA	1.24 (0.85–1.82)	0.262			0.62 (0.31–1.24)	0.180
Surgical margin (R0 as ref.)
R1	1.37 (0.91–2.05)	0.132			1.08 (0.60–1.92)	0.803
Factors associated with RFA of recurrent CLM
Interval from hepatectomy to recurrence (> 12 months as ref.)
≤ 12 months	2.08 (1.28–3.40)	0.003	2.07 (1.24–3.44)	0.005	1.07 (0.54–2.13)	0.840
No. of CLM (unique as ref.)
Multiple	1.27 (0.88–1.84)	0.206			1.40 (0.82–2.41)	0.221
Size of largest CLM (≤ 3 cm as ref.)
> 3 cm	1.36 (0.62–2.99)	0.439			1.36 (0.42–4.36)	0.607
CEA level at ablation (≤ 5 ng/ml as ref.)
> 5 ng/ml	1.86 (1.28–2.71)	0.001	1.55 (1.06–2.28)	0.026	2.73 (1.52–4.90)	< 0.001	1.99 (1.04–3.80)	0.039
Extrahepatic disease (no as ref.)
Yes	1.07 (0.69–1.67)	0.751			3.50 (2.02–6.06)	< 0.001	1.84 (1.01–3.36)	0.047
Preablation chemotherapy (none as ref.)
Done	1.13 (0.77–1.64)	0.536			0.89 (0.51–1.56)	0.690
Postablation chemotherapy (none as ref.)
Done	0.88 (0.61–1.26)	0.488			1.44 (0.84–2.46)	0.185
Ablation margin (≥ 5 mm as ref.)
< 5 mm	2.18 (1.52–3.14)	< 0.001	1.91 (1.30–2.80)	0.001	2.81 (1.61–4.88)	< 0.001	1.90 (1.01–3.56)	0.046
RFA, radiofrequency ablation; CLM, colorectal liver metastases; CEA, carcinoembryonic antigen; rIHR, repeat intrahepatic recurrence; OS, overall survival; SHR, subdistribution hazard ratio; HR, hazard ratio

Univariable analysis identified five factors that significantly affected OS after RFA: RAS mutation, largest CLM at hepatectomy, CEA level at ablation, extrahepatic disease, and ablation margin. Multivariable Cox regression analysis found that the same five variables exhibited independent prognostic significance in relation to OS. Specifically, RAS mutation (hazard ratio [HR], 2.24; 95% CI, 1.27–3.95), largest CLM at hepatectomy > 3 cm (HR, 2.26; 95% CI, 1.28–3.98), CEA level at ablation > 5 ng/ml (HR, 1.99; 95% CI, 1.04–3.80), extrahepatic disease (HR, 1.84; 95% CI, 1.01–3.36) and ablation margin < 5 mm (HR, 1.90; 95% CI, 1.01–3.56) were independent predictors of shortened OS (Table 2).

Construction and validation of nomograms for rIHR and OS after RFA for recurrent CLMs

Nomograms were constructed based on the multivariable model to estimate the rIHR and OS rates after RFA for recurrent CLMs (Figs. 1 and 2). The C-indices of the nomograms for predicting rIHR and OS were 0.694 (95% CI, 0.647–0.741) and 0.743 (95% CI, 0.665–0.821), respectively. The calibration curves showed good agreement between the predicted rIHR and OS rates and actual observations (Fig. 3). The cohort was divided into low-risk (≤ 189) and high-risk (> 189) groups according to the median nomogram-predicted rIHR and low-risk (≤ 163) and high-risk (> 163) groups according to the median nomogram-predicted OS (Fig. 4). The 2-year rIHR rates for the low-risk and high-risk groups were 52% and 88% (p < 0.001), and the 5-year OS rates were 71.0% and 23.1% (p < 0.001), respectively.

The recent expansion of surgical indications has increased the number of patients with potentially resectable disease, but it has also been accompanied by an increased risk of recurrence.¹⁰ Thermal ablation is one curative treatment option for small recurrent CLMs.¹¹ This single-centre cohort study reviewed our institution’s 10 years of experience with RFA in patients with recurrent CLMs and constructed nomograms to accurately predict rIHR and OS after RFA.

In this study, the 1-, 2-, and 3-year rIHR rates were 59%, 69%, and 74%, respectively. High rIHR rates after RFA have been reported by prior studies. Valls et al.¹² reported that of 59 recurrent CLM cases treated with RFA, the 1- and 2-year liver disease-free survival rates were 54% and 24%, respectively. Zimmermann et al.⁷ analysed 23 patients treated with RFA for recurrent CLMs after major hepatectomy and reported a 1-year rIHR rate of 65%. Taken together, these findings emphasize that about 60% of patients with recurrent CLMs will develop rIHR within 1 years after RFA. Compared with rIHR, OS provides a more direct evaluation of prognosis. The 5-year OS of 47% in this cohort was higher than that of prior studies.^{7, 12, 13} Prior studies reflect analyses of more historic practices. All of the patients in this cohort were treated in 2012 or later, and the OS in the study cohort may reflect the observations of more contemporary analyses.

Nomograms are a statistical tool that use a simple line graph for prediction. Published models have been designed for all CLM populations.^14–16 However, prognostic factors may change dramatically with disease recurrence.¹⁷ In this study, we constructed a novel nomogram for rIHR after RFA of recurrent CLMs that incorporated four independent predictors, including RAS mutation (mutant type, 90 points), interval from hepatectomy to intrahepatic recurrence (≤ 12 months, 100 points), CEA level at ablation (> 5 ng/ml, 61 points) and ablation margin (< 5 mm, 89 points). The C-index of this nomogram was 0.694. RAS mutation (mutant type, 99 points), largest CLM at hepatectomy (> 3 cm, 100 points), CEA level at ablation (> 5 ng/ml, 84 points), extrahepatic disease (Yes, 75 points), and ablation margin (< 5 mm, 79 points) were incorporated in the OS nomogram, which had a high accuracy for OS with a C-index of 0.743. These prognostic nomograms are useful tools for clinical decision-making, use easily available variables, and have the advantage of combining different factors to estimate probability rather than using individual variables for prediction.

RAS mutations occur in approximately 40–50% of patients undergoing CLM resection¹⁸ and have been associated with lower effectiveness of preoperative chemotherapy¹⁹ and poor OS in patients with resectable CLMs.²⁰ Many studies have reported that patients with RAS-mutated tumours have a higher risk of intrahepatic recurrence after local treatment.^{14, 21–23} In this study, RAS mutation was a predictor of a higher rIHR rate and worse OS after RFA for recurrent CLMs, probably because the tumour biology is more migratory and infiltrative.²⁴

Many studies have shown that ablation margin is a critical predictor of LTP.^{23, 25–27} An ablation margin > 10 mm was associated with the best local tumour control, especially for RAS mutational tumours.²⁶ Similar to previous reports, our study revealed that the ablation margin was a significant predictor of rIHR and OS after RFA. Ablation margins cannot be determined with certainty preoperatively, but with experience and high-level imaging technology, they can be estimated by the radiologist team.

Currently, CEA is the most widely used biomarker in CRC and a predictor for the benefit of perioperative chemotherapy.²⁸ In this study, patients with CEA levels > 5 ng/mL exhibited a higher rIHR rate and a worse OS rate than those with lower levels. Therefore, elevated CEA levels might reflect the presence of micrometastases and aggressive tumour biology.²⁸

A short interval from hepatectomy to recurrence usually reflects unidentified metastases or microscopic remnant disease.²⁹ In our study, patients who presented with intrahepatic recurrence within 12 months of hepatectomy experienced rIHR more frequently. Therefore, several publications recommended RFA as a “test-of-time” strategy for patients with early recurrence.¹³ Local tumour control by RFA provides time for the development of unresectable multifocal disease, allowing these patients to avoid unnecessary surgery.⁶ Additionally, approximately 10% of patients had concomitant extrahepatic disease at the time of intrahepatic recurrence after hepatectomy.²⁹ Although the involvement of extrahepatic organs indicates poor outcomes, patients with limited and treatable extrahepatic diseases can also benefit from ablation for CLMs.³⁰ In general, tumour size and number at RFA have been considered the key predictors for recurrence and survival, but these indicators failed to show statistical significance in our data. This may be explained by the fact that recurrent CLMs are detected early after hepatectomy due to the close follow-up regimen, meaning that usually only small-sized and solitary recurrent CLMs are observed.¹¹

Although approximately 70% of patients develop rIHR within 2 years, RFA can be easily repeated to treat tumour recurrence⁵ and can offer improved long-term survival¹⁰. Hence, the current nomogram may provide prognostic benefits to patients at high risk of rIHR through more frequent radiological follow-up. Furthermore, the application of the OS nomogram may improve patient selection.

There are some limitations in this study. First, since this was a retrospective analysis of a single-institution prospective database, information and selection bias may be present. Thus, external validation in a multicentre prospective study is still needed to confirm the performance of our nomograms. Second, although inclusion of RAS mutation in the rIHR nomogram led to improved prognostic accuracy, the discrimination of the nomogram remained modest (C-index < 0.70); future studies are needed to incorporate additional somatic gene mutations to update the nomogram.

In conclusion, the established nomograms may accurately predict the individual risk of rIHR and OS in recurrent CLM patients treated with RFA and contribute to better individualized management.

Competing interests

There were no any conflicts of interest for all authors.

Funding

This work was supported by Capital’s Funds for Health Improvement and Research (2020-2-2152).

Data Availability

The data presented in this study are available on request from the corresponding authors.

Ethics approval and Consent to participate

This study was a retrospective analysis. The study was approved by Institutional Review Board (IRB) of our institute, and the requirement to obtain informed written consent was waived.

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No competing interests reported.

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RAS mutation nomograms to predict prognosis after radiofrequency ablation of recurrent colorectal liver metastases

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Abstract

Figures

Introduction

Methods

Subjects

Radiofrequency ablation procedure

Imaging follow-up

Ablation margins and RAS gene analysis

Candidate predictor variables

Statistical analysis

Results

Patient characteristics

Prognostic factors of rIHR and OS after RFA for recurrent CLMs

Construction and validation of nomograms for rIHR and OS after RFA for recurrent CLMs

Discussion

Declarations

References

Additional Declarations

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