Initial non-resectable hepatocellular carcinoma postoperative drug-free monitoring method and system based on complete pathology remission

Abstract

The invention belongs to the technical field of medical treatment, and discloses an initial non-resectable hepatocellular carcinoma postoperative drug-free monitoring method based on complete pathology remission, and the method comprises the following steps: selecting a patient; all patients are subjected to systemic treatment or combined transarterial treatment; dosage adjustment and temporary interruption of treatment are allowed according to adverse reaction conditions; the transcatheter treatment comprises transcatheter arterial chemoembolization TACE and hepatic arterial perfusion chemotherapy HAIC; in assessing the tumor response, contrast enhanced computed tomography (CT) or magnetic resonance imaging (MRI) is used every 6 to 8 weeks, based on the mRECIST and RECIST 1.1 criteria; postoperative adjuvant therapy is usually started 4-8 weeks after an operation, and is usually based on a preoperative transformation treatment scheme; the adverse reactions are evaluated by comparing the baseline value changes during the first post-operative follow-up with the subsequent follow-up.

Description

Technical Field

[0001] This invention belongs to, but is not limited to, the field of medical technology, and particularly relates to a method and system for monitoring drug-free postoperative care of initial unresectable hepatocellular carcinoma based on pathological complete remission. Background Technology

[0002] Existing technology 1. Successful radical resection and prognostic analysis after conversion therapy

[0003] Studies have shown that through conversion therapy combining immune checkpoint inhibitors (ICIs) with targeted drugs, some patients with initially unresectable hepatocellular carcinoma (uHCC) can successfully undergo radical resection and achieve pathological complete remission (pCR) postoperatively. Follow-up data show that the one-year recurrence-free survival (RFS) rate for these patients is approximately 75% [75% 12-month RFS], indicating a good long-term survival prognosis.

[0004] Existing technology 2. Research on the value of pCR as a postoperative prognostic indicator

[0005] Other studies have shown that pCR has significant prognostic value in the postoperative assessment of HCC radical surgery, meaning that pCR can predict better survival outcomes.

[0006] Although the above studies provide some statistical results regarding postoperative prognosis and pCR after conversion therapy, they still have the following limitations:

[0007] 1. Lack of a complete strategy for "drug-free surveillance"

[0008] While existing technologies focus on the prognosis of patients after pCR, they do not propose a "drug-free monitoring" management model and lack a systematic follow-up process that includes treatment record archiving, regular imaging assessments, multidisciplinary decision-making, and adverse reaction monitoring.

[0009] 2. Not included in multidisciplinary decision-making and comprehensive evaluation mechanisms

[0010] Existing studies mainly analyze single indicators (such as pCR and RFS) and lack a multidisciplinary team (MDT) recommendation decision-making mechanism based on imaging, clinical status and patient wishes.

[0011] 3. Lack of standardized follow-up system and statistical analysis framework

[0012] Most current reports focus on survival rates or prognostic correlation studies, without specifying the frequency of postoperative follow-up visits, monitoring content (such as imaging, laboratory tests, HBV DNA), or detailed statistical analysis methods (such as Kaplan-Meier, Cox regression models, etc.). Summary of the Invention

[0013] To address the problems existing in the prior art, this invention provides a method for monitoring drug-free postoperative care of initial unresectable hepatocellular carcinoma based on pathological complete remission.

[0014] This invention is implemented as follows: a method for monitoring drug-free postoperative care in patients with initial unresectable hepatocellular carcinoma based on pathological complete remission, comprising:

[0015] a. Case screening: Select patients with initial non-metastatic hepatocellular carcinoma who have undergone systemic conversion therapy and completed radical resection, and whose pathological remission has been confirmed by histopathology.

[0016] b. Treatment record archiving: Record the systemic or combined transarterial treatment regimens received by the patient before surgery and all dosage adjustment information;

[0017] c. Imaging assessment: Starting from the first month after surgery, contrast-enhanced computed tomography or magnetic resonance imaging should be used every 6-8 weeks to assess residual lesions and tumor thrombosis activity, and the results should be interpreted by two independent radiologists.

[0018] d. Multidisciplinary decision-making: Determine the subsequent treatment plan based on imaging results, performance status score, tumor burden, and patient wishes;

[0019] e. Adverse reaction monitoring: Compare laboratory indicators and symptom records at each follow-up stage with baseline, and rate them according to the general terminology standard;

[0020] f. Follow-up management: Follow-up visit is scheduled for the first month after surgery, and then every 3-4 months for the next 24 months, followed by every 4-6 months thereafter. Follow-up visits include imaging examinations, blood cell counts, biochemical indicators, tumor markers, and hepatitis B virus deoxyribonucleic acid levels.

[0021] g. Data analysis: The Kaplan-Meier method was used to calculate the overall survival rate, the log-rank test was used to compare different variable groups, and the multivariate Cox regression model was used to determine the influencing factors.

[0022] Furthermore, the pCR is defined as: surgical pathological examination showing intact tumor and necrosis of tumor thrombi; no distant or lymph node metastasis.

[0023] Furthermore, the systemic treatment includes tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), and vascular endothelial growth factor (VEGF) inhibitors; TKIs include sorafenib (400 mg twice daily), lenvatinib (8 mg once daily), donafenib (200 mg twice daily), and apatinib (250 mg once daily); ICIs are administered intravenously every 3 to 4 weeks and can be used alone or in combination with TKIs or bevacizumab (15 mg / kg).

[0024] Based on the above technical solutions and the technical problems solved, the advantages and positive effects of the technical solution to be protected by this invention are as follows:

[0025] By establishing a systematic drug-free monitoring process for patients with pathological complete remission (pCR), unnecessary long-term drug exposure can be avoided while ensuring that the risk of disease relapse is manageable, thereby reducing the incidence and severity of treatment-related adverse reactions. This approach can reduce the burden of toxic side effects and improve patient tolerability and adherence in clinical management.

[0026] The study results showed that for patients who successfully converted from systemic therapy and underwent radical resection, the overall survival (OS) and recurrence-free survival (RFS) obtained by active imaging and laboratory monitoring were comparable to those of patients who continued adjuvant therapy after surgery, but with higher safety, a simpler treatment process, and significantly improved quality of life, making it particularly suitable for long-term management.

[0027] For patients whose alpha-fetoprotein (AFP) levels return to normal after surgery, the "tumor-free, drug-free" strategy proposed in this invention is a clinically feasible follow-up model that can maintain survival benefits while avoiding the economic and physiological burden caused by drugs, providing a new basis for clinical decision-making in developing individualized follow-up plans. Attached Figure Description

[0028] Figure 1 This is a flowchart of a drug-free monitoring method for initial unresectable hepatocellular carcinoma based on pathological complete remission, provided by an embodiment of the present invention.

[0029] Figure 2 This is a diagram of the postoperative drug-free monitoring system provided in an embodiment of the present invention. Detailed Implementation

[0030] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0031] Figure 1 The method for monitoring drug-free postoperative care of initial unresectable hepatocellular carcinoma based on pathological complete remission provided in this embodiment of the invention includes the following steps:

[0032] S101, Case screening: Select patients with initially unresectable hepatocellular carcinoma who have undergone systemic conversion therapy and completed radical resection, and whose pathological remission has been confirmed by histopathology.

[0033] S102, Treatment record archiving: Record the systemic or combined transarterial treatment regimens and all dose adjustment information received by the patient before surgery;

[0034] S103, Imaging assessment: Starting from the first month after surgery, use contrast-enhanced computed tomography or magnetic resonance imaging every 6-8 weeks to assess residual lesions and tumor thrombosis activity, and have it interpreted by two independent radiologists.

[0035] S104, Multidisciplinary Decision Making: Determine the subsequent treatment plan based on imaging results, performance status score, tumor burden and patient wishes;

[0036] S105, Adverse reaction monitoring: Compare laboratory indicators and symptom records at each follow-up stage with baseline, and rate them according to the general terminology standard;

[0037] S106, Follow-up Management: Follow-up visit in the first month after surgery, then every 3-4 months for the next 24 months, and then every 4-6 months thereafter. The follow-up visits include imaging examinations, blood cell counts, biochemical indicators, tumor markers, and hepatitis B virus deoxyribonucleic acid levels.

[0038] S107, Data Analysis: The Kaplan-Meier method was used to calculate the overall survival rate, the log-rank test was used to compare different variable groups, and the multivariate Cox regression model was used to determine the influencing factors.

[0039] This method first screens cases through strict inclusion criteria to ensure that all included patients with hepatocellular carcinoma who were initially unresectable without distant metastases, had undergone systemic therapy to become resectable, and had performed R0 resection, and whose pathological complete response (pCR) was confirmed by histopathology. This step ensures the homogeneity of the study population, eliminates the interference of residual pathological lesions on subsequent monitoring and analysis results, and thus obtains a representative and comparable research sample in the implementation of the method.

[0040] After case enrollment, comprehensive preoperative treatment information is archived, including the types of systemic drugs used, combined local treatments (such as transarterial chemoembolization (TACE), dosing cycles, and details of any dose adjustments or interruptions. This step aims to establish individualized baseline disease progression data for each patient, enabling subsequent monitoring results to be correlated with prior treatment exposures, thereby assessing the impact of different treatment pathways on postoperative drug-free monitoring outcomes.

[0041] Starting one month post-surgery, contrast-enhanced CT or MRI scans are performed every 6–8 weeks to assess for signs of recurrence, using changes in arterial phase enhancement, T2-weighted imaging, and diffusion-weighted imaging signals. Interpretation is conducted by two independent radiologists, with third-party consultation as needed, to minimize subjective error and ensure the sensitivity and specificity of monitoring.

[0042] Based on imaging assessments, combined with the patient's performance status score (e.g., ECOG), preoperative tumor burden, and personal preferences, a multidisciplinary team (MDT) comprised of hepatobiliary surgeons, medical oncologists, radiologists, and pathologists jointly develops subsequent treatment strategies. For patients without recurrence and in good condition, drug-free monitoring continues; if imaging or laboratory findings indicate a recurrence trend, the decision to initiate further intervention (local or systemic therapy) is assessed. This mechanism ensures scientific and individualized decision-making.

[0043] Throughout the monitoring process, laboratory indicators and symptom records at each follow-up point were regularly compared with postoperative baseline, and graded according to CTCAE v5.0 to ensure timely identification and management of adverse reactions. Follow-up was conducted at a frequency of "1 month postoperatively, every 3–4 months for the first 2 years, and every 4–6 months thereafter," covering imaging, blood cell counts, biochemistry, tumor markers, and HBV DNA testing. Finally, the monitoring data were included in statistical analysis. The Kaplan-Meier method was used for survival curve plotting, the log-rank test was used to compare differences between groups, and multivariate Cox regression was used to identify independent prognostic factors, providing evidence-based support for clinical practice.

[0044] The systemic treatment provided in this embodiment of the invention includes any of the following options:

[0045] a. Tyrosine kinase inhibitor regimen, using sorafenib 400 mg twice daily, or lenvatinib 8 mg once daily, or donafenib 200 mg twice daily, or apatinib 250 mg once daily.

[0046] b. Immune checkpoint inhibitor regimen, administered intravenously every 3-4 weeks;

[0047] c. Combination regimen of tyrosine kinase inhibitors and immune checkpoint inhibitors;

[0048] d. A combination regimen of immune checkpoint inhibitors and bevacizumab at 15 mg / kg body weight.

[0049] The imaging assessment provided in this embodiment of the invention grades tumor response according to the mRECIST criteria and the RECIST 1.1 criteria, and defines no tumor thrombus activity as no enhancement in the arterial phase and no high signal on T2-weighted and diffusion-weighted imaging.

[0050] The present invention provides a method for detecting serum hepatitis B virus deoxyribonucleic acid levels in patients with hepatitis B virus infection at each follow-up visit, and for promptly initiating or intensifying antiviral treatment when viral replication is active.

[0051] like Figure 2 As shown, an embodiment of the present invention provides a postoperative drug-free monitoring system comprising:

[0052] a. Data acquisition unit, used to acquire patient imaging data, laboratory data, and symptomatology records;

[0053] b. Image assessment module, used to perform mRECIST and RECIST 1.1 grading and determine tumor thrombus activity;

[0054] c. Multidisciplinary decision-making module, used to integrate imaging assessment results, performance status scores, and tumor burden generation treatment recommendations;

[0055] d. Adverse reaction assessment module, used to classify toxicity according to common terminology standards;

[0056] e. Survival analysis module, used to perform Kaplan-Meier and Cox regression analysis on the collected data, and output survival rate curves and influencing factors.

[0057] The image evaluation module provided in this embodiment of the invention is configured to automatically retrieve image data and generate a comparison report every 6-8 weeks for online interpretation by two radiologists with senior professional titles.

[0058] The adverse reaction assessment module provided in this embodiment of the invention is configured to automatically push toxicity management suggestions and generate dose adjustment records when laboratory indicators show abnormalities of level three or above.

[0059] An embodiment of the present invention provides a computer-readable storage medium having instructions stored thereon, which, when executed by a processor, cause the processor to perform the method described thereon.

[0060] According to the computer-readable storage medium provided in this embodiment of the invention, the instructions further cause the processor to generate a Kaplan-Meier survival curve and output the log-rank test result.

[0061] According to the method described in this embodiment of the invention, in the follow-up management step, the correlation analysis between the tumor marker alpha-fetoprotein (AFP) and the accompanying imaging results in the first year after surgery is performed, and additional imaging examinations are added in advance when AFP continues to rise.

[0062] This method targets patients with initially unresectable hepatocellular carcinoma (uHCC) who achieved pathological complete remission (pCR) after systemic conversion therapy. First, strict criteria were set for patient selection: only cases diagnosed according to the AASLD guidelines, without extrahepatic metastasis, who underwent R0 radical resection after completing systemic conversion therapy and whose postoperative pathology confirmed pCR were included; patients with concomitant or previous malignancies, incomplete follow-up or laboratory and imaging data, and significant impairment of vital organ function were excluded to ensure the homogeneity of the study population and the integrity of the data.

[0063] All enrolled patients received a conversion regimen based on systemic therapy before surgery, and the dosage could be flexibly adjusted or the medication temporarily discontinued according to adverse reactions; when necessary, transcatheter arterial chemoembolization (TACE) and hepatic artery infusion chemotherapy (HAIC) were used as adjuncts to minimize the tumor burden and increase the chance of resection.

[0064] Treatment efficacy was assessed using contrast-enhanced CT or MRI every 6–8 weeks, interpreted according to mRECIST and RECIST 1.1 criteria, and independently performed by two senior radiologists. Tumor thrombus activity was identified using multi-contrast enhanced MRI. A multidisciplinary team (MDT) discussed and decided on strategies such as surgery, continued systemic therapy, transarterial therapy, thermal ablation, SBRT, or monitoring based on imaging results, tumor burden, ECOG score, and patient preferences, ensuring individualized and feasible treatment decisions.

[0065] Adjuvant therapy is initiated 4–8 weeks post-surgery. The regimen usually follows the pre-operative conversion therapy system. Single-drug or combination therapy can be selected based on the adverse reaction profile, baseline organ function, and patient preferences. Dosage adjustments or temporary discontinuation of medication are permitted to control toxicity and maintain long-term safety.

[0066] Adverse reaction monitoring is based on the first postoperative follow-up as the baseline, and subsequent outpatient follow-ups are compared longitudinally. Event grading follows the CTCAE standard, laboratory indicators are extracted from the institutional database, and symptomatic events are recorded from outpatient medical records to ensure the systematization and traceability of AE data.

[0067] Follow-up strategies included imaging (CT / MRI), blood cell counts, biochemical indicators, and tumor markers; serum HBV DNA testing was added for HBV-infected patients. The first follow-up was conducted one month post-surgery, followed by follow-up every 3–4 months for the first two years, and then every 4–6 months thereafter, with data up to June 1, 2025. Recurrence and metastasis were primarily diagnosed via imaging, with biopsy performed as needed for confirmation. The primary endpoint was overall survival (OS), and secondary endpoints included recurrence-free survival (RFS) and the incidence of treatment-related adverse events (AEs). Statistically, survival curves were estimated using the Kaplan-Meier method, and differences were compared using the log-rank test; variables with univariate P < 0.10 were included in a multivariate Cox regression model, with two-sided P < 0.05 considered significant. All analyses were performed using RStudio and SPSS.

[0068] This invention provides a method for monitoring drug-free surgery after initial unresectable hepatocellular carcinoma based on pathological complete remission, the method comprising:

[0069] S1: This invention includes patients with initially unresectable hepatocellular carcinoma (uHCC) who have successfully undergone systemic therapy and radical resection with postoperative pathological confirmation of complete remission (pCR). Inclusion criteria require a diagnosis of hepatocellular carcinoma according to the American Association for the Study of the Liver (AASLD) guidelines, imaging confirmation of no extrahepatic metastasis, completion of a systemic therapy-based conversion regimen followed by surgery with R0 resection, and postoperative pathological confirmation of pCR. All cases with concomitant or prior malignant tumors, as well as patients with incomplete laboratory, imaging, or follow-up data, or significant impairment of vital organ function, are excluded to ensure the homogeneity of the study population and the reliability of the data.

[0070] S2: All patients received systemic therapy or a combination of transarterial therapy; dose adjustments and temporary interruptions of treatment were permitted based on adverse events; transarterial therapy included transcatheter arterial chemoembolization (TACE) and hepatic artery infusion chemotherapy (HAIC);

[0071] S3: When assessing tumor response, contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) is performed every 6 to 8 weeks, based on mRECIST and RECIST 1.1 criteria; two experienced radiologists independently evaluate the images; multi-contrast MRI is used to assess tumor thrombus activity, with no active thrombus defined as no arterial phase enhancement and no high signal on T2-weighted or diffusion-weighted imaging; a multidisciplinary team including hepatobiliary surgeons, medical oncologists, interventional radiologists, diagnostic radiologists, radiation oncologists, and hepatologists discusses patients deemed resectable; treatment options include surgery, continued systemic therapy, transarterial therapy, thermal ablation, stereotactic body radiotherapy (SBRT), or monitoring; the final treatment decision is based on tumor burden and distribution, performance status score (ECOG), imaging results, and patient preferences, etc.

[0072] S4: Postoperative adjuvant therapy usually begins 4-8 weeks after surgery, typically based on the preoperative conversion therapy regimen; the choice of treatment regimen, monotherapy or combination therapy, is based on the AEs profile, baseline organ function, and patient preference; dosage adjustments or treatment interruptions are permitted as needed to manage toxicity;

[0073] S5: Adverse reactions were assessed by comparing changes in baseline values ​​between the first postoperative follow-up and subsequent follow-ups; events were graded according to the Common Terminology Standard; laboratory AEs were identified from the institutional database, while symptomatic AEs were recorded in the outpatient progress notes;

[0074] S6: Postoperative monitoring included standardized imaging CT or MRI and laboratory assessments of blood cell counts, biochemistry, and tumor markers; for HBV-infected patients, serum HBV DNA was monitored; follow-up occurred 1 month post-surgery, then every 3–4 months for the first two years, and then every 4–6 months thereafter; the analysis cutoff date was June 1, 2025; recurrence and metastasis were diagnosed by imaging, possibly with biopsy confirmation; the primary endpoint was overall survival, defined as from surgery to death or last follow-up; secondary endpoints included recurrence-free survival and the incidence of treatment-related adverse events (AEs); survival outcomes were estimated using Kaplan-Meier regression and compared using the log-rank test; univariate Cox regression was used to identify variables in the overall cohort that were relevant to survival; variables with P < 0.10 were included in the multivariate Cox regression model; a two-sided P < 0.05 was considered statistically significant; statistical analysis was performed using R Studio and SPSS Statistics.

[0075] The pCR is defined as: surgical pathological examination showing intact tumor and necrosis of tumor thrombus; no distant or lymph node metastasis.

[0076] The systemic treatment includes tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors, and vascular endothelial growth factor (VEGF) inhibitors; TKIs include sorafenib (400 mg twice daily), lenvatinib (8 mg once daily), donafenib (200 mg twice daily), and apatinib (250 mg once daily); ICIs are administered intravenously every 3 to 4 weeks and can be used alone or in combination with TKIs or bevacizumab 15 mg / kg.

[0077] This patient population exhibited excellent long-term survival outcomes, with no significant difference in recurrence-free survival (RFS) and overall survival (OS) between patients receiving postoperative adjuvant therapy and those receiving active surveillance. These results support the clinical feasibility of implementing an active surveillance strategy in patients achieving pCR after conversion resection. Although the proportion of uHCC patients achieving pCR after conversion therapy based on systemic therapy remains relatively low, those who do achieve pCR typically have very favorable outcomes.

[0078] In this invention, 15.8% (257 / 1623) of patients achieved pCR after conversion therapy based on systemic therapy, slightly lower than the previously reported range of 16.7% to 38.1%. Previous studies have shown encouraging survival outcomes in these patients, with 3-year RFS and OS rates of 71.4% and 95.6%, respectively. In this larger, longer-follow-up multicenter cohort study, the 3-year RFS and OS rates were 60.3% and 91.1%, respectively, and the 5-year rates were 58.3% and 85.5%, respectively. These results surpass those of studies in patients achieving radiographic complete remission (rCR) based on immunotherapy regimens, where the 5-year RFS and OS rates were 43% and 77%, respectively. It is noteworthy that rCR (as defined by mRECIST) and pCR are not always correlated. Previous studies have shown that only 41.3% (31 / 75) of patients with rCR who underwent resection were confirmed to have pCR. In this study, only 62.6% (161 / 257) of patients who achieved pCR showed rCR on preoperative imaging assessment. Therefore, further research is needed to determine indicators that can reliably predict pCR after conversion therapy.

[0079] Although patients achieving pCR generally have a good prognosis, the role of postoperative adjuvant therapy in this situation remains unclear. On the one hand, uHCC is often associated with high tumor burden, vascular invasion, and a high risk of recurrence. Continued effective preoperative systemic therapy may help eliminate residual micrometastases and reduce the risk of recurrence. This concept is reflected in the Chinese expert consensus, which recommends 6 to 12 months of adjuvant therapy after successful conversion resection. On the other hand, patients who achieve pCR may already be in a tumor-free state, and additional treatment may offer limited benefit while exposing patients to unnecessary toxicity. In this study, pCR patients who received postoperative adjuvant therapy (median duration 6.05 months) did not show significant improvements in RFS or OS. These findings are consistent with previous research results that patients achieving rCR have good long-term survival outcomes even without further treatment or surgical resection. These data collectively support active surveillance as a reasonable management strategy for hepatocellular carcinoma patients who achieve pCR after conversion resection.

[0080] Subgroup analyses did not identify any patient population that clearly benefited from adjuvant therapy. In fact, in the matched cohort, the active surveillance group showed better remission-free survival (RFS) for patients with preoperative large vessel invasion. This seemingly contradictory result can be explained by the fact that patients with advanced tumors are less likely to achieve pCR compared to those with early-stage tumors. Therefore, the finite subset achieving pCR may represent a unique cohort with exceptionally strong anti-tumor immunity, resulting in excellent outcomes that may render adjuvant therapy unnecessary. This observation is consistent with the report by Bernhard Scheiner et al. Furthermore, long-term survival data showed that for patients with preoperative large vessel invasion who achieved pCR after conversion therapy, their overall survival (OS) was comparable to that without large vessel invasion, regardless of whether they received adjuvant therapy. These findings suggest that treatment outcomes in patients with advanced disease who achieve pCR after conversion therapy may be comparable to those in early-stage hepatocellular carcinoma.

[0081] Multivariate analysis showed that postoperative alpha-fetoprotein (AFP) positivity was an independent risk factor for both recurrent spontaneous lesions (RFS) and overall survival (OS), consistent with previous studies that have confirmed that elevated AFP levels in newly treated HCC patients undergoing radical resection are often associated with poor prognosis. This observation suggests that patients achieving pCR but with elevated postoperative AFP levels may have minimal residual disease (MRD) and could potentially benefit from adjuvant therapy. However, in this cohort, most patients achieving pCR had normalized AFP levels postoperatively, with only a small percentage (13.6%, 35 / 257) showing elevated AFP levels. In these patients, adjuvant therapy did not show a significant trend toward improved RFS (hazard ratio [HR] 0.53, 95% confidence interval [CI]: 0.23–1.22; P = 0.134). Due to the limited number of deaths in this subgroup (n=8), no significant benefit in overall survival was observed (HR 0.63, 95% CI: 0.16–2.54; P=0.521). Given the small sample size and limited statistical power, the potential benefit of adjuvant therapy in AFP-positive pCR patients remains uncertain and requires further validation in larger prospective studies.

[0082] Postoperative adjuvant therapy places an additional burden on liver function and patients' quality of life, especially for those who have already received systemic therapy and hepatectomy. Although it is difficult to fully capture adverse event data in retrospective studies, 66.3% of patients in the active surveillance group experienced adverse events, significantly higher than the incidence in patients with primary resection. The incidence of adverse events was significantly higher in the adjuvant therapy group, although most events were grade 1-2 severity. Importantly, systemic therapy administered during the postoperative period (when patients are recovering from surgery) may exacerbate inflammation, impair liver regeneration, and may promote recurrence or lead to long-term adverse outcomes. Based on these findings, we propose a "discontinuation upon disease-free status" management strategy for patients who achieve pCR after conversion therapy, particularly those with normal postoperative AFP levels. This strategy emphasizes timely discontinuation of systemic therapy in the absence of residual disease, potentially preserving quality of life and reducing treatment-related toxicities without compromising oncological outcomes.

[0083] This multicenter retrospective analysis included 257 newly diagnosed unresectable hepatocellular carcinoma (uHCC) patients who achieved pathological complete response (pCR) after radical resection at three tertiary hospitals in China (Sun Yat-sen University Cancer Center, the First Affiliated Hospital of Sun Yat-sen University, and Hunan Provincial People's Hospital) between January 2020 and December 2023. Inclusion criteria included: HCC diagnosis according to the AASLD guidelines; no extrahepatic metastasis; conversion to resectable status after systemic therapy and completion of R0 resection; and postoperative pathological confirmation of pCR. Exclusion criteria included: history of other malignancies, incomplete clinical data, and severe organ dysfunction. Unresectable status was determined by a multidisciplinary team (MDT) based on the ratio of fl-remission to scleral vesicle volume (SLV) and the stage of BCLC or CNLC.

[0084] All patients received systemic therapy, sometimes in combination with local therapy. Systemic therapy included TKIs (sorafenib 400 mg bid, lenvatinib 8 mg qd, donafenib 200 mg bid, and apatinib 250 mg qd), PD-1 / PD-L1 immune checkpoint inhibitors (ICIs), and VEGF inhibitors (bevacizumab 15 mg / kg q3-4w), either as monotherapy or in combination. Dosage adjustments or temporary interruptions were permitted during treatment based on adverse events (AEs).

[0085] According to the mRECIST criteria, enhanced CT or MRI should be performed every 6-8 weeks to assess tumor response, and the images should be interpreted independently by two radiologists. For large vessel invasion, tumor thrombus activity is determined by multiphasic MRI; tumors without enhancement in the arterial phase and without high signal intensity on T2WI or DWI are considered to have inactive tumor thrombi.

[0086] MDT (Multidisciplinary Team) determines the surgical approach based on a comprehensive consideration of oncological characteristics, patient condition, imaging results, and patient wishes. Surgical indications include adequate FLR (Fluid-Free Resection), definite radiographic response, and feasible R0 resection. Preoperative comprehensive imaging and functional assessment is performed, and intraoperative ultrasound is used to confirm the resection margins. Pathological examination follows standardized protocols, with whole-tumor bed sampling as necessary. pCR (Prognostic Resection Complete) is defined as the absence of viable tumor cells in all sections; necrosis or fibrosis is not considered residual active tumor. Two pathologists independently interpret the tissue samples and reach a consensus.

[0087] 4-8 weeks post-surgery, the MDT (Multidisciplinary Team) determines whether to continue adjuvant therapy based on the patient's condition, with the protocol largely consistent with pre-operative guidelines. AEs (Adverse Events) are classified according to CTCAE v5.0, and both laboratory abnormalities and symptomatic AEs are documented. Follow-up includes regular imaging (CT / MRI), laboratory tests, and HBV DNA monitoring (for HBV-positive patients), with a follow-up examination one month post-surgery, every 3-4 months for the first two years, and then every 4-6 months until June 1, 2025. The primary outcome is overall survival (OS), and secondary outcomes are recurrence-free survival (RFS) and the incidence of treatment-related AEs.

[0088] Continuous variables are expressed as mean ± SD or median (IQR), and comparisons between groups are performed using t-tests or Mann-Whitney U tests; categorical variables are expressed using χ² tests. 2 The Kaplan-Meier test or Fisher's exact test was used. OS and RFS were estimated using the Kaplan-Meier method and compared using the log-rank test, with a significance level set at two-sided P < 0.05. Cox regression was used to screen for prognostic factors; univariate P < 0.10 was used for multivariate analysis. To reduce selection bias between the adjuvant therapy and monitoring groups, 1:2 nearest neighbor propensity score matching (PSM) was used. Matching variables included gender, etiology, resection margin status, degree of cirrhosis, number and size of tumors, large vessel invasion, and AFP level. Matching was implemented using the MatchIt package in R.

[0089] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any modifications, equivalent substitutions, and improvements made by those skilled in the art within the scope of the technology disclosed in the present invention, and within the spirit and principles of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A method of monitoring the absence of drug after initial non-resectable hepatocellular carcinoma surgery based on pathological complete remission, characterized in that, The method comprises the following steps: a. Case screening: selecting patients with initially unresectable hepatocellular carcinoma who have received systemic therapy and completed radical resection, and who have been confirmed to achieve pathological complete remission by histopathology; b. Treatment record archiving: recording the systemic therapy or combined transarterial treatment regimen received by the patient before surgery and all dose adjustment information; c. Image evaluation: from the first month after surgery, every 6-8 weeks, using contrast-enhanced computed tomography or magnetic resonance imaging to evaluate residual lesions and tumor thrombus activity, and the evaluation is performed by two independent radiologists; d. Multidisciplinary decision making: determining the follow-up treatment plan based on the imaging results, physical status score, tumor burden, and patient's willingness; e. Adverse reaction monitoring: comparing the laboratory indicators and symptom records at each follow-up stage with the baseline, and grading the toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE); f. Follow-up management: re-examination at the first month after surgery, every 3-4 months within 24 months, and every 4-6 months thereafter, and the re-examination includes imaging examination, blood count, biochemical indicators, tumor markers, and hepatitis B virus deoxyribonucleic acid (HBV DNA) level; g. Data analysis: calculating the overall survival rate using the Kaplan-Meier method, comparing different variable groups using the log-rank test, and determining the influencing factors using the multivariate Cox regression model.

2. The method of claim 1, wherein, The systemic therapy includes any of the following: a. Tyrosine kinase inhibitor regimen, using sorafenib 400 mg twice a day, or lenvatinib 8 mg once a day, or donafenib 200 mg twice a day, or apatinib 250 mg once a day; b. Immune checkpoint inhibitor regimen, intravenous injection once every 3-4 weeks; c. Combination regimen of tyrosine kinase inhibitor and immune checkpoint inhibitor; d. Combination regimen of immune checkpoint inhibitor and bevacizumab 15 mg / kg.

3. The method of claim 1, wherein, The image evaluation classifies tumor response according to the mRECIST standard and the RECIST 1.1 standard, and defines the absence of arterial phase enhancement and the absence of high signal on T2-weighted and diffusion-weighted imaging as the absence of tumor thrombus activity.

4. The method of claim 1, wherein, For patients infected with hepatitis B virus, the serum HBV DNA level is detected at each follow-up, and antiviral treatment is initiated or intensified when the virus is actively replicating.

5. A post-operative drug-free monitoring system, characterized by, It comprises: a. Data acquisition unit for obtaining patient imaging data, laboratory data, and symptom records; b. Image evaluation module for performing mRECIST and RECIST 1.1 classification and determining tumor thrombus activity; c. Multidisciplinary decision making module for generating treatment recommendations by integrating image evaluation results, physical status score, and tumor burden; d. Adverse reaction evaluation module for grading toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE); e. Survival analysis module for performing Kaplan-Meier and Cox regression analysis on the collected data, and outputting survival rate curves and influencing factors.

6. The system of claim 5, wherein, The image evaluation module is configured to automatically call image data every 6-8 weeks and generate a comparison report for online interpretation by two radiologists with senior professional titles.

7. The system of claim 5, wherein, The adverse reaction evaluation module is configured to automatically push toxicity management suggestions and generate dose adjustment records when laboratory indicators show three or more abnormalities. 8.A computer readable storage medium having instructions stored thereon, the instructions, when executed by a processor, causing the processor to perform the method of any one of claims 1.

9. The computer-readable storage medium of claim 8, wherein, The instructions further cause the processor to generate a Kaplan-Meier survival curve and output a log-rank test result.

10. The method of claim 1, wherein, In the follow-up management step, correlation analysis is performed between tumor marker alpha-fetoprotein in the first year after surgery and accompanying image results, and additional imaging examination is added in advance when alpha-fetoprotein continuously increases.

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