Adjuvant chemotherapy following chemoradiotherapy as primary treatment for locally advanced cervical cancer versus chemoradiotherapy alone (OUTBACK): an international, open-label, randomised, phase 3 trial.

BACKGROUND: Standard treatment for locally advanced cervical cancer is chemoradiotherapy, but many patients relapse and die of metastatic disease. We aimed to determine the effects on survival of adjuvant chemotherapy after chemoradiotherapy. METHODS: The OUTBACK trial was a multicentre, open-label, randomised, phase 3 trial done in 157 hospitals in Australia, China, Canada, New Zealand, Saudi Arabia, Singapore, and the USA. Eligible participants were aged 18 year or older with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, II, IIIB, or IVA disease), Eastern Cooperative Oncology Group performance status 0-2, and adequate bone marrow and organ function. Participants were randomly assigned centrally (1:1) using a minimisation approach and stratified by pelvic or common iliac nodal involvement, requirement for extended-field radiotherapy, FIGO 2008 stage, age, and site to receive standard cisplatin-based chemoradiotherapy (40 mg/m2 cisplatin intravenously once-a-week for 5 weeks, during radiotherapy with 45·0-50·4 Gy external beam radiotherapy delivered in fractions of 1·8 Gy to the whole pelvis plus brachytherapy; chemoradiotherapy only group) or standard cisplatin-based chemoradiotherapy followed by adjuvant chemotherapy with four cycles of carboplatin (area under the receiver operator curve 5) and paclitaxel (155 mg/m2) given intravenously on day 1 of a 21 day cycle (adjuvant chemotherapy group). The primary endpoint was overall survival at 5 years, analysed in the intention-to-treat population (ie, all eligible patients who were randomly assigned). Safety was assessed in all patients in the chemoradiotherapy only group who started chemoradiotherapy and all patients in the adjuvant chemotherapy group who received at least one dose of adjuvant chemotherapy. The OUTBACK trial is registered with ClinicalTrials.gov, NCT01414608, and the Australia New Zealand Clinical Trial Registry, ACTRN12610000732088. FINDINGS: Between April 15, 2011, and June 26, 2017, 926 patients were enrolled and randomly assigned to the chemoradiotherapy only group (n=461) or the adjuvant chemotherapy group (n=465), of whom 919 were eligible (456 in the chemoradiotherapy only group and 463 in the adjuvant chemotherapy group; median age 46 years [IQR 37 to 55]; 663 [72%] were White, 121 [13%] were Black or African American, 53 [6%] were Asian, 24 [3%] were Aboriginal or Pacific islander, and 57 [6%] were other races) and included in the analysis. As of data cutoff (April 12, 2021), median follow-up was 60 months (IQR 45 to 65). 5-year overall survival was 72% (95% CI 67 to 76) in the adjuvant chemotherapy group (105 deaths) and 71% (66 to 75) in the chemoradiotherapy only group (116 deaths; difference 1% [95% CI -6 to 7]; hazard ratio 0·90 [95% CI 0·70 to 1·17]; p=0·81). In the safety population, the most common clinically significant grade 3-4 adverse events were decreased neutrophils (71 [20%] in the adjuvant chemotherapy group vs 34 [8%] in the chemoradiotherapy only group), and anaemia (66 [18%] vs 34 [8%]). Serious adverse events occurred in 107 (30%) in the adjuvant chemotherapy group versus 98 (22%) in the chemoradiotherapy only group, most commonly due to infectious complications. There were no treatment-related deaths. INTERPRETATION: Adjuvant carboplatin and paclitaxel chemotherapy given after standard cisplatin-based chemoradiotherapy for unselected locally advanced cervical cancer increased short-term toxicity and did not improve overall survival; therefore, it should not be given in this setting. FUNDING: National Health and Medical Research Council and National Cancer Institute.

ZAP-X Gyroscopic Radiosurgery System: A Preliminary Analysis of Clinical Applications within a Retrospective Case Series.

INTRODUCTION: The ZAP-X Gyroscopic Radiosurgery system (ZAP Surgical Systems, Inc., San Carlos, CA, USA) is a novel high-dose targeted stereotactic radiosurgery platform for outpatient use that includes self-shielding, X-ray image guidance, and the capacity to aim the radiation beam gyroscopically at an intracranial lesion using 5 independent degrees of freedom. The ZAP-X Gyroscopic Radiosurgery system accomplishes these actions while meeting widely accepted standards for dose gradient and accuracy. This retrospective study examined data of patients treated with gyroscopic radiosurgery (GRS) to document clinical outcomes. METHODS: Medical records of all outpatients treated with GRS over a 20-month period from January 2019 to August 2020 were searched to extract relevant details, including follow-up data until August 2021 (32-month study interval). Patients with <6 months of radiographical follow-up data were excluded unless death occurred. Data collection included pretreatment clinical history, pathological diagnosis, radiographical features, treatment parameters, and long-term clinical and radiographical follow-up. RESULTS: Sixty-eight patients received outpatient treatment with GRS during the 20-month treatment interval, with 59 patients remaining after exclusion for the minimum follow-up threshold, with a mean (standard deviation [SD]) fractionation of 1.85 (1.63). Eighty-two lesions were treated across a very heterogeneous patient population, including meningiomas (42.4%), metastases (39.0%), gliomas (6.8%), schwannomas (1.7%), and pituitary tumor (1.7%). Mean (SD) radiographical follow-up data (14.7 [6.60] months) were available for 56 patients. During that interval, 13 treated lesions in 13 patients (15.9%) demonstrated progression, 9 of which were stable during the initial posttreatment imaging surveillance period. Mean lesion volume was stable from pretreatment (2.54 cm3 [4.37 cm3]) to most recent follow-up (2.80 cm3 [8.20 cm3]) (t [79] = -0.310; p = 0.76). Minor adverse clinical events were noted in 3 (5.1%) of the 59 patients during the posttreatment phase that may have been related to the treatment. Ten (16.9%) patients died within the 32-month study interval. DISCUSSION/CONCLUSION: This preliminary assessment of the first series of patients treated with the Zap-X Gyroscopic Radiosurgery system documents its overall feasibility in clinical applications. Although the duration of follow-up was brief, GRS appeared to be both safe and effective. Additional analysis, with an ongoing prospective registry, is underway.

Expression and prognostic impact of immune modulatory molecule PD-L1 in meningioma.

While immunotherapy may offer promising new approaches for high grade meningiomas, little is currently known of the immune landscape in meningiomas. We sought to characterize the immune microenvironment and a potentially targetable antigen mesothelin across WHO grade I-III cases of meningiomas, and how infiltrating immune populations relate to patient outcomes. Immunohistochemistry was performed on tissue microarrays constructed from 96 meningioma cases. The cohort included 16 WHO grade I, 62 WHO grade II, and 18 WHO grade III tumors. Immunohistochemistry was performed using antibodies against CD3, CD8, CD20, CD68, PD-L1, and mesothelin. Dual staining using anti-PD-L1 and anti-CD68 antibodies was performed, and automated cell detection and positive staining detection algorithms were utilized. Greater degree of PD-L1 expression was found in higher grade tumors. More specifically, higher grade tumors contained increased numbers of intratumoral CD68-, PD-L1+ cells (p = 0.022), but did not contain higher numbers of infiltrating CD68+, PD-L1+ cells (p = 0.30). Higher PD-L1+/CD68- expression was independently predictive of worse overall survival in our cohort when accounting for grade, performance status, extent of resection, and recurrence history (p = 0.014). Higher expression of PD-L1+/CD68- was also present in tumors that had undergone prior radiotherapy (p = 0.024). Approximately quarter of meningiomas overexpressed mesothelin to levels equivalent to those found in pancreatic carcinomas and malignant mesotheliomas. The association with poor survival outcomes in our study suggests that PD-L1 may play a significant biologic role in the aggressive phenotype of higher grade meningiomas. Thus, immunotherapeutic strategies such as checkpoint inhibition may have clinical utility in PD-L1 overexpressing meningiomas.

Assessment of image quality and dose calculation accuracy on kV CBCT, MV CBCT, and MV CT images for urgent palliative radiotherapy treatments.

A clinical workflow was developed for urgent palliative radiotherapy treatments that integrates patient simulation, planning, quality assurance, and treatment in one 30-minute session. This has been successfully tested and implemented clinically on a linac with MV CBCT capabilities. To make this approach available to all clin-ics equipped with common imaging systems, dose calculation accuracy based on treatment sites was assessed for other imaging units. We evaluated the feasibility of palliative treatment planning using on-board imaging with respect to image quality and technical challenges. The purpose was to test multiple systems using their commercial setup, disregarding any additional in-house development. kV CT, kV CBCT, MV CBCT, and MV CT images of water and anthropomorphic phantoms were acquired on five different imaging units (Philips MX8000 CT Scanner, and Varian TrueBeam, Elekta VersaHD, Siemens Artiste, and Accuray Tomotherapy linacs). Image quality (noise, contrast, uniformity, spatial resolution) was evaluated and compared across all machines. Using individual image value to density calibrations, dose calculation accuracies for simple treatment plans were assessed for the same phantom images. Finally, image artifacts on clinical patient images were evaluated and compared among the machines. Image contrast to visualize bony anatomy was sufficient on all machines. Despite a high noise level and low contrast, MV CT images provided the most accurate treatment plans relative to kV CT-based planning. Spatial resolution was poorest for MV CBCT, but did not limit the visualization of small anatomical structures. A comparison of treatment plans showed that monitor units calculated based on a prescription point were within 5% difference relative to kV CT-based plans for all machines and all studied treatment sites (brain, neck, and pelvis). Local dose differences > 5% were found near the phantom edges. The gamma index for 3%/3 mm criteria was ≥ 95% in most cases. Best dose calculation results were obtained when the treatment isocenter was near the image isocenter for all machines. A large field of view and immediate image export to the treatment planning system were essential for a smooth workflow and were not provided on all devices. Based on this phantom study, image quality of the studied kV CBCT, MV CBCT, and MV CT on-board imaging devices was sufficient for treatment planning in all tested cases. Treatment plans provided dose calculation accuracies within an acceptable range for simple, urgently planned palliative treatments. However, dose calculation accuracy was compromised towards the edges of an image. Feasibility for clinical implementation should be assessed separately and may be complicated by machine specific features. Image artifacts in patient images and the effect on dose calculation accuracy should be assessed in a separate, machine-specific study.

Response assessment criteria for brain metastases: proposal from the RANO group.

CNS metastases are the most common cause of malignant brain tumours in adults. Historically, patients with brain metastases have been excluded from most clinical trials, but their inclusion is now becoming more common. The medical literature is difficult to interpret because of substantial variation in the response and progression criteria used across clinical trials. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group is an international, multidisciplinary effort to develop standard response and progression criteria for use in clinical trials of treatment for brain metastases. Previous efforts have focused on aspects of trial design, such as patient population, variations in existing response and progression criteria, and challenges when incorporating neurological, neuro-cognitive, and quality-of-life endpoints into trials of patients with brain metastases. Here, we present our recommendations for standard response and progression criteria for the assessment of brain metastases in clinical trials. The proposed criteria will hopefully facilitate the development of novel approaches to this difficult problem by providing more uniformity in the assessment of CNS metastases across trials.

Radiation therapy of glioblastoma.

Glioblastoma multiforme (GBM) is the most common malignant brain tumor that affects approximately 17,000 patients annually. Clear survival advantages have been demonstrated with postoperative radiation therapy (RT) to doses of 5,000-6,000 cGy but dose-escalation attempts beyond 6,000 cGy have resulted in increased toxicity but no additional survival benefit. To improve local control and limit toxicity to normal brain tissue with these infiltrating tumors, novel imaging techniques are actively being explored to better define tumor extent and associated RT treatment fields. Hyperfractionated RT has been associated with a survival detriment. Current standard-of-care treatment involves concurrent use of temozolomide and RT to 6,000 cGy over 30 days followed by adjuvant temozolomide treatment for 6 months. Brachytherapy and stereotactic radiosurgery are effective therapies for relapsed GBM but tend to be associated with notable toxicity. More recently, re-irradiation strategies employ concurrent use of bevacizumab to limit treatment-related injury while still permitting delivery of meaningful doses. These clinical trials are ongoing and merits of these strategies are not yet clear but appear promising.

Surgery is cost-effective treatment for young patients with vestibular schwannomas: decision tree modeling of surgery, radiation, and observation.

OBJECT: Vestibular schwannomas (VSs) are managed in 3 ways: observation ("wait and scan"); Gamma Knife surgery (GKS); or microsurgery. Whereas there is considerable literature regarding which management approach is superior, there are only a few studies addressing the cost of treating VSs, and there are no cost-utility analyses in the US to date. METHODS: In this study, the authors used the University of California at San Francisco medical record and hospital accounting databases to determine total hospital charges and costs for 33 patients who underwent open surgery, 42 patients who had GKS, and 12 patients who were observed between 2010 and 2013. The authors then performed decision-tree analysis to determine which treatment paradigm produces the highest quality-adjusted life years and to calculate the incremental cost-effectiveness ratio, depending on the patient's age at VS diagnosis. RESULTS: The average total hospital cost over a 3-year period for surgically treated patients was $80,074 (± $49,678) versus $9737 (± $5522) for patients receiving radiosurgery and $1746 (± $2792) for patients who were observed. When modeling the most debilitating symptoms and worst outcomes of VSs (vertigo and death) at different ages at diagnosis, radiation is dominant to observation at all ages up to 70 years. Surgery is cost-effective when compared with radiation (incremental cost-effectiveness ratio < $150,000) at younger ages at diagnosis (< 45 years old). CONCLUSIONS: In this model, surgery is a cost-effective alternative to radiation when VS is diagnosed in patients at < 45 years. For patients ≥ 45 years, radiation is the most cost-effective treatment option.

Challenges relating to solid tumour brain metastases in clinical trials, part 2: neurocognitive, neurological, and quality-of-life outcomes. A report from the RANO group.

Neurocognitive function, neurological symptoms, functional independence, and health-related quality of life are major concerns for patients with brain metastases. The inclusion of these endpoints in trials of brain metastases and the methods by which these measures are assessed vary substantially. If functional independence or health-related quality of life are planned as key study outcomes, then the reliability and validity of these endpoints can be crucial because methodological issues might affect the interpretation and acceptance of findings. The Response Assessment in Neuro-Oncology (RANO) working group is an independent, international, and collaborative effort to improve the design of clinical trials in patients with brain tumours. In this report, the second in a two-part series, we review clinical trials of brain metastases in relation to measures of clinical benefit and provide a framework for the design and conduct of future trials.

Challenges relating to solid tumour brain metastases in clinical trials, part 1: patient population, response, and progression. A report from the RANO group.

Therapeutic outcomes for patients with brain metastases need to improve. A critical review of trials specifically addressing brain metastases shows key issues that could prevent acceptance of results by regulatory agencies, including enrolment of heterogeneous groups of patients and varying definitions of clinical endpoints. Considerations specific to disease, modality, and treatment are not consistently addressed. Additionally, the schedule of CNS imaging and consequences of detection of new or progressive brain metastases in trials mainly exploring the extra-CNS activity of systemic drugs are highly variable. The Response Assessment in Neuro-Oncology (RANO) working group is an independent, international, collaborative effort to improve the design of trials in patients with brain tumours. In this two-part series, we review the state of clinical trials of brain metastases and suggest a consensus recommendation for the development of criteria for future clinical trials.

Radiotherapy Plan Quality Assurance in NRG Oncology Trials for Brain and Head/Neck Cancers: An AI-Enhanced Knowledge-Based Approach.

The quality of radiation therapy (RT) treatment plans directly affects the outcomes of clinical trials. KBP solutions have been utilized in RT plan quality assurance (QA). In this study, we evaluated the quality of RT plans for brain and head/neck cancers enrolled in multi-institutional clinical trials utilizing a KBP approach. The evaluation was conducted on 203 glioblastoma (GBM) patients enrolled in NRG-BN001 and 70 nasopharyngeal carcinoma (NPC) patients enrolled in NRG-HN001. For each trial, fifty high-quality photon plans were utilized to build a KBP photon model. A KBP proton model was generated using intensity-modulated proton therapy (IMPT) plans generated on 50 patients originally treated with photon RT. These models were then applied to generate KBP plans for the remaining patients, which were compared against the submitted plans for quality evaluation, including in terms of protocol compliance, target coverage, and organ-at-risk (OAR) doses. RT plans generated by the KBP models were demonstrated to have superior quality compared to the submitted plans. KBP IMPT plans can decrease the variation of proton plan quality and could possibly be used as a tool for developing improved plans in the future. Additionally, the KBP tool proved to be an effective instrument for RT plan QA in multi-center clinical trials.

Low-risk meningioma: Initial outcomes from NRG Oncology/RTOG 0539.

BACKGROUND: Three- and five-year progression-free survival (PFS) for low-risk meningioma managed with surgery and observation reportedly exceeds 90%. Herewith we summarize outcomes for low-risk meningioma patients enrolled on NRG/RTOG 0539. METHODS: This phase II trial allocated patients to one of three groups per World Health Organization grade, recurrence status, and resection extent. Low-risk patients had either gross total (GTR) or subtotal resection (STR) for a newly diagnosed grade 1 meningioma and were observed after surgery. The primary endpoint was 3-year PFS. Adverse events (AEs) were scored using Common Terminology Criteria for Adverse Events (CTCAE) version 3. RESULTS: Among 60 evaluable patients, the median follow-up was 9.1 years. The 3-, 5-, and 10-year rates were 91.4% (95% CI, 84.2 to 98.6), 89.4% (95% CI, 81.3 to 97.5), 85.0% (95% CI, 75.3 to 94.7) for PFS and 98.3% (95% CI, 94.9 to 100), 98.3%, (95% CI, 94.9 to 100), 93.8% (95% CI, 87.0 to 100) for overall survival (OS), respectively. With centrally confirmed GTR, 3/5/10y PFS and OS rates were 94.3/94.3/87.6% and 97.1/97.1/90.4%. With STR, 3/5/10y PFS rates were 83.1/72.7/72.7% and 10y OS 100%. Five patients reported one grade 3, four grade 2, and five grade 1 AEs. There were no grade 4 or 5 AEs. CONCLUSIONS: These results prospectively validate high PFS and OS for low-risk meningioma managed surgically but raise questions regarding optimal management following STR, a subcohort that could potentially benefit from adjuvant therapy.

The long-term postsurgical prognosis of patients with pineoblastoma.

BACKGROUND: For this report, the authors comprehensively summarized the existing literature on patients with pineoblastoma and identified the variables and treatments that had an impact patient on outcomes. METHODS: A comprehensive search identified 109 studies that collectively described the outcomes of patients with pineoblastoma. Individual patient data were classified based on treatment and were subjected to univariate comparisons. Cox regression analysis included comparisons of survival outcomes controlling for age, extent of resection, and treatment group, and between-group survival comparisons were performed using the Kendall tau (rank correlation) statistic. RESULTS: Two hundred ninety-nine patients met inclusion criteria. The overall survival rate was 54% (175 of 299 patients) at a mean follow-up of 31 ± 1.9 months (range, 1-159 months). The analyses demonstrated a markedly worse prognosis for children aged ≤ 5 years compared with older patients (5-year survival rate: 15% for children aged ≤ 5 years vs 57% for children aged ≥ 5 years; log-rank P < .00001). In addition, a graded increase in survival was observed with increasing degrees of resection (5-year survival rate: 84% for patients who underwent gross total resection vs 53% for patients who underwent subtotal resection vs 29% for patients who underwent debulking; log-rank P < .0001). Multivariate analysis indicated that not achieving gross total resection markedly worsened patient survival (subtotal resection: hazard ratio, 6.47; 95% confidence interval, 2.3-19; P = .001. debulking: hazard ratio, 9.27; 95% confidence interval, 3.2-27; P < .0001). CONCLUSIONS: The current findings emphasize the importance of aggressive surgical resection in the treatment of pineoblastoma. In addition, the authors conclude that clinical trials should not mix young patients with older patients or patients who undergo subtotal resection with patients who undergo gross total resection, because such heterogeneity may alter the variability of responses to treatment and reduce the likelihood of success.

Intracranial hemangiopericytoma: clinical experience and treatment considerations in a modern series of 40 adult patients.

INTRODUCTION: Intracranial hemangiopericytoma (HPC) is a malignant meningothelial tumor. Because of its rarity, few guidelines exist for optimal management. METHODS: University of California at San Francisco patients managed for intracranial HPC were compiled into a single database based on a retrospective review of patient records. Univariate and multivariate regression was performed to determine factors that independently predicted treatment outcomes. RESULTS: A total of 40 patients with intracranial HPC were treated from 1989 to 2010. Treatment and follow-up information was available for analysis on 35 patients. The median survival for all patients was 16.2 years after date of diagnosis, with 1-year, 5-year, and 10-year survival rates of 100%, 92%, and 68%, respectively. Nineteen patients (54%) had HPC recurrence. The median time until recurrence was 5 years, with 1-year, 5-year, and 10-year progression-free survival rates of 96%, 49%, and 28%, respectively. Seven patients (20%) developed extracranial metastasis. Tumor characteristics associated with earlier recurrence included size ≥6 cm (log-rank, P < .05) and nonskull base location (log-rank, P < .05). Strategies combining adjuvant radiation with tumor resection appeared to hinder tumor progression, but had no effect on overall survival or the development of metastasis. Greater extent of resection was associated with increased overall survival (log-rank, P < .05). CONCLUSIONS: Adjuvant radiation may show promise in preventing tumor progression, but recurrence remains a common treatment outcome regardless of initial strategy. When safe and feasible, gross total resection should be pursued as an initial surgical strategy to maximize overall survival. The propensity of these tumors to metastasize makes detailed staging imaging necessary.

Stereotactic radiosurgery for benign meningiomas.

Meningiomas are the second most common primary tumor of the brain. Surgical resection is the preferred treatment for easily accessible tumors that can be safely removed. However, many tumors arise deep within the skull base making complete surgical resection difficult or impossible. Stereotactic radiosurgery is a highly effective alternative to surgical resection that has been used as a primary therapy for benign meningiomas as well as an adjuvant treatment for residual or recurrent tumors. The 5-year tumor control rates for stereotactic radiosurgery are equivalent to gross-total resection with lower morbidity than surgery, especially for skull base lesions. Additionally, adjuvant treatment of subtotally resected tumors results in tumor control rates equivalent to gross-total resection. Stereotactic radiosurgery has been used extensively for the treatment of small and medium sized skull base meningiomas. This technique has also been applied to large meningiomas and superficial tumors such as convexity and parasagittal meningiomas. However, multiple studies demonstrate that tumor control is decreased for superficial lesions and with increasing tumor size. In addition, radiation toxicity increases with increasing tumor size and superficial location. Based on a thorough review of the literature, stereotactic radiosurgery should be considered the primary treatment for skull base meningiomas with high surgical risk and in cases of superficial meningiomas where surgery is contraindicated.

Endocrinologic, neurologic, and visual morbidity after treatment for craniopharyngioma.

Craniopharyngiomas are locally aggressive tumors which typically are focused in the sellar and suprasellar region near a number of critical neural and vascular structures mediating endocrinologic, behavioral, and visual functions. The present study aims to summarize and compare the published literature regarding morbidity resulting from treatment of craniopharyngioma. We performed a comprehensive search of the published English language literature to identify studies publishing outcome data of patients undergoing surgery for craniopharyngioma. Comparisons of the rates of endocrine, vascular, neurological, and visual complications were performed using Pearson's chi-squared test, and covariates of interest were fitted into a multivariate logistic regression model. In our data set, 540 patients underwent surgical resection of their tumor. 138 patients received biopsy alone followed by some form of radiotherapy. Mean overall follow-up for all patients in these studies was 54 ± 1.8 months. The overall rate of new endocrinopathy for all patients undergoing surgical resection of their mass was 37% (95% CI = 33-41). Patients receiving GTR had over 2.5 times the rate of developing at least one endocrinopathy compared to patients receiving STR alone or STR + XRT (52 vs. 19 vs. 20%, χ(2) P < 0.00001). On multivariate analysis, GTR conferred a significant increase in the risk of endocrinopathy compared to STR + XRT (OR = 3.45, 95% CI = 2.05-5.81, P < 0.00001), after controlling for study size and the presence of significant hypothalamic involvement. There was a statistical trend towards worse visual outcomes in patients receiving XRT after STR compared to GTR or STR alone (GTR = 3.5% vs. STR 2.1% vs. STR + XRT 6.4%, P = 0.11). Given the difficulty in obtaining class 1 data regarding the treatment of this tumor, this study can serve as an estimate of expected outcomes for these patients, and guide decision making until these data are available.

Physics strategies for sparing neural stem cells during whole-brain radiation treatments.

PURPOSE: Currently, there are no successful long-term treatments or preventive strategies for radiation-induced cognitive impairments, and only a few possibilities have been suggested. One such approach involves reducing the dose to neural stem cell compartments (within and outside of the hippocampus) during whole-brain radiation treatments for brain metastases. This study investigates the fundamental physics issues associated with the sparing of neural stem cells during photon radiotherapy for brain metastases. METHODS: Several factors influence the stem cell dose: intracranial scattering, collimator leakage, beam energy, and total number of beams. The relative importance of these factors is investigated through a set of radiation therapy plans, which are all variations of an initial 6 MV intensity-modulated radiation therapy (IMRT) plan designed to simultaneously deliver a whole-brain dose of 30 Gy and maximally reduce stem cell compartment dose. Additionally, an in-house leaf segmentation algorithm was developed that utilizes jaw motion to minimize the collimator leakage. RESULTS: The plans are all normalized such that 50% of the PTV receives 30 Gy. For the initial 6 MV IMRT plan, 50% of the stem cells receive a dose greater than 6.3 Gy. Calculations indicate that 3.6 Gy of this dose originates from intracranial scattering. The jaw-tracking segmentation algorithm, used in conjunction with direct machine parameter optimization, reduces the 50% stem cell dose to 4.3 and 3.7 Gy for 6 and 10 MV treatment beams, respectively. CONCLUSIONS: Intracranial scattering alone is responsible for a large dose contribution to the stem cell compartment. It is, therefore, important to minimize other contributing factors, particularly the collimator leakage, to maximally reduce dose to these critical structures. The use of collimator jaw tracking in conjunction with modern collimators can minimize this leakage.

Treatment planning system and beam data validation for the ZAP-X: A novel self-shielded stereotactic radiosurgery system.

PURPOSE: To evaluate the treatment planning system (TPS) performance of the ZAP-X stereotactic radiosurgery (SRS) system through nondosimetric, dosimetric, and end-to-end (E2E) tests. METHODS: A comprehensive set of TPS commissioning and validation tests was developed using published guidelines. Nondosimetric validation tests included information transfer, computed tomography-magnetic resonance (CT-MR) image registration, structure/contouring, geometry, dose tools, and CT density. Dosimetric validation included comparisons between TPS and water tank/Solid Water measurements for various geometries and beam arrangements and end-to-end (E2E) tests. Patient-specific quality assurance was performed with an ion chamber in the Lucy phantom and with Gafchromic EBT3 film in the CyberKnife head phantom. RadCalc was used for independent verification of monitor units. Additional E2E tests were performed using the RPC Gamma Knife thermoluminescent dosimeter (TLD) phantom, MD Anderson SRS head phantom, and PseudoPatient gel phantom for independent absolute dose verification. RESULTS: CT-MR image registrations with known translational and rotational offsets were within tolerance (<0.5 × maximum voxel dimension). Slice thickness and distance accuracy were within 0.1 mm, and volume accuracy was within 0 to 0.11 cm3 . Treatment planning system volume measurement uncertainty was within 0.1 to 0.4 cm3 . Ion chamber point-dose measurements for a single beam in a water phantom agreed to TPS-calculated values within ±4% for collimator diameters 10 to 25 mm, and ±6% for 7.5 mm, for all measured depths (7, 50, 100, 150, and 200 mm). In homogeneous Solid Water, point-dose measurements agreed to within ±4% for cones sizes 7.5 to 25 mm. With 1-cm high/low density inserts, measurements were within ±4.2% for cone sizes 10 to 25 mm. Film-based E2E using 4/5-mm cones resulted in a gamma passing rate (%GP) of 99.8% (2%/1.5 mm). Point-dose measurements in a Lucy phantom with an ion chamber using 36 beams distributed along three noncoplanar arcs agreed to within ±4% for cone sizes 10 to 25 mm. The RPC Gamma Knife TLD phantom yielded passing results with a measured-to-expected TLD dose ratio of 1.02. The MD Anderson SRS head phantom yielded passing results, with 4% TLD agreement and %GP of 95%/93% (5%/3 mm) for coronal/sagittal film planes. The RTsafe gel phantom gave %GP of >95% (5%/2 mm) for all four targets. For our first 58 patients, film-based patient-specific quality assurance has resulted in an average %GP of 98.7% (range, 94-100%) at 2%/2 mm. CONCLUSIONS: Core ZAP-X features were found to be functional. On the basis of our results, point-dose and planar measurements were in agreement with TPS calculations using multiple phantoms and setup geometries, validating the ZAP-X TPS beam model for clinical use.

Small-field beam data acquisition, detector dependency, and film-based validation for a novel self-shielded stereotactic radiosurgery system.

PURPOSE: This study reports a single-institution experience with beam data acquisition and film-based validation for a novel self-shielded sterotactic radiosurgery unit and investigates detector dependency on field output factors (OFs), off-axis ratios (OARs), and percent depth dose (PDD) measurements within the context of small-field dosimetry. METHODS: The delivery platform for this unit consists of a 2.7-MV S-band linear accelerator mounted on coupled gimbals that rotate around a common isocenter (source-to-axis distance [SAD] = 450 mm), allowing for more than 260 noncoplanar beam angles. Beam collimation is achieved via a tungsten collimator wheel with eight circular apertures ranging from 4 mm to 25 mm in diameter. Three diodes (PTW 60012 Diode E, PTW 60018 SRS Diode, and Sun Nuclear EDGE) and a synthetic diamond detector (PTW 60019 micro Diamond [µD] detector) were used for OAR, PDD, and OF measurements. OFs were also acquired with a PTW 31022 PinPoint ionization chamber. Beam scanning was performed using a 3D water tank at depths of 7, 50, 100, 200, and 250 mm with a source-to-surface distance of 450 mm. OFs were measured at the depth of maximum dose (dmax  = 7 mm) with the SAD at 450 mm. Gafchromic EBT3 film was used to validate OF and profile measurements and as a reference detector for estimating correction factors for active detector OFs. Deviations in field size, penumbra, and PDDs across the different detectors were quantified. RESULTS: Relative OFs (ROFs) for the diodes were within 1.4% for all collimators except for 5 and 7.5 mm, for which SRS Diode measurements were higher by 1.6% and 2.6% versus Diode E. The µD ROFs were within 1.4% of the diode measurements. PinPoint ROFs were lower by >10% for the 4-mm and 5-mm collimators versus the Diode E and µD. Corrections to OFs using EBT3 film as a reference were within 1.2% for all diodes and the µD detector for collimators 10 mm and greater and within 2.0%, 2.8%, and 1.1% for the 7.5-, 5-, and 4-mm collimators, respectively. The maximum difference in full width at half maximum (FWHM) between the Diode E and the other active detectors was for the 25-mm collimator and was 0.09 mm (µD), 0.16 mm (SRS Diode), and 0.65 mm (EDGE). Differences seen in PDDs beyond the depth of dmax were <1% across the three diodes and the µD. FWHM and penumbra measurements made using EBT3 film were within 1.34% and 3.26%, respectively, of the processed profile data entered into the treatment planning system. CONCLUSIONS: Minimal differences were seen in OAR and PDD measurements acquired with the diodes and the µD. ROFs measured with the three diodes were within 2.6% and within 1.4% versus the µD. Gafchromic Film measurements provided independent verification of the OAR and OF measurements. Estimated corrections to OFs using film as a reference were <1.6% for the Diode E, EDGE, and µD detector.

Craniopharyngioma: a comparison of tumor control with various treatment strategies.

OBJECT: Craniopharyngiomas have a propensity to recur after resection, potentially causing death through their aggressive local behavior in their critical site of origin. Recent data suggest that subtotal resection (STR) followed by adjuvant radiotherapy (XRT) may be an appealing substitute for gross-total resection (GTR), providing similar rates of tumor control without the morbidity associated with aggressive resection. Here, the authors summarize the published literature regarding rates of tumor control with various treatment modalities for craniopharyngiomas. METHODS: The authors performed a comprehensive search of the English language literature to identify studies publishing outcome data on patients undergoing surgery for craniopharyngioma. Rates of progression-free survival (PFS) and overall survival (OS) were determined through Kaplan-Meier analysis. RESULTS: There were 442 patients who underwent tumor resection. Among these patients, GTR was achieved in 256 cases (58%), STR in 101 cases (23%), and STR+XRT in 85 cases (19%). The 2- and 5-year PFS rates for the GTR group versus the STR+XRT group were 88 versus 91%, and 67 versus 69%, respectively. The 5- and 10-year OS rates for the GTR group versus the STR+XRT group were 98 versus 99%, and 98 versus 95%, respectively. There was no significant difference in PFS (log-rank test) or OS with GTR (log-rank test). CONCLUSIONS: Given the relative rarity of craniopharyngioma, this study provides estimates of outcome for a variety of treatment combinations, as not all treatments are an option for all patients with these tumors.

Phase 2 Study of a Temozolomide-Based Chemoradiation Therapy Regimen for High-Risk, Low-Grade Gliomas: Long-Term Results of Radiation Therapy Oncology Group 0424.

PURPOSE: To report the long-term outcomes of the RTOG 0424 study of a high-risk, low-grade glioma population treated with concurrent and adjuvant temozolomide (TMZ) and radiation therapy (RT). METHODS AND MATERIALS: For this single-arm, phase 2 study, patients with low-grade gliomas with ≥3 risk factors (age ≥40 years, astrocytoma, bihemispheric tumor, size ≥6 cm, or preoperative neurologic function status >1) received RT (54 Gy in 30 fractions) with TMZ and up to 12 cycles of post-RT TMZ. The initial primary endpoint P was overall survival (OS) at 3 years after registration. Secondary endpoints included progression-free survival (PFS) and the association of survival outcomes with methylation status. The initial 3-year report of this study was published in 2015. RESULTS: The study accrued 136 patients, of whom 129 were analyzable. The median follow-up for surviving patients was 9.0 years. The 3-year OS was 73.5% (95% confidence interval, 65.8%-81.1%), numerically superior to the 3-year OS historical control of 54% (P < .001). The median survival time was 8.2 years (95% confidence interval, 5.6-9.1). Five- and 10-year OS rates were 60.9% and 34.6%, respectively, and 5- and 10-year PFS rates were 46.8% and 25.5%, respectively. CONCLUSIONS: The long-term results confirmed the findings from the initial report for efficacy, suggesting OS and PFS outcomes with the RT-TMZ regimen exceeded historical control groups treated with radiation alone. Toxicity was acceptable.