BackgroundRadiotherapy (RT) is involved in about 50% of all cancer patients, making it a very important treatment modality. The most common type of RT is external beam RT, which consists of delivering the radiation to the tumor from outside the body. One novel treatment delivery method is volumetric modulated arc therapy (VMAT), where the gantry continuously rotates around the patient during the radiation delivery.PurposeAccurate tumor position monitoring during stereotactic body radiotherapy (SBRT) for lung tumors can help to ensure that the tumor is only irradiated when it is inside the planning target volume. This can maximize tumor control and reduce uncertainty margins, lowering organ‐at‐risk dose. Conventional tracking methods are prone to errors, or have a low tracking rate, especially for small tumors that are in close vicinity to bony structures.MethodsWe investigated patient‐specific deep Siamese networks for real‐time tumor tracking, during VMAT. Due to lack of ground truth tumor locations in the kilovoltage (kV) images, each patient‐specific model was trained on synthetic data (DRRs), generated from the 4D planning CT scans, and evaluated on clinical data (x‐rays). Since there are no annotated datasets with kV images, we evaluated the model on a 3D printed anthropomorphic phantom but also on six patients by computing the correlation coefficient with the breathing‐related vertical displacement of the surface‐mounted marker (RPM). For each patient/phantom, we used 80% of DRRs for training and 20% for validation.ResultsThe proposed Siamese model outperformed the conventional benchmark template matching‐based method (RTR): (1) when evaluating both methods on the 3D phantom, the Siamese model obtained a 0.57–0.79‐mm mean absolute distance to the ground truth tumor locations, compared to 1.04–1.56 mm obtained by RTR; (2) on patient data, the Siamese‐determined longitudinal tumor position had a correlation coefficient of 0.71–0.98 with the RPM, compared to 0.07–0.85 for RTR; (3) the Siamese model had a 100% tracking rate, compared to 62%–82% for RTR.ConclusionsBased on these results, we argue that Siamese‐based real‐time 2D markerless tumor tracking during radiation delivery is possible. Further investigation and development of 3D tracking is warranted.