TCP and NTCP Calculations Based on Treatment Doses Instead of Planned Doses for Daily Adaptive Proton Therapy of Lung Cancer

Calculation of tumor control probability (TCP) and normal tissue complication probability (NTCP) is becoming increasingly relevant for optimizing treatment strategies, for example the selection of patients for proton therapy. While radiobiological models are typically built and evaluated on the planned treatment dose, no consensus exists for their evaluation in the context of varying patient anatomy during treatment. For example, different adaptive strategies can lead to different expected treatment outcomes for the same planned dose. This shows that TCP/NTCP needs to be calculated from the cumulative treatment dose resulting from multiple fraction doses and patient geometries. In this study, different methods of applying TCP and NTCP models to treatments with anatomical changes are developed and compared. These methods were evaluated on an example of locally advanced non-small cell lung cancer (NSCLC) patients using two extreme scenarios: no adaption vs online daily adaptive proton therapy (DAPT).Three methods to calculate TCP/NTCP in the context of anatomical changes were compared: (I) based on the accumulated treatment doses. Six different deformable image registration (DIR) algorithms were used to accumulate the dose, then the TCP/NTCP was calculated on all accumulated doses showing the variation due to the DIR. (II) based on the cumulative effective uniform dose (EUD) of each fraction. (III) based on each fraction dose directly, permitting an evaluation of the mean and variation of TCP/NTCP during treatment. To test and compare these methods, proton therapy treatment plans were generated on deep inspiration breath-hold (DIBH) planning CTs for 5 NSCLC patients (66 Gy-RBE, 33 fractions). Non-adapted and DAPT treatment doses were created by recalculating and reoptimizing these plans on nine repeated CTs. TCP/NTCP calculations were performed with all three methods.All methods showed consistent results between no adaption and DAPT. Two patients showed substantial TCP reductions up to 33% without adaption. Three patients, despite anatomical changes and dose differences, did not show a reduced calculated TCP with all methods. For most patients, NTCP differences between DAPT and no adaption were moderate, but one showed improvement in predicted 2-year survival based on heart toxicity with DAPT. Furthermore, the absolute NTCP calculated with method (I) showed variations of up to 7% depending on the DIR algorithm used for dose accumulation.The three proposed methods of calculating clinical outcome based on treatment doses showed consistent result between DAPT and non-adapted treatments. Three patients showed benefits with DAPT, so the calculated NTCP could be reduced or calculated TCP maintained. For two patients the dose differences with adaption did not translate in clinically relevant effects. The proposed outcome calculation methods enable a more realistic quantification of TCP/NTCP of different adaptive strategies.