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Background The current standard of care (SOC) for whole breast radiotherapy (WBRT) in the US is conventional tangential photon fields. Advanced WBRT techniques may provide similar tumor control and better normal tissue sparing, but it is controversial whether the medical benefits of an advanced technology are significant enough to justify its higher cost. Objective To analyze the cost-effectiveness of six advanced WBRT techniques compared with SOC. Methods We developed a Markov model to simulate health states for one cohort of women (65-year-old) with early-stage breast cancer over 15 years after WBRT. The cost effectiveness analyses of field-in-field (FIF), hybrid intensity modulated radiotherapy (IMRT), full IMRT, standard volumetric modulated arc therapy (STD-VMAT), multiple arc VMAT (MA-VMAT), non-coplanar VMAT (NC-VMAT) compared with SOC were performed with both tumor control and radiogenic side effects considered. Transition probabilities and utilities for each health state were obtained from literature. Costs incurred by payers were adopted from literature and Medicare data. Quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated. One-way sensitivity analyses and probabilistic sensitivity analyses (PSA) were performed to evaluate the impact of uncertainties on the final results. Results FIF has the lowest ICER value of 1,511 $/QALY. The one-way analyses show that the cost-effectiveness of advanced WBRT techniques is most sensitive to the probability of developing contralateral breast cancer. PSAs show that SOC is more cost effective than almost all advanced WBRT techniques at a willingness-to-pay (WTP) threshold of 50,000 $/QALY, while FIF, hybrid IMRT and MA-VMAT are more cost-effective than SOC with a probability of 59.2%, 72.3% and 72.6% at a WTP threshold of 100,000 $/QALY, respectively. Conclusions FIF might be the most cost-effective option for WBRT patients at a WTP threshold of 50,000 $/QALY, while hybrid IMRT and MA-VMAT might be the most cost-effective options at a WTP threshold of 100,000 $/QALY.

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