Establishing the feasibility of the dosimetric compliance criteria of RTOG 1308: phase III randomized trial comparing overall survival after photon versus proton radiochemotherapy for inoperable stage II-IIIB NSCLC.

BACKGROUND: To establish the feasibility of the dosimetric compliance criteria of the RTOG 1308 trial through testing against Intensity Modulation Radiation Therapy (IMRT) and Passive Scattering Proton Therapy (PSPT) plans. METHODS: Twenty-six lung IMRT and 26 proton PSPT plans were included in the study. Dose Volume Histograms (DVHs) for targets and normal structures were analyzed. The quality of IMRT plans was assessed using a knowledge-based engineering tool. RESULTS: Most of the RTOG 1308 dosimetric criteria were achieved. The deviation unacceptable rates were less than 10 % for most criteria; however, a deviation unacceptable rate of more than 20 % was computed for the planning target volume minimum dose compliance criterion. Dose parameters for the target volume were very close for the IMRT and PSPT plans. However, the PSPT plans led to lower dose values for normal structures. The dose parameters in which PSPT plans resulted in lower values than IMRT plans were: lung V5Gy (%) (34.4 in PSPT and 47.2 in IMRT); maximum spinal cord dose (31.7 Gy in PSPT and 43.5 Gy in IMRT); heart V5Gy (%) (19 in PSPT and 47 in IMRT); heart V30Gy (%) (11 in PSPT and 19 in IMRT); heart V45Gy (%) (7.8 in PSPT and 12.1 in IMRT); heart V50% (Gy) (7.1 in PSPT and 9.8 in IMRT) and mean heart dose (7.7 Gy in PSPT and 14.9 Gy in IMRT). CONCLUSIONS: The revised RTOG 1308 dosimetric compliance criteria are feasible and achievable.

Evaluating proton stereotactic body radiotherapy to reduce chest wall dose in the treatment of lung cancer.

Stereotactic body radiotherapy (SBRT) can produce excellent local control of several types of solid tumor; however, toxicity to nearby critical structures is a concern. We found previously that in SBRT for lung cancer, the chest wall (CW) volume receiving 20, 30, or 40Gy (V20, V30, or V40) was linked with the development of neuropathy. Here we sought to determine whether the dosimetric advantages of protons could produce lower CW doses than traditional photon-based SBRT. We searched an institutional database to identify patients treated with photon SBRT for lung cancer with tumors within < 2.5cm of the CW. We found 260 cases; of these, chronic grade ≥ 2 CW pain was identified in 23 patients. We then selected 10 representative patients from this group and generated proton SBRT treatment plans, using the identical dose of 50Gy in 4 fractions, and assessed potential differences in CW dose between the 2 plans. The proton SBRT plans reduced the CW doses at all dose levels measured. The median CW V20 was 364.0cm(3) and 160.0cm(3) (p < 0.0001), V30 was 144.6cm(3)vs 77.0cm(3) (p = 0.0012), V35 was 93.9cm(3)vs 57.9cm(3) (p = 0.005), V40 was 66.5cm(3)vs 45.4cm(3) (p = 0.0112), and mean lung dose was 5.9Gy vs 3.8Gy (p = 0.0001) for photons and protons, respectively. Coverage of the planning target volume (PTV) was comparable between the 2 sets of plans (96.4% for photons and 97% for protons). From a dosimetric standpoint, proton SBRT can achieve the same coverage of the PTV while significantly reducing the dose to the CW and lung relative to photon SBRT and therefore may be beneficial for the treatment of lesions closer to critical structures.

Effects of respiratory motion on passively scattered proton therapy versus intensity modulated photon therapy for stage III lung cancer: are proton plans more sensitive to breathing motion?

PURPOSE: To quantify and compare the effects of respiratory motion on paired passively scattered proton therapy (PSPT) and intensity modulated photon therapy (IMRT) plans; and to establish the relationship between the magnitude of tumor motion and the respiratory-induced dose difference for both modalities. METHODS AND MATERIALS: In a randomized clinical trial comparing PSPT and IMRT, radiation therapy plans have been designed according to common planning protocols. Four-dimensional (4D) dose was computed for PSPT and IMRT plans for a patient cohort with respiratory motion ranging from 3 to 17 mm. Image registration and dose accumulation were performed using grayscale-based deformable image registration algorithms. The dose-volume histogram (DVH) differences (4D-3D [3D = 3-dimensional]) were compared for PSPT and IMRT. Changes in 4D-3D dose were correlated to the magnitude of tumor respiratory motion. RESULTS: The average 4D-3D dose to 95% of the internal target volume was close to zero, with 19 of 20 patients within 1% of prescribed dose for both modalities. The mean 4D-3D between the 2 modalities was not statistically significant (P<.05) for all dose-volume histogram indices (mean ± SD) except the lung V5 (PSPT: +1.1% ± 0.9%; IMRT: +0.4% ± 1.2%) and maximum cord dose (PSPT: +1.5 ± 2.9 Gy; IMRT: 0.0 ± 0.2 Gy). Changes in 4D-3D dose were correlated to tumor motion for only 2 indices: dose to 95% planning target volume, and heterogeneity index. CONCLUSIONS: With our current margin formalisms, target coverage was maintained in the presence of respiratory motion up to 17 mm for both PSPT and IMRT. Only 2 of 11 4D-3D indices (lung V5 and spinal cord maximum) were statistically distinguishable between PSPT and IMRT, contrary to the notion that proton therapy will be more susceptible to respiratory motion. Because of the lack of strong correlations with 4D-3D dose differences in PSPT and IMRT, the extent of tumor motion was not an adequate predictor of potential dosimetric error caused by breathing motion.

Analysis of esophageal-sparing treatment plans for patients with high-grade esophagitis.

We retrospectively generated IMRT plans for 14 NSCLC patients who had experienced grade 2 or 3 esophagitis (CTCAE version 3.0). We generated 11-beam and reduced esophagus dose plan types to compare changes in the volume and length of esophagus receiving doses of 50, 55, 60, 65, and 70 Gy. Changes in planning target volume (PTV) dose coverage were also compared. If necessary, plans were renormalized to restore 95% PTV coverage. The critical organ doses examined were mean lung dose, mean heart dose, and volume of spinal cord receiving 50 Gy. The effect of interfractional motion was determined by applying a three-dimensional rigid shift to the dose grid. For the esophagus plan, the mean reduction in esophagus V50, V55, V60, V65, and V70 Gy was 2.8, 4.1, 5.9, 7.3, and 9.5 cm(3), respectively, compared with the clinical plan. The mean reductions in LE50, LE55, LE60, LE65, and LE70 Gy were 2.0, 3.0, 3.8, 4.0, and 4.6 cm, respectively. The mean heart and lung dose decreased 3.0 Gy and 2.4 Gy, respectively. The mean decreases in 90% and 95% PTV coverage were 1.7 Gy and 2.8 Gy, respectively. The normalized plans' mean reduction of esophagus V50, V55, V60, V65, and V70 Gy were 1.6, 2.0, 2.9, 3.9, and 5.5 cm(3), respectively, compared with the clinical plans. The normalized plans' mean reductions in LE50, LE55, LE60, LE65, and LE70 Gy were 4.9, 5.2, 5.4, 4.9, and 4.8 cm, respectively. The mean reduction in maximum esophagus dose with simulated interfractional motion was 3.0 Gy and 1.4 Gy for the clinical plan type and the esophagus plan type, respectively. In many cases, the esophagus dose can be greatly reduced while maintaining critical structure dose constraints. PTV coverage can be restored by increasing beam output, while still obtaining a dose reduction to the esophagus and maintaining dose constraints.

Prescribing radiation dose to lung cancer patients based on personalized toxicity estimates.

INTRODUCTION: The lung radiosensitivity of the most sensitive patients limits doses that can be given to the majority of lung cancer patients. The purpose of the current study was to illustrate the concept of personalizing prescription dose by performing a retrospective study in which the prescription is determined using an individualized dose-volume constraint that is calculated from a toxicity prediction model. We test whether using a model-generated personalized lung-dose limit results in a clinically significant change to the prescription. METHODS: A model consisting of a dose-volume component and a genetic component (single-nucleotide polymorphism information) was used to determine iso-risk mean lung-dose (MLD) limits for each patient. The prescription dose for each patient was scaled according to the individualized MLD constraint and population-based constraints for the cord, esophagus, and heart. The difference between the model-determined prescription dose and the prescription the patient was originally treated with was evaluated. RESULTS: For 59% of the patients the change in prescription using the model-determined limit was greater than 5 Gy (either dose escalation or de-escalation). For 96% of the patients who developed radiation pneumonitis the model predicted that the prescription should have been lowered. CONCLUSIONS: Our results indicate that using a model-generated personalized MLD results in a clinically different (≥ 5 Gy) prescription. A model used in the manner described by the study can help physicians further personalize radiation therapy and aid them in determining how much dose can safely be delivered to the tumor and normal tissues.

Dosimetric comparison of three-dimensional conformal proton radiotherapy, intensity-modulated proton therapy, and intensity-modulated radiotherapy for treatment of pediatric craniopharyngiomas.

PURPOSE: Cranial irradiation in pediatric patients is associated with serious long-term adverse effects. We sought to determine whether both three-dimensional conformal proton radiotherapy (3D-PRT) and intensity-modulated proton therapy (IMPT) compared with intensity-modulated radiotherapy (IMRT) decrease integral dose to brain areas known to harbor neuronal stem cells, major blood vessels, and other normal brain structures for pediatric patients with craniopharyngiomas. METHODS AND MATERIALS: IMRT, forward planned, passive scattering proton, and IMPT plans were generated and optimized for 10 pediatric patients. The dose was 50.4 Gy (or cobalt Gy equivalent) delivered in 28 fractions with the requirement for planning target volume (PTV) coverage of 95% or better. Integral dose data were calculated from differential dose-volume histograms. RESULTS: The PTV target coverage was adequate for all modalities. IMRT and IMPT yielded the most conformal plans in comparison to 3D-PRT. Compared with IMRT, 3D-PRT and IMPT plans had a relative reduction of integral dose to the hippocampus (3D-PRT, 20.4; IMPT, 51.3%*), dentate gyrus (27.3, 75.0%*), and subventricular zone (4.5, 57.8%*). Vascular organs at risk also had reduced integral dose with the use of proton therapy (anterior cerebral arteries, 33.3*, 100.0%*; middle cerebral arteries, 25.9%*, 100%*; anterior communicating arteries, 30.8*, 41.7%*; and carotid arteries, 51.5*, 77.6*). Relative reduction of integral dose to the infratentorial brain (190.7*, 109.7%*), supratentorial brain without PTV (9.6, 26.8%*), brainstem (45.6, 22.4%*), and whole brain without PTV (19.4*, 34.4%*) were recorded with the use of proton therapy. (*Differences were significant based on Friedman's test with Bonferroni-Dunn correction, α = 0.05) CONCLUSIONS: The current study found that proton therapy was able to avoid excess integral radiation dose to a variety of normal structures at all dose levels while maintaining equal target coverage. Future studies will examine the clinical benefits of these dosimetric advantages.

Toxicity and patterns of failure of adaptive/ablative proton therapy for early-stage, medically inoperable non-small cell lung cancer.

PURPOSE: To analyze the toxicity and patterns of failure of proton therapy given in ablative doses for medically inoperable early-stage non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Eighteen patients with medically inoperable T1N0M0 (central location) or T2-3N0M0 (any location) NSCLC were treated with proton therapy at 87.5 Gy (relative biological effectiveness) at 2.5 Gy /fraction in this Phase I/II study. All patients underwent treatment simulation with four-dimensional CT; internal gross tumor volumes were delineated on maximal intensity projection images and modified by visual verification of the target volume in 10 breathing phases. The internal gross tumor volumes with maximal intensity projection density was used to design compensators and apertures to account for tumor motion. Therapy consisted of passively scattered protons. All patients underwent repeat four-dimensional CT simulations during treatment to assess the need for adaptive replanning. RESULTS: At a median follow-up time of 16.3 months (range, 4.8-36.3 months), no patient had experienced Grade 4 or 5 toxicity. The most common adverse effect was dermatitis (Grade 2, 67%; Grade 3, 17%), followed by Grade 2 fatigue (44%), Grade 2 pneumonitis (11%), Grade 2 esophagitis (6%), and Grade 2 chest wall pain (6%). Rates of local control were 88.9%, regional lymph node failure 11.1%, and distant metastasis 27.8%. Twelve patients (67%) were still alive at the last follow-up; five had died of metastatic disease and one of preexisting cardiac disease. CONCLUSIONS: Proton therapy to ablative doses is well tolerated and produces promising local control rates for medically inoperable early-stage NSCLC.

Spot scanning proton beam therapy for prostate cancer: treatment planning technique and analysis of consequences of rotational and translational alignment errors.

PURPOSE: Conventional proton therapy with passively scattered beams is used to treat a number of tumor sites, including prostate cancer. Spot scanning proton therapy is a treatment delivery means that improves conformal coverage of the clinical target volume (CTV). Placement of individual spots within a target is dependent on traversed tissue density. Errors in patient alignment perturb dose distributions. Moreover, there is a need for a rational planning approach that can mitigate the dosimetric effect of random alignment errors. We propose a treatment planning approach and then analyze the consequences of various simulated alignment errors on prostate treatments. METHODS AND MATERIALS: Ten control patients with localized prostate cancer underwent treatment planning for spot scanning proton therapy. After delineation of the clinical target volume, a scanning target volume (STV) was created to guide dose coverage. Errors in patient alignment in two axes (rotational and yaw) as well as translational errors in the anteroposterior direction were then simulated, and dose to the CTV and normal tissues were reanalyzed. RESULTS: Coverage of the CTV remained high even in the setting of extreme rotational and yaw misalignments. Changes in the rectum and bladder V45 and V70 were similarly minimal, except in the case of translational errors, where, as a result of opposed lateral beam arrangements, much larger dosimetric perturbations were observed. CONCLUSIONS: The concept of the STV as applied to spot scanning radiation therapy and as presented in this report leads to robust coverage of the CTV even in the setting of extreme patient misalignments.

Dosimetric changes resulting from patient rotational setup errors in proton therapy prostate plans.

PURPOSE: To evaluate the dose changes to the target and critical structures from rotational setup errors in prostate cancer patients treated with proton therapy. METHODS AND MATERIALS: A total of 70 plans were analyzed for 10 patients treated with parallel-opposed proton beams to a dose of 7,600 (60)Co-cGy-equivalent (CcGE) in 200 CcGE fractions to the clinical target volume (i.e., prostate and proximal seminal vesicles). Rotational setup errors of +3 degrees , -3 degrees , +5 degrees , and -5 degrees (to simulate pelvic tilt) were generated by adjusting the gantry. Horizontal couch shifts of +3 degrees and -3 degrees (to simulate longitudinal setup variability) were also generated. Verification plans were recomputed, keeping the same treatment parameters as the control. RESULTS: All changes shown are for 38 fractions. The mean clinical target volume dose was 7,780 CcGE. The mean change in the clinical target volume dose in the worse case scenario for all shifts was 2 CcGE (absolute range in worst case scenario, 7,729-7,848 CcGE). The mean changes in the critical organ dose in the worst case scenario was 6 CcGE (bladder), 18 CcGE (rectum), 36 CcGE (anterior rectal wall), and 141 CcGE (femoral heads) for all plans. In general, the percentage of change in the worse case scenario for all shifts to the critical structures was <5%. Deviations in the absolute percentage of volume of organ receiving 45 and 70 Gy for the bladder and rectum were <2% for all plans. CONCLUSION: Patient rotational movements of 3 degrees and 5 degrees and horizontal couch shifts of 3 degrees in prostate proton planning did not confer clinically significant dose changes to the target volumes or critical structures.