Acute Esophageal Toxicity Research Articles

Dosimetric and NTCP advantages of robust proton therapy over robust VMAT for Stage III NSCLC in the immunotherapy era

AimsTo assess the robustness and to define the dosimetric and NTCP advantages of pencil-beam-scanning proton therapy (PBSPT) compared with VMAT for unresectable Stage III non-small lung cancer (NSCLC) in the immunotherapy era. Material and methods10 patients were re-planned with VMAT and PBSPT using: 1) ITV-based robust optimization with 0.5 cm setup uncertainties and (for PBSPT) 3.5 % range uncertainties on free-breathing CT 2) CTV-based RO including all 4DCTs anatomies. Target coverage (TC), organs at risk dose and TC robustness (TCR), set at V95%, were compared. The NTCP risk for radiation pneumonitis (RP), 24-month mortality (24MM), G2 + acute esophageal toxicity (ET), the dose to the immune system (EDIC) and the left anterior descending (LAD) coronary artery V15 < 10 % were registered. Wilcoxon test was used. ResultsBoth PBSPT methods improved TC and TCR (p < 0.01). The mean lung dose and lung V20 were lower with PBSPT (p < 0.01). Median mean heart dose reduction with PBSPT was 8 Gy (p < 0.001). PT lowered median LAD V15 (p = 0.004).ΔNTCP > 5 % with PBSPT was observed for two patients for RP and for five patients for 24 MM. ΔNTCP for ≥ G2 ET was not in favor of PBSPT for all patients. PBSPT halved median EDIC (4.9/5.1 Gy for ITV/CTV-based VMAT vs 2.3 Gy for both ITV/CTV-based PBSPT, p < 0.01). ConclusionsPBSPT is a robust approach with significant dosimetric and NTCP advantages over VMAT; the EDIC reduction could allow for a better integration with immunotherapy. A clinical benefit for a subset of NSCLC patients is expected.

Comparison of photon intensity modulated, hybrid and volumetric modulated arc radiation treatment techniques in locally advanced non-small cell lung cancer

Background and purposeThere is no consensus on the best photon radiation technique for non-small cell lung cancer (NSCLC). This study quantified the differences between commonly used treatment techniques in NSCLC to find the optimal technique. Materials and methodsTreatment plans were retrospectively generated according to clinical guidelines for 26 stage III NSCLC patients using intensity modulated radiation therapy (IMRT), hybrid, and volumetric modulated arc therapy (VMATC, and VMATV5 optimized for lower lung and heart dose). Plans were evaluated for target coverage, organs at risk dose (including heart substructures) and normal tissue complication probabilities (NTCP). ResultsThe comparison showed significant and largest median differences (>1 Gy or >5%) in favor of IMRT for the mediastinal envelope and heart (maximum dose), in favor of the hybrid technique for the lungs (V5Gy of the total lungs and V5Gy of the contralateral lung) and in favor of VMATC for the heart (Dmean), most of the substructures of the heart, and the spinal cord (maximum dose). The VMATV5 technique had significantly lower heart dose compared to the hybrid technique and significantly lower lung dose compared to the VMATC, combining both advantages in one technique. The mean ΔNTCP did not exceed the 2 percent point (pp) for grade 5 (mortality), and 10 pp for grade ≥2 toxicities (radiation pneumonitis and acute esophageal toxicity), but ΔNTCP was mostly in favor of VMATC/V5 for individual patients. ConclusionThis planning study showed that VMATV5 was preferred as it achieved low lung and heart doses, as well as low NTCPs, simultaneously.

Improving knowledge-based treatment planning for lung cancer radiotherapy with automatic multi-criteria optimized training plans

Background Knowledge-based planning (KBP) is a method for automated radiotherapy treatment planning where appropriate optimization objectives for new patients are predicted based on a library of training plans. KBP can save time and improve organ at-risk sparing and inter-patient consistency compared to manual planning, but its performance depends on the quality of the training plans. We used another system for automated planning, which generates multi-criteria optimized (MCO) plans based on a wish list, to create training plans for the KBP model, to allow seamless integration of knowledge from a new system into clinical routine. Model performance was compared for KBP models trained with manually created and automatic MCO treatment plans. Material and Methods Two RapidPlan models with the same 30 locally advanced non-small cell lung cancer patients included were created, one containing manually created clinical plans (RP_CLIN) and one containing fully automatic multi-criteria optimized plans (RP_MCO). For 15 validation patients, model performance was compared in terms of dose-volume parameters and normal tissue complication probabilities, and an oncologist performed a blind comparison of the clinical (CLIN), RP_CLIN, and RP_MCO plans. Results The heart and esophagus doses were lower for RP_MCO compared to RP_CLIN, resulting in an average reduction in the risk of 2-year mortality by 0.9 percentage points and the risk of acute esophageal toxicity by 1.6 percentage points with RP_MCO. The oncologist preferred the RP_MCO plan for 8 patients and the CLIN plan for 7 patients, while the RP_CLIN plan was not preferred for any patients. Conclusion RP_MCO improved OAR sparing compared to RP_CLIN and was selected for implementation in the clinic. Training a KBP model with clinical plans may lead to suboptimal output plans, and making an extra effort to optimize the library plans in the KBP model creation phase can improve the plan quality for many future patients.

Observation of Acute Toxicity Events in Lung Cancer Patients Treated Concurrently with a Tyrosine Kinase Inhibitor

<h3>Purpose/Objective(s)</h3> Available tyrosine kinase inhibitors (TKI) for patients with non-small-cell lung cancer (NSCLC) have long half-lives. If thoracic radiation is given, it can be impractical to hold the TKI long enough for a washout. We set out to determine whether patients taking a TKI are at elevated risk for acute esophageal, pulmonary, or cardiac toxicity following thoracic radiation. <h3>Materials/Methods</h3> We performed a single-institution retrospective study of patients who had lung radiation from March 2011 to December 2021. Concurrent TKI use was defined as drug use within 3 months before or after radiation. Patients completed palliative or definitive thoracic radiation courses (including SBRT) for any primary lung cancer. Radiation doses and dosimetric parameters (esophagus mean and V30, heart mean and V25, lung mean and V20) were converted to biologically effective doses (BED₁₀) using an a/b ratio of 10 Gy. CTCAE acute toxicity outcomes were determined within 12 months of completion of radiation and compared using chi-square tests, Fisher's exact tests, and multivariate logistic regressions. <h3>Results</h3> A total of 105 patients receiving lung radiation were identified with median follow up of 12 months (range 0.6–114 months). Histologies included adenocarcinoma (51.4%), squamous cell carcinoma (23.8%), other NSCLC (15.2%), and SCLC (9.5%). 33 patients (31.4%) had metastatic disease at the time of radiation treatment. Median dose was 72 BED₁₀ Gy (range 15.7 to 151.2 BED₁₀ Gy). A total of 14.3% (n=15/105) of patients received concurrent TKI. The rate of grade 2-3 acute esophagitis was 20.0% (18/90) and 53.3% (8/15) for patients receiving radiotherapy without and with concurrent TKI, respectively (p = 0.006). There were no grade 4-5 esophagitis events. When controlling for mean esophageal dose and concurrent chemotherapy, concurrent TKI use was found to be an independent predictor for grade 2-3 esophagitis (OR = 6.91, 95% CI = 1.99 – 26.03, p = 0.003). Acute esophagitis was most frequently seen with osimertinib (4/7 = 57.1%), lorlatinib (2/2 = 100.0%), and crizotinib (2/3 = 67.7%). The rate of grade 2-3 pneumonitis was 5.6% (5/90) and 15.3% (2/13) without and with concurrent TKI, respectively (p = 0.261). On multivariate analysis, TKI use was not associated with pneumonitis. There were no acute grade 4-5 pneumonitis events or grade 2-5 cardiac toxicities. <h3>Conclusion</h3> This study raises the hypothesis that acute esophageal toxicity may be higher after radiation for patients receiving many of the most common TKIs. Thoracic radiation plays a crucial role in the management of NSCLC, and as the use of TKIs expands, it is critical to quickly identify potential complications associated with concurrent thoracic radiation.

Locally advanced NSCLC: a plea for sparing the ipsilateral normal lung—prospective, clinical trial with DART-bid (dose-differentiated accelerated radiation therapy, 1.8 Gy twice daily) by VMAT

BackgroundIn radiation treatment of locally advanced non-small cell lung cancer (LA-NSCLC), ‘margins’ from internal target volumes to planning target volumes in the range of 12 to 23 mm are reported, and avoiding exposure of the contralateral lung is common practice. We investigated prospectively an approach with tight margins (7 mm) and maximal sparing of the ipsilateral normal lung. Mature results for the first endpoint (pneumonitis) and further toxicities are reported.MethodsPrimary tumors were treated by VMAT with 73.8–90.0 Gy in positive correlation to tumor volumes, nodes with 61.2 Gy, a restricted volume of nodes electively with 45 Gy. Fractional doses of 1.8 Gy bid, interval 8 h. Before radiotherapy, two cycles platin-based chemotherapy were given. 12 patients finished maintenance therapy with Durvalumab. Median follow up time for all patients is 19.4 months, for patients alive 27.0 months (3.4–66.5 months).Results100 consecutive, unselected patients with LA-NSCLC in stages II through IVA were enrolled (UICC/AJCC, 8th edition). No acute grade 4/5 toxicity occurred. Pneumonitis grade 2 and 3 was observed in 12% and 2% of patients, respectively; lowering the risk of pneumonitis grade ≥ 2 in comparison to the largest study in the literature investigating pneumonitis in LA-NSCLC, is significant (p < 0.0006). Acute esophageal toxicity grade 1, 2 and 3 occurred in 12%, 57% and 3% of patients, respectively. Two patients showed late bronchial stricture/atelectasis grade 2. In two patients with lethal pulmonary haemorrhages a treatment correlation cannot be excluded. Median overall survival for all stage III patients, and for those with ‘RTOG 0617 inclusion criteria’ is 46.6 and 50.0 months, respectively.ConclusionsOverall toxicity is low. In comparison to results in the literature, maximal sparing the ipsilateral normal lung lowers the risk for pneumonitis significantly.Trial registrationEthics committee of Vorarlberg, Austria; EK-0.04-105, Registered 04/09/2017—Retrospectively registered. http://www.ethikkommission-vorarlberg.at

CONCURRENT CHEMORADIOTHERAPY VERSUS ACCELERATED RADIOTHERAPY AFTER INDUCTION CHEMOTHERAPY IN INOPERABLE STAGE III NON-SMALL CELL LUNG CARCINOMA: A PROSPECTIVE COMPARATIVE STUD

INTRODUCTION: There is considerable debate over ideal treatment approach for inoperable stage III non-small cell lung carcinoma. Accelerated radiotherapy is an emerging modality based on it's radio-biological advantage of inhibiting accelerated repopulation and negate the development of radioresistance. .Our study was aimed at comparing the response rate and toxicity pattern between concurrent chemoradiotherapy and accelerated radiotherapy in non-resectable stage III NSCLC patient who have already received induction chemotherapy. MATERIALAND METHODS: Patients with histologically proven non-metastatic, inoperable stage III Non-small cell carcinoma of lung were 2 2 randomized into two groups and was given three cycles of induction chemotherapy with paclitxel (175mg/m ) and cisplatin (80mg/m ). After that 2 patients of control arm received EBRT at a dose of 66Gy (2Gy/fraction/day, 5 days in a week) with concurrent cisplatin (40mg/m ) weekly and patients of study arm received EBRT alone at a dose of 66 Gy (2 Gy /fraction/day, 6 days in a week).Patients were evaluated weekly for acute toxicity during radiation therapy, then six weeks after completion of treatment for response assessment and thereafter every three months for at least twelve months . RESULTS: Overall response rate (Complete response+ Partial response) was higher in study arm (62.5% VS 69.5%,p-value 0.963). Signicantly less higher grade of acute pharyngeal and esophageal toxicity was seen in accelerated radiotherapy arm(45.8% vs 13%,p-value 0.033) than concurrent chemoradiotherapy arm. DFS,PFS were comparable between two arms. CONCLUSION: In the treatment of inoperable stage III NSCLC, after induction chemotherapy both the Accelerated radiotherapy and concurrent chemoradiotherapy were comparable in terms of loco-regional control, toxicity prole, disease free survival and progression free survival.

CLINICAL OUTCOME USING WEEKLY PACLITAXEL WITH RADIATION IN LOCALLY ADVANCED LUNG CANCER

Background: Non-small cell lung cancer is the second most common malignancy worldwide with very high mortality rate. The aim of this study is to evaluate the locoregional response and toxicity prole using weekly paclitaxel along with radiation in locally advanced inoperable non-small cell lung cancer in a tertiary care centre. A prospective analysis was Methods: carried out on non-metastatic locoregionally advanced non-small cell lung cancer patients who were treated in the Radiotherapy Department, Medical College, Kolkata from January 2014 to July 2015. The patients received concurrent chemoradiotherapy with weekly paclitaxel. Out of 54 patients Results: analysed, overall response rate was 81.48% and complete response rate was 12.96%. The progression free survival rate at 1 year was 41.30%. Median progression free survival was 10.00 ±0.40 months. The most common toxicities were acute pharyngeal and esophageal toxicity. The toxicity was acceptable and response was Conclusion: comparable with other platinum based concurrent chemoradiation regimens.

A PROSPECTIVE COMPARATIVE STUDY BETWEEN CONCURRENT CHEMO RADIOTHERAPY WITH CISPLATIN AND ETOPOSIDE VERSUS PACLITAXEL AND CARBOPLATIN IN LOCALLY ADVANCED NON SMALL CELL LUNG CARCINOMA

Background-The current standard of treatment for unresectable locally advanced Non-small cell lung carcinoma is radiation with concurrent platinum based doublet chemotherapy. But there remains considerable debate over the optimal concurrent regimen , with some advocating Cisplatin-Etoposide , others prefer carboplatin-paclitaxel as an equally effective and better tolerable concurrent regimen.. With this background, our study was aimed at comparing loco-regional control and toxicity prole between these two regimens. Material And Methods- Locally advanced non-metastatic Non-small cell lung carcinoma patients were randomized in two groups- study group received External beam radiotherapy(60Gy/30 fractions/6 weeks) in conventional fractionation along with concurrent weekly chemotherapy with Inj.paclitaxel (45 mg/m2 ) and Inj. Carboplatin (AUC2 ) and control group received same radiotherapy dose with concurrent Inj.cisplatin (50mg/m2) Day 1,8,29,36 and Inj.Etoposide (50 mg/m2) Day 1-5 and Day 29-33. After treatment completion , Locoregional Tumor response was assessed . Patients were evaluated weekly for acute toxicity during radiation therapy, then once at 6-8 weeks after completion of treatment and thereafter every three months for at least 6 months. Results- Overall treatment Response in Study Arm was higher than control arm (73% vs 70%). Complete response rate was also higher in study arm (40% vs 30%) though these differences were not statistically signicant [p value 0.701]. Although statistically not signicant ,Grade III haematological toxicity was less (3% vs 6%) in study arm .Other toxicity proles including acute lung, esophageal and skin toxicities are comparable in both the arms of the study. Conclusion- Concurrent chemo- radiotherapy with cisplatin -etoposide versus paclitaxel -carboplatin in locally advanced NSCLC are comparable in terms of loco-regional control and acute toxicity.

Acute and Late Esophageal Toxicity After SABR to Thoracic Tumors Near or Abutting the Esophagus

Our purpose was to evaluate the incidence of acute and late esophageal toxicity in patients with thoracic tumors near or abutting the esophagus treated with SABR. Among patients with thoracic tumors treated with SABR, we identified those with tumors near or abutting the esophagus. Using the linear-quadratic model with an α/ß ratio of 10, we determined the correlation between dosimetric parameters and esophageal toxicity graded using the Common Terminology Criteria for Adverse Events, version 5.0. Out of 2200 patients treated with thoracic SABR, 767 patients were analyzable for esophageal dosimetry. We identified 55 patients with tumors near the esophagus (52 evaluable for esophagitis grade) and 28 with planning target volume (PTV) overlapping the esophagus. Dose gradients across the esophagus were consistently sharp. Median follow-up and overall survival were 16 and 23 months, respectively. Thirteen patients (25%) developed temporary grade 2 acute esophageal toxicity, 11 (85%) of whom had PTV overlapping the esophagus. Symptoms resolved within 1 to 3 months in 12 patients and 6 months in all patients. No grade 3 to 5 toxicity was observed. Only 3 patients (6%) developed late or persistent grade 2 dysphagia or dyspepsia of uncertain relationship to SABR. The cumulative incidence of acute esophagitis was 15% and 25% at 14 and 60 days, respectively. Acute toxicity correlated on univariate analysis with esophageal Dmax, D1cc, D2cc, Dmax/Dprescription, and whether the PTV was overlapping the esophagus. Esophageal Dmax (BED10) <62 Gy, D1cc (BED10) <48 Gy, D2cc (BED10) <43 Gy, and Dmax/Dprescription <85% were associated with <20% risk of grade 2 acute esophagitis. Only 2 local recurrences occurred. Although 25% of patients with tumors near the esophagus developed acute esophagitis (39% of those with PTV overlapping the esophagus), these toxicities were all grade 2 and all temporary. This suggests the safety and efficacy of thoracic SABR for tumors near or abutting the esophagus when treating with high conformity and sharp dose gradients.

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

PurposeThis 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 MethodsTwenty-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.ResultsThe 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.ConclusionProton therapy plans improved target coverage and reduced risk of coronary artery event and secondary lung cancer while increasing the risk of radiation dermatitis.

Comparison of dose volumetric parameters of oesophagus in the radiation treatment of carcinoma breast with and without oesophagus delineation

Abstract Aim: There are only limited studies available in literature that discuss methods to reduce the oesophageal dose and acute oesophagitis during breast cancer radiotherapy. The aim of this study is to compare dose volumetric parameters of oesophagus in radiation treatment of breast with and without oesophagus delineation. Methods: Treatment plans of 44 patients, who underwent chest wall and supraclavicular fossa irradiation, were selected for the study. Oesophagus was later delineated and treatment replanned using three-dimensional conformal radiotherapy (3DCRT) considering oesophagus as an organ at risk (OAR). The dose prescribed was 40 Gy/15 fractions to the planning target volume (PTV). Dose volumetric parameters of oesophagus such as maximum dose (Dmax), mean dose (Dmean), the percentage of oesophagus volume receiving ≥15Gy (V15), ≥25Gy(V25), ≥33Gy(V33) and ipsilateral lung volume parameters V4, V8 and V16 were compared with already executed plans in which oesophagus was not delineated. Results: Contouring the oesophagus as an OAR as a part of the radiotherapy treatment for Carcinoma Breast resulted in statistically significant reduction in dose to the oesophagus. No statistically significant change was found in the ipsilateral lung volume parameters. No compromise in plan quality was required as evident from the statistically non-significant differences in Homogeneity index and Conformity index. Findings: 3DCRT planning with oesophagus delineation can be considered as a method to reduce oesophageal dose and the acute oesophageal toxicity during radiotherapy for carcinoma breast.

Duration of acute esophageal toxicity in concomitant radio-chemotherapy for non-small cell lung cancer with different fractionation schedules.

In our previous prospective trial on accelerated hypofractionated concomitant radiochemotherapy (AHRT-CHT) for non-small-cell lung cancer (NSCLC), the incidence of grade ≥3 acute esophageal toxicity (AET) was similar to that reported for conventionally fractionated concomitant radiochemotherapy (CFRT-CHT), but its duration was prolonged. Thus, we aimed to compare the duration of grade ≥3 AET between AHRT-CHT and CFRT-CHT. Clinical data of 76 NSCLC patients treated with CFRT-CHT (60-66 Gy/2 Gy) during 2015-2020 were retrospectively compared with the data of 92 patients treated with AHRT-CHT (58.8 Gy/2.8 Gy) in the prospective trial. The maximum grade of AET, incidence, and duration of grade ≥3 AET were the end points. Univariate and multivariate analyses were applied to correlate clinical and treatment variables with these end points. Neither the maximum grade of AET (p = 0.71), nor the incidence of grade ≥3 AET (p = 0.87) differed between the two groups. The number of CHT cycles delivered (2 vs 1, p = 0.005) and higher esophagus mean BED (p = 0.009) were significant predictors for a higher maximum grade of AET; older age was a significant predictor for higher incidence of grade ≥3 AET (p = 0.03). The median duration of grade ≥3 AET in AHRT-CHT and CFRT-CHT group was 30 days (range 5-150) vs 7 days (range 3-20), respectively, p = 0.0005. In multivariate analysis, only the AHRT-CHT schedule (p=0.003) was a significant predictor for a longer duration of grade ≥3 AET. Despite similar incidence of grade ≥3 AET, its duration is significantly prolonged in NSCLC patients treated with AHRT-CHT compared to CFRT-CHT. Reporting only the rate of grade ≥3 AET in clinical trials may underestimate the real extent of the esophageal toxicity; its duration should also be routinely reported.

PO-1176 Duration of acute esophageal toxicity in RT-CHT for NSCLC with different fractionation schedules

PO-1176 Duration of acute esophageal toxicity in RT-CHT for NSCLC with different fractionation schedules

Prevention and management of acute esophageal toxicity during concomitant chemoradiotherapy for locally advanced lung cancer.

Standard treatment for locally advanced non-small cell lung cancer (LA-NSCLC) is concomitant chemoradiotherapy. The survival benefit of combined treatment is partially counterbalanced by an increased rate of acute esophageal toxicity. Several pharmaceutical products are available for prevention and management of esophagitis, including Faringel Plus. To assess the incidence and the grade, identify the correlations with clinical, dosimetric, and therapeutic variables, and analyse the role of Faringel Plus as a pharmaceutical preventive measure against acute esophageal toxicity. Patients with LA-NSCLC treated with concomitant radiochemotherapy were retrospectively reviewed. Acute esophagitis and dysphagia were graded according to Common Terminology Criteria for Adverse Events version 5.0. Clinical, dosimetric, and therapeutic correlations were investigated using χ2 test. Among the 23 analysed patients, 18 (78.3%) and 1 (4.3%) developed G2 and G3 esophagitis, respectively; G1-2 dysphagia were reported in 11 cases (47.8%). No statistically significant correlation between the variables considered and acute esophageal toxicity was identified. In the group of patients who received Faringel Plus as preventive treatment (10 subjects, 43.5%), dysphagia presentation time was significantly longer (p = 0.038); esophagitis onset time was longer and symptoms duration was shorter. Faringel Plus allowed a reduction in the use of analgesic drugs. Acute mild esophageal toxicity was confirmed to be a common side effect in this setting. No clinical-dosimetric parameter has been demonstrated to be effective in predicting acute esophageal toxicity. The use of Faringel Plus appears effective as a therapeutic and prophylactic tool to manage acute esophageal toxicity.

Twice-daily chemoradiotherapy in limited-stage small-cell lung cancer

Acute radiation-induced oesophagitis has been associated with adverse events such as weight loss, substantial effect on quality of life, and reduced survival.1 Concurrent chemotherapy given with hyperfractionated radiation therapy has been associated with an increased incidence of acute oesophageal toxicity.2 Several dosimetric parameters and high doses have been associated with an increased risk of acute oesophagitis.1 However, radiotherapy technical developments (eg, use of intensity-modulated radiotherapy and omission of elective nodal irradiation) allow a reduced dose to the organs at risk, including the oesophagus.

Correlation between toxicity and dosimetric parameters for adjuvant intensity modulated radiation therapy of breast cancer: a prospective study

ORCID: 0000–0001-6019–7309. In the treatment of breast cancer, intensity-modulated radiation therapy (IMRT) reportedly reduces the high-dose irradiation of at-risk organs and decreases the frequency of adverse events (AEs). Comparisons with conventional radiotherapy have shown that IMRT is associated with lower frequencies of acute and late-onset AEs. Here, we extended a prospective, observational, single-center study of the safety of IMRT to a second investigating center. Patients scheduled for adjuvant IMRT after partial or total mastectomy were given a dose of 50 Gy (25 fractions of 2 Gy over 5 weeks), with a simultaneous integrated boost in patients having undergone conservative surgery. 300 patients were included in the study, and 288 were analyzed. The median follow-up period was 2.1 years. The 2-year disease-free survival rate [95% CI] was 93.4% [89.2–96.0%]. Most AEs were mild. The most common AEs were skin-related—mainly radiodermatitis [in 266 patients (92.4%)] and hyperpigmentation (in 178 (61.8%)). 35% and 6% of the patients presented with grade 2 acute skin and esophageal toxicity, respectively. Only 4 patients presented with a grade 3 event (radiodermatitis). Smoking (odds ratio) [95% CI] = 2.10 [1.14–3.87]; p = 0.017), no prior chemotherapy (0.52 [0.27–0.98]; p = 0.044), and D98% for subclavicular skin (1.030 [1.001–1.061]; p = 0.045) were associated with grade ≥ 2 acute AEs. In a univariate analysis, the mean dose, (p < 0.0001), D2% (p < 0.0001), D50% (p = 0.037), D95% (p = 0.0005), D98% (p = 0.0007), V30Gy (p < 0.0001), and V45Gy (p = 0.0001) were significantly associated with grade ≥ 1 acute esophageal AEs. In a multivariate analysis, D95% for the skin (p < 0.001), D98% for the subclavicular skin and low D95% for the internal mammary lymph nodes were associated with grade ≥ 1 medium-term AEs. The safety profile of adjuvant IMRT after partial or total mastectomy is influenced by dosimetric parameters.Trial registration: ClinicalTrials.gov NCT02281149.

RONC-23. NOVEL APPROACH TO REDUCE ACUTE ESOPHAGEAL TOXICITY IN CRANIO-SPINAL IRRADIATION USING INTENSITY MODULATED PROTON THERAPY

INTRODUCTIONWe present our experience of a novel approach using intensity modulated proton therapy(IMPT) for cranio-spinal irradiation(CSI) leading to reduced acute esophageal toxicity and reduced treatment interruptions. MATERIAL ANDMETHODSSeven children younger than 12 years old treated consecutively with CSI using IMPT were included in this study. Three among 7 children received concurrent chemotherapy(CCT). Entire vertebral body(VB) was part of target volume in all patients. The IMPT plan was generated using 3 fields with single field optimisation technique. Last 5 patients were treated using dose gradient(DG) (98-93%) deliberately created in anterior most 3-5mm of VB. Initial 2 patients were treated with intention of covering entire VB with 98% isodose. Monte Carlo algorithm was used for dose calculations and optimisation, and robustness assessed for 3mm setup and 3.5% range uncertainty.RESULTSThe CSI dose ranged from 21.6GyE to 35GyE. In patients without DG, maximum and mean dose to esophagus(36.67GyE vs. 25.45GyE, 31.53GyE vs. 20.41GyE), midline mucosa(28.95GyE vs. 25.31GyE, 21.8GyE vs. 14.61GyE) and bowel bag(32.9GyE vs. 24.27GyE, 3.59GyE vs. 3.21GyE) were higher compared to patients with DG. Both patients where DG was not created, developed grade 2 esophageal toxicities requiring supportive care and treatment interruptions(4 and 2days). All 5 patients with DG did not develop significant esophageal toxicity and had no interruptions.CONCLUSIONCreating a dose gradient over anterior VB using IMPT reduces dose to esophagus and midline mucosa leading to lower acute esophageal toxicity which potentially avoids treatment interruptions during CSI.

Radiomics analysis of 3D dose distributions to predict toxicity of radiotherapy for lung cancer

Purpose(Chemo)–radiotherapy (RT) is the gold standard treatment for patients with locally advanced lung cancer non accessible for surgery. However, current toxicity prediction models rely on clinical and dose volume histograms (DVHs) and remain unsufficient. The goal of this work is to investigate the added predictive value of the radiomics approach applied to dose maps regarding acute and late toxicities in both the lungs and esophagus. MethodsAcute and late toxicities scored using the CTCAE v4.0 were retrospectively collected on patients treated with RT in our institution. Radiomic features were extracted from 3D dose maps considering Gy values as grey-levels in images. DVH and usual clinical factors were also considered. Three toxicity prediction models (clinical only, clinical + DVH and combined, i.e., including clinical + DVH + radiomics) were incrementally trained using a neural network on 70% of the patients for prediction of grade ≥2 acute and late pulmonary toxicities (APT/LPT) and grade ≥2 acute esophageal toxicities (AET). After bootstrapping (n = 1000), optimal cut-off values were determined based on the Youden Index. The trained models were then evaluated in the remaining 30% of patients using balanced accuracy (BAcc). Results167 patients were treated from 2015 to 2018: 78% non small-cell lung cancers, 14% small-cell lung cancers and 8% other histology with a median age at treatment of 66 years. Respectively, 22.2%, 16.8% and 30.0% experienced APT, LPT and AET. In the training set (n = 117), the corresponding BAcc for clinical only/clinical + DVH/combined were 0.68/0.79/0.92, 0.66/0.77/0.87 and 0.68/0.73/0.84. In the testing evaluation (n = 50), these trained models obtained a corresponding BAcc of 0.69/0.69/0.92, 0.76/0.80/0.89 and 0.58/0.73/0.72. ConclusionIn patients with a lung cancer treated with RT, radiomic features extracted from 3D dose maps seem to surpass usual models based on clinical factors and DVHs for the prediction of APT and LPT.

Accelerated hypofractionated radiotherapy with concurrent full dose chemotherapy for locally advanced non-small cell lung cancer: A phase I/II study

IntroductionWe report the results of toxicity and survival in stage III NSCLC patients treated with concurrent accelerated hypofractionated AHRT–CHT within a prospective study. Methods92 patients received 3D-CRT or IMRT-planned RT: 58.8 Gy /21 fractions (2.8 Gy/fraction, 4 weeks) with 2 cycles of CHT (Cisplatin 80 mg/m2 D1 and D22; and Vinorelbine 25 mg/m2, D1, D8, D22, and D29) started with D1 of RT. Non-hematological toxicity was evaluated using RTOG-EORTC criteria, every week during treatment, one month after treatment completion, and every three months thereafter. ResultsTwo patients did not receive the prescribed RT dose; 22 (24%) received only one CHT cycle. Median follow-up was 21.5 months (range: 1–65) for all patients and 32 months (range: 8–65) for living patients. There were: 13 (14%) cases of grade ≥III acute esophageal toxicity; 3 grade III acute pneumonitis, and 2 grade III late pulmonary toxicities. Two toxic deaths occurred within 3 months after treatment: fatal hemoptysis (1) and complications of esophageal toxicity (1). Five other deaths that occurred within one year after treatment were probably treatment-related: lung abscess (1), fatal hemoptysis (2), death from undetermined cause (2). Median overall survival was 38 months (95%CI:27–49), median progression free survival was 25 months (95%CI:14–36). ConclusionsSurvival rates are encouraging, but the observed rate of toxic and probably toxic deaths is of potential concern. We proceed with the use of AHRT with concomitant full dose CHT, but patients with large PTV and major vascular abutment are excluded due to potentially increased risk of toxic death.

The use of real-world evidence to audit normal tissue complication probability models for acute esophageal toxicity in non-small cell lung cancer patients

IntroductionThe aim of this work is to assess the validity of real world data (RWD) derived from an electronic toxicity registration (ETR). As a showcase, the NTCP-models of acute esophageal toxicity (AET) for concurrent chemoradiation (CCRT) for NSCLC patients were used to validate the ETR of AET before/after dose de-escalation to the mediastinal lymph nodes. Material and methodsOne hundred and one patients received 24 × 2.75 Gy and 116 patients received de-escalated dose of 24 × 2.42 Gy to the mediastinal lymph nodes. The validity and completeness of the ETR was analyzed. The grade ≥2 AET probability was defined according the V50 Gy and V60 Gy NTCP-models from literature. Validity of the models was assessed by calibration and discrimination. Furthermore, sensitivity and specificity for different cut-off points were determined. ResultsThe compliance of ETR was 73–80%, with sensitivity and specificity rates of 83% and 86% for grade ≥2 AET, respectively. Discrimination of both NTCP-models demonstrated a moderate accuracy (V50 model, AUC 0.71; V60-model, AUC 0.69). Dose de-escalation did not influence the accuracy of the V50-model; AUC before: 0.69, and AUC after: 0.71. For the V60-model the model-accuracy decreased after dose de-escalation; AUC before: 0.72 and AUC after: 0.62, respectively. ConclusionRWD is a useful method to audit NTCP models in clinical practice. The NTCP models to predict AET in NSCLC patients showed moderate predictive accuracy. For clinical practice, the V50Gy seems to be most stable for dose de-escalation without compromising safety and efficacy.