Tumor Treatment Response Guided Adaptive Dose De-escalation/Escalation Strategy for Concurrent Chemoradiotherapy of Nasopharyngeal Carcinoma.

Purpose: A novel tumor dose response guided adaptive chemo-radiotherapy process for nasopharyngeal carcinoma (NPC) was constructed and evaluated prospectively and retrospectively. In this process, tumor voxel dose response matrices quantified using two-point Fluorodeoxyglucose (FDG) Positron Emission Tomography/Magnetic Resonance (PET/MR) images acquired before and after an induction chemotherapy (IC) were utilized to guide quantitatively the individual patient dose de-escalation/ escalation for NPC patients in the post-IC concurrent chemo-radiotherapy (CCRT).

Methods and materials: Two FDG-PET/MR images were obtained before and after IC for each of 21 patients with stage III and IV NPC who underwent IC + CCRT. The changes of tumor voxel Standardized Uptake Value (SUV₀) on the pre-treatment baseline image and the baseline voxel volume were tracked on the post IC image using a deformable image registration tool and utilized to construct the tumor voxel dose response matrix (DRM) as the surrogate of tumor in situ SF₂ at the voxel level. Equivalent dose in the IC treatment was determined assuming that the IC treatment achieved the same mean DRM to the one achieved using a dose in the CCRT treatment alone. Therefore, the equivalent dose should not be extrapolated with respect to any other clinical endpoints. The tumor voxel SUV₀ and DRM were used to predict the treatment outcome and create retrospectively the expected treatment dose for the post-IC CCRT treatment. For few patients who were expected for a large dose escalation, new treatment plans targeting the highly resistant tumors were generated to assess clinical feasibility of adaptive dose fractionation painting schema.

Results: The equivalent dose in 2Gy per fraction (EQD₂) for 3 cycles IC (Gemcitabine + Cisplatin) was approximately 40Gy. The mean and coefficient variation (CV) of SUV₀ and DRM for all the primary tumors (Gross Tumor Volume - nasopharynx (GTVnx) group) were 5.98 (62%) and 0.42 (72%) respectively, which were significantly larger than 5.22 (59%) and 0.37 (55%) for the positive nodes (GTVnd group) (p < 0.001). Both GTVnx and GTVnd groups exhibited significantly larger intra-tumoral variations on SUV₀ compared to the inter-tumoral variations, (55%, 54%) vs (29%, 24%), meanwhile similar intra/inter-tumoral variations on DRM, (47%, 39%) vs (54%, 39%). Individual tumor local control probabilities (TCPs) for the 21 patients calculated using the individual tumor voxel (SUV₀, DRM) were from 0.54 to 1.0. To achieve TCP = 0.99, 18/21 patients could have their CCRT treatment dose be de-escalated for one of GTVnx and GTVnd, or both. In addition, 6/21 patients needed the CCRT treatment dose for at least one GTV to be escalated to 78∼126Gy (EQD₂); 2 of the 6 needed to escalate the treatment dose for both the primary and positive node GTVs. Adaptive plans on the 2 highly resistant tumors demonstrated that the dose fractionation painting was clinically feasible with regarding the normal tissue tolerance and clinical delivery technology, which could improve their tumor local control from TCP = 0.54 and 0.60 in the standard IC+CCRT treatment to TCP = 0.95 and 0.94 with the adaptive dose escalation respectively.

Conclusions: NPC, although relatively sensitive to the chemoradiotherapy, demonstrated very large spatial heterogeneities on both the tumor cell density and dose response within the individual tumors. The spatial tumor dose response assessed using the two-point FDG-PET imaging before and after the IC treatment can be used to design quantitatively the individual treatment dose required in the CCRT. The CCRT treatment dose could be de-escalated for > 50% of the GTVs (GTVnx and GTVnd groups), meanwhile escalated for about 16% of the GTVs with the local hypofractionation to the highly dose resistance regions.

Clinical trial registration number: ChiCTR2300067580.