Spot-scanning proton therapy for early breast cancer in free breathing versus deep inspiration breath-hold.

BACKGROUND AND PURPOSE: Proton therapy for breast cancer is usually given in free breathing (FB). With the use of deep inspiration breath-hold (DIBH) technique, the location of the heart is displaced inferiorly, away from the internal mammary nodes and, thus, the dose to the heart can potentially be reduced. The aim of this study was to explore the potential benefit of proton therapy in DIBH compared to FB for highly selected patients to reduce exposure of the heart and other organs at risk. We aimed at creating proton plans with delivery times feasible with treatment in DIBH. MATERIAL AND METHODS: Sixteen patients with left-sided breast cancer receiving loco-regional proton therapy were included. The FB and DIBH plans were created for each patient using spot-scanning proton therapy with 2-3 fields, robust and single field optimization. For the DIBH plans, minimum monitor unit per spot and spot spacing were increased to reduce treatment delivery time. RESULTS: All plans complied with target coverage constraints. The median mean heart dose was statistically significant reduced from 1.1 to 0.6 Gy relative biological effectiveness (RBE) by applying DIBH. No statistical significant difference was seen for mean dose and V17Gy RBE to the ipsilateral lung. The median treatment delivery time for the DIBH plans was reduced by 27% compared to the FB plans without compromising the plan quality. INTERPRETATION: The median absolute reduction in dose to the heart was limited. Proton treatment in DIBH may only be relevant for a subset of these patients with the largest reduction in heart exposure.

Intrafraction tumor motion monitoring and dose reconstruction for liver pencil beam scanning proton therapy.

Background: Pencil beam scanning (PBS) proton therapy can provide highly conformal target dose distributions and healthy tissue sparing. However, proton therapy of hepatocellular carcinoma (HCC) is prone to dosimetrical uncertainties induced by respiratory motion. This study aims to develop intra-treatment tumor motion monitoring during respiratory gated proton therapy and combine it with motion-including dose reconstruction to estimate the delivered tumor doses for individual HCC treatment fractions. Methods: Three HCC-patients were planned to receive 58 GyRBE (n=2) or 67.5 GyRBE (n=1) of exhale respiratory gated PBS proton therapy in 15 fractions. The treatment planning was based on the exhale phase of a 4-dimensional CT scan. Daily setup was based on cone-beam CT (CBCT) imaging of three implanted fiducial markers. An external marker block (RPM) on the patient's abdomen was used for exhale gating in free breathing. This study was based on 5 fractions (patient 1), 1 fraction (patient 2) and 6 fractions (patient 3) where a post-treatment control CBCT was available. After treatment, segmented 2D marker positions in the post-treatment CBCT projections provided the estimated 3D motion trajectory during the CBCT by a probability-based method. An external-internal correlation model (ECM) that estimated the tumor motion from the RPM motion was built from the synchronized RPM signal and marker motion in the CBCT. The ECM was then used to estimate intra-treatment tumor motion. Finally, the motion-including CTV dose was estimated using a dose reconstruction method that emulates tumor motion in beam's eye view as lateral spot shifts and in-depth motion as changes in the proton beam energy. The CTV homogeneity index (HI) The CTV homogeneity index (HI) was calculated as D 2 %  -  D 98 % D 50 %   × 100 % . Results: The tumor position during spot delivery had a root-mean-square error of 1.3 mm in left-right, 2.8 mm in cranio-caudal and 1.7 mm in anterior-posterior directions compared to the planned position. On average, the CTV HI was larger than planned by 3.7%-points (range: 1.0-6.6%-points) for individual fractions and by 0.7%-points (range: 0.3-1.1%-points) for the average dose of 5 or 6 fractions. Conclusions: A method to estimate internal tumor motion and reconstruct the motion-including fraction dose for PBS proton therapy of HCC was developed and demonstrated successfully clinically.

Accuracy and consistency of intensity-based deformable image registration in 4DCT for tumor motion estimation in liver radiotherapy planning.

We investigate the accuracy of intensity-based deformable image registration (DIR) for tumor localization in liver stereotactic body radiotherapy (SBRT). We included 4DCT scans to capture the breathing motion of eight patients receiving SBRT for liver metastases within a retrospective clinical study. Each patient had three fiducial markers implanted. The liver and the tumor were delineated in the mid-ventilation phase, and their positions in the other phases were estimated with deformable image registration. We tested referenced and sequential registrations strategies. The fiducial markers were the gold standard to evaluate registration accuracy. The registration errors related to measured versus estimated fiducial markers showed a mean value less than 1.6mm. The positions of some fiducial markers appeared not stable on the 4DCT throughout the respiratory phases. Markers' center of mass tends to be a more reliable measurement. Distance errors of tumor location based on registration versus markers center of mass were less than 2mm. There were no statistically significant differences between the reference and the sequential registration, i.e., consistency and errors were comparable to resolution errors. We demonstrated that intensity-based DIR is accurate up to resolution level for locating the tumor in the liver during breathing motion.

Radiation-Induced Toxicity Risks in Photon Versus Proton Therapy for Synchronous Bilateral Breast Cancer.

Purpose: This study compares photon and proton therapy plans for patients with synchronous bilateral early breast cancer and estimates risks of early and late radiation-induced toxicities. Materials and Methods: Twenty-four patients with synchronous bilateral early breast cancer receiving adjuvant radiation therapy using photons, 3-dimensional conformal radiation therapy or volumetric modulated arc therapy, were included and competing pencil beam scanning proton therapy plans were created. Risks of dermatitis, pneumonitis, acute esophageal toxicity, lung and breast fibrosis, hypothyroidism, secondary lung and esophageal cancer and coronary artery events were estimated using published dose-response relationships and normal tissue complication probability (NTCP) models. Results: The primary clinical target volume V95% and/or nodal clinical target volume V90% were less than 95% in 17 photon therapy plans and none of the proton plans. Median NTCP of radiation dermatitis ≥ grade 2 was 18.3% (range, 5.4-41.7) with photon therapy and 58.4% (range, 31.4-69.7) with proton therapy. Median excess absolute risk (EAR) of secondary lung cancer at age 80 for current and former smokers was 4.8% (range, 0.0-17.0) using photons and 2.7% (range, 0.0-13.6) using protons. Median EAR of coronary event at age 80, assuming all patients have preexisting cardiac risk factors, was 1.0% (range, 0.0-5.6) with photons and 0.2% (range, 0.0-1.3) with protons. Conclusion: Proton therapy plans improved target coverage and reduced risk of coronary artery event and secondary lung cancer while increasing the risk of radiation dermatitis.

Spot-scanning proton therapy for targets with adjacent cardiac implantable electronic devices - Strategies for breast and head & neck cancer.

BACKGROUND AND PURPOSE: Cardiac implantable electronic device (CIED) malfunctions can be induced by secondary neutron dose from spot-scanning proton therapy. A recent in-vitro study investigating secondary neutron dose to CIEDs up to 7 mSv per fraction found that exposure of secondary neutrons in this range was clinically manageable. This study presents decision algorithms proposed by a national expert group for selection of patients with breast and head & neck (H&N) cancer with CIEDs adjacent to target for proton therapy based on the 7 mSv threshold. METHODS AND MATERIALS: Ten patients with breast cancer and five with H&N cancer were included in the study. Five patients with breast cancer received photon therapy with CIED and proton plans were retrospectively created. The remaining patients received proton therapy without CIED and a worst-case position of a virtual CIED was retrospectively delineated. Secondary neutron dose was estimated as ambient dose equivalent H*(10) using Monte Carlo simulations. RESULTS: For patients with breast cancer and with contralateral CIED, the secondary neutron dose to the CIED was below 7 mSv per fraction for CTV < 1500 cm3 in 2 Gy fractions and CTV < 1000 cm3 in 2.67 Gy fractions. The secondary neutron dose to the CIED was below 7 mSv per fraction for all patients with H&N cancer. CONCLUSIONS: Simulations of neutron exposure suggest that proton therapy is feasible for most patients with CIED adjacent to target. This forms the basis for decision algorithms for selection of patients with CIED for proton therapy.

Proton therapy for early breast cancer patients in the DBCG proton trial: planning, adaptation, and clinical experience from the first 43 patients.

BACKGROUND: The Danish Breast Cancer Group (DBCG) Proton Trial randomizes breast cancer patients selected on high mean heart dose (MHD) or high lung dose (V20Gy/V17Gy) in the photon plan between photon and proton therapy. This study presents the proton plans and adaptation strategy for the first 43 breast cancer patients treated with protons in Denmark. MATERIAL AND METHODS: Forty-four proton plans (one patient with bilateral cancer) were included; 2 local and 42 loco-regional including internal mammary nodes (IMN). Nineteen patients had a mastectomy and 25 a lumpectomy. The prescribed dose was either 50 Gy in 25 fractions (n = 30) or 40 Gy in 15 fractions (n = 14) wherefrom five received simultaneous integrated boost to the tumor bed. Using 2-3 en face proton fields, single-field optimization, robust optimization and a 5 cm range shifter ensured robustness towards breathing motion, setup- and range uncertainties. An anatomical evaluation was performed by evaluating the dose after adding/removing 3 mm and 5 mm tissue to/from the body-outline and used to define treatment tolerances for anatomical changes. RESULTS: The nominal and robust criteria were met for all patients except two. The median MHD was 1.5 Gy (0.5-3.4 Gy, 50 Gy) and 1.1 Gy (0.0-1.5 Gy, 40 Gy). The anatomical evaluations showed how 5 mm shrinkage approximately doubled the MHD while 5 mm swelling reduced target coverage of the IMN below constraints. Ensuring 3-5 mm robustness toward swelling was prioritized but not always achieved by robust optimization alone emphasizing the need for a distal margin. Twenty-eight patients received plan adaptation, eight patients received two, and one received five. CONCLUSION: This proton planning strategy ensured robust treatment plans within a pre-defined level of acceptable anatomical changes that fulfilled the planning criteria for most of the patients and ensured low MHD.

Selection criteria for early breast cancer patients in the DBCG proton trial - The randomised phase III trial strategy.

BACKGROUND AND PURPOSE: Adjuvant radiotherapy of internal mammary nodes (IMN) improves survival in high-risk early breast cancer patients but inevitably leads to more dose to heart and lung. Target coverage is often compromised to meet heart/lung dose constraints. We estimate heart and lung dose when target coverage is not compromised in consecutive patients. These estimates are used to guide the choice of selection criteria for the randomised Danish Breast Cancer Group (DBCG) Proton Trial. MATERIALS AND METHODS: 179 breast cancer patients already treated with loco-regional IMN radiotherapy from 18 European departments were included. If the clinically delivered treatment plan did not comply with defined target coverage requirements, the plan was modified retrospectively until sufficient coverage was reached. The choice of selection criteria was based on the estimated number of eligible patients for different heart and lung dose thresholds in combination with proton therapy capacity limitations and dose-response relationships for heart and lung. RESULTS: Median mean heart dose was 3.0 Gy (range, 1.1-8.2 Gy) for left-sided and 1.4 Gy (0.4-11.5 Gy) for right-sided treatment plans. Median V17Gy/V20Gy (hypofractionated/normofractionated plans) for ipsilateral lung was 31% (9-57%). The DBCG Radiotherapy Committee chose mean heart dose ≥ 4 Gy and/or lung V17Gy/V20Gy ≥ 37% as thresholds for inclusion in the randomised trial. Using these thresholds, we estimate that 22% of patients requiring loco-regional IMN radiotherapy will be eligible for the trial. CONCLUSION: The patient selection criteria for the DBCG Proton Trial are mean heart dose ≥ 4 Gy and/or lung V17Gy/V20Gy ≥ 37%.

Intrafractional fiducial marker position variations in stereotactic liver radiotherapy during voluntary deep inspiration breath-hold.

OBJECTIVES: To evaluate intrafractional fiducial marker position variations during stereotactic body radiotherapy (SBRT) in patients treated for liver metastases in visually guided, voluntary deep inspiration breath-hold (DIBH). METHODS: 10 patients with implanted fiducial markers were studied. Respiratory coaching with visual guidance was used to ensure comfortable voluntary breath-holds for SBRT imaging and delivery. Three DIBH CTs were acquired for treatment planning. Pre- and post-treatment CBCTs were acquired for each of the three treatment fractions. Per-fraction marker position was evaluated on planar 2D kV images acquired during treatment fractions for 4 of the 10 patients. RESULTS: The median difference in marker position was 0.3 cm (range, 0.0-0.9 cm) between the three DIBH CTs and 0.3 cm (range, 0.1 to 1.4 cm) between pre- and post-treatment CBCTs. The maximum intrafractional variation in marker position in craniocaudal (CC) direction on planar kV images was 0.7 to 1.3 cm and up to 1.0 cm during a single DIBH. CONCLUSION: Difference in marker position of up to 1.0 cm was observed during a single DIBH despite use of narrow external gating window and visual feedback. Stability examination on pre-treatment DIBH CTs was not sufficient to guarantee per-fraction stability. Evaluation of differences in marker position on pre- and post-treatment CBCT did not always reveal the full magnitude of the intrafractional variation. ADVANCES IN KNOWLEDGE: To increase treatment accuracy, it is necessary to apply real-time monitoring of the tumour or a reliable internal surrogate when delivering liver SBRT in voluntary DIBH.

Biological optimization for mediastinal lymphoma radiotherapy - a preliminary study.

Purpose: In current radiotherapy (RT) planning and delivery, population-based dose-volume constraints are used to limit the risk of toxicity from incidental irradiation of organs at risks (OARs). However, weighing tradeoffs between target coverage and doses to OARs (or prioritizing different OARs) in a quantitative way for each patient is challenging. We introduce a novel RT planning approach for patients with mediastinal Hodgkin lymphoma (HL) that aims to maximize overall outcome for each patient by optimizing on tumor control and mortality from late effects simultaneously.Material and Methods: We retrospectively analyzed 34 HL patients treated with conformal RT (3DCRT). We used published data to model recurrence and radiation-induced mortality from coronary heart disease and secondary lung and breast cancers. Patient-specific doses to the heart, lung, breast, and target were incorporated in the models as well as age, sex, and cardiac risk factors (CRFs). A preliminary plan of candidate beams was created for each patient in a commercial treatment planning system. From these candidate beams, outcome-optimized (O-OPT) plans for each patient were created with an in-house optimization code that minimized the individual risk of recurrence and mortality from late effects. O-OPT plans were compared to VMAT plans and clinical 3DCRT plans.Results: O-OPT plans generally had the lowest risk, followed by the clinical 3DCRT plans, then the VMAT plans with the highest risk with median (maximum) total risk values of 4.9 (11.1), 5.1 (17.7), and 7.6 (20.3)%, respectively (no CRFs). Compared to clinical 3DCRT plans, O-OPT planning reduced the total risk by at least 1% for 9/34 cases assuming no CRFs and 11/34 cases assuming presence of CRFs.Conclusions: We developed an individualized, outcome-optimized planning technique for HL. Some of the resulting plans were substantially different from clinical plans. The results varied depending on how risk models were defined or prioritized.

Inverse radiotherapy planning based on bioeffect modelling for locally advanced left-sided breast cancer.

BACKGROUND AND PURPOSE: Treatment planning of radiotherapy (RT) for left-sided breast cancer is a challenging case. Several competing concerns are incorporated at present through protocol-defined dose-volume constraints, e.g. cardiac exposure and target coverage. Such constraints are limited by neglecting patient-specific risk factors (RFs). We propose an alternative RT planning method based solely on bioeffect models to minimize the estimated risks of breast cancer recurrence (BCR) and radiation-induced mortality endpoints considering patient-specific factors. METHODS AND MATERIALS: Thirty-nine patients with left-sided breast cancer treated with comprehensive post-lumpectomy loco-regional conformal RT were included. An in-house particle swarm optimization (PSO) engine was used to choose fields from a large set of predefined fields and optimize monitor units to minimize the total risk of BCR and mortality caused by radiation-induced ischaemic heart disease (IHD), secondary lung cancer (SLC) and secondary breast cancer (SBC). Risk models included patient age, smoking status and cardiac risk and were developed using published multi-institutional data. RESULTS: For the clinical plans the normal tissue complication probability, i.e. summed risk of IHD, SLC and SBC, was <3.7% and the risk of BCR was <6.1% for all patients. Median total decrease in mortality or recurrence achieved with individualized PSO plans was 0.4% (range, 0.06-2.0%)/0.5% (range, 0.11-2.2%) without/with risk factors. CONCLUSIONS: Inverse RT plan optimization using bioeffect probability models allows individualization according to patient-specific risk factors. The modelled benefit when compared to clinical plans is, however, modest in most patients, demonstrating that current clinical plans are close to optimal. Larger gains may be achievable with morbidity endpoints rather than mortality.

Individualized estimates of overall survival in radiation therapy plan optimization - A concept study.

PURPOSE: Current radiation therapy planning uses a set of defined dose-volume constraints to ensure a specified level of tumor coverage while constraining the dose distribution in the organs at risk. Such constraints are aggregated, population-based quantities that do not adequately consider patient-specific risk factors. Furthermore, these constraints are calculated for each organ independently and it is therefore not guaranteed that the optimal trade-off between organs is achieved. We introduce a novel radiotherapy planning approach where a patient-specific all-cause mortality risk is minimized using inverse plan optimization. As illustration of concept, our outcome risk model incorporates patient age, sex, cardiac risk factor (CRF), and smoking. METHODS AND MATERIALS: We retrospectively analyzed a left-sided breast cancer case and a Hodgkin's lymphoma case, both clinically treated with three-dimensional conformal radiotherapy (3D-CRT). Our objective function for inverse plan optimization was an equally weighted summation of risk models for cancer recurrence and mortality from radiation-induced coronary heart disease and secondary lung and breast cancers incorporating patient age, sex, CRF, and smoking. We allowed the optimization algorithm to choose from a large set of gantry angles. The optimization task was to choose beams and optimize monitor units (MUs) so that overall survival was maximized (and the total risk of cancer recurrence and mortality from radiation-induced causes were minimized). The sensitivity analysis was performed in the lymphoma case by changing the tumor control probability model from using mean dose (Model 1) to using generalized equivalent uniform dose (Model 2). RESULTS: For the breast case in this study, the 3D-CRT clinical plan used eight beams while the proposed 3D-CRT outcome-optimized plan used five beams, reducing the total risk - summation of the risks of recurrence and secondary disease mortality - from 3% to 2%. The mean doses to clinical target volume (CTV) and internal mammary nodes (IMN) were increased in the outcome-optimized plan by 1.9 and 1.8 Gy, respectively. For the Hodgkin's lymphoma case, the clinical 3D-CRT plan used two beams, while the proposed 3D-CRT outcome-optimized plan used three beams, reducing the total risk by 6% (from 16% to 10%). Using either of the two tumor control models for the lymphoma case resulted in outcome-optimized plans where tumor control was compensated at the cost of saving organs at risk. However, the impact of sensitivity to models was comparatively large. Using Model 1 resulted in a reduction in mean target dose by 15.2 vs 7.1 Gy for Model 2. In all cases, the chosen beams in outcome-optimized plans were different from clinically used beams. CONCLUSIONS: The proposed optimization strategy, supplanting dosimetric objectives with comprehensive individual risk estimates, has the potential to yield improved outcomes in terms of reduced mortality risk in cancer patients treated with radiotherapy. The approach is, however, currently limited by gaps in knowledge about the effect of compromising dose to part of the target, for example, in order to spare cardiac structures.