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Abstract Background We investigated the clinical outcomes of involved‐field high‐dose (≥66 Gy) chemoradiotherapy (CRT) combined with respiratory motion management for esophageal squamous cell carcinoma (ESCC). Methods Patients who underwent definitive CRT for histologically confirmed ESCC in our department between 2012 and 2018 were retrospectively analyzed. Respiratory motion management strategies included breath‐holding (63%) and mask immobilization (29%) based on individual measurements of respiratory tumor motion using radiographic fluoroscopy with endoscopically placed clip markers as landmarks. We evaluated patient characteristics, treatment efficacy, failure patterns, and toxicities. Results We enrolled 35 patients with a prescribed dose of 66–70 Gy in 33–35 fractions. The overall response rate within 6 months post‐CRT was 94.3%; the median follow‐up period for survivors was 43 months. The 2‐year overall survival (OS), progression‐free survival, and locoregional failure‐free survival rates were 51.4%, 42.9%, and 42.9%, respectively. A significant difference in OS was observed between patients with and without esophageal fistulas after CRT (p = 0.002, log‐rank test). Disease failure occurred in 16 patients (45.7%), including one (2.9%) with out‐of‐field regional nodal failure. Major grade 3 or higher toxicities included decreased white blood cell count (48.6%), neutrophil count (34.3%), and esophageal stenosis (31.4%). No grade 3 or higher cardiopulmonary toxicities were observed. Bronchial/tracheal tumor compression and a higher radiotherapy dose (70 Gy) were significantly correlated with esophageal fistulas. Conclusion Involved‐field high‐dose CRT with respiratory motion management may be a feasible treatment option for ESCC. However, a comprehensive assessment of esophageal fistula risk is required to identify suitable candidates.

Abstract Introduction Cetuximab, used to treat head and neck squamous cell carcinoma and metastatic colorectal cancer, can cause severe infusion reactions. Case presentation We report an 87-year-old East Asian woman with stage IV ileocecal signet ring cell carcinoma who experienced severe allergic reactions to cetuximab despite pre-treatment. A dose escalation method, involving weekly incremental doses with comprehensive pre-treatment and close monitoring, was employed, successfully reducing allergic reactions and allowing safe administration. Conclusion This approach demonstrates a viable alternative for patients with hypersensitivity to cetuximab, warranting further research for personalized treatment optimization.

Abstract Introduction Anaplastic meningiomas, categorized as WHO grade 3 tumors, are rare and highly aggressive, accounting for 1-2% of all meningioma cases. Despite aggressive treatment, including surgery and Radiation, they exhibit a high recurrence rate and poor survival outcomes. The aggressive histopathological features emphasize the urgent need for effective management strategies. Methods A retrospective multi-institutional analysis was conducted on patients with recurrent anaplastic meningioma who underwent re-irradiation between 2017 and 2023. Clinical, dosimetric, and outcome data were collected and analyzed, focusing on local control, progression free survival and treatment-related adverse events. Results Thirty-four cases were analyzed, with a median follow-up 11 months after re-irradiation. Progression-free survival at 12 months was 61.9%, with higher doses correlating with better outcomes. Concomitant Bevacizumab improves progression-free survival and reduces the risk of radiation necrosis. CDKN2A homozygote deletion correlated with a higher risk of local failure. Symptomatic radiation necrosis occurred in 20.5% of cases, but its incidence was lower with concomitant Bevacizumab treatment. Conclusion Re-irradiation presents a viable option for recurrent anaplastic meningioma despite the associated risk of radiation necrosis. Higher doses with concomitant Bevacizumab improve clinical outcomes and reduce toxicity. Individualized treatment approaches are necessary, emphasizing the importance of further research to refine management strategies for this challenging disease.

Introduction: Tildrakizumab, a humanized monoclonal antibody targeting the p19 subunit of interleukin-23 (IL-23), has shown promise in the management of moderate-to-severe plaque psoriasis, offering potential improvements in clinical outcomes and quality of life. Objectives: The study aimed to identify patient characteristics that indicate the initiation of a 200-mg dosage of tildrakizumab in a real-world setting, focusing on factors that enhance treatment efficacy and safety. Methods: This prospective study included 54 adult patients with moderate-to-severe plaque psoriasis treated with tildrakizumab 200 mg from March 2023 to March 2024 across 13 Italian Dermatology Units. Data collected included demographics, disease duration, comorbidities, and previous treatments. PASI, BSA, and DLQI scores were recorded at baseline, week 4, 16, and 28. Safety was assessed through adverse event reporting. Univariate analysis was performed to identify baseline characteristics significantly associated with achieving PASI ≤ 5 at week 16. Results: Significant reductions in PASI scores were observed at week 4 (9 ± 6.9, p 30) had higher odds (OR = 4.333, p < 0.05) of achieving PASI ≤ 5. Longer disease duration and starting with a 100 mg dose also correlated with better outcomes. The safety profile was favorable, with minimal adverse events reported. Conclusions: Tildrakizumab 200 mg is effective and safe for moderate-to-severe psoriasis, particularly in obese patients. These findings support its use as a long-term treatment option.

Focal boost to intra-prostatic lesions (IPLs) in radiotherapy could enhance treatment efficacy. Brachytherapy (BT), delivering highly conformal dose with sharp dose gradients emerges as a potentially optimal approach for precise dose escalation to IPLs. This study aims to consolidate clinical and planning studies that implemented whole gland prostate BT and focal dose escalation to IPLs, with the view to synthesize evidence on the strategy’s effectiveness and variability. In this review, we identified nine clinical studies and ten planning/simulation studies focusing on whole gland prostate BT with IPL dose escalation. From the clinical studies, the use of whole gland prostate BT with focal dose escalation in combination with external beam radiotherapy (EBRT) appears to be a safe and effective 21 form of treatment for men with T1b – T2c prostate cancer with average five-year biochemical failure22 free survival (BFFS) of 94 % (range 81.1 %−100 %) and minimal grade three toxicities reported. Both clinical and planning studies exemplified the high level of focal dose escalation achievable using BT with a mean IPL D90 % of 132 % and 146 %, respectively (expressed as a % of the whole gland prescription dose). There was considerable variation in the reporting of clinical and technical data in the identified studies. To facilitate a more widespread and uniform adoption of the technique, recommendations on essential and desirable items to be included in future studies incorporating whole gland prostate BT with focal boost to IPLs are provided.

In non-small-cell lung cancer (NSCLC), improving local control through radiotherapy dose escalation might improve survival. However, a photon-based RCT showed increased organ at risk dose exposure and worse overall survival in the dose escalation arm. In this study, intensity-modulated proton therapy plans with dose escalation to the primary tumour were created for 20 NSCLC patients. The mediastinal envelope was delineated to spare structures around the heart. It was possible to increase primary tumour dose up to 74.0 Gy without a significant increase in organ at risk doses and predicted toxicity.

Background: The PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06; NCT05871021) is designed to determine whether a dose escalation with 75.0 Gy in 30 fractions can enhance the median overall survival (OS) in patients with methylguanine methyltransferase (MGMT) promotor unmethylated glioblastoma compared to historical median OS rates, while being isotoxic to historical cohorts through the addition of concurrent bevacizumab (BEV). To ensure protocol-compliant irradiation planning with all study centers, a dummy run was planned and the plan quality was evaluated. Methods: A suitable patient case was selected and the computed tomography (CT), magnetic resonance imaging (MRI) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) contours were made available. Participants at the various intended study sites performed radiation planning according to the PRIDE clinical trial protocol. The treatment plans and dose grids were uploaded as Digital Imaging and Communications in Medicine (DICOM) files to a cloud-based platform. Plan quality and protocol adherence were analyzed using a standardized checklist, scorecards and indices such as Dice Score (DSC) and Hausdorff Distance (HD). Results: Median DSC was 0.89, 0.90, 0.88 for PTV60, PTV60ex (planning target volume receiving 60.0 Gy for the standard and the experimental plan, respectively) and PTV75 (PTV receiving 75.0 Gy in the experimental plan), respectively. Median HD values were 17.0 mm, 13.9 mm and 12.1 mm, respectively. These differences were also evident in the volumes: The PTV60 had a volume range of 219.1–391.3 cc (median: 261.9 cc) for the standard plans, while the PTV75 volumes for the experimental plans ranged from 71.5–142.7 cc (median: 92.3 cc). The structures with the largest deviations in Dice score were the pituitary gland (median 0.37, range 0.00–0.69) and the right lacrimal gland (median 0.59, range 0.42–0.78). Conclusions: The deviations revealed the necessity of systematic trainings with appropriate feedback before the start of clinical trials in radiation oncology and the constant monitoring of protocol compliance throw-out the study. Trial registration: NCT05871021

Abstract Background Life expectancy of patients with metastatic castration-resistant prostate cancer (mCRPC) is still limited despite several systemic treatments. Within five years after diagnosis of primary prostate cancer, 10–20% of the patients have mCRPC and curation is not an option. Radionuclide therapy (RNT) targeted against prostate-specific membrane antigen (PSMA) emerged as a new treatment option and showed effective results in patients with mCRPC. Survival benefit after [177Lu]Lu-PSMA RNT has already been demonstrated in several clinical trials. However, [225Ac]Ac-PSMA (225Ac-PSMA) appears to be an even more promising radiopharmaceutical for the treatment of mCRPC. The use of alpha emitting radionuclides offers advantages over beta emitting radionuclides due to the high linear energy transfer effective for killing tumor cells and the limited range to reduce the radiation effects on the healthy tissue. However, these results are based on retrospective data and safety data of 225Ac-PSMA are still limited. Therefore, a prospective trial is needed to determine the optimal amount of activity that can be administered. Methods The 225Ac-PSMA-Imaging & Therapy (I&T) trial is an investigator-initiated phase I, single-center, open label, repeated dose-escalation and expansion trial. Patient with PSMA-positive mCRPC after at least one line of chemotherapy and/or one line of nonsteroidal antiandrogen will be treated with 225Ac-PSMA-I&T in increasing amount of activity per cycle. Dose-escalation following an accelerated 3 + 3 design which allows to open the next dose-level cohort in the absence of dose limiting toxicity while the previous one is still ongoing. Up to 4 treatment cohorts will be explored including up to 3 dose-escalation cohorts and one expansion cohort where patients will be administered with the recommended dose. A total of up to 30 patients will be enrolled in this trial. All patients will be evaluated for safety. Additionally, dosimetry was performed for the patients in the dose-escalation cohorts after the first 225Ac-PSMA-I&T administration. Discussion This trial will assess the safety and tolerability of 225Ac-PSMA-I&T in patients with mCRPC to recommend the optimal dose for the phase II trial. Trial registration ClinicalTrials.gov, (NCT05902247). Retrospectively registered 13 June 2023.

Abstract Introduction With locally advanced pancreatic cancer (LAPC), uncontrolled local tumor growth frequently leads to mortality. Advancements in radiotherapy (RT) techniques have enabled conformal delivery of escalated‐dose RT (EDR), which may have potential local control and overall survival (OS) benefits based on retrospective and early prospective studies. With evidence for EDR emerging, we characterized the adoption of EDR across the United States and its associated outcomes. Methods We searched the National Cancer Database for nonsurgically managed LAPC patients diagnosed between 2004 and 2019. Pancreas‐directed RT with biologically effective doses (BED10) ≥39 and ≤70 Gy was labeled conventional‐dose RT (CDR), and BED10 >70 and ≤132 Gy was labeled EDR. We identified associations of EDR and OS using logistic and Cox regressions, respectively. Results Among the definitive therapy subset (n = 54,115) of the entire study cohort (n = 91,493), the most common treatments were chemotherapy alone (69%), chemotherapy and radiation (29%), and RT alone (2%). For the radiation therapy subset (n = 16,978), use of pancreas‐directed RT remained between 13% and 17% over the study period (ptrend > 0.999). Using multivariable logistic regression, treatment at an academic/research facility (adjusted odds ratio [aOR] 1.46, p

Abstract Background Olipudase alfa is a recombinant human acid sphingomyelinase enzyme replacement therapy for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). The ASCEND randomized placebo-controlled trial in adults with ASMD demonstrated reductions in sphingomyelin storage, organomegaly, interstitial lung disease and impaired diffusion capacity of the lung (DLCO), during the first year of olipudase alfa treatment. In an ongoing open-label extension of the ASCEND trial, individuals in the placebo group crossed over to olipudase alfa, and those in the olipudase alfa group continued treatment. Results Thirty-five of 36 participants continued in the extension trial, and 33 completed year 2. Change-from-baseline results are presented as least-square mean percent change ± SEM. Improvements in the cross-over group after 1 year of treatment paralleled those of the olipudase alfa group from the primary analysis, while clinical improvement continued for those receiving olipudase alfa for 2 years. In the cross-over group, percent-predicted DLCO increased by 28.0 ± 6.2%, spleen volume decreased by 36.0 ± 3.0% and liver volume decreased by 30.7 ± 2.5%. For those with 2 years of olipudase alfa treatment, the percent predicted DLCO increased by 28.5 ± 6.2%, spleen volume decreased by 47.0 ± 2.7%, and liver volume decreased by 33.4 ± 2.2%. Lipid profiles and elevated liver transaminase levels improved or normalized by 1 year and remained stable through 2 years of treatment. Overall, 99% of treatment-emergent adverse events were mild or moderate, with one treatment-related serious adverse event (extrasystoles; previously documented cardiomyopathy). No individual discontinued due to an adverse event. Conclusion Treatment with olipudase alfa is well tolerated and reduces manifestations of chronic ASMD with sustained efficacy. Trial registration NCT02004691 registered 9 December 2013, https://clinicaltrials.gov/ct2/show/NCT02004691

Abstract Background Approximately 40% of patients with hormone receptor (HR)‐positive and human epidermal growth factor receptor 2 (HER2)‐negative advanced breast cancer (ABC) exhibit PIK3CA mutations. Aims This study aims to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of HS‐10352, a selective PI3Kα inhibitor, in this patient population. Materials and Methods Conducted as a phase 1 dose‐escalation trial, HS‐10352 was administered orally once‐daily (QD) at dose levels of 2, 4, 6, and 8 mg. The primary endpoints were dose‐limiting toxicity (DLT) and the maximum tolerated dose (MTD). This study is registered at ClinicalTrials.gov (NCT04631835). Results Between August 2020 and March 2022, a total of 18 female patients were enrolled. DLT, manifested as hyperglycemia, occurred in two patients in the 8 mg QD group, establishing an MTD of 6 mg QD. The most common treatment‐related adverse events were hyperglycemia (88.9%) and weight loss (61.3%). In the 6 mg QD group, four patients (66.7%) had a partial response (PR), and one (16.7%) had stable disease (SD). Among the four patients with PIK3CA mutated tumors in this dosage group, three (75.0%) had PR and one (25.0%) had SD. The median progression‐free survival was not reached (95% confidence interval, 11.1‐NA). Discussion and Conclusion HS‐10352 at 6 mg QD was well‐tolerated in patients with HR‐positive, HER2‐negative ABC, and showed preliminary antitumor activity in patients with PIK3CA mutated tumors. These findings support the further clinical development of HS‐10352.

Abstract Background The THUNDER-2 phase II single institutional trial investigates the benefits of MRI-guided radiotherapy (MRIgRT) in treating locally advanced rectal cancer (LARC). This study focuses on evaluating the impact of escalating radiation therapy dose in non-responder patients using the Early Tumour Regression Index (ERI) for predicting complete response (CR). The trial’s primary endpoint is to increase the CR rate in non-responders by 10% and assess the feasibility of the delta radiomics-based MRIgRT predictive model. This interim analysis assesses the feasibility and safety of the proposed MRIgRT dose escalation strategy in terms of acute toxicity (gastrointestinal, genitourinary and haematological) and treatment adherence. Methods Stage cT2-3, N0-2, or cT4 patients with anal sphincter involvement, N0-2a, M0, but without high-risk features were enrolled. MRIgRT treatment consisted of a standard dose of 55 Gy to the Gross Tumor Volume (GTV) and mesorectum, and 45 Gy to the mesorectum and drainage nodes in 25 fractions with concomitant chemotherapy. 0.35 T MRI was used for simulation imaging and daily alignment. ERI was calculated at the 10th fraction. Non-responders with an ERI above 13.1 received intensified dose escalation from the 11th fraction, resulting in a total dose of 60.1 Gy. Acute toxicity was assessed using the CTCAE v.5 scale. Results From March 2021 to November 2022, 33 out of the total number of 63 patients to be enrolled (52.4%) were included, with one withdrawal unrelated to treatment. Sixteen patients (50%) underwent dose escalation. Treatment was well tolerated, with only one patient (3.1%) in the standard treatment group experiencing acute Grade 3 diarrhea, proctitis, and cystitis. No significant differences in toxicity were observed between the two groups (p = 0.5463). Conclusions MRIgRT treatment with dose escalation up to 60.1 Gy is well tolerated in LARC patients predicted as non-responders by ERI, confirming the feasibility and safety of this approach. The THUNDER-2 trial’s primary and secondary endpoints will be fully analyzed when all planned patients will be enrolled.

Abstract Background This phase I study aimed to assess the safety, dose‐limiting toxicity (DLT), maximum tolerated dose (MTD) and preliminary effect of nanoparticle albumin‐bound (nab)‐paclitaxel in combination with concurrent chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma (ESCC). Methods Patients with locally advanced ESCC who were ineligible or refused surgery were enrolled. Nab‐paclitaxel (60 mg/m2, 75 mg/m2, and 90 mg/m2) and cisplatin (25 mg/m2) were administered intravenously weekly on days 1, 8, 15, 22, and 29 on the basis of the 3 + 3 dose escalation method. The total dose of radiation was 50–64 Gy. The primary endpoint was the safety of chemotherapy. Results The study enrolled 12 patients across three dose levels. No treatment‐related deaths occurred. One patient in the 60 mg/m2 dose level occurred dose‐limiting Grade 3 febrile neutropenia. No DLT was found in the 90 mg/m2 dose level thus the MTD was not reached. The phase II study's recommended dose was 75 mg/m2 based on the available preclinical and clinical data including pharmacokinetics, pharmacodynamics, efficacy, and toxicity. The frequent hematologic toxicities were leukocytopenia (Grade 1–2 of 66.7% and Grade 3–4 of 33.3%), neutropenia (Grade 1–2 of 91.7% and Grade 3–4 of 8.3%). Nonhematologic toxicities were mild and manageable. Overall response rate (ORR) of all patients achieved 100%. Conclusions Weekly schedule of cisplatin and nab‐paclitaxel in combination with concurrent radiotherapy showed manageable toxicities and promising antitumor activity in patients with locally advanced ESCC. The recommended dose of nab‐paclitaxel for further studies is 75 mg/m2.

Background and purpose: The PRIDE trial (NOA-28; ARO-2022-12; NCT05871021) is scheduled to start recruitment in October 2023. Its primary objective is to enhance median overall survival (OS), compared to historical median OS rates, in patients with methylguanine methlyltransferase (MGMT) promotor unmethylated glioblastoma by incorporating isotoxic dose escalation to 75 Gy in 30 fractions. To achieve isotoxicity and counteract the elevated risk of radiation necrosis (RN) associated with dose-escalated regimens, the addition of protective concurrent bevacizumab (BEV) serves as an innovative approach. The current study aims to assess the dosimetric feasibility of the proposed concept. Materials and methods: A total of ten patients diagnosed with glioblastoma were included in this dosimetric analysis. Delineation of target volumes for the reference plans adhered to the ESTRO-EANO 2023 guideline. The experimental plans included an additional volume for the integrated boost. Additionally, the 60 Gy-volume was reduced by using a margin of 1.0 cm instead of 1.5 cm. To assess the risk of symptomatic RN, the Normal Tissue Complication Probability (NTCP) was calculated and compared between the reference and experimental plans. Results: Median NTCP of the reference plan (NTCPref) and of the experimental plan (NTCPex) were 0.24 (range 0.11–0.29) and 0.42 (range 0.18–0.54), respectively. NTCPex was a median of 1.77 (range 1.60–1.99) times as high as the NTXPref. In a logarithmic comparison, the risk of RN is enhanced by a factor of median 2.00 (range 1.66–2.35). The defined constraints for the organs at risk were feasible. Conclusion: When considering the potential protective effect of BEV, which we hypothesized might reduce the risk of RN by approximately two-fold, achieving isotoxicity with the proposed dose-escalated experimental plan for the PRIDE trial seems feasible.

Abstract Background This study aimed to evaluate the factors that affect the local control (LC) of bone metastases from radioresistant carcinomas (renal cell carcinoma, hepatocellular carcinoma [HCC], and colorectal carcinoma [CRC]) treated with palliative external-beam radiotherapy (EBRT). Methods and materials Between January 2010 and December 2020, 211 bone metastases in 134 patients were treated with EBRT in two hospitals (a cancer center and university hospital). Based on follow-up CT, these cases were reviewed retrospectively to evaluate LC at the EBRT site. Results The median EBRT dose (BED10) was 39.0 Gy (range, 14.4–66.3 Gy). The median follow-up time of the imaging studies was 6 months (range, 1–107 months). The 0.5-year overall survival and LC rates of the EBRT sites were 73% and 73%, respectively. Multivariate analysis revealed that the primary sites (HCC/CRC), low EBRT dose (BED10) (≤ 39.0 Gy), and non-administration of post-EBRT bone modifying agents (BMAs) and/or antineoplastic agents (ATs) were statistically significant factors that negatively affected the LC of EBRT sites. In the absence of BMAs or ATs, the EBRT dose (BED10) escalation from 39.0 Gy improved the LC of EBRT sites. Based on ATs administration, the LC of EBRT sites was significantly affected by tyrosine kinase inhibitors and/or immune checkpoint inhibitors. Conclusions Dose escalation improves LC in bone metastases from radioresistant carcinomas. Higher EBRT doses are needed to treat patients for whom few effective systemic therapies remain available.

Abstract Background Local recurrence is the most common pattern of failure in head and neck cancer. It can therefore be hypothesised that some of these patients would benefit from an intensified local treatment, such as radiation dose escalation of the primary tumour. This study compares treatment and toxicity outcomes from two different boost modalities in oropharyngeal cancer: simultaneous integrated boost (SIB) and brachytherapy boost. Methods Two hundred and forty-four consecutive patients treated with > 72 Gy for oropharyngeal squamous cell carcinoma between 2011 and 2018 at our institution were retrospectively analysed. Data on side effects were collected from a local quality registry and supplemented with a review of medical records. Patients receiving a brachytherapy boost first had external beam radiotherapy consisting of 68 Gy in 2 Gy fractions to the gross tumour volume (GTV), and elective radiotherapy to the neck bilaterally. The brachytherapy boost was typically given using pulsed dose rate, 15 fractions and 0.56–0.66 Gy per fraction [total dose in EQD2 = 75.4–76.8 Gy (α/β = 10)]. The typical dose escalated radiotherapy with external beam radiotherapy only, was delivered using SIB with 74,8 Gy in 2.2 Gy fractions [EQD2 = 76.0 Gy (α/β = 10)] to the primary tumour, 68 Gy in 2 Gy fractions to GTV + 10 mm margin and elective radiotherapy to the neck bilaterally. Results Dose escalation by SIB was given to 111 patients and brachytherapy boost to 134 patients. The most common type of cancer was base of tongue (55%), followed by tonsillar cancer (42%). The majority of patients had T3- or T4-tumours and 84% were HPV-positive. The 5-year OS was 72,4% (95% CI 66.9–78.3) and the median follow-up was 6.1 years. Comparing the two different dose escalation modalities we found no significant differences in OS or PFS and these results remained after a propensity-score matched analysis was performed. The analysis of grade ≥ 3 side effects showed no significant differences between the two different dose escalation techniques. Conclusions We found no significant differences in survival or grade ≥ 3 side effects comparing simultaneous integrated boost and brachytherapy boost as alternative dose escalation modalities in the treatment of oropharyngeal cancer.

Aim To compare real-world dose escalation of risankizumab with other US Food and Drug Administration (FDA)-approved biologic treatments for management of moderate-to-severe psoriasis (PsO) in the United States. Methods The Merative® MarketScan® Research Database was used to identify adults with ≥2 medical claims for PsO, ≥3 claims of the index biologic medication in the maintenance period, and ≥6 months continuous enrollment pre-induction and ≥6 months after initiation of the maintenance period. Dose escalation was defined as ≥2 dosing intervals where the average daily dose was ≥30% higher than the expected daily dose (per FDA-approved dosing). Comparisons between risankizumab and other cohorts were made using chi-square tests and logistic regression models. Results At the 30% threshold, the percentage of patients with dose escalation in the full maintenance period was significantly lower with risankizumab (2.0%) compared with other drug classes (tumor necrosis factor, interleukin (IL)-12/23, IL-17, or other IL-23 inhibitors: 17.6%, 10.0%, 18.3%, or 7.1%, respectively; p

Regorafenib, an oral multikinase inhibitor, has improved survival in metastatic colorectal cancer (mCRC) patients who have progressed on standard therapies. Our study aimed to evaluate prognostic factors influencing regorafenib treatment and assess the optimal dosing regimen in a real-life setting. We retrospectively analysed 263 patients with mCRC from multiple medical oncology clinics in Turkey. Treatment responses and prognostic factors for survival were evaluated using univariate and multivariate analysis. Of the patients, 120 were male, and 143 were female; 28.9% of tumors were located in the rectum. RAS mutations were present in 3.0% of tumors, while BRAF, K-RAS, and N-RAS mutations were found in 3.0%, 29.7%, and 25.9% of tumor tissues, respectively. Dose escalation was preferred in 105 (39.9%) patients. The median treatment duration was 3.0 months, with an objective response rate (ORR) of 4.9%. Grade ≥ 3 treatment-related toxicity occurred in 133 patients, leading to discontinuation, interruption, and modification rates of 50.6%, 43.7%, and 79.0%, respectively. Median progression-free survival (PFS) and overall survival (OS) were 3.0 and 8.1 months, respectively. RAS/RAF mutation (hazard ratio [HR] 1.5, 95% confidence interval [CI] 1.1-2.3; P = 0.01), pretreatment carcinoembryonic antigen (CEA) levels (HR 1.6, 95% CI 1.1-2.3; P = 0.008), and toxicity-related treatment interruption or dose adjustment (HR 1.6, 95% CI 1.1-2.4; P = 0.01) were identified as independent prognostic factors for PFS. Dose escalation had no significant effect on PFS but was associated with improved OS (P < 0.001). Independent prognostic factors for OS were the initial TNM stage (HR 1.3, 95% CI 1.0-1.9; P = 0.04) and dose interruption/adjustment (HR 0.4, 95% CI 0.2-0.9; P = 0.03). Our findings demonstrate the efficacy and safety of regorafenib. Treatment line influences the response, with dose escalation being more favorable than adjustment or interruption, thus impacting survival.

Purpose: To report on the late toxicity and local control (LC) of head and neck cancer patients treated with adaptive FDG-PET/CT response-guided radiotherapy (ADMIRE) with dose escalation (NCT03376386). Materials and methods: Between December 2017 and April 2019, 20 patients with stage II-IV squamous cell carcinoma of the larynx, hypopharynx or oropharynx were treated within the ADMIRE study where FDG-PET/CT response-guided (Week 2&4) dose escalation was applied (total dose 70–78 Gy). Cisplatin or cetuximab was added to radiotherapy in case of T3-4 and/or N2c disease. To compare the LC and late toxicity of the study population, we used an external control group (n = 67) consisting of all eligible patients for the study (but not participated). These patients were treated in our institution during the same period with the current standard of 70 Gy radiotherapy. To reduce the effect of confounding, logistic regression analyses was done using stabilized inverse probability of treatment weighting (SIPTW). Results: After median follow-up of 40 and 43 months for the ADMIRE and control groups, the 3-year LC-rates were 74% and 78%, respectively (adjusted HR after SIPTW 0.80, 95 %CI 0.25–2.52, p = 0.70). The incidences of any late G3 toxicity were 35% and 18%, respectively. The adjusted OR for any late G3 toxicity was 5.09 (95 %CI 1.64–15.8, p = 0.005), for any late G ≥ 2 toxicity was 3.67 (95 %CI 1.2–11.7, p = 0.02), for persistent laryngeal edema was 10.95 (95% CI 2.71–44.29, p = 0.001), for persistent mucosal ulcers was 4.67 (95% CI 1.23–17.7, p = 0.023), and for late G3 radionecrosis was 15.69 (95 %CI 2.43–101.39, p = 0.004). Conclusion: Given the comparable LC rates with increased late toxicity in the ADMIRE group, selection criteria for future adaptive dose escalation trials (preferably randomized) need to be refined to include only patients at higher risk of local failure and/or lower risk of severe late toxicity.

Severe bronchopulmonary dysplasia (BPD) is a chronic lung disorder that primarily affects premature babies with extremely low birth weight and involves in multiple organ system; no effective pharmacotherapy for this disease exists, and mortality remains high. Based on the evidence from previous preclinical studies and phase I clinical trials, this study aims to test the safety of intravenous application of a single dose of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in patients with severe BPD. The Mesenchymal Stem cells for Bronchopulmonary Dysplasia Treatment (MSBDT) trial is a single center, open-label, dose-escalation phase I clinical trial. Severe BPD patients were enrolled in Children Hospital of Chongqing Medical University, Chongqing, China. The first six patients were treated with low-dose hUC-MSCs (1 × 106 cells/kg) and the next seven patients were treated with high-dose hUC-MSCs (5 × 106 cells/kg). This study is registered with ClinicalTrials.gov, number NCT03558334. No prespecified infusion-associated adverse events, immediate complication, respiratory or cardiovascular compromise were observed during infusion and 24 h after infusion. No significant changes in safety laboratory values were observed. One death event occurred in the low-dose group on study day 10, and one death event occurred in the high-dose group on study day 24, while, after review in detail, the two cases are not believed to be infusion-associated events. In conclusion, intravenous application of a single dose of hUC-MSCs was tolerated in thirteen patients with severe BPD.

Abstract Background Combinations of drugs are becoming increasingly common in oncology treatment. In some cases, patients can benefit from the interaction between two drugs, although there is usually a higher risk of developing toxicity. Due to drug–drug interactions, multidrug combinations often exhibit different toxicity profiles than those of single drugs, leading to a complex trial scenario. Numerous methods have been proposed for the design of phase I drug combination trials. For example, the two-dimensional Bayesian optimal interval design for combination drug (BOINcomb) is simple to implement and has desirable performance. However, in scenarios where the lowest and starting dose is close to being toxic, the BOINcomb design may tend to allocate more patients to overly toxic doses, and select an overly toxic dose combination as the maximum tolerated dose combination. Method To improve the performance of BOINcomb in the above extreme scenarios, we widen the range of variation of the boundaries by setting the self-shrinking dose escalation and de-escalation boundaries. We refer to the new design as adaptive shrinking Bayesian optimal interval design for combination drug (asBOINcomb). We conduct a simulation study to evaluate the performance of the proposed design using a real clinical trial example. Results Our simulation results show that asBOINcomb is more accurate and stable than BOINcomb, especially in some extreme scenarios. Specifically, in all ten scenarios, the percentage of correct selection is higher than the BOINcomb design within 30 to 60 patients. Conclusion The proposed asBOINcomb design is transparent and simple to implement and can reduce the trial sample size while maintaining accuracy compared with the BOINcomb design.

Abstract Background Olipudase alfa is a recombinant human acid sphingomyelinase (ASM) enzyme replacement therapy (ERT) for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). We report 2-year cumulative safety and efficacy data after olipudase alfa treatment in 20 children (four adolescents [12–17 year], nine children [6–11 year], and seven infants/early child [1–5 year]) with baseline splenomegaly and growth deficits who completed the 1-year ASCEND-Peds clinical trial (NCT02292654) and who continue to receive olipudase alfa in a long-term study (NCT02004704). Efficacy endpoints include spleen and liver volumes, diffusing capacity of the lung for carbon monoxide (DLCO), high-resolution computed tomography (HRCT) lung imaging, lipid profiles, liver function tests, and height Z-scores. Results All 20 former ASCEND-Peds patients completed at least 2 years of olipudase alfa treatment. No patient discontinued and no new safety issue arose during the second year of treatment; 99% of adverse events were mild or moderate. During year 2, one patient had two treatment-related serious events of hypersensitivity that resolved. Mean reductions from baseline in spleen and liver volumes were 61% and 49%, respectively (p

Itaru Miura,1 Kei Watabe,2 Reiko Sakaguchi,3 Keisuke Okamoto,4 Hidenori Maruyama5 1Department of Neuropsychiatry, Fukushima Medical University, Fukushima, Japan; 2Department of Data Science, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 3Department of Clinical Research, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 4Department of Clinical Operation, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 5Medical Affairs, Sumitomo Pharma Co., Ltd, Tokyo, JapanCorrespondence: Itaru Miura, Department of Neuropsychiatry, Fukushima Medical University 1 Hikarigaoka, Fukushima, 960-1295, Japan, Tel +81-24-547-1331, Fax +81-24-548-6735, Email itaru@fmu.ac.jpPurpose: To evaluate the effectiveness and safety of lurasidone 80 mg/day (versus the 40 mg/day dose) during a 12-week, open-label extension study in patients with an acute exacerbation of schizophrenia who had completed a 6-week double-blind study of lurasidone.Patients and Methods: A total of 289 adult patients with schizophrenia completed the double-blind study and enrolled in the 12-week extension study. Lurasidone was flexibly dosed at 40 or 80 mg/day. Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) subscale scores, Clinical Global Impression-Severity Scale (CGI-S), and Calgary Depression Scale for Schizophrenia (CDSS), analyzed based on last observation carried forward (LOCF-endpoint). Safety/tolerability assessments included adverse events, body weight, laboratory tests, and discontinuation due to adverse events.Results: Mean endpoint change was greater for lurasidone in modal doses of 80 mg/d (N=136) vs 40 mg/d (N=153) on the PANSS positive subscale (− 3.0 vs − 2.3), PANSS negative subscale (− 1.9 vs − 1.7), PANSS General Psychopathology subscale (− 5.1 vs − 3.8), the CGI-S score (− 0.5 vs − 0.4), and the CDSS score (− 0.7 vs − 0.1). Discontinuation rates due to adverse events on lurasidone modal 80 mg/d vs 40 mg/d were 4.4% vs 7.2%; and the most common adverse events in the modal 80 mg/d group were nasopharyngitis, 7.4% (vs 4.6% on modal 40 mg/d), constipation, 5.9% (vs 2.0%), and headache, 5.9% (vs 2.0%).Conclusion: In patients with acute schizophrenia treated with lurasidone 40 mg/d, increasing the dose to 80 mg/d was well tolerated, and was associated with greater improvement in PANSS subscale scores compared to continued treatment with a dose of 40 mg/d.Keywords: lurasidone, schizophrenia, extension treatment, dose escalation, effectiveness, safety

Introduction: Non-surgical management of rectal cancer aiming for organ-preservation is an important development to improve rectal cancer treatment. Dose escalated radiotherapy represents one approach to increase clinical complete response (cCR) rates. In the present study we present feasibility and outcome data on rectal cancer patients who were treated with dose escalated radiotherapy using an MR guided online response-adaptive workflow. Material and methods: A total of five patients were treated with 45 Gy in 25 fractions to the mesorectum and the internal iliac lymph nodes and a simultaneous integrated boost to the primary tumor with 50 Gy in 25 fractions on a conventional linac. In addition, weekly response-adaptive boost fractions with 3 Gy per fraction were scheduled on a 1.5 T MR-Linac. Concomitant chemotherapy with 5-fluorouracil was given as continuous venous infusion during the first and last week of treatment. Response was evaluated approximately-three months after the end of treatment and surgery was omitted in case of a clinical complete response (cCR) or a near cCR. Toxicity was graded by using PRO-CTCAE, Quality of life by the EORTC-QLQ-C30 questionnaire and continence according to the Wexner scale. Results: Response-adaptive dose escalated radiotherapy was feasible and well tolerated by all patients. Four reached a clinical complete response, one had a local excision confirming pathological complete response (pCR). All PRO-CTCAE grade 3 toxicities resolved within six months after the end of treatment. Quality of life and continence scores during follow-up were comparable to baseline levels. Conclusion: Dose-escalated online response-adaptive MR-guided radiotherapy appears to be a very promising treatment with the goal of organ preservation in rectal cancer leading to high response rates, excellent organ function and limited side effects. Further prospective evaluation is needed.

Abstract Background and purpose Dose escalation for positive node maybe improve the regional control of patients with node-positive cervical cancer, but the optimal dose for nodes of different sizes remains controversial. The purpose of this study was to explore the individualized dose escalation for lymph nodes (LNs) with different sizes in the definitive radiotherapy of cervical cancer. Methods A total of 1002 cervical cancer patients with the International Federation of Gynecology and Obstetrics (FIGO 2009) stage IB1–IVA, who were treated by definitively radiotherapy between September 2013 and December 2016 were enrolled. All LNs identified by computed tomography/magnetic resonance imaging (CT/MRI) were assigned into three groups according to the short diameters of 60 Gy) (control rate, 99.4% vs. 99.3% vs. 100%, P = 0.647) (5-year OS, 76.2% vs. 79% vs. 81.6%, P = 0.682) (5-year PFS, 74.1% vs. 73.9% vs. 78.9% P = 0.713). Among LNs of 1–2 cm, the control and PFS rates were significantly higher in the group of dose ≥ 55 Gy than the group of dose

Abstract Background Localized pancreatic adenocarcinoma carries a poor prognosis even after aggressive therapy. Up to 40% of patients may develop locoregional disease as the first site of failure. As such, there may be a role for intensification of local therapy such as radiation therapy. Radiation dose escalation for pancreatic cancer is limited by proximity of the tumor to the duodenum. However, the duodenum is removed during Whipple procedure, allowing the opportunity to dose escalate with intraoperative radiation therapy (IORT). Although prior studies have shown potential benefit of IORT in pancreatic cancer, these studies did not utilize ablative doses (biologically effective dose [BED10] > 100 Gy). Furthermore, the optimal radiation target volume in this setting is unclear. There has been increased interest in a “Triangle Volume” (TV), bordered by the celiac axis, superior mesenteric artery, common hepatic artery, portal vein, and superior mesenteric vein. Dissection of this area, has been advocated for by surgeons from Heidelberg as it contains extra-pancreatic perineural and lymphatic tracts, which may harbor microscopic disease at risk of mediating local failure. Interestingly, a recent analysis from our institution indicated that nearly all local failures occur in the TV. Therefore, the purpose of this protocol is to evaluate the safety of delivering an ablative radiation dose to the TV with IORT following neoadjuvant chemotherapy and stereotactic body radiation therapy (SBRT). Methods Patients with non-metastatic pancreatic adenocarcinoma centered in the head or neck of the pancreas will be enrolled. Following treatment with multi-agent neoadjuvant chemotherapy, patients will undergo SBRT (40 Gy/5 fractions) followed by IORT (15 Gy/1 fraction) to the TV during the Whipple procedure. The primary objective is acute ( 90 days) toxicity after IORT measured by Clavien-Dindo classification, overall survival, local progression-free survival, distant metastasis-free survival, and progression-free survival. Discussion If the results show that delivering an ablative radiation dose to the TV with IORT after neoadjuvant chemotherapy and SBRT is safe and feasible, it warrants further investigation in a phase II trial to evaluate efficacy of this approach. Trial Registration This study was registered at ClinicalTrials.gov on 12/2/2021 (NCT05141513). https://clinicaltrials.gov/ct2/show/NCT05141513

Carbon-ion radiotherapy (CIRT) is an important part of modern radiotherapy. Compared to conventional photon radiotherapy modalities, CIRT brings two major types of advantages to physical and biological aspects respectively. The physical advantages include a substantial dose delivery to the tumoral area and a minimization of dose damage to the surrounding tissue. The biological advantages include an increase in double-strand breaks (DSBs) in DNA structures, an upturn in oxygen enhancement ratio and an improvement of radiosensitivity compared with X-ray radiotherapy. The two advantages of CIRT are that the therapy not only inflicts major cytotoxic lesions on tumor cells, but it also protects the surrounding tissue. According to annual diagnoses, lung cancer is the second most common cancer worldwide, followed by breast cancer. However, lung cancer is the leading cause of cancer death. Patients with stage I non-small cell lung cancer (NSCLC) who are optimally received the treatment of lobectomy. Some patients with comorbidities or combined cardiopulmonary insufficiency have been shown to be unable to tolerate the treatment when combined with surgery. Consequentially, radiotherapy may be the best treatment option for this patient category. Multiple radiotherapy options are available for these cases, such as stereotactic body radiotherapy (SBRT), volumetric modulated arc therapy (VMAT), and intensity-modulated radiotherapy (IMRT). Although these treatments have brought some clinical benefits to some patients, the resulting adverse events (AEs), which include cardiotoxicity and radiation pneumonia, cannot be ignored. The damage and toxicity to normal tissue also limit the increase of tumor dose. Due to the significant physical and biological advantages brought by CIRT, some toxicity induced by radiotherapy may be avoided with CIRT Bragg Peak. CIRT brought clinical benefits to lung cancer patients, especially geriatric patients. This review introduced the clinical efficacy and research results for non-small cell lung cancer (NSCLC) with CIRT.

The aim of the study was to evaluate the development of treatment of primary high-risk prostate cancer in regards to biochemical no evidence of disease (bNED), acute and late gastrointestinal (GI) and genitourinary (GU) side effects.

Abstract Background We aimed to determine the safety and efficacy of nintedanib, an oral anti-angiogenic tyrosine kinase inhibitor, in combination with pembrolizumab, an anti-PD1 immunotherapy, in patients with advanced solid tumors (PEMBIB trial; NCT02856425). Methods In this monocentric phase Ib dose escalation cohort, we evaluated escalating doses of nintedanib (Dose level 1 (DL1) = 150 mg bid [bis in die, as twice a day]; DL2 = 200 mg bid, oral delivery) in combination with pembrolizumab (200 mg Q3W, IV). Patients received a 1-week lead-in dose of nintedanib monotherapy prior starting pembrolizumab. The primary objective was to establish the maximum tolerated dose (MTD) of the combination based on dose limiting toxicity (DLT) occurrence during the first 4 weeks. Secondary objectives were to assess the anti-tumor efficacy and to identify the associated immune and angiogenic parameters in order to establish the recommended nintedanib dose for expansion cohorts. Flow cytometry (FC), Immuno-Histo-Chemistry (IHC) and electrochemiluminescence multi-arrays were prospectively performed on baseline & on-treatment tumor and blood samples to identify immune correlates of efficacy. Results A total of 12/13 patients enrolled were evaluable for DLT (1 patient withdrew consent prior receiving pembrolizumab). Three patients at 200 mg bid experienced a DLT (grade 3 liver enzymes increase). Four patients developed grade 1–2 immune related adverse events (irAE). Eight patients died because of cancer progression. Median follow-up was 23.7 months (95%CI: 5.55–40.5). Three patients developed a partial response (PR) (ORR = 25%) and five patients (42%) had durable clinical benefit (DCB), defined as PR or stable disease (SD) ≥ 6 months. At baseline, patients with DCB had higher plasma levels of Tie2, CXCL10, CCL22 and circulating CD4+ PD1+ OX40+ T cells than patients without DCB. Patients with DCB presented also with more DC-LAMP+ dendritic cells, CD3+ T cells and FOXP3+ Tregs in baseline tumor biopsies. For DCB patients, the nintedanib lead-in monotherapy resulted in higher blood CCL3, Tregs and CCR4+ CXCR3+ CXCR5− memory CD4 T cells. After the first pembrolizumab infusion, patients with DCB showed lower IL-6, IL-8, IL-27 plasma levels. Conclusion Nintedanib 150 mg bid is the recommended dose for combination with pembrolizumab and is currently investigated in multiple expansion cohorts. Early tumoral and circulating immune factors were associated with cancer outcome under nintedanib & pembrolizumab therapy. Trial registration ClinicalTrials.gov, NCT02856425 . Registered August 4, 2016 — Prospectively registered.

Abstract We report the safety and pharmacokinetic properties of the HIV‐1 maturation inhibitor GSK3739937 (GSK'937) in healthy participants. This was a phase I, first‐in‐human, double‐blind, randomized, placebo‐controlled, single‐ (part 1) and multiple‐ (part 2) dose escalation study with an additional open‐label relative bioavailability and food effect study (part 3). Participants received oral ascending single doses (10–800 mg) in part 1, up to 18 once‐daily 25‐ to 100‐mg or 3 once‐weekly 500‐mg doses in part 2, and single 100‐mg doses as powder‐in‐bottle or tablet (in fed and fasted states) formulations in part 3. Primary and secondary objectives were safety and pharmacokinetic assessments, respectively. Ninety‐one participants were enrolled; 38 reported 81 total adverse events (AEs). All AEs in participants receiving GSK'937 were grade 1 or 2 and resolved during the study. Most drug‐related AEs were gastrointestinal (14/17, 82%). The terminal phase half‐life of GSK'937 was ~3 days for all doses following single and repeat dosing. Geometric mean maximum concentration and total drug exposures exhibited dose‐proportional increases during part 1. Accumulation in exposure following repeat dosing was 6‐ to 7‐fold with daily dosing and ~1.7‐fold after weekly treatment, as expected due to the long half‐life. Bioavailability of GSK'937 after a meal was 1.35‐ to 1.40‐fold greater as a tablet versus powder‐in‐bottle and >2‐fold higher in fed versus fasted states when provided as a tablet. No unexpected or dose‐limiting safety events occurred. Pharmacokinetic parameters of long half‐life and accumulation of exposure following repeat dosing suggest the potential for weekly oral dosing. ClinicalTrials.gov identifier: NCT04493684.

Wendy Y Cheng,1 Sujata P Sarda,2 Nikita Mody-Patel,2 Sangeeta Krishnan,2 Mihran Yenikomshian,1 Colin Kunzweiler,1 Jensen Duy Vu,1 Hoi Ching Cheung,1 Mei Sheng Duh1 1Analysis Group, Inc., Boston, MA, USA; 2Apellis Pharmaceuticals, Inc., Waltham, MA, USACorrespondence: Wendy Y Cheng, Analysis Group, Inc., 111 Huntington Ave, 14th Floor, Boston, MA, 02199, USA, Tel +1 617 425 8219, Fax +1 617 425 8000, Email Wendy.Cheng@analysisgroup.comPurpose: Current pharmacologic management of paroxysmal nocturnal hemoglobinuria (PNH) consists of C5 inhibitors, eculizumab and ravulizumab; however, because patients experience incomplete symptom control, off-label doses may be utilized. We conducted a retrospective, longitudinal cohort study of provider-based claims data to assess the real-world eculizumab dosing patterns in PNH patients.Patients and Methods: Patients were ≥ 12 years, received ≥ 2 eculizumab infusions between January 1, 2015 and September 30, 2019, and had ≥ 3 months of continuous clinical activity prior to index. The index date was the first claim for eculizumab. Patients with ≥ 1 diagnosis of another indication for eculizumab were excluded. Treatment patterns including the proportion with high, label-recommended, and low dosages during induction (first 28 days) and maintenance (beginning day 29) phases were described. The proportion and time-to-first dose escalation, defined as an increase in dose or frequency of infusion, were assessed among a subset of patients (ie, escalation analysis cohort).Results: A total of 707 patients were examined. Mean (standard deviation [SD]) starting dose was 862mg (412mg) and was higher than label-recommended 600mg for 64% of the patients. Mean (SD) dose per infusion was 859mg (391mg) during the induction phase; average dose was higher than label-recommended 600mg for 68%. Mean (SD) dose per infusion during the maintenance phase was 1005mg (335mg); average dose was higher than label-recommended 900mg for 43%. Dose escalation occurred in 40/121 escalation analysis cohort patients. Median time-to-first dose escalation was ∼ 12 months.Conclusion: Results suggest that deviations from label-recommended dosing patterns were common. Future budget impact assessments of eculizumab should account for real-world dosing patterns to comprehensively assess costs and benefits.Keywords: complement inhibitors, dose escalation, dosing patterns, eculizumab, paroxysmal nocturnal hemoglobinuria

Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) have limited treatment options, particularly if they are transplantation or chimeric antigen receptor (CAR) T-cell ineligible, and novel therapeutics are needed. An 86-year-old woman with relapsed DLBCL received a novel, first-in-class small molecule inhibitor of N-myristoyltransferase (NMT) as the initial patient on a phase I dose escalation trial. Daily oral administration of 20 mg PCLX-001 tablets produced a pharmacokinetic profile suitable for single daily dosing: rapid oral absorption, followed by an apparent elimination half-life of 16 h, without systemic accumulation of drug by day 15. Pharmacodynamic tests showed no clear change in NMT1 and NMT2 levels or selected NMT substrate Lyn and HGAL protein levels in normal circulating blood mononuclear cells, suggesting a higher dose will be required for normal tissue toxicity. The patient did not experience any dose-limiting toxicities but had disease progression after 28 days of study therapy. Dose escalation continues in other patients in this first-in-human study of a new class of anticancer drug. We conclude that PCLX-001 oral monotherapy has suitable pharmacokinetic parameters for dose escalation, and that higher doses are required to achieve pharmacodynamic evidence of on-target activity in normal tissues. The current protocol is appropriately designed to achieve these ends, and the study proceeds without modification.

Abstract Background A significant proportion of patients with poor prognosis squamous cell cancer of the oropharynx relapse loco-regionally despite radical (chemo)radiotherapy. If a predictive biomarker for disease control can be identified during treatment then individualised and adaptive treatment strategies may be employed. The aim of this study is to assess the feasibility of adaptive and dose-escalated RT to the gross tumour volume without increasing surrounding planning target volume doses and maintaining clinically acceptable organs at risk doses. Materials and methods Twenty representative patients with poor prognosis locally advanced OPSCC who were known to have relapsed post RT, were re-planned retrospectively using Eclipse TPS v15.5, RapidPlan™ and multi-criteria optimisation. In our centre, PTV65 is treated with 65 Gy in 30 fractions while areas at risk of containing microscopic disease (PTV54) are treated synchronously to 54 Gy in 30 fractions. The original clinical plans were re-optimised to act as controls (Group I). These plans were split into two plans of 15 fractions each, with the latter 15 fractions used to escalate the dose to the GTV to 73 Gy (Group II) and 82 Gy (Group III). Plan sums were created for the total 30 fractions to record plan evaluation parameters along with assessments of plan deliverability. Results For all groups, the dose coverage at D98% and D50% for the PTVs were comparable. The D2% dose levels for PTV65-GTV increased. All dose levels associated with PTV54 remained largely unaffected by the dose escalation regimens. Conformity indices for PTV65 and PTVAll (PTV65 plus PTV54) reveal comparable target volume coverage across all three groups. Despite the GTV being escalated by 12.3% and 26.2% in groups II and III, the volume of GTV receiving > 84 Gy was considerably less than 1.75 cc. While OAR doses increased for the escalated groups, these increases were not clinically significant. Conclusion This planning feasibility study exploring RapidPlan™ combined with multi-criteria optimisation has demonstrated that doses to the GTV may be escalated without increasing PTV65-GTV, PTV54 or OAR doses considerably, suggesting an interventional clinical trial using this approach would be feasible.

Abstract Background Trametinib is an oral MEK 1/2 inhibitor, with a single agent recommended phase 2 dose (RP2D) of 2 mg daily (QD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib in patients with advanced solid tumors who had various degrees of hepatic dysfunction (HD). Methods Advanced cancer patients were stratified into 4 HD groups based on Organ Dysfunction Working Group hepatic function stratification criteria: normal (Norm), mild (Mild), moderate (Mod), severe (Sev). Dose escalation was based on “3 + 3” design within each HD group. PK samples were collected at cycle 1 days 15-16. Results Forty-six patients were enrolled with 44 evaluable for safety [Norm=17, Mild=7, Mod (1.5 mg)=4, Mod (2 mg)=5, Sev (1 mg)=9, Sev (1.5 mg)=2] and 22 for PK analysis. Treatment related adverse events were consistent with prior trametinib studies. No treatment related deaths occurred. Dose limiting toxicities (DLTs) were evaluable in 15 patients (Mild=6, Mod (1.5 mg)=3, Mod (2 mg)=2, Sev (1 mg)=3 and Sev (1.5 mg)=1). One DLT (grade 3 acneiform rash) was observed in a Sev patient (1.5 mg). Dose interruptions or reductions due to treatment related adverse events occurred in 15 patients (34%) [Norm=9, 53%; Mild=2, 29%; Mod (1.5 mg)=1, 33%; Mod (2 mg)=2, 33%; Sev (1 mg)=1, 11%; Sev (1.5 mg)=1; 50%]. There were no significant differences across HD groups for all PK parameters when trametinib was normalized to 2 mg. However, only limited PK data were available for the Mod (n = 3) and Sev (n = 3) groups compared to Norm (n = 10) and Mild (n = 6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p = 0.26). Conclusions RP2D for trametinib in Mild HD patients is 2 mg QD. There are insufficient number of evaluable patients due to difficulty of patient accrual to declare RP2D and MTD for Mod and Sev HD groups. DLTs were not observed in the highest dose cohorts that reached three evaluable patients – 1.5 mg QD in Mod group, and 1 mg QD in Sev group. Trial registration This study was registered in the ClinicalTrials.gov website ( NCT 02070549 ) on February 25, 2014. .

Radiotherapy is the attractive treatment option for prostate cancer and has a clear role in all stages of the disease. Over the last decade, advances in technology, imaging capabilities, and improved radiobiological understanding have deeply transformed radiotherapy for prostate cancer, allowing dose escalation and wide adoption of hypofractionation. Furthermore, the integration of magnetic resonance imaging (MRI) and improved physical precision of dose delivery have given an impetus to additionally target intraprostatic tumor lesions, previously agnostic to conventional radiotherapy target definition concept. The emerging data from randomized clinical trials and observation research show that ultra-hypofractionation is a safe approach while further follow-up is needed to assess its efficacy compared to standard fractionation. There is an ongoing uncertainty surrounding true alpha/beta ratio for prostate cancer since hypofractionation has so far failed to yield theoretically envisioned superior biochemical control outcomes. Finally, recently published randomized trial settled ongoing controversy regarding the role of elective pelvic lymph node radiotherapy in patients with high-risk prostate cancer, showing clear benefit when pelvic nodes were treated to 50 Gy. The role of partial gland dose escalation/tumor boosting is evolving, and more data is needed to adopt this approach in routine clinical care. Going forward, molecular imaging will be crucial to assess biology of the disease, predict a response potentially, and optimally personalize radiotherapy treatment decisions. In this narrative review, we critically analyzed the published literature and provided practical summary of recent prostate radiotherapy advances for busy clinicians.

Abstract Background To explore the maximum tolerated dose (MTD) and evaluate the safety of dose escalation using hypofractionated simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) concurrent with chemotherapy for unresectable stage III non-small cell lung cancer (NSCLC). Methods Four escalating radiation dose levels were used. This study included 25 patients with previously untreated NSCLC who received six concurrent weekly chemotherapy cycles comprising cisplatin and docetaxel. Dose-limiting toxicity (DLT) was defined as any acute toxicity that interrupted radiotherapy for more than 1 week. MTD was defined as the highest dose level that didn’t induce DLT or grade 5 toxicity in two patients. Results All 25 patients received the prescribed escalating radiation dose from the start dose up to LEVEL 4. Two patients experienced DLT at dose LEVEL 4. One patient died because of upper gastrointestinal hemorrhage within 6 months after radiotherapy, whereas another patient among the additional five patients died because of grade 5 radiation pneumonitis within 2 months after radiotherapy. Dose LEVEL 3 was defined as MTD. The 1- and 2-year local controls were 82.8 and 67.8%, respectively. The median progression-free survival was 15.4 months, whereas the median overall survival was 27.3 months. Conclusions Dose escalation was safely achieved up to LEVEL 3 [the planning gross target volume (PTVG) 60.5 Gy/22 Fx, 2.75 Gy/Fx; the planning clinical target volume (PTVC) 49.5 Gy/22 Fx] using SIB-IMRT concurrently with chemotherapy for unresectable stage III NSCLC, and the acute toxicities were generally well tolerated. Further prospective studies on long-term outcomes and late toxicities are warranted. Trial registration Retrospective registration, ChiCTR1900027290 (08/11/2019).

Abstract Background Modern designs for dose-finding studies (e.g., model-based designs such as continual reassessment method) have been shown to substantially improve the ability to determine a suitable dose for efficacy testing when compared to traditional designs such as the 3 + 3 design. However, implementing such designs requires time and specialist knowledge. Methods We present a practical approach to developing a model-based design to help support uptake of these methods; in particular, we lay out how to derive the necessary parameters and who should input, and when, to these decisions. Designing a model-based, dose-finding trial is demonstrated using a treatment within the AGILE platform trial, a phase I/II adaptive design for novel COVID-19 treatments. Results We present discussion of the practical delivery of AGILE, covering what information was found to support principled decision making by the Safety Review Committee, and what could be contained within a statistical analysis plan. We also discuss additional challenges we encountered in the study and discuss more generally what (unplanned) adaptations may be acceptable (or not) in studies using model-based designs. Conclusions This example demonstrates both how to design and deliver an adaptive dose-finding trial in order to support uptake of these methods.

Background: Glioblastoma is a high-grade aggressive neoplasm whose outcomes have not changed in decades. In the current treatment pathway, tumour growth continues and remains untreated for several weeks post-diagnosis. Intensified upfront therapy could target otherwise untreated tumour cells and improve the treatment outcome. POBIG will evaluate the safety and feasibility of single-fraction preoperative radiotherapy for newly diagnosed glioblastoma, assessed by the maximum tolerated dose (MTD) and maximum tolerated irradiation volume (MTIV). Methods: POBIG is an open-label, dual-centre phase I dose and volume escalation trial that has received ethical approval. Patients with a new radiological diagnosis of glioblastoma will be screened for eligibility. This is deemed sufficient due to the high accuracy of imaging and to avoid treatment delay. Eligible patients will receive a single fraction of preoperative radiotherapy ranging from 6 to 14 Gy followed by their standard of care treatment comprising maximal safe resection and postoperative chemoradiotherapy (60 Gy/30 fr) with concurrent and adjuvant temozolomide). Preoperative radiotherapy will be directed to the part of the tumour that is highest risk for remaining as postoperative residual disease (hot spot). Part of the tumour will remain unirradiated (cold spot) and sampled separately for diagnostic purposes. Dose/volume escalation will be guided by a Continual Reassessment Method (CRM) model. Translational opportunities will be afforded through comparison of irradiated and unirradiated primary glioblastoma tissue. Discussion: POBIG will help establish the role of radiotherapy in preoperative modalities for glioblastoma. Trial registration: NCT03582514 (clinicaltrials.gov).

(1) Background: the aims of this study were to determine the total extent of pancreatic cancer’s internal motions, using Calypso® extracranial tracking, and to indicate possible clinical advantages of continuous intrafractional fiducial-based tumor motion tracking during SABR. (2) Methods: thirty-four patients were treated with SABR for LAPC using Calypso® for motion management. Planning MSCTs in FB and DBH, and 4D-CTs were performed. Using data from Calypso® and 4D-CTs, the movements of the lesions in the CC, AP and LR directions, as well as the volumes of the 4D-CT-based ITV and the volumes of the Calypso®-based ITV were compared. (3) Results: significantly larger medians of tumor excursions were found with Calypso® than with 4D-CT: CC: 29 mm (p < 0.001); AP: 14 mm (p < 0.001) and LR: 11 mm (p < 0.039). The median volume of the Calypso®-based ITV was significantly larger than that of the 4D-CT based ITV (p < 0.001). (4) Conclusion: beside known respiratory-induced internal motions, pancreatic cancer seems to have significant additional motions which should be considered during respiratory motion management. Only direct and continuous intrafractional fiducial-based motion tracking seems to provide complete coverage of the target lesion with the prescribed isodose, which could allow for safe tumor dose escalation.

Enzyme replacement therapy (ERT) with recombinant α-galactosidase A (AGAL) can lead to the formation of neutralizing anti-drug antibodies (ADA), which significantly limit treatment efficacy in patients with Fabry disease (FD). The effects of dose escalation on ADA titer and plasma globotriaosylsphingosine (lyso-Gb3) level are unknown. We screened 250 FD patients (200 males, 50 females) under ERT for ADAs and assessed the impact of an approved dose escalation in affected patients, focusing on ADA titers and plasma lyso-Gb3. ADA-positive patients were identified by serum-mediated inhibition assays, followed by titration assays to determine the individual inhibitory capacities of ADAs against agalsidase-alfa and agalsidase-beta. 70 (35%) of the male patients were ADA-positive, with a mean inhibitory capacity of 83.5 ± 113.7mg AGAL. Although patients receiving agalsidase-beta showed higher inhibitory capacities (84.7 ± 34.7mg) than patients under agalsidase-alfa (60.3 ± 126.7mg, p

Background and purpose: Radiation dose escalation to improve poor outcomes with chemoradiation in locally advanced esophageal carcinoma is limited in part by increased toxicity. This Phase I study investigates the use of IMRT to improve tolerability of dose escalation. Materials and methods: A single-institution, prospective study was conducted between 2007 and 2013 for individuals with inoperable esophageal carcinoma. Gross disease received 60 Gy in 30 fractions and at-risk sites received 54 Gy with simultaneous integrated boost. Concurrent chemotherapy primarily consisted of cisplatin/5-FU. The primary objective was to assess feasibility (

Stereotactic body radiotherapy (SBRT) is a technologically sophisticated form of radiotherapy that holds significant potential to effectively treat high-risk prostate cancer (HRPC). Prostate SBRT has been the subject of intense investigation in the context of low- and intermediate-risk disease, but less so for HRPC. However, emerging data are demonstrating its potential to safely and efficiently delivery curative doses of radiotherapy, both to the prostate and elective lymph nodes. SBRT theoretically hits harder through radiobiological dose escalation facilitated by ultra-hypofractionation (UHRT), faster with only five treatment fractions, and smarter by using targeted, focal dose escalation to maximally ablate the dominant intraprostatic lesion (while maximally protecting normal tissues). To achieve this, advanced imaging modalities like magnetic resonance imaging and prostate specific membrane antigen positron emmission tomography (PSMA-PET) are leveraged in combination with cutting-edge radiotherapy planning and delivery technology. In this focused narrative review, we discuss key evidence and upcoming clinical trials evaluating SBRT for HRPC with a focus on dose escalation, elective nodal irradiation, and focal boost.

Objective: To assess the feasibility of dose escalation guided by 18F-deoxyglucose positron emission tomography/computer tomography (18F-FDG PET/CT) for esophageal cancer (EC). Methods and materials: Ten random patients treated with definitive chemoradiotherapy and pre-therapeutic 18F-FDG PET/CT were included in this study. Retrospectively, a threshold of 50% of SUVmax was used to define the high FDG uptake region of the GTV (GTVPET). Three intensity-modulated radiation therapy (IMRT) plans were generated, delivering three dose levels to three different planning target volumes (PTVs). 50.4 ​Gy delivered to PTV50.4 was defined on computed tomography (CT) as Plan50.4, 63 ​Gy was delivered to PTV63 was defined as GTV plus a uniform margin of 0.5 ​cm as Plan63, and 70 ​Gy delivered to PTV70 was defined as GTVPET plus a 0.5 ​cm margin as Plan70. A dosimetric comparison was performed based on normal tissue complication probability (NTCP) for the lung and heart. Results: Clinically acceptable dose escalation failed for 2 of 10 patients in Plan63 due to heart dose constraints. One patient failed heart dose constraint for Plan70. Two patients failed spinal cord constraint for Plan63. Three patients failed lung dose constraints for both Plan63 and Plan70, two of which were even not suitable for Plan50.4 for the same reason.NTCP modeling for lung showed increased risk for Plan63 and Plan70 compared to Plan50.4. The difference between Plan63 and Plan70 was insignificant. NTCP modeling for heart showed an increased risk from 6.38% of Plan50.4 to 8.88% of Plan70 (P ​= ​0.009) or 9.79% of Plan63 (P ​= ​0.007). The risk of heart mortality was significantly higher for Plan63 than Plan70 (P ​= ​0.047). Conclusions: Selective boosting of sub-volumes based on 18F-FDG PET/CT is feasible way with a modest increase in the risk of cardiac and lung toxicities.

Purpose: To compare the dosimetric results of an in-silico study among intensity-modulated photon (IMRT) and robustly optimized intensity-modulated proton (IMPT) treatment techniques using a dose-escalated simultaneously integrated boost (SIB) approach in locally recurrent or advanced pancreatic cancer patients. Material and methods: For each of 15 locally advanced pancreatic cancer patients, a volumetric-modulated arc therapy (VMAT), a Tomotherapy (TOMO), and an IMPT treatment plan was optimized on free-breathing treatment planning computed tomography (CT) images. For the photon treatment plans, doses of 66 Gy and 51 Gy, both as SIB in 30 fractions, were prescribed to the gross tumor volume (GTV) and to the planning target volume (PTV), respectively. For the proton plans, a dose prescription of 66 Gy(RBE) to the GTV and of 51 Gy(RBE) to the clinical target volume (CTV) was planned. For each SIB-treatment plan, doses to the targets and OARs were evaluated and statistically compared. Results: All treatment techniques reached the prescribed doses to the GTV and CTV or PTV. The stomach and the bowel, in particular the duodenum and the small bowel, were found to be frequently exposed to doses exceeding 50 Gy, irrespective of the treatment technique. For doses below 50 Gy, the IMPT technique was statistically significant superior to both IMRT techniques regarding decreasing dose to the OARs, e.g. volume of the bowel receiving 15 Gy (V15Gy) was reduced for IMPT compared to VMAT (p = 0.003) and TOMO (p

Abstract Background The introductions of anti‐ human epidermal growth factor receptor‐2 (HER2) agents have significantly improved the treatment outcome of patients with HER2‐positive breast cancer. BAT8001 is a novel antibody‐drug conjugate targeting human epidermal growth factor receptor‐2 (HER2)‐expressing cells composed of a trastuzumab biosimilar linked to the drug‐linker Batansine. This dose‐escalation, phase I study was designed to assess the safety, tolerability, pharmacokinetics, and preliminary anti‐tumor activity of BAT8001 in patients with HER2‐positive locally advanced or metastatic breast cancer. Methods This trial was conducted in subjects with histologically confirmed HER2‐positive breast cancer (having evaluable lesions and an Eastern Cooperative Oncology Group performance status of 0 or 1) using a 3 + 3 design of escalating BAT8001 doses. Patients received BAT8001 intravenously in a 21‐day cycle, with dose escalation in 5 cohorts: 1.2, 2.4, 3.6, 4.8, and 6.0 mg/kg. The primary objective was to evaluate the safety and tolerability of BAT8001. Preliminary activity of BAT8001 was also assessed as a secondary objective. Results Between March 2017 to May 2018, 29 HER2‐positive breast cancer patients were enrolled. The observed dose‐limiting toxicities were grade 4 thrombocytopenia and grade 3 elevated transaminase. The maximum tolerated dose was determined to be 3.6 mg/kg. Grade 3 or greater adverse events (AEs) occurred in 14 (48.3%) of 29 patients, including thrombocytopenia in 12 (41.4%) patients, aspartate aminotransferase increased in 4 (13.8%) patients, γ‐glutamyl transferase increased in 2 (6.9%) patients, alanine aminotransferase increased in 2 (6.9%) patients, diarrhea in 2 (6.9%) patients. Objective response was observed in 12 (41.4%; 95% confidence interval [CI] = 23.5%‐61.1%) and disease control (including patients achieving objective response and stable disease) was observed in 24 (82.8%; 95% CI = 64.2%‐94.2%) patients. Conclusions BAT8001 demonstrated favorable safety profiles, with promising anti‐tumor activity in patients with HER2‐positive locally advanced or metastatic breast cancer. BAT8001 has the potential to provide a new therapeutic option in patients with metastatic HER2‐positive breast cancer.

Introduction: The number of beams used in a Radiotherapy (RT) plan effects the overall quality of the plan and hence the treatment. The inclusion of radiobiological concepts in finding the optimum number of beams for a particular planning technique has the potential to provide a step ahead of the routine clinical practice where clinical decisions are more dependent on the physical dose parameters. Aim: To optimise the number of beams for Intensity Modulated Radiotherapy (IMRT) plan based on Tumour Control Probability (TCP) and Normal Tissue Complication Probability (NTCP) biological parameters. Materials and Methods: This retrospective study was done on 30 patients with pituitary macro-adenoma who underwent radiotherapy with a prescribed dose of 50.4 Gy in 28 fractions in Delhi State Cancer Institutes, Delhi, India from December 2012 to August 2018. The study data was collected and analysed between June 2018 and April 2020. These patients were treated with step and shoot IMRT technique on ONCORTM Expression linear accelerator (Siemens Healthineers, USA). But, the number of beams used to deliver IMRT plans were different as decided by the medical physicist and hence planner dependent rather than the disease. Being a centrally located disease, a symmetric beam arrangement was adopted for IMRT planning. For dosimetric comparison, three IMRT plans with five, seven, and nine equispaced beams were generated in Monaco treatment planning system for each patient and thus, a total of 90 IMRT plans were created and evaluated. For fair comparison, same IMRT planning parameters were utilised in all three plans of each patient. Monte Carlo (MC) dose calculation algorithm was used for all the plans. Resulting Cumulative Dose Volume Histograms (CDVHs) were exported to MATLAB, where these cDVHs were processed as per Niemierko’s radiobiological model to calculate the values of TCP and NTCP based on the Equivalent Uniform Dose (EUD). After this, the analysis of variance, ANOVA test was conducted over the resulting values of EUD, TCP, and NTCP to assess the difference of quality among plans having different beam arrangements at 0.05 level of significance. Results: The mean tumour control probability (TCP) for IMRT plans with seven and nine beams were found to be 89.0±0.8% and 89.1±0.9% respectively for planning target volume (PTV). These values were not significantly different from each other. However, the mean TCP value for IMRT plans with five beams was found to be 88.4±1.1% for PTV. Further, this TCP value was proved to be significantly lower as compared to IMRT plans with seven and nine beams with a p-value of 0.008 and 0.004, respectively. On the other hand, the mean Normal Tissue Complication Probability (NTCP) was assessed to be less than 1% for all critical organs irrespective of the beam arrangement, indicating almost no probability of radiation induced toxicity in any of the organ. Conclusion: This study concludes that the plan efficiency can be improved by using optimum number of beams for IMRT planning of pituitary adenoma.

Abstract Background and purpose Patients with locally advanced oropharynx squamous cell carcinoma have suboptimal outcomes with standard chemoradiation. Here, we evaluated toxicity and oncologic outcomes of dose escalation using radiosurgical boost for patients with unfavorable oropharynx squamous cell carcinoma. Materials and methods Between 2010–2017, Thirty four patients with intermediate- or high-risk oropharynx squamous cell carcinoma were enrolled onto this prospective phase I trial. Each patient received concurrent cisplatin and fractionated radiotherapy totaling 60 Gy or 66 Gy followed by radiosurgery boost to areas of residual gross tumor: single fraction of 8 Gy or 10 Gy, or two fractions of 5 Gy each. Primary endpoint was treatment toxicity. Secondary endpoints were local, regional, and distant disease control. Results Eleven, sixteen and seven patients received radiosurgery boost with 8 Gy in 1 fraction, 10 Gy in 1 fraction, and 10 Gy in 2 fractions respectively. Acute toxicities include 4 patients with tumor necrosis causing grade 3 dysphagia, of which 3 developed grade 4 pharyngeal hemorrhage requiring surgical intervention. At 24 months after treatment, 7%, 9%, and 15% had grade 2 dysgeusia, xerostomia, and dysphagia, respectively, and two patients remained feeding tube dependent. No grade 5 toxicities occurred secondary to treatment. Local, regional, and distant control at a median follow up of 4.2 years were 85.3%, 85.3% and 88.2%, respectively. Five patients died resulting in overall survival of 85.3%. Conclusions This study is the first to report the use of radiosurgery boost dose escalation in patients with unfavorable oropharynx squamous cell carcinoma. Longer follow-up, larger cohorts, and further refinement of boost methodology are needed prior to implementation in routine clinical practice. Trial Registration: Northwell Health Protocol #09-309A (NCT02703493) ( https://clinicaltrials.gov/ct2/show/NCT02703493 )

Cure- and toxicity rates after intensity-modulated radiotherapy (IMRT) of prostate cancer are dose-and volume dependent. We prospectively studied the potential for organ at risk (OAR) sparing and compensation of tumor movement with the coverage probability (CovP) concept.

Abstract Background The ESCALOX trial was designed as a multicenter, randomized prospective dose escalation study for head and neck cancer. Therefore, feasibility of treatment planning via different treatment planning systems (TPS) and radiotherapy (RT) techniques is essential. We hypothesized the comparability of dose distributions for simultaneous integrated boost (SIB) volumes respecting the constraints by different TPS and RT techniques. Methods CT data sets of the first six patients (all male, mean age: 61.3 years) of the pre-study (up to 77 Gy) were used for comparison of IMRT, VMAT, and helical tomotherapy (HT). Oropharynx was the primary tumor location. Normalization of the three step SIB (77 Gy, 70 Gy, 56 Gy) was D95% = 77 Gy. Coverage (CVF), healthy tissue conformity index (HTCI), conformation number (CN), and dose homogeneity (HI) were compared for PTVs and conformation index (COIN) for parotids. Results All RT techniques achieved good coverage. For SIB77Gy, CVF was best for IMRT and VMAT, HT achieved highest CN followed by VMAT and IMRT. HT reached good HTCI value, and HI compared to both other techniques. For SIB70Gy, CVF was best by IMRT. HTCI favored HT, consequently CN as well. HI was slightly better for HT. For SIB56Gy, CVF resulted comparably. Conformity favors VMAT as seen by HTCI and CN. Dmean of ipsilateral and contralateral parotids favor HT. Conclusion Different TPS for dose escalation reliably achieved high plan quality. Despite the very good results of HT planning for coverage, conformity, and homogeneity, the TPS also achieved acceptable results for IMRT and VMAT. Trial registration ClinicalTrials.gov Identifier: NCT 01212354, EudraCT-No.: 2010-021139-15. ARO: ARO 14-01