Machine Learning Predictive Model to Guide Treatment Allocation for Recurrent Hepatocellular Carcinoma After Surgery
Authors: Famularo Simone , Donadon Matteo , Cipriani Federica , Fazio Federico , Ardito Francesco , Iaria Maurizio , Perri Pasquale , Conci Simone , Dominioni Tommaso , Lai Quirino , La Barba Giuliano , Patauner Stefan , Molfino Sarah , Germani Paola , Zimmitti Giuseppe , Pinotti Enrico , Zanello Matteo , Fumagalli Luca , Ferrari Cecilia , Romano Maurizio , Delvecchio Antonella , Valsecchi Maria Grazia , Antonucci Adelmo , Piscaglia Fabio , Farinati Fabio , Kawaguchi Yoshikuni , Hasegawa Kiyoshi , Memeo Riccardo , Zanus Giacomo , Griseri Guido , Chiarelli Marco , Jovine Elio , Zago Mauro , Abu Hilal Moh’d , Tarchi Paola , Baiocchi Gian Luca , Frena Antonio , Ercolani Giorgio , Rossi Massimo , Maestri Marcello , Ruzzenente Andrea , Grazi Gian Luca , Dalla Valle Raffaele , Romano Fabrizio , Giuliante Felice , Ferrero Alessandro , Aldrighetti Luca , Bernasconi Davide P. , Torzilli Guido ,   HE.RC.O.LE.S. Group, COSTA GUIDO , MILANA FLAVIO , RATTI FRANCESCA , RUSSOLILLO NADIA , RAZIONALE FRANCESCO , GIANI ALESSANDRO , CARISSIMI FRANCESCA , GIUFFRIDA MARIO , DE PEPPO VALERIO , MARCHITELLI IVAN , DE STEFANO FRANCESCA , LARGHI LAURERIO ZOE , CUCCHETTI ALESSANDRO , NOTTE FRANCESCA , COSOLA DAVIDE , CORLEONE PIO , MANZONI ALBERTO , MONTUORI MAURO , FRANCESCHI ANGELO , SALVADOR LUCA , CONTICCHIO MARIA , BRAGA MARCO , MORI SILVIA 
Published: December 2022

ImportanceClear indications on how to select retreatments for recurrent hepatocellular carcinoma (HCC) are still lacking.ObjectiveTo create a machine learning predictive model of survival after HCC recurrence to allocate patients to their best potential treatment.Design, Setting, and ParticipantsReal-life data were obtained from an Italian registry of hepatocellular carcinoma between January 2008 and December 2019 after a median (IQR) follow-up of 27 (12-51) months. External validation was made on data derived by another Italian cohort and a Japanese cohort. Patients who experienced a recurrent HCC after a first surgical approach were included. Patients were profiled, and factors predicting survival after recurrence under different treatments that acted also as treatment effect modifiers were assessed. The model was then fitted individually to identify the best potential treatment. Analysis took place between January and April 2021.ExposuresPatients were enrolled if treated by reoperative hepatectomy or thermoablation, chemoembolization, or sorafenib.Main Outcomes and MeasuresSurvival after recurrence was the end point.ResultsA total of 701 patients with recurrent HCC were enrolled (mean [SD] age, 71 [9] years; 151 [21.5%] female). Of those, 293 patients (41.8%) received reoperative hepatectomy or thermoablation, 188 (26.8%) received sorafenib, and 220 (31.4%) received chemoembolization. Treatment, age, cirrhosis, number, size, and lobar localization of the recurrent nodules, extrahepatic spread, and time to recurrence were all treatment effect modifiers and survival after recurrence predictors. The area under the receiver operating characteristic curve of the predictive model was 78.5% (95% CI, 71.7%-85.3%) at 5 years after recurrence. According to the model, 611 patients (87.2%) would have benefited from reoperative hepatectomy or thermoablation, 37 (5.2%) from sorafenib, and 53 (7.6%) from chemoembolization in terms of potential survival after recurrence. Compared with patients for which the best potential treatment was reoperative hepatectomy or thermoablation, sorafenib and chemoembolization would be the best potential treatment for older patients (median [IQR] age, 78.5 [75.2-83.4] years, 77.02 [73.89-80.46] years, and 71.59 [64.76-76.06] years for sorafenib, chemoembolization, and reoperative hepatectomy or thermoablation, respectively), with a lower median (IQR) number of multiple recurrent nodules (1.00 [1.00-2.00] for sorafenib, 1.00 [1.00-2.00] for chemoembolization, and 2.00 [1.00-3.00] for reoperative hepatectomy or thermoablation). Extrahepatic recurrence was observed in 43.2% (n = 16) for sorafenib as the best potential treatment vs 14.6% (n = 89) for reoperative hepatectomy or thermoablation as the best potential treatment and 0% for chemoembolization as the best potential treatment. Those profiles were used to constitute a patient-tailored algorithm for the best potential treatment allocation.Conclusions and RelevanceThe herein presented algorithm should help in allocating patients with recurrent HCC to the best potential treatment according to their specific characteristics in a treatment hierarchy fashion.