Stereotactic body radiotherapy with or without selective dismutase mimetic in pancreatic adenocarcinoma: an adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial.

BACKGROUND: Stereotactic body radiotherapy (SBRT) has the potential to ablate localised pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitise tumours while reducing normal tissue toxicity. This trial was designed to establish the efficacy and toxicity afforded by the selective dismutase mimetic avasopasem manganese when combined with ablative SBRT for localised pancreatic ductal adenocarcinoma. METHODS: In this adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial, patients aged 18 years or older with borderline resectable or locally advanced pancreatic cancer who had received at least 3 months of chemotherapy and had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at six academic sites in the USA. Eligible patients were randomly assigned (1:1), with block randomisation (block sizes of 6-12) with a maximum of 24 patients per group, to receive daily avasopasem (90 mg) or placebo intravenously directly before (ie, within 180 min) SBRT (50, 55, or 60 Gy in five fractions, adaptively assigned in real time by Bayesian estimates of 90-day safety and efficacy). Patients and physicians were masked to treatment group allocation, but not to SBRT dose. The primary objective was to find the optimal dose of SBRT with avasopasem or placebo as determined by the late onset EffTox method. All analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT03340974, and is complete. FINDINGS: Between Jan 25, 2018, and April 29, 2020, 47 patients were screened, of whom 42 were enrolled (median age was 71 years [IQR 63-75], 23 [55%] were male, 19 [45%] were female, 37 [88%] were White, three [7%] were Black, and one [2%] each were unknown or other races) and randomly assigned to avasopasem (n=24) or placebo (n=18); the placebo group was terminated early after failing to meet prespecified efficacy parameters. At data cutoff (June 28, 2021), the avasopasem group satisfied boundaries for both efficacy and toxicity. Late onset EffTox efficacy response was observed in 16 (89%) of 18 patients at 50 Gy and six (100%) of six patients at 55 Gy in the avasopasem group, and was observed in three (50%) of six patients at 50 Gy and nine (75%) of 12 patients at 55 Gy in the placebo group, and the Bayesian model recommended 50 Gy or 55 Gy in five fractions with avasopasem for further study. Serious adverse events of any cause were reported in three (17%) of 18 patients in the placebo group and six (25%) of 24 in the avasopasem group. In the placebo group, grade 3 adverse events within 90 days of SBRT were abdominal pain, acute cholangitis, pyrexia, increased blood lactic acid, and increased lipase (one [6%] each); no grade 4 events occurred. In the avasopasem group, grade 3-4 adverse events within 90 days of SBRT were acute kidney injury, increased blood alkaline phosphatase, haematoma, colitis, gastric obstruction, lung infection, abdominal abscess, post-surgical atrial fibrillation, and pneumonia leading to respiratory failure (one [4%] each).There were no treatment-related deaths but one late death in the avasopasem group due to sepsis in the setting of duodenal obstruction after off-study treatment was reported as potentially related to SBRT. INTERPRETATION: SBRT that uses 50 or 55 Gy in five fractions can be considered for patients with localised pancreatic ductal adenocarcinoma. The addition of avasopasem might further enhance disease outcomes. A larger phase 2 trial (GRECO-2, NCT04698915) is underway to validate these results. FUNDING: Galera Therapeutics.

Dosimetric Uncertainties Resulting From Interfractional Anatomic Variations for Patients Receiving Pancreas Stereotactic Body Radiation Therapy and Cone Beam Computed Tomography Image Guidance.

PURPOSE: To estimate the effects of interfractional anatomic changes on dose to organs at risk (OARs) and tumors, as measured with cone beam computed tomography (CBCT) image guidance for pancreatic stereotactic body radiation therapy. METHODS AND MATERIALS: We evaluated 11 patients with pancreatic cancer whom were treated with stereotactic body radiation therapy (33-40 Gy in 5 fractions) using daily CT-on-rails (CTOR) image guidance immediately before treatment with breath-hold motion management. CBCT alignment was simulated in the treatment planning software by aligning the original planning CT to each fractional CTOR image set via fiducial markers. CTOR data sets were used to calculate fractional doses after alignment by applying the rigid shift of the planning CT and CTOR image sets to the planning treatment isocenter and recalculating the fractional dose. Accumulated dose to the gross tumor volume (GTV), tumor vessel interface, duodenum, small bowel, and stomach were calculated by summing the 5 fractional absolute dose-volume histograms into a single dose-volume histogram for comparison with the original planned dose. RESULTS: Four patients had a GTV D100% of at least 1.5 Gy less than the fractional planned value in several fractions; 4 patients had fractional underestimation of duodenum dose by 1.0 Gy per fraction. The D1.0 cm3 <35 Gy constraint was violated for at least 1 OAR in 3 patients, with either the duodenum (n = 2) or small bowel (n = 1) D1.0 cm3 being higher on the accumulated dose distribution (P = .01). D100% was significantly lower according to accumulated dose GTV (P = .01) and tumor vessel interface (P = .02), with 4 and 2 patients having accumulated D100%  ≥4 Gy lower than the planned value for the GTV and tumor vessel interface, respectively. CONCLUSIONS: For some patients, CBCT image guidance based on fiducial alignment may cause large dosimetric uncertainties for OARs and target structures, according to accumulated dose.

Dose-Escalated Radiation Therapy for Pancreatic Cancer: A Simultaneous Integrated Boost Approach.

PURPOSE: To provide a detailed description of practical approaches to dose escalation in pancreatic cancer. METHODS AND MATERIALS: The current paper represents an international collaborative effort of radiation oncologists from the MR-linac consortium with expertise in pancreatic dose escalation. RESULTS: A 15-fraction hypofractionated intensity modulated radiation therapy (67.5 Gy in 15 fractions) and 5-fraction stereotactic body radiation therapy case (50 Gy in 5 fractions) are presented with information regarding patient selection, target volumes, organs at risk, dose constraints, and specific considerations regarding quality assurance. Additionally, we address barriers to dose escalation and briefly discuss future directions in dose escalation for pancreatic cancer, including particle therapy and magnetic resonance guided radiation therapy. CONCLUSIONS: This article on dose escalation for pancreatic cancer may help to guide academic and community based physicians and to serve as a reference for future therapeutic trials.

End-to-end testing of automatic plan optimization using RayStation scripting for hypofractionated multimetastatic brain stereotactic radiosurgery.

For external beam stereotactic radiosurgery of multiple brain metastatic lesions, it is difficult to select optimal treatment isocenters because the orientation and volume of each planning target volume (PTV) and its proximity to critical structures are unique for each patient. The RayStation treatment planning system offers Python-based scripting to optimize the placement of the treatment isocenter by comparing scenario-based plans. This can improve the plan quality by reducing the dose to the normal brain and increasing planning efficiency. The purpose of the current study was to compare the isocenter-optimized plans generated by RayStation with clinical plans created by the Pinnacle treatment planning system and to validate the RayStation treatment planning and delivery with end-to-end testing. Ten patient plans were automatically regenerated using the script in RayStation. For each patient, 4 plans with 4 different types of isocenters were generated: (1) 2 separate isocenters at the PTV centroids, (2) a single isocenter at the mid-point of 2 centroids, (3) a single isocenter at PTV1, and (4) a single isocenter at PTV2. The best plans were compared with paired Pinnacle plans using plan quality parameters, including normal brain volume excluding PTVs receiving 4 Gy (V4Gy), normal brain volume excluding PTVs receiving 12 Gy (V12Gy), maximum dose to the brainstem, homogeneity index, conformity indices, gradient index of each PTV, and monitor units per fraction. All plans were verified with a cylindrical quality assurance phantom, and end-to-end testing was performed with an anthropomorphic head phantom with a radiochromic film. The script was executed within 5-6 minutes to generate 4 scenario-based automatic plans. The homogeneity index and conformity indices showed small but statistically significant improvement with the RayStation plans. The gradient index (3.9 ± 0.9 for Pinnacle and 3.5 ± 0.6 for RayStation, p = 0.04) was also more favorable in the RayStation plans. V12Gy was significantly reduced by 13% and V4Gy was reduced by 5%. The total monitor units per fraction was significantly reduced by 20% for the RayStation plans. Plan optimization time using RayStation was reduced by 64%. The measured doses at each PTV centroid agreed within 3%, and all RayStation plans passed quality assurance verification tests. Scenario-based automatic plan generation using Python scripting helps identify an optimal treatment isocenter to reduce the dose to the normal brain and improve planning efficiency. RayStation plans provided better plan quality, especially lower doses to the normal brain, than Pinnacle plans. Thus, RayStation is a suitable planning modality for hypofractionated stereotactic radiosurgery for multiple brain metastases.

Dose escalation for locally advanced pancreatic cancer: How high can we go?

PURPOSE: There are limited treatment options for locally advanced, unresectable pancreatic cancer (LAPC) and no likelihood of cure without surgery. Radiation offers an option for local control, but radiation dose has previously been limited by nearby bowel toxicity. Advances in on-board imaging and treatment planning may allow for dose escalation not previously feasible and improve local control. In preparation for development of clinical trials of dose escalation in LAPC, we undertook a dosimetric study to determine the maximum possible dose escalation while maintaining known normal tissue constraints. METHODS AND MATERIALS: Twenty patients treated at our institution with either SBRT or dose-escalated hypofractionated IMRT (DE-IMRT) were re-planned using dose escalated SBRT to 70 Gy in 5 fractions to the GTV and 40 Gy in 5 fractions to the PTV. Standard accepted organ at risk (OAR) constraints were used for planning. Descriptive statistics were generated for homogeneity, conformality, OAR's and GTV/PTV. RESULTS: Mean iGTV coverage by 50 Gy was 91% (±0.07%), by 60 Gy was 61.3% (±0.08%) and by 70 Gy was 24.4% (±0.05%). Maximum PTV coverage by 70 Gy was 33%. Maximum PTV coverage by 60 Gy was 77.5%. The following organ at risk (OAR) constraints were achieved for 90% of generated plans: Duodenum V20 < 30 cc, V30 < 3 cc, V35 < 1 cc; Small Bowel V20 < 15 cc, V30 < 1 cc, V35 < 0.1 cc; Stomach V20 < 20 cc, V30 < 2 cc, V35 < 1 cc. V40 < 0.5 cc was achieved for all OAR. CONCLUSIONS: Dose escalation to 60 Gy is dosimetrically feasible with adequate GTV coverage. The identified constraints for OAR's will be used in ongoing clinical trials.

Spine stereotactic radiosurgery for metastatic sarcoma: patterns of failure and radiation treatment volume considerations.

OBJECTIVE Given the relatively lower radiosensitivity of sarcomas and the locally infiltrative patterns of spread, the authors sought to investigate spine stereotactic radiosurgery (SSRS) outcomes for metastatic sarcomas and to analyze patterns of failure. METHODS The records of 48 patients with 66 sarcoma spinal metastases consecutively treated with SSRS between 2002 and 2013 were reviewed. The Kaplan-Meier method was used to estimate rates of overall survival (OS) and local control (LC). Local recurrences were categorized as occurring infield (within the 95% isodose line [IDL]), marginally (between the 20% and 95% IDLs), or out of field. RESULTS Median follow-up time was 19 months (range 1-121 months), and median age was 53 years (range 17-85 years). The most commonly treated histology was leiomyosarcoma (42%). Approximately two-thirds of the patients were treated with definitive SSRS (44 [67%]) versus postoperatively (22 [33%]). The actuarial 1-year OS and LC rates were 67% and 81%, respectively. Eighteen patients had a local relapse, which was more significantly associated with postoperative SSRS (p = 0.04). On multivariate modeling, receipt of postoperative SSRS neared significance for poorer LC (p = 0.06, subhazard ratio [SHR] 2.33), while only 2 covariates emerged as significantly correlated with LC: 1) biological equivalent dose (BED) > 48 Gy (vs BED ≤ 48 Gy, p = 0.006, SHR 0.21) and 2) single vertebral body involvement (vs multiple bodies, p = 0.03, SHR 0.27). Of the 18 local recurrences, 14 (78%) occurred at the margin, and while the majority of these cases relapsed within the epidural space, 4 relapsed within the paraspinal soft tissue. In addition, 1 relapse occurred out of field. Finally, the most common acute toxicity was fatigue (15 cases), with few late toxicities (4 insufficiency fractures, 3 neuropathies). CONCLUSIONS For metastatic sarcomas, SSRS provides durable tumor control with minimal toxicity. High-dose single-fraction regimens offer optimal LC, and given the infiltrative nature of sarcomas, when paraspinal soft tissues are involved, larger treatment volumes may be warranted.

Outcomes for Spine Stereotactic Body Radiation Therapy and an Analysis of Predictors of Local Recurrence.

PURPOSE: To investigate local control, survival outcomes, and predictors of local relapse for patients treated with spine stereotactic body radiation therapy. METHODS AND MATERIALS: We reviewed the records of 332 spinal metastases consecutively treated with stereotactic body radiation therapy between 2002 and 2012. The median follow-up for all living patients was 33 months (range, 0-111 months). Endpoints were overall survival and local control (LC); recurrences were classified as either in-field or marginal. RESULTS: The 1-year actuarial LC and overall survival rates were 88% and 64%, respectively. Patients with local relapses had poorer dosimetric coverage of the gross tumor volume (GTV) compared with patients without recurrence (minimum dose [Dmin] biologically equivalent dose [BED] 23.9 vs 35.1 Gy, P<.001; D98 BED 41.8 vs 48.1 Gy, P=.001; D95 BED 47.2 vs 50.5 Gy, P=.004). Furthermore, patients with marginal recurrences had poorer prescription coverage of the GTV (86% vs 93%, P=.01) compared with those with in-field recurrences, potentially because of more upfront spinal canal disease (78% vs 24%, P=.001). Using a Cox regression univariate analysis, patients with a GTV BED Dmin ≥33.4 Gy (median dose) (equivalent to 14 Gy in 1 fraction) had a significantly higher 1-year LC rate (94% vs 80%, P=.001) compared with patients with a lower GTV BED Dmin; this factor was the only significant variable on multivariate Cox analysis associated with LC (P=.001, hazard ratio 0.29, 95% confidence interval 0.14-0.60) and also was the only variable significant in a separate competing risk multivariate model (P=.001, hazard ratio 0.30, 95% confidence interval 0.15-0.62). CONCLUSIONS: Stereotactic body radiation therapy offers durable control for spinal metastases, but there is a subset of patients that recur locally. Patients with local relapse had significantly poorer tumor coverage, which was likely attributable to treatment planning directives that prioritized the spinal cord constraints over tumor coverage. When possible, we recommend maintaining a GTV Dmin above 14 Gy in 1 fraction and 21 Gy in 3 fractions.

Incidence and predictors of severe acute esophagitis and subsequent esophageal stricture in patients treated with accelerated hyperfractionated chemoradiation for limited-stage small cell lung cancer.

PURPOSE: Clinical and dosimetric predictors of severe (grade 3 or greater) acute esophageal toxicity and subsequent esophageal dilation were explored in patients with limited-stage small cell lung cancer treated with accelerated hyperfractionated chemoradiation. METHODS AND MATERIALS: A total of 130 patients were identified who were treated to 45 Gy in 1.5-Gy twice-daily fractions with concurrent platinum-based chemotherapy between 2000 and 2009. Data on clinical, disease-related, and treatment-related variables were collected. Patients with percutaneous endoscopic gastrostomy tube insertion or intravenous hydration because of poor oral intake were designated as having acute grade 3 esophagitis. Univariate and multivariate analyses that associated treatment characteristics with esophagitis were assessed via logistic regression, and optimal cut points were identified with recursive partitioning analysis. RESULTS: Twenty-five patients developed severe acute esophagitis, at a rate of 26% (18/69) in patients treated with earlier 3-dimensional conformal radiation therapy techniques and 11.5% (7/61) in patients treated with intensity modulated radiation therapy techniques and omission of elective nodal irradiation. The incidence of esophageal stricture was 6% overall (8 of 128 eligible) but 26% (6/23) among those who experienced prior grade 3 acute esophagitis and 2% (2/105) among those with acute esophagitis less than or equal to grade 2. Significant multivariate predictors of acute esophagitis were mean dose and volume of esophagus receiving at least 5% to 35% of the prescribed dose (V5 to V40). Patients with V5 ≥ 74% had a 44.4% risk of severe acute esophagitis (12/27) versus 12.6% (13/103) among those with V5 < 74%. V45 was the only dosimetric predictor for esophageal stricture, with 13.7% of patients in whom V45 was ≥37.5% requiring subsequent dilation. CONCLUSIONS: Modern radiation techniques are associated with a lower frequency of severe acute esophagitis than previous paradigms. The proportion of esophagus receiving low- to moderate-range doses (mean, V5 through V40) predicts acute esophagitis, whereas the proportion of esophagus that receives high doses (V45) predicts the development of esophageal stricture that requires dilation. Patients who develop grade 3 acute esophagitis are at significant risk for subsequent esophageal stricture, whereas those with acute esophagitis of grade 2 or less display minimal risk.

Stereotactic ablative radiation therapy for centrally located early stage or isolated parenchymal recurrences of non-small cell lung cancer: how to fly in a "no fly zone".

PURPOSE: We extended our previous experience with stereotactic ablative radiation therapy (SABR; 50 Gy in 4 fractions) for centrally located non-small cell lung cancer (NSCLC); explored the use of 70 Gy in 10 fractions for cases in which dose-volume constraints could not be met with the previous regimen; and suggested modified dose-volume constraints. METHODS AND MATERIALS: Four-dimensional computed tomography (4DCT)-based volumetric image-guided SABR was used for 100 patients with biopsy-proven, central T1-T2N0M0 (n=81) or isolated parenchymal recurrence of NSCLC (n=19). All disease was staged with positron emission tomography/CT; all tumors were within 2 cm of the bronchial tree, trachea, major vessels, esophagus, heart, pericardium, brachial plexus, or vertebral body. Endpoints were toxicity, overall survival (OS), local and regional control, and distant metastasis. RESULTS: At a median follow-up time of 30.6 months, median OS time was 55.6 months, and the 3-year OS rate was 70.5%. Three-year cumulative actuarial local, regional, and distant control rates were 96.5%, 87.9%, and 77.2%, respectively. The most common toxicities were chest-wall pain (18% grade 1, 13% grade 2) and radiation pneumonitis (11% grade 2 and 1% grade 3). No patient experienced grade 4 or 5 toxicity. Among the 82 patients receiving 50 Gy in 4 fractions, multivariate analyses showed mean total lung dose >6 Gy, V20 >12%, or ipsilateral lung V30 >15% to independently predict radiation pneumonitis; and 3 of 9 patients with brachial plexus Dmax >35 Gy experienced brachial neuropathy versus none of 73 patients with brachial Dmax <35 Gy (P=.001). Other toxicities were analyzed and new dose-volume constraints are proposed. CONCLUSIONS: SABR for centrally located lesions produces clinical outcomes similar to those for peripheral lesions when normal tissue constraints are respected.

Cardiac ¹8F-fluorodeoxyglucose uptake on positron emission tomography after thoracic stereotactic body radiation therapy.

BACKGROUND AND PURPOSE: Previous studies have shown that increased cardiac uptake of (18)F-fluorodeoxyglucose (FDG) on positron emission tomography (PET) may be an indicator of myocardial injury after radiotherapy. We reviewed patients treated with thoracic stereotactic body radiation therapy (SBRT) and established correlations between SBRT dose and observed changes in cardiac FDG-PET uptake. MATERIAL AND METHODS: Retrospective analysis identified 39 patients that were treated with SBRT for lung tumors close to the heart. Patients were grouped according to whether or not they had changes in cardiac FDG-PET uptake within the planned SBRT field. RESULTS: At a median follow-up interval of 39 months (range, 6-81 months), nine patients (23%) showed increased cardiac FDG uptake associated with the heart V20. Of the 19 patients who received 20 Gy to ≥5 cm(3) of the heart, nine (47%) developed increased FDG uptake (vs. 0% for the 20 patients who received 20 Gy to <5 cm(3)) (P=0.0004), all within the 20-Gy isodose line. Patients with hypercholesterolemia prior to SBRT were also more likely to show increased cardiac FDG uptake (P=0.0190). CONCLUSION: Increased FDG uptake in the heart after SBRT was observed when the 20 Gy isodose line exceeded 5 cm(3) of the heart.

Aortic dose constraints when reirradiating thoracic tumors.

BACKGROUND AND PURPOSE: Improved radiation delivery and planning has allowed, in some instances, for the retreatment of thoracic tumors. We investigated the dose limits of the aorta wherein grade 5 aortic toxicity was observed after reirradiation of lung tumors. MATERIAL AND METHODS: In a retrospective analysis, 35 patients were identified, between 1993 and 2008, who received two rounds of external beam irradiation that included the aorta in the radiation fields of both the initial and retreatment plans. We determined the maximum cumulative dose to 1 cm(3) of the aorta (the composite dose) for each patient, normalized these doses to 1.8 Gy/fraction, and corrected them for long-term tissue recovery between treatments (NIDR). RESULTS: The median time interval between treatments was 30 months (range, 1-185 months). The median follow-up of patients alive at analysis was 42 months (range, 14-70 months). Two of the 35 patients (6%) were identified as having grade 5 aortic toxicities. There was a 25% rate of grade 5 aortic toxicity for patients receiving composite doses ≥120.0 Gy (vs. 0% for patients receiving <120.0 Gy) (P=0.047). CONCLUSIONS: Grade 5 aortic toxicities were observed with composite doses ≥120.0 Gy (NIDR ≥90.0 Gy) to 1cm(3) of the aorta.

Generalizable class solutions for treatment planning of spinal stereotactic body radiation therapy.

PURPOSE: Spinal stereotactic body radiation therapy (SBRT) continues to emerge as an effective therapeutic approach to spinal metastases; however, treatment planning and delivery remain resource intensive at many centers, which may hamper efficient implementation in clinical practice. We sought to develop a generalizable class solution approach for spinal SBRT treatment planning that would allow confidence that a given plan provides optimal target coverage, reduce integral dose, and maximize planning efficiency. METHODS AND MATERIALS: We examined 91 patients treated with spinal SBRT at our institution. Treatment plans were categorized by lesion location, clinical target volume (CTV) configuration, and dose fractionation scheme, and then analyzed to determine the technically achievable dose gradient. A radial cord expansion was subtracted from the CTV to yield a planning CTV (pCTV) construct for plan evaluation. We reviewed the treatment plans with respect to target coverage, dose gradient, integral dose, conformality, and maximum cord dose to select the best plans and develop a set of class solutions. RESULTS: The class solution technique generated plans that maintained target coverage and improved conformality (1.2-fold increase in the 95% van't Riet Conformation Number describing the conformality of a reference dose to the target) while reducing normal tissue integral dose (1.3-fold decrease in the volume receiving 4 Gy (V(4Gy)) and machine output (19% monitor unit (MU) reduction). In trials of planning efficiency, the class solution technique reduced treatment planning time by 30% to 60% and MUs required by ∼20%: an effect independent of prior planning experience. CONCLUSIONS: We have developed a set of class solutions for spinal SBRT that incorporate a pCTV metric for plan evaluation while yielding dosimetrically superior treatment plans with increased planning efficiency. Our technique thus allows for efficient, reproducible, and high-quality spinal SBRT treatment planning.

Effect of brain stem and dorsal vagus complex dosimetry on nausea and vomiting in head and neck intensity-modulated radiation therapy.

Intensity-modulated radiation therapy (IMRT) is becoming the treatment of choice for many head and neck cancer patients. IMRT reduces some toxicities by reducing radiation dose to uninvolved normal tissue near tumor targets; however, other tissues not irradiated using previous 3D techniques may receive clinically significant doses, causing undesirable side effects including nausea and vomiting (NV). Irradiation of the brainstem, and more specifically, the area postrema and dorsal vagal complex (DVC), has been linked to NV. We previously reported preliminary hypothesis-generating dose effects associated with NV in IMRT patients. The goal of this study is to relate brainstem dose to NV symptoms. We retrospectively studied 100 consecutive patients that were treated for oropharyngeal cancer with IMRT. We contoured the brainstem, area postrema, and DVC with the assistance of an expert diagnostic neuroradiologist. We correlated dosimetry for the 3 areas contoured with weekly NV rates during IMRT. NV rates were significantly higher for patients who received concurrent chemotherapy. Post hoc analysis demonstrated that chemoradiation cases exhibited a trend towards the same dose-response relationship with both brainstem mean dose (p = 0.0025) and area postrema mean dose (p = 0.004); however, both failed to meet statistical significance at the p ≤ 0.002 level. Duration of toxicity was also greater for chemoradiation patients, who averaged 3.3 weeks with reported Common Terminology Criteria for Adverse Events (CTC-AE), compared with an average of 2 weeks for definitive RT patients (p = 0.002). For definitive RT cases, no dose-response trend could be ascertained. The mean brainstem dose emerged as a key parameter of interest; however, no one dose parameter (mean/median/EUD) best correlated with NV. This study does not address extraneous factors that would affect NV incidence, including the use of antiemetics, nor chemotherapy dose schedule specifics before and during RT. A prospective study will be required to depict exactly how IMRT dose affects NV.

Radiation for Hodgkin's lymphoma in young female patients: a new technique to avoid the breasts and decrease the dose to the heart.

PURPOSE: To demonstrate how, in young female patients with Hodgkin's lymphoma, using an inclined board technique can further decrease the volume of breasts and heart in the treatment field. METHODS AND MATERIALS: An inclined board was constructed with the ability to mount an Aquaplast face mask, a Vacu-Lock, and a hip stopper. Eight female patients with early-stage Hodgkin's lymphoma were planned and compared using the conventional flat position and the inclined board position. All patients on the inclined board were planned with 90° degree table position and 15° gantry angle rotation to compensate for the beam divergence resulting from the patient's position on the inclined board. Dose-volume histograms were generated, as well as the mean V30 and V5 of both breasts and heart using both treatment positions. RESULTS: The mean value of V30 of the right breast, left breast, and heart decreased from 3%, 3%, and 13%, respectively, using the flat position to 0, 0.4%, and 5%, respectively, using the inclined board. The mean value of V5 of the right breast, left breast, and heart decreased from 6%, 13%, and 36%, respectively, using the flat position to 2%, 8%, and 29%, respectively, using the inclined board. CONCLUSIONS: Compared with conventional flat positioning, this simple device and technique allows better sparing of the breasts and the heart while maintaining comparable target coverage and total lung dose.

Exploring the feasibility of dose escalation positron emission tomography-positive disease with intensity-modulated radiation therapy and the effects on normal tissue structures for thoracic malignancies.

The pattern of failure is one of the major causes of mortality among thoracic patients. Studies have shown a correlation between local control and dose. Intensity-modulated radiation therapy (IMRT) has resulted in conformal dose distributions while limiting dose to normal tissue. However, thoracic malignancies treated with IMRT to highly conformal doses up to 70 Gy still have been found to fail. Thus, the need for dose escalation through simultaneous integrated boost (SIB) may prove effective in minimizing reoccurrences. For our study, 28 thoracic IMRT plans were reoptimized via dose escalation to the gross tumor volume (GTV) and planning target volume (PTV) of 79.2 Gy and 68.4 Gy, respectively. Reoccurrences in surrounding regions of microscopic disease are rare therefore, dose-escalating regional nodes (outside GTV) were not included. Hence, the need to edit GTV margins was acceptable for our retrospective study. A median dose escalation of approximately 15 Gy (64.8-79.2 Gy) via IMRT using SIB was deemed achievable with minimal percent differences received by critical structures compared with the original treatment plan. The target's mean doses were significantly increased based on p-value analysis, while the normal tissue structures were not significantly changed.

Stereotactic body radiation therapy for patients with lung cancer previously treated with thoracic radiation.

PURPOSE: Stereotactic body radiation therapy (SBRT) provides excellent local control with acceptable toxicity for patients with early-stage non-small cell lung cancer. However, the efficacy and safety of SBRT for patients previously given thoracic radiation therapy is not known. In this study, we retrospectively reviewed outcomes after SBRT for recurrent disease among patients previously given radiation therapy to the chest. MATERIALS AND METHODS: A search of medical records for patients treated with SBRT to the thorax after prior fractionated radiation therapy to the chest at The University of Texas M. D. Anderson Cancer Center revealed 36 such cases. The median follow-up time after SBRT was 15 months. The endpoints analyzed were overall survival, local control, and the incidence and severity of treatment-related toxicity. RESULTS: SBRT provided in-field local control for 92% of patients; at 2 years, the actuarial overall survival rate was 59%, and the actuarial progression-free survival rate was 26%, with the primary site of failure being intrathoracic relapse. Fifty percent of patients experienced worsening of dyspnea after SBRT, with 19% requiring oxygen supplementation; 30% of patients experienced chest wall pain and 8% Grade 3 esophagitis. No Grade 4 or 5 toxic effects were noted. CONCLUSIONS: SBRT can provide excellent in-field tumor control in patients who have received prior radiation therapy. Toxicity was significant but manageable. The high rate of intrathoracic failure indicates the need for further study to identify patients who would derive the most benefit from SBRT for this purpose.

Beam path toxicities to non-target structures during intensity-modulated radiation therapy for head and neck cancer.

BACKGROUND: Intensity-modulated radiation therapy (IMRT) beams traverse nontarget normal structures not irradiated during three-dimensional conformal RT (3D-CRT) for head and neck cancer (HNC). This study estimates the doses and toxicities to nontarget structures during IMRT. MATERIALS AND METHODS: Oropharyngeal cancer IMRT and 3D-CRT cases were reviewed. Dose-volume histograms (DVH) were used to evaluate radiation dose to the lip, cochlea, brainstem, occipital scalp, and segments of the mandible. Toxicity rates were compared for 3D-CRT, IMRT alone, or IMRT with concurrent cisplatin. Descriptive statistics and exploratory recursive partitioning analysis were used to estimate dose "breakpoints" associated with observed toxicities. RESULTS: A total of 160 patients were evaluated for toxicity; 60 had detailed DVH evaluation and 15 had 3D-CRT plan comparison. Comparing IMRT with 3D-CRT, there was significant (p 36 Gy, occipital scalp dose >30 Gy, and anterior mandible dose >34 Gy, respectively. CONCLUSIONS: Dose reduction to specified structures during IMRT implies an increased beam path dose to alternate nontarget structures that may result in clinical toxicities that were uncommon with previous, less conformal approaches. These findings have implications for IMRT treatment planning and research, toxicity assessment, and multidisciplinary patient management.

Evaluation of peritumoral edema in the delineation of radiotherapy clinical target volumes for glioblastoma.

PURPOSE: To evaluate the spatial relationship between peritumoral edema and recurrence pattern in patients with glioblastoma (GBM). METHODS AND MATERIALS: Forty-eight primary GBM patients received three-dimensional conformal radiotherapy that did not intentionally include peritumoral edema within the clinical target volume between July 2000 and June 2001. All 48 patients have subsequently recurred, and their original treatment planning parameters were used for this study. New theoretical radiation treatment plans were created for the same 48 patients, based on Radiation Therapy Oncology Group (RTOG) target delineation guidelines that specify inclusion of peritumoral edema. Target volume and recurrent tumor coverage, as well as percent volume of normal brain irradiated, were assessed for both methods of target delineation using dose-volume histograms. RESULTS: A comparison between the location of recurrent tumor and peritumoral edema volumes from all 48 cases failed to show correlation by linear regression modeling (r(2) = 0.0007; p = 0.3). For patients with edema >75 cm(3), the percent volume of brain irradiated to 46 Gy was significantly greater in treatment plans that intentionally included peritumoral edema compared with those that did not (38% vs. 31%; p = 0.003). The pattern of failure was identical between the two sets of plans (40 central, 3 in-field, 3 marginal, and 2 distant recurrence). CONCLUSION: Clinical target volume delineation based on a 2-cm margin rather than on peritumoral edema did not seem to alter the central pattern of failure for patients with GBM. For patients with peritumoral edema >75 cm(3), using a constant 2-cm margin resulted in a smaller median percent volume of brain being irradiated to 30 Gy, 46 Gy, and 50 Gy compared with corresponding theoretical RTOG plans that deliberately included peritumoral edema.