Exceptional and Sustained Response to Belzutifan in Von Hippel-Lindau Disease-Associated Central Nervous System Hemangioblastoma.

Von Hippiel-Lindau (VHL) disease is a rare genetic disorder characterized by a variety of benign and malignant neoplastic growths arising in multiple different organ systems. About 60%-84% of patients develop hemangioblastomas, benign tumors comprised of newly formed blood vessels that often occur in the central nervous system (CNS) and retinas. Treatment options for this disease were limited before the Food and Drug Administration (FDA) approval of belzutifan, a HIF2α inhibitor. We present a case of a 25-year-old woman with VHL who underwent treatment with belzutifan over 18 months. It was noted that her CNS lesions decreased significantly in size over the course of her treatment, and she had minimal adverse effects. Her excellent and sustained therapeutic response to the treatment highlights the real-world clinical benefit of belzutifan and the possibility that this could play a crucial role in treating VHL by postponing or completely avoiding repeated surgical and radiotherapeutic intervention and their associated comorbidities.

Advancing the Role of Proton Therapy for Spine Metastases Through Diagnostic Scan-Based Planning.

Purpose: Many patients with metastatic cancer live years beyond diagnosis, and there remains a need to improve the therapeutic ratio of metastasis-directed radiation for these patients. This study aimed to assess a process for delivering cost-effective palliative proton therapy to the spine using diagnostic scan-based planning (DSBP) and prefabricated treatment delivery devices. Materials and Methods: We designed and characterized a reusable proton aperture system that adjusts to multiple lengths for spine treatment. Next, we retrospectively identified 10 patients scan treated with thoracic proton therapy who also had a diagnostic computed tomography within 4 months of simulation. We contoured a T6-T9 target volume on both the diagnostic scans (DS) and simulation scans (SS). Using the aperture system, we generated proton plans on the DS using a posterior-anterior beam with no custom range compensator to treat T6-T9 to 8 Gy × 1. Plans were transferred to the SS to compare coverage and normal tissue doses, followed by robustness analysis. Finally, we compared normal tissue doses and costs between proton and photon plans. Results were compared using the Wilcoxon signed-rank test. Results: Median D95% on the DS plans was 101% (range, 100%-102%) of the prescription dose. Median Dmax was 107% (range, 105%-108%). When transferred to SS, coverage and hot spots remained acceptable for all cases. Heart and esophagus doses did not vary between the DS and SS proton plans (P >.2). Robustness analysis with 5 mm X/Y/Z shifts showed acceptable coverage (D95% > 98%) for all cases. Compared with the proton plans, the mean heart dose was higher for both anterior-posterior/posterior-anterior and volumetric modulated arc therapy plans (P < .01). Cost for proton DSBP was comparable to more commonly used photon regimens. Conclusion: Proton DSBP is technically feasible and robust, with superior sparing of the heart compared with photons. Eliminating simulation and custom devices increases the value of this approach in carefully selected patients.

Evaluating Carbon Footprint of Proton Therapy Based on Power Consumption and Possible Mitigation Strategies.

PURPOSE: There is increasing concern about rising carbon dioxide (CO2) emissions and their hazardous effect on human health. This study quantifies the energy utilization of proton therapy, assesses the corresponding carbon footprint, and discusses possible offsetting strategies toward carbon-neutral health care operations. METHODS AND MATERIALS: Patients treated between July 2020 and June 2021 using the Mevion proton system were evaluated. Current measurements were converted to kilowatts of power consumption. Patients were reviewed for disease, dose, number of fractions, and duration of beam. The Environmental Protection Agency calculator was used to convert power consumption to tons of CO2 equivalent (CO2e) for scope-based carbon footprint accounting. RESULTS: There were 185 patients treated and a total of 5176 fractions delivered (average, 28). Power consumption was 55.8 kW in standby/night mode and 64.4 kW during BeamOn, for an annual total of 490 MWh. BeamOn time was 149.6 hours, and BeamOn consumption accounted for 2% of the machine total. Power consumption was 52 kWh per patient (breast, highest at 140 kWh; prostate, lowest at 28 kWh). Annual power consumption of the administrative areas was approximately 96 MWh, for a program total of 586 MWh. The carbon footprint for BeamOn time was 4.17 metric tons of CO2e, or 23 kg per patient course (breast cancer, 60 kg; prostate, 12 kg). The annual carbon footprint for the machine was 212.2 tons CO2e, and for the proton program, 253.7 tons CO2e, with an attributed footprint of 1372 kg CO2e per patient. The corresponding CO2e offset for the program could be 4192 new trees planted and grown for 10 years (23 trees per patient). CONCLUSIONS: The carbon footprint varied by disease treated. On average, the carbon footprint was 23 kg of CO2e per patient and 253.7 tons of CO2e for the proton program. There are a number of reduction, mitigation, and offset strategies possible for radiation oncologists that should be explored, such as waste minimization, less treatment commuting, efficient energy use, and renewable electricity power use.

Operational Performance of a Compact Proton Therapy System: A 5-Year Experience.

Purpose: We present an analysis of various operational metrics for a novel compact proton therapy system, including clinical case mix, subsystems utilization, and quality assurance trends in beam delivery parameters over a period of 5 years. Materials and Methods: Patient-specific data from a total of 850 patients (25,567 fractions) have been collected and analyzed. The patient mix include a variety of simple, intermediate, and complex cases. Beam-specific delivery parameters for a total of 3585 beams were analyzed. In-room imaging system usage for off-line adaptive purpose is reported. We also report key machine performances metrics based on routine quality assurance in addition to uptime. Results: Our analysis shows that system subcomponents including gantry and patient positioning system have maintained a tight mechanical tolerance over the 5-year period. Various beam parameters were all within acceptable tolerances with no clear trends. Utilization frequency histograms of gantry and patient positioning system show that only a small fraction of all available angles was used for patient deliveries with cardinal angels as the most usable. Similarly, beam-specific metrics, such as range, modulation, and air gaps, were clustered unevenly over the available range indicating that this compact system was more than capable to treat the complex variety of tumors of our patient mix. Conclusion: Our data show that this compact system is versatile, robust, and capable of delivering complex treatments like a large full-gantry system. Utilization data show that a fraction of all subcomponents range of angular motion has been used. Compilation of beam-specific metrics, such as range and modulation, show uneven distributions with specific clustering over the entire usable range. Our findings could be used to further optimize the performance and cost-effectiveness of future compact proton systems.

Management of Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases: ASCO Guideline Update.

PURPOSE: To provide updated evidence- and consensus-based guideline recommendations to practicing oncologists and others on the management of brain metastases for patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer up to 2021. METHODS: An Expert Panel conducted a targeted systematic literature review (for both systemic therapy for non-CNS metastases and for CNS metastases of HER2+ guideline updates) that identified 545 articles. Outcomes of interest included overall survival, progression-free survival, and adverse events. RESULTS: Of the 545 publications identified and reviewed, six on systemic therapy were identified to form the evidentiary basis for the systemic therapy for CNS metastases guideline recommendations. RECOMMENDATIONS: Patients with brain metastases should receive appropriate local therapy and systemic therapy, if indicated. Local therapies include surgery, whole-brain radiotherapy, and stereotactic radiosurgery. Memantine and hippocampal avoidance should be added to whole-brain radiotherapy when possible. Treatments depend on factors such as patient prognosis, presence of symptoms, resectability, number and size of metastases, prior therapy, and whether metastases are diffuse. Other options include systemic therapy, best supportive care, enrollment onto a clinical trial, and/or palliative care. There are insufficient data to recommend for or against performing routine magnetic resonance imaging to screen for brain metastases; clinicians should have a low threshold for magnetic resonance imaging of the brain because of the high incidence of brain metastases among patients with HER2-positive advanced breast cancer.Additional information is available at www.asco.org/breast-cancer-guidelines.

Systemic Therapy for Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: ASCO Guideline Update.

PURPOSE: To update evidence-based guideline recommendations to practicing oncologists and others on systemic therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. METHODS: An Expert Panel conducted a targeted systematic literature review (for both systemic treatment and CNS metastases) and identified 545 articles. Outcomes of interest included efficacy and safety. RESULTS: Of the 545 publications identified and reviewed, 14 were identified to form the evidentiary basis for the guideline recommendations. RECOMMENDATIONS: HER2-targeted therapy is recommended for patients with HER2-positive advanced breast cancer, except for those with clinical congestive heart failure or significantly compromised left ventricular ejection fraction, who should be evaluated on a case-by-case basis. Trastuzumab, pertuzumab, and taxane for first-line treatment and trastuzumab deruxtecan for second-line treatment are recommended. In the third-line setting, clinicians should offer other HER2-targeted therapy combinations. There is a lack of head-to-head trials; therefore, there is insufficient evidence to recommend one regimen over another. The patient and the clinician should discuss differences in treatment schedule, route, toxicities, etc during the decision-making process. Options include regimens with tucatinib, trastuzumab emtansine, trastuzumab deruxtecan (if either not previously administered), neratinib, lapatinib, chemotherapy, margetuximab, hormonal therapy, and abemaciclib plus trastuzumab plus fulvestrant, and may offer pertuzumab if the patient has not previously received it. Optimal duration of chemotherapy is at least 4-6 months or until maximum response, depending on toxicity and in the absence of progression. HER2-targeted therapy can continue until time of progression or unacceptable toxicities. For patients with HER2-positive and estrogen receptor-positive or progesterone receptor-positive breast cancer, clinicians may recommend either standard first-line therapy or, for selected patients, endocrine therapy plus HER2-targeted therapy or endocrine therapy alone.Additional information is available at www.asco.org/breast-cancer-guidelines.

Intrafraction motion during frameless radiosurgery using Varian HyperArcTM and BrainLab ElementsTM immobilization systems.

Commercial systems such as Varian HyperArcTM and BrainLab Elements MultiMetTM have been developed that allow radiosurgery treatment of multiple brain metastases using a single isocenter. Each software package places increased demands on frameless immobilization and requires the use of a specific immobilization system: the QFix-Encompass system for Varian and the BrainLab frameless-mask system for BrainLab. At our institution, patients receiving traditional radiosurgery (one isocenter per target lesion) were treated using both immobilization systems. Intrafraction motion was determined for each patient using multiple cone-beam CT scans and the same image-registration software during treatment. There were no statistically-significant differences in mean absolute translational shifts between the two mask systems, with a mean 3D-vector motion of approximately 0.43 mm for both systems. There were also no statistically-significant differences in the mean absolute rotational shifts between the two mask systems. Although the average residual errors were insignificant between the mask systems, special attention should be paid to individual maximum shifts with both systems. Large maximum rotational misalignments could present significant misalignment of lesions as distance increases from the isocenter. Finally, large maximum shifts highlight the need for real-time monitoring of patient movement during radiosurgery of multiple lesions using a single isocenter.

Technical Report: Diagnostic Scan-Based Planning (DSBP), A Method to Improve the Speed and Safety of Radiation Therapy for the Treatment of Critically Ill Patients.

PURPOSE: Treating critically ill patients in radiation oncology departments poses multiple safety risks. This study describes a method to improve the speed of radiation treatment for patients in the intensive care unit by eliminating the need for computed tomography (CT) simulation or on-table treatment planning using patients' previously acquired diagnostic CT scans. METHODS AND MATERIALS: Initially, a retrospective planning study was performed to assess the applicability and safety of diagnostic scan-based planning (DSBP) for 3 typical indications for radiation therapy in patients in the intensive care unit: heterotopic ossification (10), spine metastases (cord compression; 10), and obstructive lung lesions (5). After identification of an appropriate diagnostic CT scan, treatment planning was performed using the diagnostic scan data set. These treatment plans were then transferred to the patients' simulation scans, and a dosimetric comparison was performed between the 2 sets of plans. Additionally, a time study of the first 10 patients treated with DSBP in our department was performed. RESULTS: The retrospective analysis demonstrated that DSBP resulted in treatment plans that, when transferred to the CT simulation data sets, provided excellent target coverage, a median D95% of 96% (range, 86%-100%) of the prescription dose with acceptable hot spots, and a median Dmax108% (range, 102%-113%). Subsequently, DSBP has been used for 10 critically ill patients. The patients were treated without CT simulation, and the median time between patient check-in to the department and completion of radiation therapy was 28 minutes (range, 18-47 minutes.) CONCLUSIONS: This study demonstrates that it is possible to safely use DSBP for the treatment of critically ill patients. This method has the potential to simplify the treatment process and improve the speed and safety of treatment.

An optimized approach for robust spot placement in proton pencil beam scanning.

Maintaining a sharp lateral dose falloff in pencil beam scanning (PBS) proton therapy is crucial for sparing organs at risk (OARs), especially when they are in close proximity to the target volume. The most common approach to improve lateral dose falloff is through the use of physical beam shaping devices, such as brass apertures or collimator based systems. A recently proposed approach focuses on proton beam spot placements, moving away from traditional grid-based placements to concentric-contours based schemes. This improves lateral dose falloff in two ways: (1) by better conforming all spots to the tumor boundary and (2) allowing for 'edge enhancement', where boundary spots deliver higher fluence than more central spots, thereby creating a steeper lateral dose falloff. However, these benefits come at the expense of maintaining uniformity of spot distribution inside the target volume. In this work we have developed a new optimized spot placement scheme that provides robust spot distributions inside the target. This approach achieves the boundary conformity of a concentric-contours based approach and uses a fast-iterative method to distribute the interior spots in a highly uniform fashion in an attempt to improve both the lateral dose falloff and uniformity. Furthermore, we quantified the impact of this new approach through direct comparison with grid, contour, and hybrid spot placements schemes, showing improvements for this new approach. The results were validated in homogeneous medium for two different target shapes having concave and convex geometry.

Patterns of proton therapy use in pediatric cancer management in 2016: An international survey.

PURPOSE: To facilitate the initiation of observational studies on late effects of proton therapy in pediatric patients, we report on current patterns of proton therapy use worldwide in patients aged less than 22 years. MATERIALS & METHODS: Fifty-four proton centers treating pediatric patients in 2016 in 11 countries were invited to respond to a survey about the number of patients treated during that year by age group, intent of treatment, delivery technique and tumor types. RESULTS: Among the 40 participating centers (participation rate: 74%), a total of 1,860 patients were treated in 2016 (North America: 1205, Europe: 432, Asia: 223). The numbers of patients per center ranged from 1 to 206 (median: 29). Twenty-four percent of the patients were <5 years of age, and 50% <10 years. More than 30 pediatric tumor types were identified, mainly treated with curative intent: 48% were CNS, 25% extra-cranial sarcomas, 7% neuroblastoma, and 5% hematopoietic tumors. About half of the patients were treated with pencil beam scanning. Treatment patterns were broadly similar across the three continents. CONCLUSION: To our knowledge, this survey provides the first worldwide assessment of proton therapy use for pediatric cancer management. Since previous estimates in the United States and Europe, CNS tumors remain the cancer types most commonly treated with protons in 2016. However, the proportion of extra-cranial tumors is growing worldwide. The typically low numbers of patients treated in each center indicate the need for international research collaborations to assess long-term outcomes of proton therapy in pediatric patients.

Systemic Therapy for Patients With Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: ASCO Clinical Practice Guideline Update.

Purpose To update evidence-based guideline recommendations for practicing oncologists and others on systemic therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer to 2018. Methods An Expert Panel conducted a targeted systematic literature review (for both systemic treatment and CNS metastases) and identified 622 articles. Outcomes of interest included overall survival, progression-free survival, and adverse events. Results Of the 622 publications identified and reviewed, no additional evidence was identified that would warrant a change to the 2014 recommendations. Recommendations HER2-targeted therapy is recommended for patients with HER2-positive advanced breast cancer, except for those with clinical congestive heart failure or significantly compromised left ventricular ejection fraction, who should be evaluated on a case-by-case basis. Trastuzumab, pertuzumab, and taxane for first-line treatment and trastuzumab emtansine for second-line treatment are recommended. In the third-line setting, clinicians should offer other HER2-targeted therapy combinations or trastuzumab emtansine (if not previously administered) and may offer pertuzumab if the patient has not previously received it. Optimal duration of chemotherapy is at least 4 to 6 months or until maximum response, depending on toxicity and in the absence of progression. HER2-targeted therapy can continue until time of progression or unacceptable toxicities. For patients with HER2-positive and estrogen receptor-positive/progesterone receptor-positive breast cancer, clinicians may recommend either standard first-line therapy or, for selected patients, endocrine therapy plus HER2-targeted therapy or endocrine therapy alone. Additional information is available at www.asco.org/breast-cancer-guidelines .

Recommendations on Disease Management for Patients With Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases: ASCO Clinical Practice Guideline Update.

Purpose To update the formal expert consensus-based guideline recommendations for practicing oncologists and others on the management of brain metastases for patients with human epidermal growth factor receptor 2-positive advanced breast cancer to 2018. Methods An Expert Panel conducted a targeted systematic literature review (for both systemic treatment and CNS metastases) and identified 622 articles. Outcomes of interest included overall survival, progression-free survival, and adverse events. In 2014, the American Society of Clinical Oncology (ASCO) convened a panel of medical oncology, radiation oncology, guideline implementation, and advocacy experts, and conducted a systematic review of the literature. When that failed to yield sufficiently strong quality evidence, the Expert Panel undertook a formal expert consensus-based process to produce these recommendations. ASCO used a modified Delphi process. The panel members drafted recommendations, and a group of other experts joined them for two rounds of formal ratings of the recommendations. Results Of the 622 publications identified and reviewed, no additional evidence was identified that would warrant a change to the 2014 recommendations. Recommendations Patients with brain metastases should receive appropriate local therapy and systemic therapy, if indicated. Local therapies include surgery, whole-brain radiotherapy, and stereotactic radiosurgery. Treatments depend on factors such as patient prognosis, presence of symptoms, resectability, number and size of metastases, prior therapy, and whether metastases are diffuse. Other options include systemic therapy, best supportive care, enrollment in a clinical trial, and/or palliative care. Clinicians should not perform routine magnetic resonance imaging to screen for brain metastases, but rather should have a low threshold for magnetic resonance imaging of the brain because of the high incidence of brain metastases among patients with HER2-positive advanced breast cancer. Additional information is available at www.asco.org/breast-cancer-guidelines .

Effectiveness of base-of-skull immobilization system in a compact proton therapy setting.

PURPOSE: The purpose of this study was to investigate daily repositioning accuracy by analyzing inter- and intra-fractional uncertainties associated with patients treated for intracranial or base of skull tumors in a compact proton therapy system with 6 degrees of freedom (DOF) robotic couch and a thermoplastic head mask indexed to a base of skull (BoS) frame. MATERIALS AND METHODS: Daily orthogonal kV alignment images at setup position before and after daily treatments were analyzed for 33 patients. The system was composed of a new type of thermoplastic mask, a bite block, and carbon-fiber BoS couch-top insert specifically designed for proton therapy treatments. The correctional shifts in robotic treatment table with 6 DOF were evaluated and recorded based on over 1500 planar kV image pairs. Correctional shifts for patients with and without bite blocks were compared. RESULTS: Systematic and random errors were evaluated for all 6 DOF coordinates available for daily vector corrections. Uncertainties associated with geometrical errors and their sources, in addition to robustness analysis of various combinations of immobilization components were presented. CONCLUSIONS: Analysis of 644 fractions including patients with and without a bite block shows that the BoS immobilization system is capable of maintaining intra-fraction localization with submillimeter accuracy (in nearly 83%, 86%, 95% of cases along SI, LAT, and PA, respectively) in translational coordinates and subdegree precision (in 98.85%, 98.85%, and 96.4% of cases for roll, pitch, and yaw respectively) in rotational coordinates. The system overall fares better in intra-fraction localization precision compared to previously reported particle therapy immobilization systems. The use of a mask-attached type bite block has marginal impact on inter- or intra-fraction uncertainties compared to no bite block.

Commissioning an in-room mobile CT for adaptive proton therapy with a compact proton system.

PURPOSE: To describe the commissioning of AIRO mobile CT system (AIRO) for adaptive proton therapy on a compact double scattering proton therapy system. METHODS: A Gammex phantom was scanned with varying plug patterns, table heights, and mAs on a CT simulator (CT Sim) and on the AIRO. AIRO-specific CT-stopping power ratio (SPR) curves were created with a commonly used stoichiometric method using the Gammex phantom. A RANDO anthropomorphic thorax, pelvis, and head phantom, and a CIRS thorax and head phantom were scanned on the CT Sim and AIRO. Clinically realistic treatment plans and nonclinical plans were generated on the CT Sim images and subsequently copied onto the AIRO CT scans for dose recalculation and comparison for various AIRO SPR curves. Gamma analysis was used to evaluate dosimetric deviation between both plans. RESULTS: AIRO CT values skewed toward solid water when plugs were scanned surrounded by other plugs in phantom. Low-density materials demonstrated largest differences. Dose calculated on AIRO CT scans with stoichiometric-based SPR curves produced over-ranged proton beams when large volumes of low-density material were in the path of the beam. To create equivalent dose distributions on both data sets, the AIRO SPR curve's low-density data points were iteratively adjusted to yield better proton beam range agreement based on isodose lines. Comparison of the stoichiometric-based AIRO SPR curve and the "dose-adjusted" SPR curve showed slight improvement on gamma analysis between the treatment plan and the AIRO plan for single-field plans at the 1%, 1 mm level, but did not affect clinical plans indicating that HU number differences between the CT Sim and AIRO did not affect dose calculations for robust clinical beam arrangements. CONCLUSION: Based on this study, we believe the AIRO can be used offline for adaptive proton therapy on a compact double scattering proton therapy system.

The Mobius AIRO mobile CT for image-guided proton therapy: Characterization & commissioning.

PURPOSE: The purpose of this study was to characterize the Mobius AIRO Mobile CT System for localization and image-guided proton therapy. This is the first known application of the AIRO for proton therapy. METHODS: Five CT images of a Catphan® 504 phantom were acquired on the AIRO Mobile CT System, Varian EDGE radiosurgery system cone beam CT (CBCT), Philips Brilliance Big Bore 16 slice CT simulator, and Siemens SOMATOM Definition AS 20 slice CT simulator. DoseLAB software v.6.6 was utilized for image quality analysis. Modulation transfer function, scaling discrepancy, geometric distortion, spatial resolution, overall uniformity, minimum uniformity, contrast, high CNR, and maximum HU deviation were acquired. Low CNR was acquired manually using the CTP515 module. Localization accuracy and CT Dose Index were measured and compared to reported values on each imaging device. For treatment delivery systems (Edge and Mevion), the localization accuracy of the 3D imaging systems were compared to 2D imaging systems on each system. RESULTS: The AIRO spatial resolution was 0.21 lp mm-1 compared with 0.40 lp mm-1 for the Philips CT Simulator, 0.37 lp mm-1 for the Edge CBCT, and 0.35 lp mm-1 for the Siemens CT Simulator. AIRO/Siemens and AIRO/Philips differences exceeded 100% for scaling discrepancy (191.2% and 145.8%). The AIRO exhibited higher dose (>27 mGy) than the Philips CT Simulator. Localization accuracy (based on the MIMI phantom) was 0.6° and 0.5 mm. Localization accuracy (based on Stereophan) demonstrated maximum AIRO-kV/kV shift differences of 0.1 mm in the x-direction, 0.1 mm in the y-direction, and 0.2 mm in the z-direction. CONCLUSIONS: The localization accuracy of AIRO was determined to be within 0.6° and 0.5 mm despite its slightly lower image quality overall compared to other CT imaging systems at our institution. Based on our study, the Mobile AIRO CT system can be utilized accurately and reliably for image-guided proton therapy.

Blinded Validation of Breath Biomarkers of Lung Cancer, a Potential Ancillary to Chest CT Screening.

BACKGROUND: Breath volatile organic compounds (VOCs) have been reported as biomarkers of lung cancer, but it is not known if biomarkers identified in one group can identify disease in a separate independent cohort. Also, it is not known if combining breath biomarkers with chest CT has the potential to improve the sensitivity and specificity of lung cancer screening. METHODS: Model-building phase (unblinded): Breath VOCs were analyzed with gas chromatography mass spectrometry in 82 asymptomatic smokers having screening chest CT, 84 symptomatic high-risk subjects with a tissue diagnosis, 100 without a tissue diagnosis, and 35 healthy subjects. Multiple Monte Carlo simulations identified breath VOC mass ions with greater than random diagnostic accuracy for lung cancer, and these were combined in a multivariate predictive algorithm. Model-testing phase (blinded validation): We analyzed breath VOCs in an independent cohort of similar subjects (n = 70, 51, 75 and 19 respectively). The algorithm predicted discriminant function (DF) values in blinded replicate breath VOC samples analyzed independently at two laboratories (A and B). Outcome modeling: We modeled the expected effects of combining breath biomarkers with chest CT on the sensitivity and specificity of lung cancer screening. RESULTS: Unblinded model-building phase. The algorithm identified lung cancer with sensitivity 74.0%, specificity 70.7% and C-statistic 0.78. Blinded model-testing phase: The algorithm identified lung cancer at Laboratory A with sensitivity 68.0%, specificity 68.4%, C-statistic 0.71; and at Laboratory B with sensitivity 70.1%, specificity 68.0%, C-statistic 0.70, with linear correlation between replicates (r = 0.88). In a projected outcome model, breath biomarkers increased the sensitivity, specificity, and positive and negative predictive values of chest CT for lung cancer when the tests were combined in series or parallel. CONCLUSIONS: Breath VOC mass ion biomarkers identified lung cancer in a separate independent cohort, in a blinded replicated study. Combining breath biomarkers with chest CT could potentially improve the sensitivity and specificity of lung cancer screening. TRIAL REGISTRATION: ClinicalTrials.gov NCT00639067.

Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline.

PURPOSE: To provide evidence-based recommendations to practicing oncologists and others on systemic therapy for patients with human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer. METHODS: The American Society of Clinical Oncology convened a panel of medical oncology, radiation oncology, guideline implementation, and advocacy experts and conducted a systematic literature review from January 2009 to October 2012. Outcomes of interest included overall survival, progression-free survival (PFS), and adverse events. RESULTS: A total of 16 trials met the systematic review criteria. The CLEOPATRA trial found survival and PFS benefits for docetaxel, trastuzumab, and pertuzumab in first-line treatment, and the EMILIA trial found survival and PFS benefits for trastuzumab emtansine (T-DM1) in second-line treatment. T-DM1 also showed a third-line PFS benefit. One trial reported on duration of HER2-targeted therapy, and three others reported on endocrine therapy for patients with HER-positive advanced breast cancer. RECOMMENDATIONS: HER2-targeted therapy is recommended for patients with HER2-positive advanced breast cancer, except for those with clinical congestive heart failure or significantly compromised left ventricular ejection fraction, who should be evaluated on a case-by-case basis. Trastuzumab, pertuzumab, and taxane for first-line treatment and T-DM1 for second-line treatment are recommended. In the third-line setting, clinicians should offer other HER2-targeted therapy combinations or T-DM1 (if not previously administered) and may offer pertuzumab, if the patient has not previously received it. Optimal duration of chemotherapy is at least 4 to 6 months or until maximum response, depending on toxicity and in the absence of progression. HER2-targeted therapy can continue until time of progression or unacceptable toxicities. For patients with HER2-positive and estrogen receptor-positive/progesterone receptor-positive breast cancer, clinicians may recommend either standard first-line therapy or, for selected patients, endocrine therapy plus HER2-targeted therapy or endocrine therapy alone.

Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline.

PURPOSE: To provide formal expert consensus-based recommendations to practicing oncologists and others on the management of brain metastases for patients with human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer. METHODS: The American Society of Clinical Oncology (ASCO) convened a panel of medical oncology, radiation oncology, guideline implementation, and advocacy experts and conducted a systematic review of the literature. When that failed to yield sufficiently strong quality evidence, the Expert Panel undertook a formal expert consensus-based process to produce these recommendations. ASCO used a modified Delphi process. The panel members drafted recommendations, and a group of other experts joined them for two rounds of formal ratings of the recommendations. RESULTS: No studies or existing guidelines met the systematic review criteria; therefore, ASCO conducted a formal expert consensus-based process. RECOMMENDATIONS: Patients with brain metastases should receive appropriate local therapy and systemic therapy, if indicated. Local therapies include surgery, whole-brain radiotherapy, and stereotactic radiosurgery. Treatments depend on factors such as patient prognosis, presence of symptoms, resectability, number and size of metastases, prior therapy, and whether metastases are diffuse. Other options include systemic therapy, best supportive care, enrollment onto a clinical trial, and/or palliative care. Clinicians should not perform routine magnetic resonance imaging (MRI) to screen for brain metastases, but rather should have a low threshold for MRI of the brain because of the high incidence of brain metastases among patients with HER2-positive advanced breast cancer.