Intensity-modulated Photon Therapy Research Articles

Proton and photon radiotherapy in stage III NSCLC: Effects on hematological toxicity and adjuvant immune therapy

Background and purposeConcurrent chemo-radiotherapy (CCRT) followed by adjuvant durvalumab is standard-of-care for fit patients with unresectable stage III NSCLC. Intensity modulated proton therapy (IMPT) results in different doses to organs than intensity modulated photon therapy (IMRT). We investigated whether IMPT compared to IMRT reduce hematological toxicity and whether it affects durvalumab treatment. Materials and methodsProspectively collected series of consecutive patients with stage III NSCLC receiving CCRT between 06.16 and 12.22 (staged with FDG-PET-CT and brain imaging) were retrospectively analyzed. The primary endpoint was the incidence of lymphopenia grade ≥ 3 in IMPT vs IMRT treated patients. Results271 patients were enrolled (IMPT: n = 71, IMRT: n = 200) in four centers. All patients received platinum-based chemotherapy. Median age: 66 years, 58 % were male, 36 % had squamous NSCLC. The incidence of lymphopenia grade ≥ 3 during CCRT was 67 % and 47 % in the IMRT and IMPT group, respectively (OR 2.2, 95 % CI: 1.0–4.9, P = 0.03). The incidence of anemia grade ≥ 3 during CCRT was 26 % and 9 % in the IMRT and IMPT group respectively (OR = 4.9, 95 % CI: 1.9–12.6, P = 0.001). IMPT was associated with a lower rate of Performance Status (PS) ≥ 2 at day 21 and 42 after CCRT (13 % vs. 26 %, P = 0.04, and 24 % vs. 39 %, P = 0.02). Patients treated with IMPT had a higher probability of receiving adjuvant durvalumab (74 % vs. 52 %, OR 0.35, 95 % CI: 0.16–0.79, P = 0.01). ConclusionIMPT was associated with a lower incidence of severe lymphopenia and anemia, better PS after CCRT and a higher probability of receiving adjuvant durvalumab.

Radiotherapy and Systemic Therapies: Focus on Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) is a complex clinical entity, and its treatment strategy remains a challenge. The best practice management for individual HNSCC patients should be discussed within a multidisciplinary team. In the locally advanced disease, radiation therapy (RT) with or without concomitant cisplatin-based chemotherapy is the current standard of care for most patients treated definitively or adjuvantly after surgery. Intensity-modulated photon therapy (IMRT) is the recommended RT technique due to its ability to offer considerable treatment conformality while sparing surrounding normal critical tissues. At present, the development of novel treatment strategies, as well as alternative systemic agent combinations, is an urgent need to improve the therapeutic ratio in HNSCC patients. Despite the immune landscape suggesting a strong rationale for the use of immunotherapy agents in HNSCC, evidence-based data demonstrate that combining RT with immune checkpoint inhibitors as the primary treatment modality has not been shown to induce significant benefit on survival clinical outcomes. The objective of this article is to review the current literature on the treatment of patients with HNSCC. We initially provided a comprehensive overview of the standard of care. We then focused on the integration of systemic therapies with RT, highlighting the latest published evidence and ongoing trials which investigate different combination strategies in the definitive setting. Our hope is to summarize relevant literature in order to provide a foundation for interpreting emerging data and designing future trials to maximize care, both in disease control and patient quality of life.

Patient-specific quality assurance for deformable IMRT/IMPT dose accumulation: Proposition and validation of energy conservation based validation criterion.

Deformable image registration (DIR)-based dose accumulation (DDA) is regularly used in adaptive radiotherapy research. However, the applicability and reliability of DDA for direct clinical usage are still being debated. One primary concern is the validity of DDA, particularly for scenarios with substantial anatomical changes, for which energy-conservation problems were observed in conceptual studies. We present and validate an energy-conservation (EC)-based DDA validation workflow and further investigate its usefulness for actual patient data, specifically for lung cancer cases. For five non-small cell lung cancer (NSCLC) patients, DDA based on five selective DIR methods were calculated for five different treatment plans, which include one intensity-modulated photon therapy (IMRT), two intensity-modulated proton therapy (IMPT), and two combined proton-photon therapy (CPPT) plans. All plans were optimized on the planning CT (planCT) acquired in deep inspiration breath-hold (DIBH) and were re-optimized on the repeated DIBH CTs of three later fractions. The resulting fractional doses were warped back to the planCT using each DIR. An EC-based validation of the accumulation process was implemented and applied to all DDA results. Correlations between relative organ mass/volume variations and the extent of EC violation were then studied using Bayesian linear regression (BLR). For most OARs, EC violation within 10% is observed. However, for the PTVs and GTVs with substantial regression, severe overestimation of the fractional energy was found regardless of treatment type and applied DIR method. BLR results show that EC violation is linearly correlated to the relative mass variation (R^2>0.95) and volume variation (R^2>0.60). DDA results should be used with caution in regions with high mass/volume variation for intensity-based DIRs. EC-based validation is a useful approach to provide patient-specific quality assurance of the validity of DDA in radiotherapy.

In silico comparison of whole pelvis intensity-modulated photon versus proton therapy for the postoperative management of prostate cancer

Background Limited data exist comparing intensity-modulated photon (IMRT) and proton (IMPT) radiation therapy when treating the prostate bed and pelvic lymph nodes in the postoperative setting for prostate cancer. The aim of this study was to evaluate dosimetric differences between IMRT and IMPT when treating with whole pelvis radiation therapy (WPRT) postoperatively. Materials and methods IMRT and IMPT plans were generated for 10 post-prostatectomy patients treated between July and August 2020. The prescription was 50 Gy radiobiologic equivalent (GyE) (proton radiobiological effective dose 1.1) to the pelvis and 70 GyE to the prostate bed in 2 GyE per fraction. Paired 2-sided Wilcoxon signed-rank tests were used to compare clinical target volume (CTV) coverage and dose to organs at risk (OARs). Results CTV coverage was met for all plans with 99% of CTVs receiving ≥99% of prescription doses. Dose to OARs was significantly higher with IMRT than IMPT for the following endpoints: bladder V5-V65; bowel V5-V45; sigmoid V5-V50; rectum V5-V70; femoral head V40 and maximum dose; bone V5-V65. Select endpoints with significant differences included bladder V30 (63.5 vs. 44.4%, p < .001), bowel V15 (949 vs. 191 cc, p = .001) and V30 (386 vs. 121 cc, p < .001), rectum V40 (81.8 vs. 32.1%, p < .001) and V50 (47.6 vs. 24.9%, p < .001), femoral head maximum doses (46.4–47.1 vs. 38.3–38.6GyE, p < .001), and bone V10 (93.3 vs. 85.4%, p < . 001). Mean doses for all OARs were significantly higher with IMRT, including bladder (41.9 vs. 29.7GyE, p < .001), bowel (21.2 vs. 5.5GyE, p < .001), and rectum (50.8 vs. 27.3GyE, p < .001). Integral dose to ‘Body – CTV’ was significantly higher with IMRT (32.8 vs. 18.4 J, p < .001). Conclusion IMPT provides comparable target coverage to IMRT when treating prostate cancer with WPRT in the postoperative setting while significantly reducing dose to OARs. These data can inform the future clinical management and delivery of post-prostatectomy irradiation for prostate cancer.

Conformal Radiation Therapy for Ependymoma at Age ≤3 Years: A 25-Year Experience

Adjuvant radiation therapy (RT) affects survival after surgery for young children (age <3 years) diagnosed with intracranial ependymoma. Conformal photon RT promised to spare normal tissue and was introduced more than 25 years ago to improve outcomes for these vulnerable patients. Long-term results for those first treated with conformal methods provide valuable information and serve as a comparison against newer methods. Between 1997 and 2018, 101 patients <3.1-years-old were treated with conformal and intensity modulated photon therapy after definitive surgery for intracranial ependymoma. The median age at RT was 2.1 years and the time from diagnosis to the start of RT was 10 weeks. The extent of resection was gross-total in 82%, and 38% underwent more than 1 attempt at resection. The total prescribed dose was 54 to 59.4 Gy at 1.8 Gy per fraction. The 10-year event-free and overall survivals were 58.5% ± 5.0% and 72.6% ± 4.5%, respectively, with a median follow-up of 18.4 years (range, 4.2-23.3 years). Tumor progression occurred in 34 patients with a median time of 1.6 years. Death occurred in 34 patients from ependymoma (n=24), secondary malignancy (n=6), necrosis (n=2), shunt failure (n=1), and anaphylactic reaction (n=1). Twenty-three patients developed a secondary tumor including 6 cases of fatal high-grade glioma. Of the surviving cohort and those ≥18 years old, 98% obtained a high school diploma, 64% had a current driver's license, 89% were students or employed full or part time, 32% were living independently, and 70% received higher education or training. Long-term results of children treated using photon conformal RT after surgery demonstrate that adjuvant RT resulted in long-term disease control and functional independence. These results point to the need for new treatment strategies to improve tumor control and provide investigators hope that newer RT methods will further reduce complications.

Dosimetric evaluation of bone marrow sparing in proton radiotherapy for cervical cancer guided by MR functional imaging

BackgroundTo segment the pelvic active bone marrow (PABM) using magnetic resonance (MR) functional imaging and investigate the feasibility and dosimetric characteristics of cervical cancer proton radiotherapy for active bone marrow (ABM) sparing.MethodsWe collected CT and MR simulation images of 33 patients with cervical cancer retrospectively. The PBM was contoured on the MRI FatFrac images; the PBM was divided into high-active bone marrow (ABM-high) and low-active bone marrow based on the fat content of the PBM. Four radiotherapy plans were created for each patient, which included intensity-modulated photon therapy (IMRT), bone marrow sparing IMRT (IMRT-BMS), intensity-modulated proton therapy (IMPT), and bone marrow sparing IMPT (IMPT-BMS). The dosimetric differences among the four plans were compared.ResultsThe ABM-high volume in the enrolled patients accounted for 45.2% of the total ABM volume. The target coverage was similar among the four radiotherapy plans. IMRT-BMS, IMPT, and IMPT-BMS reduced the Dmean of ABM-high by 16.6%, 14.2%, and 44.5%, respectively, compared to the Dmean of IMRT (p < 0.05). IMPT-BMS had the best protective effect on the bone marrow. Compared to IMRT, the volume of ABM-high receiving an irradiation dose of 5–40 Gy decreased by 10.2%, 36.8%, 58.8%, 67.4%, 64.9%, and 44.5%, respectively (p < 0.001).ConclusionsThe MR functional imaging technique helped in the grading and segmentation of PABM. MR functional image-guided proton radiotherapy for cervical cancer can achieve optimal BMS.

Experimental Validation of a Real-Time Adaptive 4D-Optimized Particle Radiotherapy Approach to Treat Irregularly Moving Tumors

Treatment of locally advanced lung cancer is limited by toxicity and insufficient local control. Particle therapy could enable more conformal treatment than intensity modulated photon therapy but is challenged by irregular tumor motion, associated range changes, and tumor deformations. We propose a new strategy for robust, online adaptive particle therapy, synergizing 4-dimensional optimization with real-time adaptive beam tracking. The strategy was tested and the required motion monitoring precision was determined. In multiphase 4-dimensional dose delivery (MP4D), a dedicated quasistatic treatment plan is delivered to each motion phase of periodic 4-dimensional computed tomography (4DCT). In the new extension, "MP4D with residual tracking" (MP4DRT), lateral beam tracking compensates for the displacement of the tumor center-of-mass relative to the current phase in the planning 4DCT. We implemented this method in the dose delivery system of a clinical carbon facility and tested it experimentally for a lung cancer plan based on a periodic subset of a virtual lung 4DCT (planned motion amplitude 20mm). Treatments were delivered in a quality assurance-like setting to a moving ionization chamber array. We considered variable motion amplitudes and baseline drifts. The required motion monitoring precision was evaluated by adding noise to the motion signal. Log-file-based dose reconstructions were performed in silico on the entire 4DCT phantom data set capable of simulating nonperiodic motion. MP4DRT was compared with MP4D, rescanned beam tracking, and internal target volume plans. Treatment quality was assessed in terms of target coverage (D95), dose homogeneity (D5-D95), conformity number, and dose to heart and lung. For all considered motion scenarios and metrics, MP4DRT produced the most favorable metrics among the tested motion mitigation strategies and delivered high-quality treatments. The conformity was similar to static treatments. The motion monitoring precision required for D95 >95% was 1.9mm. With clinically feasible motion monitoring, MP4DRT can deliver highly conformal dose distributions to irregularly moving targets.

Modeling Variable Proton Relative Biological Effectiveness (RBE) Using Voxel-Level Image Density Change for Non-Small Cell Lung Cancer (NSCLC) Patients Treated with Passive Scattering Proton Therapy (PSPT) or Intensity Modulated Photon Therapy (IMRT)

<h3>Purpose/Objective(s)</h3> To test the hypothesis that radiation damage measured via lung image density change is a function of variable RBE for protons with a coefficient of determination (R²) greater than 0.8. <h3>Materials/Methods</h3> Data from 61 NSCLC patients previously treated on a prospective clinical trial with PSPT (N = 24) or IMRT (N = 37) to 74 Gy(RBE) (proton RBE of 1.1) were acquired. Patients with noticeable atelectasis or pleural effusion were excluded. For each patient, a ∼5-month post-treatment PETCT was obtained to assess response and was deformed to the planning exhale phase of the 4DCT (exCT) via a biomechanical model-based image registration algorithm. Subsequently, voxel-level image density change (IDC) within the normal ipsilateral lung was obtained by subtracting the exCT from the deformed PETCT, as a signal of biological damage. IMRT dose (D_x) was recalculated on the exCT using a commercial treatment planning system while the PSPT dose (D_p) and dose-averaged linear energy transfer (LET_d) were recalculated on the exCT using a commissioned track-repeating Monte-Carlo system. The fitted variable RBE models included a linear model (RBE = 1 + λ•LET_d) and a linear-quadratic (LQ) model (RBE = 1/(2D_p)•{√[(α/β)² + 4D_p(α/β)(p₀+(p₁•LET_d)/(α/β) + 4D_p²(p₂ + p₃•√(α/β)•LET_d)] - α/β}) with α/β = 3 Gy for lung tissue. <b>RBE was modeled against the ratio between D_x and D_p at given IDC levels.</b> We adapted Lyman-Kutcher-Burman normal tissue complication probability (NTCP) model to fit the dose-IDC relationship for each cohort by averaging the dose and IDC of voxels in 5-Gy dose intervals (adaptations: n = 1, effective dose = voxel dose, and complication probability = IDC normalized against global min and max IDC). LET_d corresponding to each D_p was approximated by averaging the LET_d of voxels that received D_p with a margin of 0.001Gy. All NTCP and RBE models were fitted using non-linear least squares with the Python SciPy package. <h3>Results</h3> For NTCP fitting, min and max IDC were 2.7 HU and 136.3 HU, respectively, and TD₅₀ and m were fitted to be 31.5 Gy and 0.51 for PSPT (R² = 0.99) and 44.4 Gy and 0.40 for IMRT (R² = 0.98). The table shows the IDC levels, the corresponding LET_d (SD), and the fitted D_x and D_p. The linear model resulted in λ = 0.154 µm/keV (R² = 0.27), and the LQ model resulted in p₀ = -0.72, p₁ = 10.02, p₂ = 1.51, and p₃ = -0.08 (R² = 0.999). <h3>Conclusion</h3> The study demonstrates that voxel-level radiation damage and image changes for proton therapy are functions of dose and LET and, thus, variable RBE.

957P Proton-therapy and concurrent chemotherapy in stage III NSCLC: Effects on toxicity and immune therapy

Concurrent chemo-radiotherapy (CCRT) followed by adjuvant durvalumab (D) represents standard of care for fit patients (pts) with unresectable stage III NSCLC. Aim: assess whether intensity modulated proton therapy (IMPT), compared to intensity modulated photon therapy (IMRT) can reduce lymphopenia (primary endpoint), and other toxicities; and whether IMPT affects immune related adverse events (irAEs) incidence.

113P Proton-therapy and concurrent chemotherapy in stage III NSCLC: Effects on durvalumab eligibility and safety profile

Concurrent chemo-radiotherapy (CCRT) followed by adjuvant Durvalumab (D) represents standard of care for patients (pts) with unresectable stage III NSCLC. The RT can be delivered with both protons and photons. An earlier start of adjuvant D after CCRT may lead to better outcome. Little is known about the effects of protons on adjuvant D efficacy and safety. We assessed whether intensity modulated proton therapy (IMPT), compared to intensity modulated photon therapy (IMRT) affects eligibility for D (primary endpoint) and immune related adverse events (IRAEs) (secondary endpoint) in pts with stage III NSCLC treated with CCRT and adjuvant D. Retrospective data completion and analysis of a 2-center prospectively collected series of pts with stage III NSCLC, receiving CCRT between 06.16 and 02.21, staged with FDG-PET and brain imaging. Main exclusion criteria were previous cancer diagnosis-within 2 years- and thoracic RT. A list of 226 pts was collected, 67 pts received adjuvant D and were included (IMPT: n=28, IMRT: n=39). Median age was 66 years, 52% were male, 33% had a squamous NSCLC and 42% had a WHO Performance Status (PS) of 0 before CCRT. All pts received 60-64 Gy of RT. Programmed death-ligand 1 (PDL-1) level was available for 76% of pts and 39% had a PDL-1 ≥ 50% (no significant differences between IMPT and IMRT). At day 21 after CCRT, 93% (IMPT) vs 72% (IMRT) treated pts had a PS≤1 (Odds Ratio 0.8, 95% CI: 0.67-0.95, p=0.03). The median time from the end of CCRT and start of D was 32 vs 38 days respectively (Not Significant (NS)). IRAEs of any grade were reported in 21% versus 31% of pts treated with IMPT versus IMRT, respectively (NS). Hypothyroidism accounted for 44% of IRAEs. Any grade (grade 3) pneumonitis during D was reported in 25% (7%) of IMPT and 23% (5%) of IMRT (NS). Median follow-up was 19.5 months and 9.5 months for IMRT and IMPT, respectively. 90% of pts were still alive and 73% were disease free. IMPT vs IMRT treated pts received a significantly lower RT dose to bone marrow, heart and lungs. PS at day 21 after CCRT was better in IMPT treated pts, potentially increasing eligibility for adjuvant D. The lower RT dose delivered with IMPT might explain our findings. IMPT appears to be as safe as IMRT regarding IRAEs during D.

Comparison of 3D Conformal Proton Therapy, Intensity-Modulated Proton Therapy, and Intensity-Modulated Photon Therapy for Retroperitoneal Sarcoma

Background External beam radiation therapy (RT) for retroperitoneal sarcoma often requires treatment of large target volumes close to critical normal tissues. Radiation may be limited by adjacent organs at risk (OAR). Intensity-modulated radiation therapy has been shown to improve target coverage and reduce doses to OAR. Objectives To compare target coverage and dose to OAR with 3D conformal proton therapy (3D CPT), intensity-modulated proton therapy (IMPT), and intensity-modulated photon therapy (IMXT). Methods We performed a comparative study of treatment plans with 3D CPT, IMPT, and IMXT for ten patients with retroperitoneal sarcomas. RT was delivered to 50.4 Gy to the clinical target volume (CTV), the structures considered at risk for microscopic disease. Results CTVs ranged from 74 to 357 cc (mean 188 cc). Dose conformity was improved with IMPT, while 3D CPT provided better dose homogeneity. Mean dose to the liver, small bowel, and stomach was reduced with IMPT compared with 3D CPT or IMXT. Conclusions IMPT, 3D CPT, and IMXT provide excellent target coverage for retroperitoneal sarcomas. OAR dose is lower with IMPT and 3D CPT, and IMPT achieves the closest conformity. These techniques offer the opportunity for further dose escalation to areas with positive margins.

Modern Therapy for Spinal and Paraspinal Ewing Sarcoma: An Update of the University of Florida Experience

In 2010, we published a comprehensive review of our institutional outcomes about treating children with spinal and paraspinal Ewing sarcoma using photon therapy. Multimodality therapy was associated with fair disease control but also with serious toxicity, including a 37% rate of grade 3 or greater toxicity. We therefore sought to assess our more recent experience about treating children with more modern technology and treatment regimens. Between 2010 and 2021, 32 pediatric patients with nonmetastatic spinal and paraspinal Ewing sarcoma were treated at University of Florida and enrolled in a retrospective outcome study. Median age at diagnosis was 9.8 years (range, 2.1-21.8 years). Within the cervical, thoracic, and lumbar spine regions, 3, 22, and 7 tumors arose, respectively. Median maximum tumor diameter was 5 cm (range, 3-19 cm). At diagnosis, 28 of 32 patients had motor, bowel, or bladder deficits. Chemotherapy was delivered according to contemporary North American and European interval-compressed regimens. Before radiation therapy, 14 patients underwent gross total resection, whereas 18 underwent a biopsy or subtotal resection with cord decompression. All patients were treated with proton therapy; 6 with hardware stabilization also received a component of intensity modulated photon therapy. Median prescription dose was 50.4 gray relative biological effectiveness (GyRBE; range, 45-55.8 GyRBE). Median maximum dose to the spinal cord was 50.2 GyRBE (range, 0-54.9 GyRBE). With a median follow-up of 4.1 years (range, 0.7-9.4 years), the 5-year local control, progression-free survival, and overall survival rates were 92%, 79%, and 85%, respectively. Ten of 30 living patients have residual motor, bowel, or bladder deficits. Overall, 22% of patients experienced Common Terminology Criteria for Adverse Events grade 3 late toxicity related to multimodality treatment: kyphosis (n=4), esophagitis (n=2), and chronic kidney disease (n=1). No patients developed grade 4 or greater toxicity, new neurologic deficits, or second malignancy. Modern treatment advances may offer an improved therapeutic ratio for pediatric patients with spinal and paraspinal Ewing sarcoma. With appropriate management, most patients can be cured with recovery of long-term neurologic function and modest side effects.

Radiotherapy alone for pediatric patients with craniopharyngioma.

Radiotherapy alone, without tumor-directed surgery, may be appropriate for selected patients with craniopharyngioma reducing the risks associated with neurosurgery. Understanding outcomes for patients with craniopharyngioma treated with radiotherapy alone will further refine patient selection and treatment options. Since 2002, 13 children, adolescents and young adults, with craniopharyngioma were treated with radiotherapy alone and followed for disease control and functional outcomes at a single institution. The median age at treatment was 13years (range, 3-21years). All patients received 54Gy/54Gy(RBE) in 30 fractions. Five patients were treated with intensity-modulated photon therapy, four with passively scattered proton therapy, and four with intensity-modulated proton therapy. With a median follow-up of 5years (range 3months-14years), all patients were alive. One experienced tumor progression 8.5years after treatment. No significant changes in vision, hearing or neurologic function attributed to radiotherapy. Hormone deficiencies and body mass index were within the expected range at baseline and 5years after treatment. There was no evidence of cognitive decline based on assessment of IQ, memory and attention. Unexpected complications included single cases of out-of-field malignancy, white matter changes, large vessel narrowing, and pontine capillary telangiectasia. Six patients had sphenoid bone abnormalities on follow-up imaging attributed to radiotherapy. Radiotherapy alone is an important treatment option to consider when radical resection is contraindicated, or surgical intervention is not required to alleviate symptoms. Disease control and functional outcomes are excellent after radiation therapy alone in appropriately selected patients.

Development and Validation of a Spatial Dose Pattern Based Model Predicting Acute Pulmonary Toxicity in Patients Treated With Volumetric Arc-Therapy for Locally Advanced Lung Cancer

<h3>Purpose/Objective(s)</h3> (Chemo)-radiotherapy is the standard treatment for patients with locally advanced lung cancer (LALC) not accessible to surgery. Despite strict application of dose constraints, acute toxicities such as acute pulmonary toxicity (APT) remain frequent, and may impact treatment's compliance and patients' quality of life. Previously, on a population treated with intensity-modulated photon therapy or passive scattering proton therapy, spatial dose patterns associated with APT were identified in the lower lungs, especially in the lower right lung. In the present study, we aim to define these spatial dose patterns on a retrospective cohort treated by volumetric-arc therapy (VMAT) and to validate our findings prospectively. <h3>Materials/Methods</h3> For the training cohort, we retrospectively included all patients treated in our institution by VMAT for a LALC between 2015 and 2018. APT was scored according to the CTCAE v4.0 scale. All dose maps were registered to a thorax phantom using a segmentation-based elastic registration. Voxel-based analysis of local dose differences was performed with a non-parametric permutation test accounting for <i>n = 10.000</i> permutations, producing a 3-dimensional significance maps on which clusters of voxels that exhibited significant dose differences (<i>P < 0.05</i>) between the two toxicity groups (APT ≥ grade 2 vs APT < grade 2) were identified. A dose cut-off was defined by maximizing the Youden-Index derived from the Receiver Operative Curve. For the validation cohort, we applied the predefined spatial dose pattern and the dose cut-off to an observational prospective cohort. The model was evaluated using the Area under the curve (AUC) and the balanced accuracy (Bacc: mean of the sensitivity and specificity). <h3>Results</h3> 167 and 42 patients were included in the training and validation cohorts, with respective APT rates of 22.2% and 21.4%. In the training cohort, a cluster of voxels was identified in the lower right lung with a cut off of 30.3 Gy for the D_mean(mean-dose). This spatial-based model resulted in an AUC of 0.69 and a Bacc of 0.71. Using the same voxel cluster and the D_meancut-off on the validation cohort, the model resulted in an AUC of 0.74 and a Bacc of 0.69. <h3>Conclusion</h3> Our model corroborates previous findings regarding the possible role of the lower right lung regarding the development of APT and successfully evaluates its robustness in a prospective cohort treated by VMAT. Regional radiosensitivity should be considered in usual lung dose constraints.

Development and prospective validation of a spatial dose pattern based model predicting acute pulmonary toxicity in patients treated with volumetric arc-therapy for locally advanced lung cancer

Introduction(Chemo)-radiotherapy is the standard treatment for patients with locally advanced lung cancer (LALC) not accessible to surgery. Despite strict application of dose constraints, acute toxicities such as acute pulmonary toxicity (APT) remain frequent, and may impact treatment’s compliance and patients’ quality of life. Previously, on a population treated with intensity-modulated photon therapy or passive scattering proton therapy, spatial dose patterns associated with APT were identified in the lower lungs, especially in the posterior right lung. In the present study, we aim to define these spatial dose patterns on a retrospective cohort treated by volumetric-arctherapy (VMAT) and to validate our findings prospectively. MethodsFor the training cohort, we retrospectively included all patients treated in our institution by VMAT for a LALC between 2015 and 2018. APT was scored according to the CTCAE v4.0 scale. All dose maps were registered to a thorax phantom using a segmentation-based elastic registration. Voxel-based analysis of local dose differences was performed with a non-parametric permutation test accounting for n = 10.000 permutations, producing a 3-dimensional significance maps on which clusters of voxels that exhibited significant dose differences (p < 0.05) between the two toxicity groups (APT ≥ grade 2 vs APT < grade 2) were identified. A prediction model (Pmap-Model) was then built using a neural network approach and then applied to an observational prospective cohort for validation. The model was evaluated using the Area under the curve (AUC) and the balanced accuracy (Bacc: mean of the sensitivity and specificity). Results165 and 42 patients were included in the training and validation cohorts, with respective APT rates of 22.4% and 19.1%. In the training cohort, a cluster of voxels (Pmap-region) was identified in the posterior right lung. In the training cohort, the Pmap-Model combining 11 features among which the mean dose to the Pmap-region resulted in an AUC of 0.99 and a Bacc of 99.2 using an 8% probability threshold. Using the same voxel cluster on the validation cohort, the Pmap-model resulted in an AUC of 0.81 and a Bacc of 82.0. ConclusionOur APT-prediction model was successfully validated in a prospective cohort treated by VMAT. Regional radiosensitivity should be considered in usual lung dose constraints, opening the possibility of easily implementable adaptive dosimetry planning.

Work Outcomes after Intensity-Modulated Proton Therapy (IMPT) versus Intensity-Modulated Photon Therapy (IMRT) for Oropharyngeal Cancer.

PurposeWe compared work outcomes in patients with oropharyngeal cancer (OPC), randomized to intensity-modulated proton (IMPT) versus intensity-modulated photon therapy (IMRT) for chemoradiation therapy (CRT).Patients and MethodsIn 147 patients with stage II-IVB squamous cell OPC participating in patient-reported outcomes assessments, a prespecified secondary aim of a randomized phase II/III trial of IMPT (n = 69) versus IMRT (n = 78), we compared absenteeism, presenteeism (i.e., the extent to which an employee is not fully functional at work), and work productivity losses. We used the work productivity and activity impairment questionnaire at baseline (pre-CRT), at the end of CRT, and at 6 months, 1 year, and 2 years. A one-sided Cochran-Armitage test was used to analyze within-arm temporal trends, and a χ2 test was used to compare between-arm differences. Among working patients, at each follow-up point, a 1-sided Wilcoxon rank-sum test was used to compare work-productivity scores.ResultsPatient characteristics in IMPT versus IMRT arms were similar. In the IMPT arm, within-arm analysis demonstrated that an increasing proportion of patients resumed working after IMPT, from 60% (40 of 67) pre-CRT and 71% (30 of 42) at 1 year to 78% (18 of 23) at 2 years (P = 0.025). In the IMRT arm, the proportion remained stable, with 57% (43 of 76) pre-CRT, 54% (21 of 39) at 1 year, and 52% (13 of 25) working at 2 years (P = 0.47). By 2 years after CRT, the between-arm difference between patients who had IMPT and those who had IMRT trended toward significance (P = 0.06). Regardless of treatment arm, among working patients, the most severe work impairments occurred from treatment initiation to the end of CRT, with significant recovery from absenteeism, presenteeism, and productivity impairments by the 2-year follow-up (P < 0.001 for all). Higher magnitudes of recovery from absenteeism (at 1 year, P = 0.05; and at 2 years, P = 0.04) and composite work impairment scores (at 1 year, P = 0.04; and at 2 years, P = 0.04) were seen in patients treated with IMPT versus those treated with IMRT.ConclusionIn patients with OPC receiving curative CRT, patients randomized to IMPT demonstrated increasing work and productivity recovery trends. Studies are needed to identify mechanisms underlying head and neck CRT treatment causing work disability and impairment.

Cardiac-Sparing and Breast-Sparing Whole Lung Irradiation Using Intensity-Modulated Proton Therapy.

PurposeWhole lung irradiation (WLI) is indicated for certain pediatric patients with lung metastases. This study investigated whether WLI delivered as intensity-modulated proton therapy (IMPT) could significantly spare the heart and breasts when compared with conventional WLI delivered with anteroposterior/posteroanterior photon fields and with intensity-modulated photon therapy (IMRT) WLI.Materials and MethodsConventional, IMRT, and IMPT plans were generated for 5 patients (aged 5-22 years). The prescription dose was 16.5 GyRBE in 1.5-GyRBE fractions. Conventional plans used 6-MV photons prescribed to the midline and a field-in-field technique to cover the planning target volume (the internal target volume [ITV] + 1 cm). IMRT plans used 6-MV photons with a 7-beam arrangement with dose prescribed to the planning target volume. IMPT plans used scenario-based optimization with 5% range uncertainty and 5-mm positional uncertainty to cover the ITV robustly. Monte Carlo dose calculation was used for all IMPT plans. Doses were compared with paired Student t test.ResultsThe ITV Dmean was similar for the IMPT, conventional, and IMRT plans, but the IMPT plans had a lower Dmin and a higher Dmax at tissue interfaces than conventional plans (Dmean ratio: 0.96, P > .05; Dmin ratio: 0.9, P < .001; Dmax ratio: 1.1, P = .014). Dmeans for breast and heart substructures were lower with IMPT plans than with conventional/IMRT plans (heart ratios, 0.63:0.73; left ventricle ratios, 0.61:0.72; right ventricle ratios, 0.45:0.57; left atrium ratios, 0.79:0.85; right atrium ratios, 0.81:0.86; left breast ratios, 0.40:0.51; right breast ratio, 0.46:0.52; all P < .05).ConclusionsIMPT resulted in comparable ITV coverage and lower mean doses to the heart and breasts when compared with other techniques. Whole lung irradiation delivered as IMPT warrants prospective evaluation in pediatric patients.

Proton Therapy for Nasopharyngeal Cancer: A Matched Case-control Study of Intensity-Modulated Proton Therapy and Intensity-Modulated Photon Therapy

Proton Therapy for Nasopharyngeal Cancer: A Matched Case-control Study of Intensity-Modulated Proton Therapy and Intensity-Modulated Photon Therapy

Results of a Phase 1/2 Trial of Chemoradiotherapy With Simultaneous Integrated Boost of Radiotherapy Dose in Unresectable Locally Advanced Esophageal Cancer

Effective treatment options for locally advanced esophageal cancer are limited, and rates of local recurrence after standard chemoradiotherapy remain high. To evaluate toxic effects, local control, and overall survival rates after chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose to the gross tumor and nodal disease for patients with unresectable locally advanced esophageal cancer. A phase 1/2, single-arm trial was conducted in 46 patients from April 28, 2010, to April 9, 2015 (median follow-up, 52 months [range, 2-86 months]), at a tertiary academic cancer center. Outcomes of the study patients were compared with those of 97 similar patients treated at the same institution from January 10, 2010, to December 5, 2014, as part of the interim analysis. Statistical analysis was performed from December 15, 2018, to February 12, 2019. Chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose (50.4 Gy to subclinical areas at risk and 63.0 Gy to the gross tumor and involved nodes, all given in 28 fractions) with concurrent docetaxel and capecitabine or fluorouracil. Toxic effects, local (in-field) control, and overall survival rates. All 46 patients (11 women and 35 men; median age, 65.5 years [range, 37.3-84.4 years]) received per-protocol therapy, as intensity-modulated photon therapy (39 [85%]) or intensity-modulated proton therapy (7 [15%]); 11 patients (24%) ultimately underwent resection. No patients experienced grade 4 or 5 toxic effects; the 10 acute grade 3 toxic events were esophagitis (4), dysphagia (3), and anorexia (3) and the 3 late grade 3 toxic events were all esophageal strictures. The actuarial local recurrence rates were 22% (95% CI, 11%-35%) at 6 months, 30% (95% CI, 18%-44%) at 1 year, and 33% (95% CI, 20%-46%) at 2 years. Overall, 15 patients (33%) experienced local failure, at a median interval of 5 months (range, 1-24 months). The median overall survival time was 21.5 months (range, 2.3-86.4 months). Exploratory comparison with a 97-patient contemporaneous institutional cohort receiving standard-dose (non-simultaneous integrated boost) chemoradiotherapy showed superior local control (hazard ratio, 0.49; 95% CI, 0.26-0.92; P = .03) and overall survival (hazard ratio, 0.66; 95% CI, 0.47-0.94; P = .02) in the group that received chemoradiotherapy with a simultaneous integrated boost. These findings suggest that chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose for locally advanced esophageal cancer is well tolerated, with encouraging local control, and thus warrants further study. ClinicalTrials.gov identifier: NCT01102088.

Impact of Intensity-Modulated Proton Therapy vs. Intensity-Modulated Photon Therapy on Preserving Work and Productivity in Oropharyngeal Cancer Patients: Outcomes of a Multi-Institution Randomized Trial

Oropharyngeal cancer (OPC) patients undergoing chemoradiation (CRT) are at high risk for “financial toxicity” from missed or lost work during and after treatment, as patients undergo intensive multimodality therapy impacting acute and long-term daily activities/function. Despite growing appreciation for the need to identify optimal CRT approaches that enable preserving work, productivity, and economic burden, no randomized studies have compared how treatments impact work outcomes in OPC. We compared the effect of intensity-modulated proton therapy (IMPT) vs intensity-modulated photon therapy (IMRT) on work and productivity outcomes in OPC patients receiving CRT on a randomized trial. From 2014-2018, 188 patients were randomized to IMPT vs. IMRT for stage II-IVB (7th ed) squamous cell carcinoma of the oropharynx, stratified by induction chemotherapy, HPV/p16 and smoking. A pre-specified aim compared patient-reported work outcomes using the validated Work Productivity and Activity Impairment (WPAI) questionnaire at baseline, end of CRT, 6 months, 1 year, and 2 years. Patients reported whether they were working, and working patients scored (0-100) levels of absenteeism, impairment while working, and productivity losses over the prior 7 days. Cochran-Armitage test analyzed differences in the proportion of patients working during follow-up. WPAI scores were compared using the Wilcoxon rank sum test. Mixed effects models tested longitudinal predictors. In 96 patients receiving IMPT and 92 IMRT, median age was 59. Baseline demographics, stage, employment, and insurance were balanced. 78% (n=147) participated in patient-reported outcomes aims, with evaluable responses in 79% of patients at 6 months, 67% at 1 year and 44% at 2 years. At baseline, there was no difference in the proportion of working IMPT patients (61%) vs. IMRT patients (58%) (P=0.71). However, among IMPT patients, the proportion who returned to/maintained work after treatment significantly increased over time, from 63%-78% (P=0.02). In contrast, among IMRT patients, the proportion working was unchanged over time, from 48%-55% (P=0.58). Among working patients, absenteeism, impaired work, and productivity loss ascribed to cancer did not differ by treatment arms, approaching baseline scores by 2 years (P= 0.17 to 0.80 for IMPT vs. IMRT scores at end of CRT, 6 months, 1 year, and 2 years). Adjusted scores were comparable in multivariate models. After CRT for OPC, patients undergoing IMPT were more frequently able to return to work with comparable productivity vs. those undergoing IMRT, demonstrating an absolute benefit of 26% at 2 years. Results provide Level 1 evidence in a randomized setting, using novel outcomes measures to demonstrate favorable societal- and patient-level economic impacts of IMPT for patients with OPC.Abstract 2977; Table 1Proportion of patients working (%)RandomizationPre-CRTEnd of CRT6 Months1 Year2 YearsPPBT61%63%71%71%78%0.02IMRT58%48%55%54%52%0.58 Open table in a new tab