Background To compare the impact of uncertainties and interplay effect on 3D and 4D robustly optimized intensity-modulated proton therapy (IMPT) plans for lung cancer in an exploratory methodology study. Methods IMPT plans were created for 11 non-randomly selected non-small-cell lung cancer (NSCLC) cases: 3D robustly optimized plans on average CTs with internal gross tumor volume density overridden to irradiate internal target volume, and 4D robustly optimized plans on 4D CTs to irradiate clinical target volume (CTV). Regular fractionation (66 Gy[RBE] in 33 fractions) were considered. In 4D optimization, the CTV of individual phases received non-uniform doses to achieve a uniform cumulative dose. The root-mean-square-dose volume histograms (RVH) measured the sensitivity of the dose to uncertainties, and the areas under the RVH curve (AUCs) were used to evaluate plan robustness. Dose evaluation software modeled time-dependent spot delivery to incorporate interplay effect with randomized starting phases of each field per fraction. Dose-volume histogram indices comparing CTV coverage, homogeneity, and normal tissue sparing were evaluated using Wilcoxon signed-rank test. Results 4D robust optimization plans led to smaller AUC for CTV (14.26 vs. 18.61 (p=0.001), better CTV coverage (Gy[RBE]) [D95% CTV: 60.6 vs 55.2 (p=0.001)], and better CTV homogeneity [D5%–D95% CTV: 10.3 vs 17.7 (p=0.002)] in the face of uncertainties. With interplay effect considered, 4D robust optimization produced plans with better target coverage [D95% CTV: 64.5 vs 63.8 (p=0.0068)], comparable target homogeneity, and comparable normal tissue protection. The benefits from 4D robust optimization were most obvious for the 2 typical stage III lung cancer patients. Conclusions Our exploratory methodology study showed that, compared to 3D robust optimization, 4D robust optimization produced significantly more robust and interplay-effect-resistant plans for targets with comparable dose distributions for normal tissues. A further study with a larger and more realistic patient population is warranted to generalize the conclusions.

Purpose We propose a robust treatment planning model that simultaneously considers proton range and patient setup uncertainties and reduces high linear energy transfer (LET) exposure in organs at risk (OARs) to minimize the relative biological effectiveness (RBE) dose in OARs for intensity-modulated proton therapy (IMPT). Our method could potentially reduce the unwanted damage to OARs. Methods We retrospectively generated plans for 10 patients including 2 prostate, 4 head and neck, and 4 lung cancer patients. The “worst-case robust optimization” model was applied. One additional term as a “biological surrogate (BS)” of OARs due to the high LET-related biological effects was added in the objective function. The biological surrogate was defined as the sum of the physical dose and extra biological effects caused by the dose-averaged LET. We generated 9 uncertainty scenarios that considered proton range and patient setup uncertainty. Corresponding to each uncertainty scenario, LET was obtained by a fast LET calculation method developed in-house and based on Monte Carlo simulations. In each optimization iteration, the model used the worst-case BS among all scenarios and then penalized overly high BS to organs. The model was solved by an efficient algorithm (limited-memory Broyden-Fletcher-Goldfarb-Shanno) in a parallel computing environment. Our new model was benchmarked with the conventional robust planning model without considering BS. Dose-volume histograms (DVHs) of the dose assuming a fixed RBE of 1.1 and BS for tumor and organs under nominal and uncertainty scenarios were compared to assess the plan quality between the two methods. Results For the 10 cases, our model outperformed the conventional robust model in avoidance of high LET in OARs. At the same time our method could achieve dose distributions and plan robustness of tumors assuming a fixed RBE of 1.1 almost the same as those of the conventional robust model. Conclusions Explicitly considering LET in IMPT robust treatment planning can reduce the high LET to OARs and minimize the possible toxicity of high RBE dose to OARs without sacrificing plan quality. We believe this will allow one to design and deliver safer proton therapy.

Robust optimization with a small spot-machine significantly improves heart and esophagus sparing, with comparable plan robustness and interplay effects compared with robust optimization with a large-spot machine. A small-spot machine uses a larger number of spots to cover the same tumors compared with a large-spot machine, which gives the planning system more freedom to compensate for the higher sensitivity to uncertainties and interplay effects for lung cancer treatments.

Two-dimensional ion chamber arrays are primarily used for conventional and intensity modulated radiotherapy quality assurance. There is no commercial device of such type available on the market that is offered for proton therapy quality assurance. We have investigated suitability of the MatriXX, a commercial two-dimensional ion chamber array detector for proton therapy QA. This device is designed to be used for photon and electron therapy QA. The device is equipped with 32 x 32 parallel plate ion chambers, each with 4.5 mm diam and 7.62 mm center-to-center separation. A 250 MeV proton beam was used to calibrate the dose measured by this device. The water equivalent thickness of the buildup material was determined to be 3.9 mm using a 160 MeV proton beam. Proton beams of different energies were used to measure the reproducibility of dose output and to evaluate the consistency in the beam flatness and symmetry measured by MatriXX. The output measurement results were compared with the clinical commissioning beam data that were obtained using a 0.6 cc Farmer chamber. The agreement was consistently found to be within 1%. The profiles were compared with film dosimetry and also with ion chamber data in water with an excellent agreement. The device is found to be well suited for quality assurance of proton therapy beams. It provides fast two-dimensional dose distribution information in real time with the accuracy comparable to that of ion chamber measurements and film dosimetry.

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