Julie A. Bradley

Incidence and dosimetric parameters of pediatric brainstem toxicity following proton therapy

Abstract Background. Proton therapy offers superior low and intermediate radiation dose distribution compared with photon-based radiation for brain and skull base tumors; yet tissue within and adjacent to the target volume may receive a comparable radiation dose. We investigated the tolerance of the pediatric brainstem to proton therapy and identified prognostic variables. Material and methods. All patients < 18 years old with tumors of the brain or skull base treated from 2007 to 2013 were reviewed; 313 who received > 50.4 CGE to the brainstem were included in this study. Brainstem toxicity was graded according to the NCI Common Terminology Criteria for Adverse Events v4.0. Results. The three most common histologies were ependymoma, craniopharyngioma, and low-grade glioma. Median patient age was 5.9 years (range 0.5–17.9 years) and median prescribed dose was 54 CGE (range 48.6–75.6 CGE). The two-year cumulative incidence of toxicity was 3.8% ± 1.1%. The two-year cumulative incidence of grade 3 + toxicity was 2.1% ± 0.9%. Univariate analysis identified age < 5 years, posterior fossa tumor location and specific dosimetric parameters as factors associated with an increased risk of toxicity. Conclusion. Utilization of current national brainstem dose guidelines is associated with a low risk of brainstem toxicity in pediatric patients. For young patients with posterior fossa tumors, particularly those who undergo aggressive surgery, our data suggest more conservative dosimetric guidelines should be considered.

Late toxicity following craniospinal radiation for early-stage medulloblastoma

Abstract Background. The purpose of this study is to review late toxicity following craniospinal radiation for early-stage medulloblastoma. Material and methods. Between 1963 and 2008, 53 children with stage M0 (n = 50) or M1 (n = 3) medulloblastoma were treated at our institution. The median age at diagnosis was 7.1 years (range 1.2–18.5). The median craniospinal irradiation (CSI) dose was 28.8 Gy (range 21.8–38.4). The median total dose, including boost, was 54 Gy (range 42.4–64.8 Gy). Since 1963, the CSI dose has been incrementally lowered and the high-risk boost volume reduced. Twenty-one patients (40%) received chemotherapy in their initial management, including 12 who received concurrent chemotherapy. Late sequelae were evaluated by analyzing medical records and conducting phone interviews with surviving patients and/or care-takers. Complications were graded using the NCI Common Terminology Criteria for Adverse Events, version 4.0. Results. The median follow-up for all patients was 15.4 years (range 0.4–44.4) and for living patients it was 24 years (range 5.6–44.4). The overall survival, cause-specific survival, and progression-free survival rates at 10 years were 67%, 67%, and 71%, respectively. Sixteen patients (41% of patients who survived five years or more) developed grade 3 + toxicity; 15 of these 16 patients received a CSI dose > 23.4 Gy. The most common grade 3 + toxicities for long-term survivors are hearing impairment requiring intervention (20.5%) and cognitive impairment (18%) prohibiting independent living. Four patients developed secondary (non-skin) malignancies, including three meningiomas, one rhabdomyosarcoma, and one glioblastoma multiforme. Three patients (5.6%) died from treatment complications, including radionecrosis, severe cerebral edema, and fatal secondary malignancy. Conclusion. Ongoing institutional and cooperative group efforts to minimize radiation exposure are justified given the high rate of serious toxicity observed in our long-term survivors. Follow-up through long-term multidisciplinary clinics is important and warranted for all patients exposed to radiotherapy in childhood.

Initial Report of a Prospective Dosimetric and Clinical Feasibility Trial Demonstrates the Potential of Protons to Increase the Therapeutic Ratio in Breast Cancer Compared With Photons.

PURPOSE To compare dosimetric endpoints between proton therapy (PT) and conventional radiation and determine the feasibility of PT for regional nodal irradiation (RNI) in women with breast cancer. METHODS AND MATERIALS From 2012 to 2014, 18 women (stage IIA-IIIB) requiring RNI prospectively enrolled on a pilot study. Median age was 51.8 years (range, 42-73 years). The cohort included breast-conserving therapy (BCT) and mastectomy patients and right- and left-sided cancers. Treatment targets and organs at risk were delineated on computed tomography scans, and PT and conventional plans were developed. Toxicity was prospectively recorded using Common Terminology Criteria for Adverse Events version 4.0. A Wilcoxon signed-rank sum test compared the dose-volume parameters. The primary endpoint was a reduction in cardiac V5. RESULTS Median follow-up was 20 months (range, 2-31 months). For all patients, the PT plan better met the dosimetric goals and was used for treatment. Proton therapy alone was used for 10 patients (9 postmastectomy, 1 after BCT) and combined proton-photon in 8 (6 BCT, 2 postmastectomy with immediate expander reconstruction). Proton therapy improved coverage of level 2 axilla (P=.0005). Adequate coverage of internal mammary nodes was consistently achieved with PT (median D95, 50.3 Gy; range, 46.6-52.1 Gy) but not with conventional radiation therapy (median D95, 48.2 Gy; range, 40.8-55 Gy; P=.0005). Median cardiac V5 was 0.6% with PT and 16.3% with conventional radiation (P<.0001). Median ipsilateral lung V5 and V20 were improved with PT (median V5 35.3% vs 60.5% [P<.0001]; and median V20, 21.6% vs 35.5% [P<.0001]). Grade 3 dermatitis developed in 4 patients (22%), which was the only grade 3 toxicity. No grade 4+ toxicities developed. CONCLUSION Proton therapy for RNI after mastectomy or BCT significantly improves cardiac dose, especially for left-sided patients, and lung V5 and V20 in all patients without excessive acute toxicity. Proton therapy simultaneously improves target coverage for the internal mammary nodes and level 2 axilla, which may positively impact long-term survival in breast cancer patients.

DYNAMIC MRI ANALYSIS OF TUMOR AND ORGAN MOTION DURING REST AND DEGLUTITION AND MARGIN ASSESSMENT FOR RADIOTHERAPY OF HEAD-AND-NECK CANCER

PURPOSE To quantify swallowing frequency and tumor and normal structure displacements during deglutition using dynamic magnetic resonance imaging (MRI) and to determine planning target volume (PTV) margins to account for resting and deglutition-induced displacements in patients with head-and-neck cancer (HNC). METHODS AND MATERIALS Twenty-two patients with HNC were imaged in the treatment position using dynamic MRI. Sagittal images were acquired. Two-dimensional displacement was analyzed using contours of normal structures and GTV drawn for one swallowing event. Deglutition-induced displacements were quantified based on position change during deglutition relative to preswallow structure location for anterior (A), posterior (P), superior (S), and inferior (I) directions. Additional long-time MRI series were obtained from a subset of 11 patients while they were resting in order to determine swallowing frequency and duration. PTV margins to account for setup error, frequency and duration of deglutition, and resting and deglutition-induced GTV motion were calculated. RESULTS Mean maximum resting displacements ranged from 1.5 to 3.1 mm for combined GTV subsites. Mean maximum swallowing GTV displacement for combined subsites ranged from 4.0 to 11.6 mm. Swallowing was nonperiodic, with a frequency ranging from 0 to 19 swallows over 12.8 min and mean swallow duration of 3.5 s. Based on the average swallowing characteristics in this cohort, the average PTV margins to account for setup error and tumor motion are estimated to be 4.7 mm anteriorly, 4.2 mm posteriorly, 4.7 mm inferiorly, and 6.0 mm superiorly. CONCLUSIONS The measurable mean maximum resting displacement for the GTV indicates that tumor motion occurs even when the patient is not swallowing. Nonuniform margins should be used as a standard PTV margin that accounts for setup error and tumor motion in radiotherapy of HNC unless adaptive radiotherapy with respect to intrafraction tumor motion is performed. The PTV margin can be individualized to a single patients swallowing characteristics or calculated as an average based on the swallowing data from the cohort.

Internal margin assessment using cine MRI analysis of deglutition in head and neck cancer radiotherapy

PURPOSE Intensity-modulated radiation therapy (IMRT) is a promising treatment modality for patients with head and neck cancer (HNC). The dose distributions from IMRT are static and, thus, are unable to account for variations and/or uncertainties in the relationship between the patient (region being treated) and the beam. Organ motion comprises one such source of this uncertainty, introduced by physiological variation in the position, size, and shape of organs during treatment. In the head and neck, the predominant source of this variation arises from deglutition (swallowing). The purpose of this study was to investigate whether cinematographic MRI (cine MRI) could be used to determine asymmetric (nonuniform) internal margin (IM) components of tumor planning target volumes based on the actual deglutition-induced tumor displacement. METHODS Five head and neck cancer patients were set up in treatment position on a 3 T MRI scanner. Two time series of single-slice, sagittal, cine images were acquired using a 2D FLASH sequence. The first time series was a 12.8 min scan designed to capture the frequency and duration of deglutition in the treatment position. The second time series was a short, 15 s scan designed to capture the displacement of deglutition in the treatment position. Deglutition frequency and mean swallow duration were estimated from the long time series acquisition. Swallowing and resting (nonswallowing) events were identified on the short time series acquisition and displacement was estimated based on contours of gross tumor volume (GTV) generated at each time point of a particular event. A simple linear relationship was derived to estimate 1D asymmetric IMs in the presence of resting- and deglutition-induced displacement. RESULTS Deglutition was nonperiodic, with frequency and duration ranging from 2.89-24.18 mHz and from 3.86 to 6.10 s, respectively. The deglutition frequency and mean duration were found to vary among patients. Deglutition-induced maximal GTV displacements ranged from 0.00 to 28.36 mm with mean and standard deviation of 4.72 +/- 3.18, 3.70 +/- 2.81, 2.75 +/- 5.24, and 10.40 +/- 10.76 mm in the A, P, I, and S directions, respectively. Resting-induced maximal GTV displacement ranged from 0.00 to 5.59 mm with mean and standard deviation of 3.01 +/- 1.80, 1.25 +/- 1.10, 3.23 +/- 2.20, and 2.47 +/- 1.11 mm in the A, P, I, and S directions, respectively. For both resting and swallowing states, displacement along the S-I direction dominated displacement along the A-P direction. The calculated IMs were dependent on deglutition frequency, ranging from 3.28-4.37 mm for the lowest deglutition frequency patient to 3.76-6.43 mm for the highest deglutition frequency patient. A statistically significant difference was detected between IMs calculated for P and S directions (p = 0.0018). CONCLUSIONS Cine MRI is able to capture tumor motion during deglutition. Swallowing events can be demarcated by MR signal intensity changes caused by anatomy containing fully relaxed spins that move medially into the imaging plane during deglutition. Deglutition is nonperiodic and results in dynamic changes in the tumor position. Deglutition-induced displacements are larger and more variable than resting displacements. The nonzero mean maximum resting displacement indicates that some tumor motion occurs even when the patient is not swallowing. Asymmetric IMs, derived from deglutition frequency, duration, and directional displacement, should be employed to account for tumor motion in HNC RT.

Local control in non-metastatic medulloblastoma.

Abstract Background. A single-institution review of long-term outcomes and factors affecting local control (LC) following radiotherapy for non-metastatic medulloblastoma. Material and methods. From 1963 to 2008, 50 children (median age, 7.3 years; range 1.2–18.5) with stage M0 medulloblastoma were treated with radiotherapy; half underwent a gross total resection (no visible residual tumor) or near-total resection (< 1.5 cm3 of gross disease remaining after resection). Median craniospinal dose was 28.8 Gy (range 21.8–38.4 Gy). Median total dose to the posterior fossa was 54.3 Gy (range 42.4–64.8 Gy). Eighteen patients (36%) received chemotherapy as part of multimodality management, including 11 who received concurrent chemotherapy. Results. Median follow-up was 15.7 years (range 0.3–44.4 years) for all patients and 26.6 years (range 7.3–44.4 years) for living patients. The 10-year overall survival, cancer-specific survival, and progression-free survival rates were 65%, 65%, and 69%. The 10-year LC rate was 84% and did not significantly change across eras. Four percent of patients experienced local progression five years after treatment. On univariate analysis, chemotherapy and overall duration of radiotherapy ≤ 45 days were associated with improved LC. Patients receiving chemotherapy had a 10-year 100% LC rate versus 76% in patients not receiving chemotherapy (p = 0.0454). When overall radiotherapy treatment lasted ≤ 45 days, patients experienced a superior 95% 10-year LC rate (vs. 73% in patients treated > 45 days; p = 0.0419). Three patients (6%) died from treatment complications, including radionecrosis/cerebellar degeneration, severe cerebral edema leading to herniation, and secondary malignancy. Conclusions. While we cannot draw definitive conclusions given the retrospective nature of our study, our long-term data suggest that reductions in craniospinal dose and boost target volume to reduce toxicity have not compromised disease control in the modern era. Our data also support analyses that implicate duration of radiotherapy, rather than interval between surgery and radiotherapy, as a factor in LC. Chemotherapy in multimodality management of medulloblastoma may have an underappreciated role in improving LC rates.

Clinical outcomes following proton therapy for children with central nervous system tumors referred overseas

International, multidisciplinary care of children with central nervous system (CNS) tumors presents unique challenges. The aim of this study is to report patient outcomes of U.K. children referred for proton therapy to a North American facility.

Fertility in childhood cancer survivors following cranial irradiation for primary central nervous system and skull base tumors

Recent advances in pediatric cancer treatment have improved disease control and survival outcomes for childhood cancers survivors, including those treated for primary central nervous system and skull base malignancies. Future research in this population will focus on identifying risk factors for infertility, novel screening techniques and recommendations, and quality-of-life outcomes improvement. The purpose of this review is to define the infertility complications observed in pediatric cancer survivors who receive cranial irradiation for central nervous system and skull base malignancies.

Late Effects After Radiotherapy for Childhood Low-grade Glioma.

Objectives: This single-institution report describes long-term disease control and late effects in pediatric patients with low-grade glioma (LGG) following radiotherapy (RT). Materials and Methods: Twenty-nine pediatric patients with LGG were treated with photon-based RT from 1970 to 2004 (mean age at time of RT, 9.8 y; range, 0.6 to 19 y). One patient underwent gross total resection, 25 underwent subtotal resection or biopsy, and 3 were treated based on radiographic characteristics alone. Three patients underwent chemotherapy before RT. The median RT dose was 54 Gy (range, 40 to 55 Gy). Results: The median follow-up was 17.8 years (range, 1.6 to 36.8 y) for all patients and 19.9 years (range, 1.6 to 36.8 y) for all living patients. The 5-, 10-, and 20-year local control and progression-free survival rates were equivalent at 82%, 74%, and 63%, respectively. The 5-, 10-, and 20-year cause-specific survival and overall survival rates were equivalent at 89%, 85%, and 58%, respectively. On univariate analysis, age below 4 years during treatment was associated with significantly inferior local control (P=0.0067), cause-specific survival (P=0.0021), and overall survival (P=0.0021). Of the 23 survivors analyzed for late toxicity, 15 (65%) developed grade 3+ toxicity. The most common Common Terminology Criteria for Adverse Events grade 3 toxicity (30% of survivors) was serious cognitive disability. Four patients (14%) died secondary to treatment complications, all occurring over a decade after completing RT. Conclusions: Over half of children diagnosed with LGG survive >20 years after RT; this report reveals the chronicity of toxicity beyond the typically reported follow-up. Our findings inform the therapeutic ratio of RT in this disease and may help guide late-effect screening recommendations.

A Technical Guide for Passive Scattering Proton Radiation Therapy for Breast Cancer

Most patients treated with proton therapy have had eye tumors, sarcomas, or, more recently, pediatric, or prostate cancers. As more proton centers have developed globally, increased capacity will permit exploration of other potential indications for proton therapy, including for the treatment of breast cancer. The rationale for proton therapy in the treatment of breast cancer is reduced inadvertent radiation dose to the heart and lung, as well as improved target coverage. As with any new technology, multiple technical parameters require optimization to deliver safe and effective radiation therapy and to maximize the benefits of the new technology. The purpose of this report is to provide a technical guide for the treatment of breast cancer with passive-scattering proton therapy and an algorithm for selecting patients with breast cancer who would benefit from proton therapy.