Sio, Terence T.

Purpose To compare the dosimetric performances of small‐spot three‐dimensional (3D) and four‐dimensional (4D) robustly optimized intensity‐modulated proton (IMPT) plans in the presence of uncertainties and interplay effect simultaneously for distal esophageal carcinoma. Method and Materials Thirteen (13) patients were selected and re‐planned with small‐spot ( ~ 2–6 mm) 3D and 4D robust optimization in IMPT, respectively. The internal clinical target volumes (CTV high3d , CTV low3d ) were used in 3D robust optimization. Different CTVs (CTV high4d , CTV low4d ) were generated by subtracting an inner margin of the motion amplitudes in three cardinal directions from the internal CTVs and used in 4D robust optimization. All patients were prescribed the same dose to CTVs (50 Gy[RBE] for CTV high3d /CTV high4d and 45 Gy[RBE] for CTV low3d /CTV low4d ). Dose–volume histogram (DVH) indices were calculated to assess plan quality. Comprehensive plan robustness evaluations that consisted of 300 perturbed scenarios (10 different motion patterns to consider irregular motion (sampled from a Gaussian distribution) and 30 different uncertainties scenarios (sampled from a 4D uniform distribution) combined), were performed to quantify robustness to uncertainties and interplay effect simultaneously. Wilcoxon signed‐rank test was used for statistical analysis. Results Compared to 3D robustly optimized plans, 4D robustly optimized plans had statistically improved target coverage and better sparing of lungs and heart (heart D mean , P = 0.001; heart V 30Gy[RBE] , P = 0.001) in the nominal scenario. 4D robustly optimized plans had better robustness in target dose coverage (CTV high4d V 100% , P = 0.002) and the protection of lungs and heart (heart D mean , P = 0.001; heart V 30Gy[RBE] , P = 0.001) when uncertainties and interplay effect were considered simultaneously. Conclusions Even with small spots in IMPT, 4D robust optimization outperformed 3D robust optimization in terms of normal tissue protection and robustness to uncertainties and interplay effect simultaneously. Our findings support the use of 4D robust optimization to treat distal esophageal carcinoma with small spots in IMPT.

Abstract Purpose To compare the dosimetric performances of intensity‐modulated proton therapy (IMPT) plans generated with two different beam angle configurations (the Right–Left oblique posterior beams and the Superior–Inferior oblique posterior beams) for the treatment of distal esophageal carcinoma in the presence of uncertainties and interplay effect. Methods and Materials Twenty patients’ IMPT plans were retrospectively selected, with 10 patients treated with the R‐L oblique posterior beams (Group R‐L) and the other 10 patients treated with the S‐I oblique posterior beams (Group S‐I). Patients in both groups were matched by their clinical target volumes (CTVs—high and low dose levels) and respiratory motion amplitudes. Dose‐volume‐histogram (DVH) indices were used to assess plan quality. DVH bandwidth was calculated to evaluate plan robustness. Interplay effect was quantified using four‐dimensional (4D) dynamic dose calculation with random respiratory starting phase of each fraction. Normal tissue complication probability (NTCP) for heart, liver, and lung was calculated, respectively, to estimate the clinical outcomes. Wilcoxon signed‐rank test was used for statistical comparison between the two groups. Results Compared with plans in Group R‐L, plans in Group S‐I resulted in significantly lower liver D mean and lung V 30Gy[RBE] with slightly higher but clinically acceptable spinal cord D max . Similar plan robustness was observed between the two groups. When interplay effect was considered, plans in Group S‐I performed statistically better for heart D mean and V 30Gy[RBE] , lung Dmean and V 5Gy[RBE] , and liver D mean , with slightly increased but clinically acceptable spinal cord D max . NTCP for liver was significantly better in Group S‐I. Conclusions IMPT plans in Group S‐I have better sparing of liver, heart, and lungs at the slight cost of spinal cord maximum dose protection, and are more interplay‐effect resilient compared to IMPT plans in Group R‐L. Our study supports the routine use of the S‐I oblique posterior beams for the treatments of distal esophageal carcinoma.

Purpose Intensity‐modulated proton therapy (IMPT) is sensitive to uncertainties from patient setup and proton beam range, as well as interplay effect. In addition, respiratory motion may vary from cycle to cycle, and also from day to day. These uncertainties can severely degrade the original plan quality and potentially affect patient’s outcome. In this work, we developed a new tool to comprehensively consider the impact of all these uncertainties and provide plan robustness evaluation under them. Methods We developed a comprehensive plan robustness evaluation tool that considered both uncertainties from patient setup and proton beam range, as well as respiratory motion simultaneously. To mimic patients' respiratory motion, the time spent in each phase was randomly sampled based on patient‐specific breathing pattern parameters as acquired during the four‐dimensional (4D)‐computed tomography (CT) simulation. Spots were then assigned to one specific phase according to the temporal relationship between spot delivery sequence and patients’ respiratory motion. Dose in each phase was calculated by summing contributions from all the spots delivered in that phase. The final 4D dynamic dose was obtained by deforming all doses in each phase to the maximum exhalation phase. Three hundred (300) scenarios (10 different breathing patterns with 30 different setup and range uncertainty scenario combinations) were calculated for each plan. The dose‐volume histograms (DVHs) band method was used to assess plan robustness. Benchmarking the tool as an application’s example, we compared plan robustness under both three‐dimensional (3D) and 4D robustly optimized IMPT plans for 10 nonrandomly selected patients with non‐small cell lung cancer. Results The developed comprehensive plan robustness tool had been successfully applied to compare the plan robustness between 3D and 4D robustly optimized IMPT plans for 10 lung cancer patients. In the presence of interplay effect with uncertainties considered simultaneously, 4D robustly optimized plans provided significantly better CTV coverage (D 95% , P = 0.002), CTV homogeneity (D 5% ‐D 95% , P = 0.002) with less target hot spots (D 5% , P = 0.002), and target coverage robustness (CTV D 95% bandwidth, P = 0.004) compared to 3D robustly optimized plans. Superior dose sparing of normal lung (lung D mean , P = 0.020) favoring 4D plans and comparable normal tissue sparing including esophagus, heart, and spinal cord for both 3D and 4D plans were observed. The calculation time for all patients included in this study was 11.4 ± 2.6 min. Conclusion A comprehensive plan robustness evaluation tool was successfully developed and benchmarked for plan robustness evaluation in the presence of interplay effect, setup and range uncertainties. The very high efficiency of this tool marks its clinical adaptation, highly practical and versatile nature, including possible real‐time intra‐fractional interplay effect evaluation as a potential application for future use.

Abstract Background Stereotactic ablative radiotherapy (SABR) is effective for thoracic cancer and metastases; however, adverse effects are greater for central tumors. We evaluated factors affecting outcomes and toxicities after SABR for patients with primary lung and oligometastatic tumors. Patients and methods We retrospectively identified consecutive patients with centrally located lung tumors that were treated at our hospital from 2009-2016. The effects of patient, disease, and treatment-related parameters on local control (LC), overall survival (OS), and toxicity-free survival (TFS) were evaluated with multivariate analyses. Results Among 65 consecutive patients identified with 70 centrally located tumors, 20 tumors (28%) were reirradiated. Median (range) total dose for all tumors was 55 (30–60) Gy in 5 (3–10) fractions. Radiographic complete response was obtained in 43 lesions (61%). None of the analyzed factors were correlated with complete response. After a median follow-up of 57 (95% CI, 48–65) months, 10 tumors (14%) relapsed and 37 patients (57%) died; the actuarial 2- and 5-year OS rates were 52% and 28%, respectively. Median OS was significantly lower in patients with grade 3 or higher toxicity vs . lower toxicity (5 vs . 39 months; P < 0.001). Among 17 severe toxicities, 5 were grade 5, and 3 of them were reirradiated to the same field. Grade 3 to 5 TFS was lower with vs . without reirradiation (2-year TFS, 63% vs . 96%; P = 0.02). Conclusions Our study showed that modern SABR is effective for central lung tumors, and toxicities are acceptable. SABR for reirradiated central lung lesions and possibly for lesions abutting the tracheobronchial tree may result in higher risk of serious toxicities.

494 Background: Our aim was to compare survival between patients receiving neoadjuvant chemoradiation and orthotopic liver transplantation (OLT group) versus definitive chemoradiation (CRT group) for extrahepatic or hilar cholangiocarcinoma. Methods: 49 patients (20 in OLT group vs. 29 in CRT group) with unresectable hilar/extrahepatic cholangiocarcinoma were treated at Mayo Clinic Arizona between Feb. 1998–Sep. 2019. Treatment included external beam radiation therapy (median 4500cGy) and boost (median 900cGy) with either continuous 5-flurouracil (dose range 180–225 mg/m2) or capecitabine (dose range 825–1000 mg/m2 BID) prior to or without OLT. Radiation boosts were delivered with EBRT or bile duct brachytherapy. Patients were between 27.9–84.3 years (median 64.3) at diagnosis. 18 patients had previous diagnosis of PSC. Results: Between Feb. 1998–Sep. 2019, 31(63%) of 49 patients died by the end of follow-up. Of patients treated with neoadjuvant therapy and OLT, 7(35%) of 20 patients died. 24(86%) of 28 patients treated with definitive therapy died. The OLT cohort were younger (mean age 56.5 vs. 69.0 years), more likely to have PSC and UC (65% vs. 17%), and had a lower CA 19-9 (median 43 vs. 535)(P < 0.003). From the end date of radiation, median overall survival was 76.8 months vs. 15.6 months for the OLT and CRT groups, respectively. Survival rates at 3 and 5 years were 78% and 69% in the OLT group compared to 19% and 6% in the CRT group (HR 7.73; 3.04-19.65:(P < 0.0001)). Progression-free survival (89% vs. 30% at 3 years), and distant metastasis-free survival (88% vs. 66% at 3 years) favored OLT versus CRT alone (HR 5.74;1.12-29.34:(P < 0.02)). Univariate analysis demonstrated that the method of treatment (OLT vs. CRT) was the only variable associated with better clinical outcomes. Conclusions: In patients with unresectable extrahepatic/hilar cholangiocarcinoma, survival was higher in those who underwent chemoradiation and OLT. Patients who received definitive chemoradiation in the absence of OLT were expected to have worse overall, progression-free, and metastasis-free survival.

Objective:Radiation therapy (RT) is the primary treatment of intracranial metastasis (ICM) from lung cancer (LC). Radiation necrosis (RN) has been reported post-RT with an incidence of 5% to 24%. We reviewed the spectrum of imaging changes in patients treated with RT for ICM from LC in an effort to identify potential risk factors for RN.Methods:We reviewed 63 patients with LC and ICM who received RT (radiosurgery [stereotactic radiosurgery] with/without whole brain radiation therapy) at our institution between 2013 and 2018. Data evaluated included demographics, tumor type, ICM burden and location, chemotherapy, surgery, and RT details as well as treatment choices and outcomes.Results:Of the 63 patients, clinical and radiographic criteria for RN were noted in 24 (38%) as early as 2 months and as late as 5 years posttreatment. Six patients required surgical resection due to refractory symptoms revealing pathology-proven RN and occasionally tumor. Patients were significantly more likely to develop RN if they had surgical resection of an ICM (45.8% vs. 20.5%,P=0.05). No differences were found in location, size, or genetic profile of lesions. In total, 80% of patients received treatment for symptoms and/or radiographic change. This was generally a combination of steroids, bevacizumab, laser interstitial thermal treatment, or surgical resection. Most patients required >1 treatment modality.Conclusions:This review of outcomes of RT for ICM in LC demonstrates a higher rate of RN than previously reported in the literature in those having had a surgical resection plus stereotactic radiosurgery. Our observation of RN as late as 5 years post-RT for ICM necessitates clinician awareness.

Abstract BACKGROUND Radiation is an integral component of the multidisciplinary treatment of patients with intracranial metastasis (ICM) from melanoma. The risk of radiation necrosis (RN) post-treatment can range from 5–25%. We retrospectively evaluated pre- and post-radiation clinical and radiographical characteristics in patients with ICM from melanoma to identify potential risk factors for RN. METHODS After IRB approval, patients with ICM from melanoma who received radiation at our institution between 2013 and 2018 were retrospectively reviewed. We recorded demographics, intracranial metastasis (burden and location), systemic therapy, resection, stereotactic radiosurgery versus whole brain radiation, and outcomes. Brain MRI was evaluated using the Response Assessment in Neuro-Oncology criteria (RANO). RESULTS A total of 27 patients were included in the study. RN was diagnosed in 14 patients (52%) at one month to three years following radiation. Cerebellar location (n=7) was significantly associated with RN (p=0.0058). Metastasis-associated hemorrhage was present in 7 patients, 6 of which developed RN (43% vs 8%, p=0.08). Surgical resection prior to radiation was performed in 9 patients, 7 of which developed RN (50% vs 15%, p=0.1). RN appeared to be less often diagnosed when ICM were treated with higher doses of radiation (24 Gy vs 20 Gy, p=0.07). Systemic treatment was administered prior to radiation in 25 patients and we found no relationship with systemic therapy type and RN. Presumed RN was treated in 12 of 14 patients (86%). Steroids or surgical resection were the primary treatment modalities, with laser ablation used in 1 case. Following treatment, improvement was noted in 3 patients radiographically and in 1 of these clinically. CONCLUSIONS This series of patients with radiotherapy-treated brain metastases from melanoma reveals cerebellar involvement, hemorrhage, and prior surgical resection as potential risk factors for radiation necrosis. Neoadjuvant systemic treatment did not appear to be a risk factor in our review.

PurposeApproximate dose calculation methods were used in the nominal dose distribution and the perturbed dose distributions due to uncertainties in a commercial treatment planning system (CTPS) for robust optimization in intensity‐modulated proton therapy (IMPT). We aimed to investigate whether the approximations influence plan quality, robustness, and interplay effect of the resulting IMPT plans for the treatment of locally advanced lung cancer patients.Materials and methodsTen consecutively treated locally advanced nonsmall cell lung cancer (NSCLC) patients were selected. Two IMPT plans were created for each patient using our in‐house developed TPS, named “Solo,” and also the CTPS, EclipseTM (Varian Medical Systems, Palo Alto, CA, USA), respectively. The plans were designed to deliver prescription doses to internal target volumes (ITV) drawn by a physician on averaged four‐dimensional computed tomography (4D‐CT). Solo plans were imported back to CTPS, and recalculated in CTPS for fair comparison. Both plans were further verified for each patient by recalculating doses in the inhalation and exhalation phases to ensure that all plans met clinical requirements. Plan robustness was quantified on all phases using dose‐volume‐histograms (DVH) indices in the worst‐case scenario. The interplay effect was evaluated for every plan using an in‐house developed software, which randomized starting phases of each field per fraction and accumulated dose in the exhalation phase based on the patient's breathing motion pattern and the proton spot delivery in a time‐dependent fashion. DVH indices were compared using Wilcoxon rank‐sum test.ResultsCompared to the plans generated using CTPS on the averaged CT, Solo plans had significantly better target dose coverage and homogeneity (normalized by the prescription dose) in the worst‐case scenario [ITV D95%: 98.04% vs 96.28%, Solo vs CTPS, P = 0.020; ITV D5%–D95%: 7.20% vs 9.03%, P = 0.049] while all DVH indices were comparable in the nominal scenario. On the inhalation phase, Solo plans had better target dose coverage and cord Dmax in the nominal scenario [ITV D95%: 99.36% vs 98.45%, Solo vs CTPS, P = 0.014; cord Dmax: 20.07 vs 23.71 Gy(RBE), P = 0.027] with better target coverage and cord Dmax in the worst‐case scenario [ITV D95%: 97.89% vs 96.47%, Solo vs CTPS, P = 0.037; cord Dmax: 24.57 vs 28.14 Gy(RBE), P = 0.037]. On the exhalation phase, similar phenomena were observed in the nominal scenario [ITV D95%: 99.63% vs 98.87%, Solo vs CTPS, P = 0.037; cord Dmax: 19.67 vs 23.66 Gy(RBE), P = 0.039] and in the worst‐case scenario [ITV D95%: 98.20% vs 96.74%, Solo vs CTPS, P = 0.027; cord Dmax: 23.47 vs 27.93 Gy(RBE), P = 0.027]. In terms of interplay effect, plans generated by Solo had significantly better target dose coverage and homogeneity, less hot spots, and lower esophageal Dmean, and cord Dmax [ITV D95%: 101.81% vs 98.68%, Solo vs CTPS, P = 0.002; ITV D5%–D95%: 2.94% vs 7.51%, P = 0.002; cord Dmax: 18.87 vs 22.29 Gy(RBE), P = 0.014].ConclusionsSolo‐generated IMPT plans provide improved cord sparing, better target robustness in all considered phases, and reduced interplay effect compared with CTPS. Consequently, the approximation methods currently used in commercial TPS programs may have space for improvement in generating optimal IMPT plans for patient cases with locally advanced lung cancer.