Dose Escalation Plan Research Articles

Interim 18F-FDG-PET based response-adaptive dose escalation of proton therapy for head and neck cancer: a treatment planning feasibility study

BackgroundImage-driven dose escalation to tumor subvolumes has been proposed to improve treatment outcome in head and neck cancer (HNC). We used 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) acquired at baseline and into treatment (interim) to identify biologic target volumes (BTVs). We assessed the feasibility of interim dose escalation to the BTV with proton therapy by simulating the effects to organs at risk (OARs). MethodsWe used the semiautomated just-enough-interaction (JEI) method to identify BTVs in 18F-FDG-PET images from nine HNC patients. Between baseline and interim FDG-PET, patients received photon radiotherapy. BTV was identified assuming that high standardized uptake value (SUV) at interim reflected tumor radioresistance. Using Eclipse (Varian Medical Systems), we simulated a 10% (6.8 Gy(RBE1.1)) and 20% (13.6 Gy(RBE1.1)) dose escalation to the BTV with protons and compared results with proton plans without dose escalation. ResultsAt interim 18F-FDG-PET, radiotherapy resulted in reduced SUV compared to baseline. However, spatial overlap between high-SUV regions at baseline and interim allowed for BTV identification. Proton therapy planning demonstrated that dose escalation to the BTV was feasible, and except for some 20% dose escalation plans, OAR doses did not significantly increase. ConclusionOur in silico analysis demonstrated the potential for interim 18F-FDG-PET response-adaptive dose escalation to the BTV with proton therapy. This approach may give more efficient treatment to HNC with radioresistant tumor subvolumes without increasing normal tissue toxicity. Studies in larger cohorts are required to determine the full potential for interim 18F-FDG-PET-guided dose escalation of proton therapy in HNC.

The design, preclinical study and phase I dose escalation plan of a HER2 targeted immunoliposome (HF-K1) for HER2 low solid tumor treatment.

3035 Background: Doxorubicin liposome formulations are being used extensively in the clinic in anthracycline chemotherapy with reduced cardiotoxicity. However, they did not improve clinical outcome because the cancer cell uptake of PEG-coated liposomes is poor. So, the concept of coating antibodies on the liposome surface was initiated and they were named immunoliposomes. There have been numerous studies conducted world-wide for the development of immunoliposomes but none have progressed to late-stage development. Our work draws on the experiences of these prior studies with a new perspective. Since the mechanism of immunoliposomes is similar to those of ADCs, we sought to compare immunoliposomes with ADCs containing the same cancer cell binding domain, for target cell binding capability, binding affinity as well as in vivo distribution, tumor tissue accumulation, and anti-tumor activities. The lessons learned from the success of many ADC products may be applicable to the development of immunoliposomes. Methods: The antibody to liposome ratio (ALR) and the drug to lipid ratio (DLR) of the immunoliposomes were selected by in vitro and in vivo anti-cancer activity screening. Cell lines with different HER2 expression levels were used to study immunoliposome binding, cell uptake, drug delivery and cytotoxicity. PK, drug distribution, efficacy and toxicities studies were conducted in respective CDX and PDX mice and non-rodent models. Based on these studies, a phase I dose escalation study plan was designed and the study is now ongoing. Results: HF-K1 was designed to have an average of 10 anti-HER2 Fab on each liposome surface and approximately 2300 doxorubicin molecules inside. The equivalent drug to antibody ratio (DAR) is 230. HF-K1 can bind to cancer cells with different levels of HER2 expression with similar kinetics and induces cells death at IC50s of 0.35-6.46 μg/ml Fab concentration. It has a long circulation behavior and enhanced permeability and retention (EPR) in tumor tissues. The clearance T1/2 of HF-K1 in mice and monkey is 12.78 h and 47.12 h, respectively. Evaluation of HF-K1 activity in vivo showed significant tumor growth inhibition >95% at the equivalent antibody dose of 3.6 mg/kg in various mouse tumor models including HER2 low and HER2 very low (HER2-). Similar activities were shown by ADCs including T-DM1 and DS-8201a at about 10 mg/kg. Conclusions: The encouraging preclinical data supported a clinical trial starting with dose escalation at equivalent antibody doses of 0.72 mg/m2, 2.16 mg/m2, 5.4 mg/m2, 10.8 mg/m2, 16.2 mg/m2, and 21.6 mg/m2. The study is ongoing to determine the safety, tolerability, PK, and preliminary antitumor efficacy in participants with HER2 positive or HER2 low expression advanced solid tumors (NCT05861895). Clinical trial information: NCT05861895 .

ANTI-SEIZURE MEDICATION IN GLIOMA PATIENTS: GETTING IT RIGHT fiRST TIME

Abstract AIMS Seizures affect between 60–90% patients with low grade glioma and between 40–60% patients with high grade glioma. There are no national guidelines for seizure management in glioma patients. This quality improvement project investigated the initiation of anti-seizure medication in glioma patients with new-onset seizures. METHOD A retrospective review was undertaken of new glioma patients’ electronic notes (2020-2022) seen in Oncology clinic at Colchester hospital. RESULTS Thirty-seven patients (twenty-five glioblastoma IDH-wt, two grade 3 astrocytoma IDH-mutant, one grade 2 astrocytoma IDH-mutant, three oligodendroglioma IDH-mutant, six radiological diagnoses of glioma) were included. Following neurosurgical discharge, twenty-three did not need anti-seizure medication, three had long standing anti-seizure medication which was not changed, one patient was advised to stop phenytoin medication after surgery, four patients were on levetiracetam 500mg twice daily and six patients were on levetiracetam 250mg twice daily, with no dose escalation plan in place. Three of these six patients were subsequently hospitalised with seizures, one of which interrupted chemoradiation. None of the four patients on 500mg BD were hospitalised with seizures. CONCLUSIONS This project highlights the need for local anti-seizure guidelines for new glioma patients, which should include consideration of personalised drug choice, dependent on seizure type and demographics. Patients should be escalated to the therapeutic levetiracetam dose to decrease the risk of morbidity from seizures. This supports the need for national guidelines on anti-seizure medication with neurology collaboration.

18F-FMISO PET-guided dose escalation with multifield optimization intensity-modulated proton therapy in nasopharyngeal carcinoma.

The purpose of this study was to evaluate the radiotherapy planning feasibility of dose escalation with intensity-modulated proton therapy (IMPT) to hypoxic tumor regions identified on 18F-Fluoromisonidazole (FMISO) positron emission tomography and computed tomography (PET-CT) in NPC. Nine patients with stages T3-4N0-3M0 NPC underwent 18F-FMISO PET-CT before and during week 3 of radiotherapy. The hypoxic volume (GTVhypo) is automatically generated by applying a subthresholding algorithm within the gross tumor volume (GTV) with a tumor to muscle standardized uptake value (SUV) ratio of 1.3 on the 18F-FMISO PET-CT scan. Two proton plans were generated for each patient, a standard plan to 70Gy and dose escalation plan with upfront boost followed by standard 70GyE plan. The stereotactic boost was planned with single-field uniform dose optimization using two fields to deliver 10 GyE in two fractions to GTVhypo. The standard plan was generated with IMPT with robust optimization to deliver 70GyE, 60GyE in 33 fractions using simultaneous integrated boost technique. A plan sum was generated for assessment. Eight of nine patients showed tumor hypoxia on the baseline 18F-FMISO PET-CT scan. The mean hypoxic tumor volume was 3.9 cm3 (range .9-11.9cm3 ). The average SUVmax of the hypoxic volume was 2.2 (range 1.44-2.98). All the dose-volume parameters met the planning objectives for target coverage. Dose escalation was not feasible in three of eight patients as the D0.03cc of temporal lobe was greater than 75GyE. The utility of boost to the hypoxic volume before standard course of radiotherapy with IMPT is dosimetrically feasible in selected patients. Clinical trials are warranted to determine the clinical outcomes of this approach.

Dose Escalation for Pancreas SBRT: Potential and Limitations of using Daily Online Adaptive Radiation Therapy and an Iterative Isotoxicity Automated Planning Approach

To determine the dosimetric limitations of daily online adaptive pancreas stereotactic body radiation treatment by using an automated dose escalation approach. We collected 108 planning and daily computed tomography (CT) scans from 18 patients (18 patients×6 CT scans) who received 5-fraction pancreas stereotactic body radiation treatment at MD Anderson Cancer Center. Dose metrics from the original non-dose-escalated clinical plan (non-DE), the dose-escalated plan created on the original planning CT (DE-ORI), and the dose-escalated plan created on daily adaptive radiation therapy CT (DE-ART) were analyzed. We developed a dose-escalation planning algorithm within the radiation treatment planning system to automate the dose-escalation planning process for efficiency and consistency. In this algorithm, the prescription dose of the dose-escalation plan was escalated before violating any organ-at-risk (OAR) dose constraint. Dose metrics for 3 targets (gross target volume [GTV], tumor vessel interface [TVI], and dose-escalated planning target volume [DE-PTV]) and 9 OARs (duodenum, large bowel, small bowel, stomach, spinal cord, kidneys, liver, and skin) for the 3 plans were compared. Furthermore, we evaluated the effectiveness of the online adaptive dose-escalation planning process by quantifying the effect of the interfractional dose distribution variations among the DE-ART plans. The median D95% dose to the GTV/TVI/DE-PTV was 33.1/36.2/32.4 Gy, 48.5/50.9/40.4 Gy, and 53.7/58.2/44.8 Gy for non-DE, DE-ORI, and DE-ART, respectively. Most OAR dose constraints were not violated for the non-DE and DE-ART plans, while OAR constraints were violated for the majority of the DE-ORI patients due to interfractional motion and lack of adaptation. The maximum difference per fraction in D95%, due to interfractional motion, was 2.5 ± 2.7 Gy, 3.0 ± 2.9 Gy, and 2.0 ± 1.8 Gy for the TVI, GTV, and DE-PTV, respectively. Most patients require daily adaptation of the radiation planning process to maximally escalate delivered dose to the pancreatic tumor without exceeding OAR constraints. Using our automated approach, patients can receive higher target dose than standard of care without violating OAR constraints.

Feasibility of Four-dimensional Adaptation of Volumetric Modulated Arc Therapy Based on Volumetric Modulated Arc Therapy-computed Tomography.

Volumetric modulated arc therapy (VMAT) has been increasingly used for cancer patients due to the fast delivery and improved dose conformity. Adaptive radiotherapy (ART) can significantly decrease dose to normal tissues and allow for dose escalation. However, current imaging techniques cannot provide four-dimensional (4D) patient anatomy or dose information during VMAT, which is critical for ART that involves respiratory motion. A novel imaging tool named VMAT-computed tomography (VMAT-CT) has the potential to reveal intra-fractional patient information. The goal of this study was to evaluate the feasibility of 4D adaptive VMAT based on 4D VMAT-CT. A commercial QUASAR respiratory phantom and an in-house deformable lung phantom were used in this study, and lung VMAT plans, including 4D union plan and 4D ART plan, were generated for the phantoms. A real lung patient's plan was also used in this feasibility study. ART plans based on 4D VMAT-CT were created for the phantoms and the real patient when planning goals were not met. Dose escalation plan based on 4D VMAT-CT was also created for the real patient. Planning target volume (PTV) coverage for the QUASAR phantom was 85.5% after breathing pattern being changed, and went up to 95% after adaptive re-planning. PTV coverage for the deformable phantom was 93% after deformation and breathing pattern being changed, and went up to 95% after re-planning. Re-planning and dose escalation were feasible and can spare normal tissues for the real patient. 4D ART plan based on 4D VMAT-CT required smaller margins than 4D union plan while maintaining the same prescription dose coverage. ART based on 4D VMAT-CT is feasible and would potentially facilitate re-planning and PTV dose escalation for VMAT patients who have the motion issue.

Establishing Rationale for the Clinical Development of Cell Therapy Products: Consensus between Risk and Benefit.

Despite long-term research achievements, the development of cell therapy (CT) products remains challenging. This is because the risks experienced by the subject and therapeutic effects in the clinical trial stage are unclear due to the various uncertainties of CT when administered to humans. Nevertheless, as autologous cell products for systemic administration have recently been approved for marketing, CT product development is accelerating, particularly in the field of unmet medical needs. The human experience of CT remains insufficient compared with other classes of pharmaceuticals, while there are countless products for clinical development. Therefore, for many sponsors, understanding the rationale of human application of an investigational product based on the consensus and improving the ability to apply it appropriately for CT are necessary. Thus, defining the level of evidence for safety and efficacy fundamentally required for initiating the clinical development and preparing it using a reliable method for CT. Furthermore, the expertise should be strengthened in the design of the first-in-human trial, such as the starting dose and dose-escalation plan, based on a sufficiently acceptable rationale. Cultivating development professionals with these skills will increase the opportunity for more candidates to enter the clinical development phase.

A Comparative Dose-Escalation Analysis for the Head and Neck Reirradiation Patients with and without Appropriate DICOM Based Dose-Volume Information of Primary Radiotherapy

<h3>Purpose/Objective(s)</h3> This study aims to compare the dose-escalation between two groups of head and neck reirradiation patients with or without availability of appropriate DICOM based dose-volume and planning information of primary RT <h3>Materials/Methods</h3> A total of 89 patients who received reirradiation for recurrent/second primary head and neck cancers between 2019-21 was included in the present study. Patients were categorized in two groups, with (D-group) and without (ND-Group) the DICOM based primary radiotherapy (RT1) information in planning system. For first group RT1 and re-irradiation (ReRT) in the present institution, for second group only ReRT in the present institution. For the D group, the dose to 0.2cc volume (D0.2cc) to the spine, brainstem, and optic apparatus was converted into structures in the RT1CT and these structures along with target volumes are copied to ReRTCT using deformable registration. Serial Structures in RT1CT and ReRTCT were merged to get the resultant structure with an intersection of D0.2 cc. A treatment plan was created using the baseline prescription (BRx) was defined by the treating physician. Further, a dose escalation (DERx) plan was created (66Gy/33fr for gross disease and 60Gy/30fr for post operative cases) respecting serial structures tolerance dose. For the ND group, no dose escalation was attempted over the BRx plan. <h3>Results</h3> 57 and 32 patients listed in D and ND-group. ReRT techniques were VMAT=72; IMRT=11, 3DCRT=6. For RT1, dose in D and ND groups 61±5.6 Gy and 30-66 Gy respectively. ReRT BRx doses for D and ND group were 52.5±10.7Gy and 50.6±6.9Gy (ΔDose=1.9±12.7 Gy). Dose escalated plan (DERx) was possible for 51 patients in D-Group with a mean DERx of 59.2±6.2Gy, and ΔDERx 6.7±12.4Gy from BRx plans. The maximum dose escalation from BRx was 21 Gy (D-Group). For 5 patients, dose escalation was not accepted for treatment due to other comorbidities, reducing actually delivered ΔDERx to 6.2± 14.4Gy. The average dose difference between D and ND-group were 8.6±9.3 Gy and 8.1±11.8 Gy on planned and accepted dose escalation. The spatial position of RT1 and ReRT Spine 0.2cc dose was within 5 mm only in 2 cases; for rest of the patients RT1 spine dose was not a big challenge for ReRT planning. It was possible to achieve the combined RT1 and ReRT Spine (<50Gy), Brainstem and Optic apparatus (<54 Gy) dose for 97% patients for D-group. For 86% cases Spine is the only challenged serial OAR for ReRT. <h3>Conclusion</h3> BRx was uniform for both the groups indicating the consistency in the institutional prescription policy. Appropriate dose mapping using DICOM information between RT1 and ReRT allows moderate to high dose escalation in recurrent Head neck re-irradiation which was otherwise not possible. Linear addition of maximum dose, without considering its spatial position, for serial structures (spine, brainstem) between RT1 and ReRT reduces dose escalation possibility as seen in the ND group and could not reach up to the recommended dose of 60/66Gy.

Safety of Inhomogeneous Dose Distribution IMRT for High-Grade Glioma Reirradiation: A Prospective Phase I/II Trial (GLIORAD TRIAL).

Simple SummaryGlioblastoma multiforme (GBM) is the most frequent primary malignant brain tumor, and despite advances in imaging techniques and treatment options, the outcome remains poor and recurrence is inevitable. Salvage therapy presents a challenge, and re-irradiation can be a therapeutic option in recurrent GBM. The decision-making process for re-irradiation is a challenge for radiation oncologists due to the expected toxicity of a second course of radiotherapy and the limited radiation tolerance of normal tissue; nevertheless, it is being increasingly used, as several studies have demonstrated its feasibility. The current study aimed to investigate the safety of moderate–high-voxel-based dose escalation radiotherapy in recurrent GBM patients after conventional concurrent chemoradiation. Twelve patients were enrolled in this prospective single-center study. Retreatment consisted of re-irradiation with a total dose range of 30–50 Gy over 5 days using the IMRT (arc VMAT) technique using dose painting planning. The treatment was well tolerated. No toxicities greater than 3 were recorded; only one patient had severe G3 acute toxicity, characterized by muscle weakness and fatigue. Median overall survival (OS2) and progression-free survival (PFS2) from the time of re-irradiation were 10.4 months and 5.7 months, respectively. Our phase I study demonstrated an acceptable tolerance profile of this approach, and the future prospective phase II study will analyze the efficacy in terms of PFS and OS.Glioblastoma multiforme (GBM) is the most aggressive astrocytic primary brain tumor, and concurrent temozolomide (TMZ) and radiotherapy (RT) followed by maintenance of adjuvant TMZ is the current standard of care. Despite advances in imaging techniques and multi-modal treatment options, the median overall survival (OS) remains poor. As an alternative to surgery, re-irradiation (re-RT) can be a therapeutic option in recurrent GBM. Re-irradiation for brain tumors is increasingly used today, and several studies have demonstrated its feasibility. Besides differing techniques, the published data include a wide range of doses, emphasizing that no standard approach exists. The current study aimed to investigate the safety of moderate–high-voxel-based dose escalation in recurrent GBM. From 2016 to 2019, 12 patients met the inclusion criteria and were enrolled in this prospective single-center study. Retreatment consisted of re-irradiation with a total dose of 30 Gy (up to 50 Gy) over 5 days using the IMRT (arc VMAT) technique. A dose painting by numbers (DPBN)/dose escalation plan were performed, and a continuous relation between the voxel intensity of the functional image set and the risk of recurrence in that voxel were used to define target and dose distribution. Re-irradiation was well tolerated in all treated patients. No toxicities greater than G3 were recorded; only one patient had severe G3 acute toxicity, characterized by muscle weakness and fatigue. Median overall survival (OS2) and progression-free survival (PFS2) from the time of re-irradiation were 10.4 months and 5.7 months, respectively; 3-, 6-, and 12-month OS2 were 92%, 75%, and 42%, respectively; and 3-, 6-, and 12-month PFS2 were 83%, 42%, and 8%, respectively. Our work demonstrated a tolerable tolerance profile of this approach, and the future prospective phase II study will analyze the efficacy in terms of PFS and OS.

P351: DOSE-ADJUSTED EPOCH + INOTUZUMAB OZOGAMICIN (DA-EPOCH-INO) IS SAFE AND ACTIVE IN ADULTS WITH RELAPSED/REFRACTORY (R/R) B LYMPHOBLASTIC LEUKEMIA (B-ALL): INITIAL RESULTS OF A PHASE I TRIAL

Background: Despite new drugs, survival with R/R B-ALL remains poor. Combination therapies may improve outcomes, but none are proven superior, and toxicities may pose limits. InO has been added to low-intensity chemotherapy, but the risks/benefits of such combinations are poorly defined. As we recently found DA-EPOCH to be effective for untreated ALL, we here tested the addition of InO to DA-EPOCH (#NCT03991884). Aims: The primary objective was to estimate the maximum tolerated dose (MTD) of InO when added to DA-EPOCH. Methods: Eligible adults had R/R CD22+ B-ALL with ≥5% blasts in blood/marrow or ≥1 site of extramedullary disease [EMD] ≥1.5 cm in diameter. No history of sinusoidal obstructive syndrome (SOS) or chronic liver disease was allowed. Other key eligibility criteria included bilirubin ≤1.5x upper limit of normal (ULN), AST/ALT ≤2.5x ULN, creatinine ≤1.5x ULN, QTc ≤500 msec, and ECOG 0-2. All patients (pts) gave written informed consent. DA-EPOCH was given on Days 1-5 with G-CSF. Three dose levels (DL) of InO given on Days 8 and 15 were studied in 28-day cycles: DL1, 0.3 and 0.3 mg/m2; DL2, 0.6 and 0.3 mg/m2; and DL3, 0.6 and 0.6 mg/m2 (respectively). In Cycles 2+, EPOCH was dose-adjusted based on the hematologic nadir from the prior cycle. Up to 4 cycles were permitted. Hepatic prophylaxis with ursodiol and CNS-directed therapy with intrathecal chemotherapy was recommended. MTD was the dose of InO yielding a true dose-limiting toxicity (DLT) rate of 33%. Initial dose-escalation plan for InO was a 6 + 6 design, but after 5 pts enrolled, this was modified to Bayesian Optimal Interval Design (BOIN) with target accrual of 24 pts. Secondary objectives were descriptions of treatment-related adverse events (TRAEs) per NCI CTCAE v5; efficacy by rate of complete remission without or with incomplete hematologic recovery (CR/CRi) and response at EMD sites per NCCN; measurable residual disease negativity (MRD-) by multiparameter flow cytometry (MFC) and high-throughput sequencing (HTS; clonoSEQ) of bone marrow aspirate; and survival. Results: To date, 17 pts have been enrolled (Table). All are evaluable for DLT. 5 pts were treated at DL1; then per BOIN, 3 pts at DL2, and 9 pts at DL3. Median number of cycles given was 2 (range, 1-3). There have been 4 DLTs: 1 at DL2 (20%; grade 4 sepsis) and 3 at DL3 (33%; grade 4 hyponatremia, grade 4 SOS, and prolonged pancytopenia). The single case (6%) of SOS occurred after allografting and is ongoing. There have been no treatment-related deaths. Grade 3+ non-heme TRAEs were seen in 13 pts (76%). Those seen in >1 pt were infections (5 pts; 8 events), neutropenic fever (5 pts; 5 events), oral mucositis (3 pts; 4 events), and increased ALT (2 pts; 3 events); all these events resolved. Other hepatic toxicity was generally mild. Of 10 pts who received ≥2 cycles, 5 (50%) escalated the dosing of EPOCH, while 2 (20%) de-escalated. 17 pts are evaluable for response. Of 13 with >5% blasts, 12 (92%; 90% confidence interval 68-100%) achieved CR/CRi, 10 (77%) after 1 cycle. MRD- by MFC was achieved in 9 (75%); 1 had prior InO. In the 5 pts with EMD, 4 (80%) responded including 3 CRs. To date, 6 pts (35%) have undergone allograft post-study. Median follow-up of survivors is 7 mo, with 7 pts in ongoing remission beyond 6 mo. Image:Summary/Conclusion: DA-EPOCH-InO has a manageable toxicity profile with infrequent DLTs and only 1 case of SOS in heavily pre-treated adults with B-ALL. Nearly all pts with >5% blasts at enrollment achieved CR, with most being MRD- by MFC. Responses in EMD were common. Enrollment is ongoing. Updated follow-up and responses by HTS will be presented.

Biologically Targeted Radiation Therapy: Incorporating Patient-Specific Hypoxia Data Derived from Quantitative Magnetic Resonance Imaging.

Simple SummaryRecent clinical trials have demonstrated the capability of safely delivering prostate radiotherapy with a simultaneous focal boost. These studies have also indicated limitations to achieving focal boosts whilst trying to limit normal tissue toxicity. More guidance in the location and level of the required boost could alleviate such limitations. Tumour hypoxia is one of the causes of clinically observed radioresistance and hypoxic volumes represent prime candidates for a focal boost. Multiparametric magnetic resonance imaging (mpMRI) has the potential to quantitatively describe the extent and spatial distribution of hypoxia in prostate cancer. In this article we demonstrate a biologically targeted radiotherapy approach that can utilise this information to target hypoxia for favourable treatment outcomes.Purpose: Hypoxia has been linked to radioresistance. Strategies to safely dose escalate dominant intraprostatic lesions have shown promising results, but further dose escalation to overcome the effects of hypoxia require a novel approach to constrain the dose in normal tissue.to safe levels. In this study, we demonstrate a biologically targeted radiotherapy (BiRT) approach that can utilise multiparametric magnetic resonance imaging (mpMRI) to target hypoxia for favourable treatment outcomes. Methods: mpMRI-derived tumour biology maps, developed via a radiogenomics study, were used to generate individualised, hypoxia-targeting prostate IMRT plans using an ultra- hypofractionation schedule. The spatial distribution of mpMRI textural features associated with hypoxia-related genetic profiles was used as a surrogate of tumour hypoxia. The effectiveness of the proposed approach was assessed by quantifying the potential benefit of a general focal boost approach on tumour control probability, and also by comparing the dose to organs at risk (OARs) with hypoxia-guided focal dose escalation (DE) plans generated for five patients. Results: Applying an appropriately guided focal boost can greatly mitigate the impact of hypoxia. Statistically significant reductions in rectal and bladder dose were observed for hypoxia-targeting, biologically optimised plans compared to isoeffective focal DE plans. Conclusion: Results of this study suggest the use of mpMRI for voxel-level targeting of hypoxia, along with biological optimisation, can provide a mechanism for guiding focal DE that is considerably more efficient than application of a general, dose-based optimisation, focal boost.

Phase I trial of pazopanib in combination with irinotecan and temozolomide (PAZIT) for children and young adults with advanced sarcoma.

10526 Background: Pro-angiogenic factors may represent therapeutic targets in sarcoma. Preclinical studies have demonstrated a potential additive or synergistic interaction between anti-angiogenic agents and chemotherapy. The purpose of this study was to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetic (PK) and pharmacodynamics (PD) effects of PAZIT in patients with advanced sarcoma. Methods: Patients 6-30 years of age with relapsed/refractory sarcomas were eligible. In the initial dose escalation plan (A), patients received pazopanib PO (225-450 mg/m2/dose) on Days 1-21 of 21-day cycles. Pazopanib was combined with fixed doses of irinotecan (IV 50 or PO 90 mg/m2/dose) and temozolomide PO 100 mg/m2/dose on Days 1-5. Due to DLTs, an amendment was made to the dose escalation plan (B) and patients received fixed doses of pazopanib PO (225 mg/m2/dose) on Days 1-21 of 21-day cycles and reduced irinotecan doses (IV 25-37.5 or PO 45-67.5 mg/m2/dose) and temozolomide PO 100 mg/m2/dose on Days 1-5. Oral cephalosporin diarrhea prophylaxis was required. Dose escalation followed a 3+3 design. Correlative studies included PK (pazopanib, irinotecan) and PD (angiogenic factors, ctDNA) effects. Results: Sixteen patients were treated (median age 16 years, range 7-21). The dose levels in the table were evaluated. First cycle DLTs occurred at all dose levels (Table) and included diarrhea, pancreatitis, colitis, neutropenia, hypertension, deep vein thrombosis, and ALT increase. Due to excessive toxicity, an MTD could not be established. One patient with osteosarcoma had a partial response. Four patients had prolonged stable disease &gt; 4 cycles, including 2 patients with Ewing sarcoma (5 and 6 cycles), rhabdomyosarcoma (9 cycles), and desmoplastic small round cell tumor (6 cycles). Mean±SD plasma exposures to pazopanib, irinotecan, and SN-38 in patients treated on dose level 1B (n = 4) on Day 4 were 601±83, 1.4±0.2 and 0.1±0.04 ug/mL*hr, respectively. Analyses of correlative studies are ongoing. Conclusions: Combination PAZIT therapy is not tolerable as evaluated at these doses/schedules. This study provides important toxicity data to inform future clinical trials using combination anti-angiogenic strategies in sarcoma. Clinical trial information: NCT03139331. [Table: see text]

Computational delineation and quantitative heterogeneity analysis of lung tumor on 18F-FDG PET for radiation dose-escalation

Quantitative measurement and analysis of tumor metabolic activities could provide a more optimal solution to personalized accurate dose painting. We collected PET images of 58 lung cancer patients, in which the tumor exhibits heterogeneous FDG uptake. We design an automated delineation and quantitative heterogeneity measurement of the lung tumor for dose-escalation. For tumor delineation, our algorithm firstly separates the tumor from its adjacent high-uptake tissues using 3D projection masks; then the tumor boundary is delineated with our stopping criterion of joint gradient and intensity affinities. For dose-escalation, tumor sub-volumes with low, moderate and high metabolic activities are extracted and measured. Based on our quantitative heterogeneity measurement, a sub-volume oriented dose-escalation plan is implemented in intensity modulated radiation therapy (IMRT) planning system. With respect to manual tumor delineations by two radiation oncologists, the paired t-test demonstrated our model outperformed the other computational methods in comparison (p < 0.05) and reduced the variability between inter-observers. Compared to standard uniform dose prescription, the dosimetry results demonstrated that the dose-escalation plan statistically boosted the dose delivered to high metabolic tumor sub-volumes (p < 0.05). Meanwhile, the doses received by organs-at-risk (OAR) including the heart, ipsilateral lung and contralateral lung were not statistically different (p > 0.05).

A Phase 1 Study of Stereotactic Body Radiation Therapy Dose Escalation for Borderline Resectable Pancreatic Cancer After Modified FOLFIRINOX (NCT01446458)

A challenge in borderline resectable pancreatic cancer (BRPC) management is the high rate of positive posterior margins (PM). Stereotactic body radiation therapy (SBRT) allows for higher radiation delivery dose with conformity. This study evaluated the maximal tolerated dose with a dose escalation plan level up to 45Gy using SBRT in BRPC. A single-institution, 3+3 phase 1 clinical trial design was used to evaluate 4 dose levels of SBRT delivered in 3 fractions to the planning target volume (PTV) with a simultaneous in-field boost (SIB) to the PM. Dose level (DL) 1 was 30Gy to the PTV, and for dose levels 2 through 4 (DL2-DL4) the dose was 36Gy. The SIB dose to the PM was 6, 6, 7.5, and 9Gy for DL-1, DL-2, DL-3, and DL-4, respectively. All patients received 4 treatments of modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) before SBRT. Thirteen patients with a median age of 64years were enrolled. The median follow-up time was 18months. The locations of the cancer were head (n=12) and uncinate/neck (n=1). One patient did not undergo SBRT. There were no grade 3 or 4 toxicities. Five patients did not undergo resection because of disease progression (1 local, 4 distant); 8 had R0 resection in the PM, and 5 of 8 had vessel reconstruction. Two patients had disease downstaged to T1 and T2 from T3 disease. Four patients are still alive, and 3 are disease free. The median overall survival for resected patients was not reached (9.3: not reached). The SBRT dose of 36Gy with a 9-Gy SIB to the PM (total 45Gy) delivered in 3 fractions is safe and well tolerated. The dose-limiting toxicity for a 45-Gy dose was not reached, and further dose escalations are needed in future trials.

Tomotherapy PET-guided dose escalation: A dosimetric feasibility study for patients with malignant pleural mesothelioma.

The aim of this study was to investigate whether a safe escalation of the dose to the pleural cavity and PET/CT-positive areas in patients with unresectable malignant pleural mesothelioma (MPM) is possible using helical tomotherapy (HT). We selected 12 patients with MPM. Three planning strategies were investigated. In the first strategy (standard treatment), treated comprised a prescribed median dose to the planning target volume (PTV) boost (PTV1) of 64.5 Gy (range: 56 Gy/28 fractions to 66 Gy/30 fractions) and 51 Gy (range: 50.4 Gy/28 fractions to 54 Gy/30 fractions) to the pleura PTV (PTV2). Thereafter, for each patient, two dose escalation plans were generated prescribing 62.5 and 70 Gy (2.5 and 2.8 Gy/fraction, respectively) to the PTV1 and 56 Gy (2.24 Gy/fraction) to the PTV2, in 25 fractions. Dose-volume histogram (DVH) constraints and normal tissue complication probability (NTCP) calculations were used to evaluate the differences between the plans. For all plans, the 95 % PTVs received at least 95 % of the prescribed dose. For all patients, it was possible to perform the dose escalation in accordance with the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) constraints for organs at risk (OARs). The average contralateral lung dose was < 8 Gy. NTCP values for OARs did not increase significantly compared with the standard treatment (p > 0.05), except for the ipsilateral lung. For all plans, the lung volume ratio was strongly correlated with the V20, V30, and V40 DVHs of the lung (p < 0.0003) and with the lung mean dose (p < 0.0001). The results of this study suggest that by using HT it is possible to safely escalate the dose delivery to at least 62.5 Gy in PET-positive areas while treating the pleural cavity to 56 Gy in 25 fractions without significantly increasing the dose to the surrounding normal organs.

PET-based dose painting in non-small cell lung cancer: Comparing uniform dose escalation with boosting hypoxic and metabolically active sub-volumes

Background and purposeWe compared two imaging biomarkers for dose-escalation in patients with advanced non-small cell lung cancer (NSCLC). Treatment plans boosting metabolically active sub-volumes defined by FDG-PET or hypoxic sub-volumes defined by HX4-PET were compared with boosting the entire tumour. Materials and methodsTen NSCLC patients underwent FDG- and HX4-PET/CT scans prior to radiotherapy. Three isotoxic dose-escalation plans were compared per patient: plan A, boosting the primary tumour (PTVprim); plan B, boosting sub-volume with FDG >50% SUVmax (PTVFDG); plan C, boosting hypoxic volume with HX4 tumour-to-background >1.4 (PTVHX4). ResultsAverage boost volumes were 507±466cm3 for PTVprim, 173±127cm3 for PTVFDG and 114±73cm3 for PTVHX4. The smaller PTVHX4 overlapped on average 87±16% with PTVFDG. Prescribed dose was escalated to 87±10Gy for PTVprim, 107±20Gy for PTVFDG, and 117±15Gy for PTVHX4, with comparable doses to the relevant organs-at-risk (OAR). Treatment plans are available online (https://www.cancerdata.org/10.1016/j.radonc.2015.07.013). ConclusionsDose escalation based on metabolic sub-volumes, hypoxic sub-volumes and the entire tumour is feasible. Highest dose was achieved for hypoxia plans, without increasing dose to OAR. For most patients, boosting the metabolic sub-volume also resulted in boosting the hypoxic volume, although to a lower dose, but not vice versa.

Feasibility of PET-CT based hypofractionated accelerated dose escalation in oropharyngeal cancers: Final dosimetric results of the VORTIGERN study. (Secondary endpoint of UK NCRI portfolio: MREC No: 08/H0907/127, UKCRN ID 7341).

Technological advances have enabled clinicians to explore dose escalation strategies in various tumor sites. Intermediate and high risk oropharyngeal cancers have poor 5 year outcomes. This study aimed to assess the feasibility and dosimetric safety of 9% dose escalation in these tumors and compare the dose received by organs at risk (OAR) in escalated plans (67.2 Gy/28 fractions) versus (65 Gy/30 fractions) standard dose plans. FDG-PET fused datasets were used to delineate gross, clinical and planning target volumes. Standard dose plans were created using two non IMRT techniques (conventional and field in field plans) whilst the patient was treated using a helical tomotherapy plan. A fourth dose escalation plan was obtained allowing comparison between the 20 plans of oropharyngeal cancer patients. It was feasible to escalate dose to the FDG-PET avid tumor within the set constraints to that of planning target volume and OAR. Comparison of the escalated dose to that of standard plans showed a statistically significant (P < 0.05) sparing of the mastication apparatus (MA) with escalated plans. Dose to the other critical and functional organs were comparable between the four plans. Hypofractionated, slightly accelerated dose escalation in oropharyngeal cancers is likely to be safe and the chance of trismus is not any higher than when standard dose radiotherapy is used. Active measures to reduce dose to the MA achieves acceptable dose volume parameters even at escalated doses.

SU‐F‐BRD‐12: Prostate Cancer Dose Escalation Including Lymph Nodes: A Planning Study

Purpose:Dose escalation improves local control for prostate cancer but not overall survival (OS), only systemic therapy such as ADT can improve OS. One explanation is that occult diseases in the lymph nodes (LNs) are either not treated, or treated at inadequate level. This study explores dose escalation using IMRT with reduced margins.Methods:14 previously treated patients were selected. The CTV1 includes prostate and seminal vesicles, and CTV2 includes pelvic LNs. OARs include rectum, bladder, small bowel, femoral heads, and penile bulb. Reference plan (RP) was designed to follow RTOG‐0521, with 10 mm margin for PTVs. In phase I, both PTVs are prescribed to 1.8 Gy/fx for 26 fractions. In phase II, PTV1 is boosted for another 16 fractions. In dose escalation plans (DEPs), margins from 0 to 10 mm are added to form PTVs, which are prescribed to 1.8 Gy/fx for 42 fractions. 95% of PTVs are covered by prescription.Results:The CTV1/CTV2 has volume of 63±20 and 415±132 cc. To keep bladder Dmean same as in RP, margin must be ≤6 mm in DEPs. Similarly, margin needs to be ≤7 mm for rectum Dmean. For small bowel, even at margin of 0, Dmean and EUDs on DEPs are higher than RP, because RP was also IMRT. Instead, QUANTEC criteria of “45Gy volume&lt;195cc” was adopted. 6/14 patients fail this criteria in RP. For the remaining 8 patients, margins of ≤7(3) mm are necessary for 6(2) patients, respectively.Conclusion:To escalate LNs to full dose, planning margins need to be ≤6 mm to achieve same tolerance for rectum and bladder. A large variation in patient anatomy exists for small bowel and dose escalation was possible for half of patients with ≤6 mm margin. Investigations of whether and how ≤6 mm margin can be achieved through image guidance are needed.

A phase 1 study of everolimus plus docetaxel plus cisplatin as induction chemotherapy for patients with locally and/or regionally advanced head and neck cancer

Activation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is common in head and neck cancers, and it has been demonstrated that inhibition of mTOR complex 1 sensitizes cell lines to platinum and taxane chemotherapy. The authors conducted a phase 1 study to evaluate the addition of oral everolimus to cisplatin and docetaxel as induction chemotherapy for head and neck cancer. In this single-institution phase 1 study, 3 doses of daily everolimus were explored: 5 mg daily, 7.5 mg daily (administered as 5 mg daily alternating with 10 mg daily), and 10 mg daily of each 21-day cycle. Cisplatin and docetaxel doses were fixed (both were 75 mg/m(2) on day 1 of 21-day cycle) at each dose level with pegfilgrastim support. A standard 3 + 3 dose-escalation plan was used. After induction, patients were removed from protocol. Eighteen patients were enrolled (15 men, 3 women), and their median Karnofsky performance status was 90. The most common toxicities were hyperglycemia, low hemoglobin, fatigue, and thrombocytopenia. Dose-limiting toxicities (DLTs) were neutropenic fever (1 event at dose level 2, 2 events at dose level 3), and all patients recovered fully from these DLTs. The maximum tolerated dose was exceeded at dose level 3. The progression-free survival rate at 1 year was 87.5% (95% confidence interval, 56.8%-96.7%); and, at 2 years, it was 76.6% (95% confidence interval, 41.2%-92.3%). Activating PI3K catalytic subunit α (PIK3CA) gene mutations were identified in 2 human papillomavirus-associated oropharyngeal cancers. The phase 2 recommended dose was 7.5 mg daily for everolimus plus cisplatin and docetaxel (both at 75 mg/m(2) on day 1 of a 21-day cycle) given with pegfilgrastim support.

Hypoxia-targeted radiotherapy dose painting for head and neck cancer using 18F-FMISO PET: A biological modeling study

Background. This study investigates the use of 18F-fluoromisonidazole (FMISO) PET-guided radiotherapy dose painting for potentially overcoming the radioresistant effects of hypoxia in head and neck squamous cell carcinoma (HNSCC). Material and methods. The study cohort consisted of eight patients with HNSCC who were planned for definitive radiotherapy. Hypoxic subvolumes were automatically generated on pre-radiotherapy FMISO PET scans. Three radiotherapy plans were generated for each patient: a standard (STD) radiotherapy plan to a dose of 70 Gy, a uniform dose escalation (UDE) plan to the standard target volumes to a dose of 84 Gy, and a hypoxia dose-painted (HDP) plan with dose escalation only to the hypoxic subvolume to 84 Gy. Plans were compared based on tumor control probability (TCP), normal tissue complication probability (NTCP), and uncomplicated tumor control probability (UTCP). Results. The mean TCP increased from 73% with STD plans to 95% with the use of UDE plans (p < 0.001) and to 93% with HDP plans (p < 0.001). The mean parotid NTCP increased from 26% to 44% with the use of UDE plans (p = 0.003), and the mean mandible NTCP increased from 2% to 27% with the use of UDE plans (p = 0.001). There were no statistically significant differences between any of the NTCPs between the STD plans and HDP plans. The mean UTCP increased from 48% with STD plans to 66% with HDP plans (p = 0.016) and dropped to 37% with UDE plans (p = 0.138). Conclusion. Hypoxia-targeted radiotherapy dose painting for head and neck cancer using FMISO PET is technically feasible, increases the TCP without increasing the NTCP, and increases the UTCP. This approach is superior to uniform dose escalation.