Development and validation of a novel online calculator for estimating survival benefit of adjuvant transcatheter arterial chemoembolization in patients undergoing surgery for hepatocellular carcinoma

Background and aims Although adjuvant transcatheter arterial chemoembolization (TACE) for resected hepatocellular carcinoma (HCC) may improve survival for some patients, identifying which patients can benefit remains challenging. The present study aimed to construct a survival prediction calculator for individualized estimating the net survival benefit of adjuvant TACE for patients with resected HCC. Methods From a multicenter database, consecutive patients undergoing curative resection for HCC were enrolled and divided into the developing and validation cohorts. Using the independent survival predictors in the developing cohort, two nomogram models were constructed for patients with and without adjuvant TACE, respectively, which predictive performance was validated internally and externally by measuring concordance index (C-index) and calibration. The difference between two estimates of the prediction models was the expected survival benefit of adjuvant TACE. Results A total of 2514 patients met the inclusion criteria for the study. The nomogram prediction models for patients with and without adjuvant TACE were, respectively, built by incorporating the same eight independent survival predictors, including portal hypertension, Child–Pugh score, alpha-fetoprotein level, tumor size and number, macrovascular and microvascular invasion, and resection margin. These two prediction models demonstrated good calibration and discrimination, with all the C-indexes of greater than 0.75 in the developing and validation cohorts. A browser-based calculator was generated for individualized estimating the net survival benefit of adjuvant TACE. Conclusions Based on large-scale real-world data, an easy-to-use online calculator can be adopted as a decision aid to predict which patients with resected HCC can benefit from adjuvant TACE. Supplementary Information The online version contains supplementary material available at 10.1186/s13045-021-01180-5.

To the editor, Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide [1]. Surgical resection represents a common approach to treat HCC and provides the possibility of cure [2]. Longterm prognosis after HCC resection is, however, still poor due to the high incidence of recurrence [3][4][5]. Transcatheter arterial chemoembolization (TACE) has been used in the postoperative setting as a means to decrease risk of recurrence and improve survival [6][7][8]. Whereas, in clinical practice, controversy persists relative to the role of adjuvant TACE for resected HCC [9][10][11]. The reasons for these disparate results are undoubtedly multifactorial, yet may relate to patient selection. Specifically, only certain high-risk patients with resected HCC may benefit from adjuvant TACE [12]. The objective of the current study was to construct a decision aid using a large multicenter database to predict which patient with resected HCC had a survival benefit from adjuvant TACE. In addition, we sought to estimate the magnitude of the survival benefit for given individual patients. A web-based decision tool was provided for clinicians and patients to aid in the decision-making process regarding adjuvant TACE after HCC resection. Patients and methods for this study are described in detail in Additional file 1.

Overall survival
All 2514 patients with HCC underwent curative liver resection were included (Additional file 2: Figure S1). Among them, 1755 and 759 patients were randomly segregated to the development and validation cohort, respectively (Table 1). Compared with patients who did not receive adjuvant TACE, patients who had adjuvant TACE had a longer survival in both the development and validation cohorts (all P < 0.001) (Additional file 3: Figure  S2).

Independent predictors of survival
Univariable and multivariable Cox regression analyses of the development cohort demonstrated that independent predictors associated with overall survival after HCC resection among patients treated with and without adjuvant TACE included portal hypertension, Child-Pugh grade, preoperative AFP level, tumor size, tumor number, macrovascular invasion, microvascular invasion, and resection margin (all P < 0.05). (Additional file 4: Table S1 and Additional file 5: Table S2).

Development of the prediction models
Two different nomogram models that integrated independent factors associated with overall survival were constructed to predict outcomes among patients who did and did not receive adjuvant TACE (Fig. 1a, b). To estimate the net survival benefit from adjuvant TACE, these two nomograms were compared and the difference between the two estimates was the expected net survival benefit from the addition of adjuvant TACE.

Construction of the online calculator
Based on the formula of the nomogram prediction models, an Internet browser-based software tool was constructed to predict the net survival benefit of adjuvant TACE for an individual patient, including the expected net survival time, and the increased 3-and 5-year survival probabilities (Fig. 1e). The corresponding score and the formula to calculate survival probability were provided (Additional file 6: Table S3). The online calculator is available for free use at: http:// asapc alcul ate. top/ Cal5_ en. html. After the user inputs all the requested information relative to the prognostic factors, the predicted survival improvement associated with the addition of adjuvant TACE, including the expected survival time and the 3-and 5-year survival probabilities, is generated and displayed.
In summary, a survival prediction model that incorporated eight independent variables associated with survival was constructed to derive an individualized estimate of the net survival benefit of adding adjuvant TACE to a patient's post-resection HCC treatment Conclusions: Based on large-scale real-world data, an easy-to-use online calculator can be adopted as a decision aid to predict which patients with resected HCC can benefit from adjuvant TACE. .0 cm, without macrovascular invasion but with microvascular invasion). His preoperative AFP level was 718 ug/L (≥ 400 ug/L), and the tumor resection margin was 0.8 cm (< 1 cm). After putting these data into these specific parameters, we can get the expected net survival time benefit of adjuvant TACE was 9.0 months, and the net survival benefits of 3-year and 5-year survival rates are 11.7% and 9.3%, respectively (See figure on next page.)

Keywords: Hepatocellular carcinoma, Hepatectomy, Transcatheter arterial chemoembolization, Adjuvant therapy, Survival
plan. The nomograms and online calculator had good predictive accuracy, and discrimination was validated. The calculator may help provide an estimate of the net survival benefit associated with adjuvant TACE for an individual patient following HCC resection. This tool may assist clinicians and patients in quantifying the