Background: Cancer and its treatments often cause symptoms. Automated warning systems could mitigate symptoms by alerting healthcare teams and enabling personalized preventative interventions. We developed a general-purpose longitudinal system for predicting symptomatic deterioration among outpatients undergoing intravenous systemic anti-cancer therapy. Methods: Patients treated for aerodigestive cancers at the Princess Margaret Cancer Centre were randomly divided into development and testing cohorts. For each treatment, machine learning was applied to preceding electronic medical record (EMR) data to predict patient-reported symptom deterioration, defined as at least a four point worsening on the Edmonton Symptom Assessment Scale. Features included diagnostic and treatment characteristics, laboratory tests, and patient-reported symptoms. Single-task (e.g., LASSO and XGboost) and multi-task (e.g., temporal CNNs, LSTM and Transformer) models were trained, tuned, and evaluated based on discrimination, calibration, and net benefit. Results: The cohort consisted of 3,998 patients who underwent 45,904 treatment sessions, with data across 400 features. Among these patients, 1,547 (38.6%) were female; median age was 64.0 (interquartile range 13.0). The most common diagnoses were lung (1,505, 37.6%), head and neck (696, 17.4%), and pancreatic cancers (685, 17.1%). The best model, a multi-task transformer, predicted symptom deterioration with an AUROC range of 0.732-0.822, marking a 1.4-6.2% improvement over the best single-task model. At a 10% alert rate, treatments associated with alerts would be enriched 4-13 fold for symptom deterioration (P<0.001). The system was calibrated and would provide a net benefit across a wide range of threshold probabilities in decision curve analysis. Conclusions: Longitudinal general-purpose multi-task machine learning systems trained using EMR data can accurately predict a wide range of symptoms. Based on these results, automated warning systems for symptoms should be implemented and evaluated in real-time clinical practice to guide preventative interventions.

^a Increase ≥4 ESAS points within 30 days ^b At the threshold corresponding to alerts with 10% of treatments