A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy

Purpose: Locoregional tumor control for locally advanced cancers with radia tion therapy has been unsatisfactory. This is in part associated with the p henomenon of tumor hypoxia. Assessing hypoxia in human tumors has been diff icult due to the lack of clinically noninvasive and reproducible methods. A recently developed positron emission tomography (PET) imaging-based hypoxi a measurement technique which employs a Cu(II)-diacetyl-bis(N-4-methylthios emicarbazone) (Cu-ATSM) tracer is of great interest. Oxygen electrode measu rements in animal experiments have demonstrated a strong correlation betwee n low tumor pO(2) and excess Cu-60-ATSM accumulation. Intensity-modulated r adiation therapy (IMRT) allows selective targeting of tumor and sparing of normal tissues. In this study, we examined the feasibility of combining the se novel technologies to develop hypoxia imaging (Cu-ATSM)-guided IMRT, whi ch may potentially deliver higher dose of radiation to the hypoxic tumor su bvolume to overcome inherent hypoxia-induced radioresistance without compro mising normal tissue sparing. Methods and Materials: A custom-designed anthropomorphic head phantom conta ining computed tomography (CT) and positron emitting tomography (PET) visib le targets consisting of plastic balls and rods distributed throughout the "cranium" was fabricated to assess the spatial accuracy of target volume ma pping after multimodality image coregistration, For head-and-neck cancer pa tients, a CT and PET imaging fiducial marker coregistration system was inte grated into the thermoplastic immobilization head mask with four CT and PET compatible markers to assist image fusion on a Voxel-Q treatment-planning computer, This system was implemented on head-and-neck cancer patients, and the gross tumor volume (GTV) was delineated based on physical and radiolog ic findings. Within GTV, regions with a Cu-60-ATSM I uptake twice that of c ontralateral normal neck muscle were operationally designated as ATSM-avid or hypoxic tumor volume (hGTV) for this feasibility study. These target vol umes along with other normal organs contours were defined and transferred t o an inverse planning computer (Corvus, NOMOS) to create a hypoxia imaging- guided IMRT treatment plan. Results: A study of the accuracy of target volume mapping showed that the s patial fidelity and imaging distortion after CT and PET image coregistratio n and fusion were within 2 mm in phantom study. Using fiducial markers to a ssist CT/PET imaging fusion in patients with carcinoma of the head-and-neck area, a heterogeneous distribution of Cu-60-ATSM within the GTV illustrate d the success of Cu-60-ATSM PET to select an ATSM-avid or hypoxic tumor sub volume (hGTV). We further demonstrated the feasibility of Cu-ATSM-guided IR IRT by showing an example in which radiation dose to the hGTV could be esc alated without compromising normal tissue (parotid glands and spinal cord) sparing. The plan delivers 80 Gy in 35 fractions to the ATSM-avid tumor sub volume and the GTV simultaneously receives 70 Gy in 35 fractions while more than one-half of the parotid glands are spared to less than 30 Gy, Conclusion: We demonstrated the feasibility of a novel Cu-ATSM-guided IMRT approach through coregistering hypoxia Cu-60-ATSM PET to the corresponding CT images for IMRT planning. Future investigation is needed to establish a clinical-pathologic correlation between Cu-60-ATSM retention and radiation curability, to understand tumor re-oxygenation kinetics, and tumor target u ncertainty during a course of radiation therapy before implementing this th erapeutic approach to patients with locally advanced tumor. (C) 2001 Elsevi er Science Inc.