Abstract: Purpose/Objective: The customization of intracavitary dose distributions for gynecologic malignancies is limited by the spatial positioning of the applicators. We tested the hypothesis that applicator-guided intensity modulated radiation therapy (AGIMRT) has the potential to deliver highly conformal dose distributions to cervical tumors, representing improvement over distributions obtained with brachytherapy. The proposed technique uses radio-opaque stents or internal markers to align the linear accelerator with respect to tumor and critical organs, thereby guiding radiation portals. Materials/Methods: A commercial 3D treatment planning system was used to create plans for ten cervical cancer patients treated at our institution. Dose distributions of conventionally designed high dose rate (HDR) plans were compared against those of AGIMRT. Tumor delineation was based on a previously published binary threshold technique, using image intensity on positron emission tomography (PET). AGIMRT treatment schedules were designed using two fraction sizes: 6.5 Gy, to directly reproduce the HDR fractionation, and 1.8 Gy, to simulate traditional external beam fractionation. Linear-quadratic conversion equations were used to derive radiobiologically equivalent prescription doses and tolerance limits for the AGIMRT plans. Results: Average minimum tumor dose was significantly greater for the AGIMRT dose distributions than for the HDR distributions (64.2 Gy vs. 33.6 Gy; p=.005). Mean tumor volume at prescription dose was higher for the AGIMRT plans (90.0% vs. 58.2%; p=.005). Using AGIMRT, mean percent volume at tolerance limit was decreased for bladder (6.1% vs. 16.6%; p =.047) but increased for rectum (4.1% vs. 2.2%; p=.646). An example of the prescription dose distributions obtained with HDR (Figure 1a) and AGIMRT (Figure 1b) are shown. Tumor dose-volume histograms for all ten patients are presented in Figure 2. Conclusions: The results obtained in our study suggest that there may be conceptual and dosimetric advantages to replacing HDR with AGIMRT for patients with large-volume cervical tumors. Further investigation is warranted to validate the assumption that tumor and critical structures can be reproducibly localized for the purpose of treatment. We are expanding the investigation, using sequential PET images to model tumor regression and compare brachytherapy and AGIMRT throughout the course of therapy. Encouraging results from these studies may lead to a limited clinical trial using AGIMRT to definitively treat cervical cancer patients that have large tumor burdens. This work was supported in part by NCI R0184409 and R0185797.