Combined clinical and research training in medical physics in a multi-institutional setting: 13-year experience of Harvard Medical Physics Residency Program.

PURPOSE: This manuscript describes the structure, management and outcomes of a multi-institutional clinical and research medical physics residency program (Harvard Medical Physics Residency Program, or HMPRP) to provide potentially useful information to the centers considering a multi-institutional approach for their training programs. METHODS: Data from the program documents and public records was used to describe HMPRP and obtain statistics about participating faculty, enrolled residents, and graduates. Challenges associated with forming and managing a multi-institutional program and developed solutions for effective coordination between several clinical centers are described. RESULTS: HMPRP was formed in 2009 and was accredited by the Commission on Accreditation of Medical Physics Education Programs (CAMPEP) in 2011. It is a 3-year therapy program, with a dedicated year of research and the 2 years of clinical training at three academic hospitals. A CAMPEP-accredited Certificate Program is embedded in HMPRP to allow enrolled residents to complete a formal didactic training in medical physics if necessary. The clinical training covers the material required by CAMPEP. In addition, training in protons, CyberKnife, MR-linac, and at network locations is included. The clinical training and academic record of the residents is outstanding. All graduates have found employment within clinical medical physics, mostly at large academic centers and graduates had a 100% pass rate at the oral American Board of Radiology exams. On average, three manuscripts per resident are published during residency, and multiple abstracts are presented at conferences. CONCLUSIONS: A multi-institutional medical physics residency program can be successfully formed and managed. With a collaborative administrative structure, the program creates an environment for high-quality clinical training of the residents and high productivity in research. The main advantage of such program is access to a wide variety of resources. The main challenge is creating a structure for efficient management of multiple resources at different locations. This report may provide valuable information to centers considering starting a multi-institutional residency program.

ß-Endorphin mediates radiation therapy fatigue.

Fatigue is a common adverse effect of external beam radiation therapy in cancer patients. Mechanisms causing radiation fatigue remain unclear, although linkage to skin irradiation has been suggested. ß-Endorphin, an endogenous opioid, is synthesized in skin following genotoxic ultraviolet irradiation and acts systemically, producing addiction. Exogenous opiates with the same receptor activity as ß-endorphin can cause fatigue. Using rodent models of radiation therapy, exposing tails and sparing vital organs, we tested whether skin-derived ß-endorphin contributes to radiation-induced fatigue. Over a 6-week radiation regimen, plasma ß-endorphin increased in rats, paralleled by opiate phenotypes (elevated pain thresholds, Straub tail) and fatigue-like behavior, which was reversed in animals treated by the opiate antagonist naloxone. Mechanistically, all these phenotypes were blocked by opiate antagonist treatment and were undetected in either ß-endorphin knockout mice or mice lacking keratinocyte p53 expression. These findings implicate skin-derived ß-endorphin in systemic effects of radiation therapy. Opioid antagonism may warrant testing in humans as treatment or prevention of radiation-induced fatigue.

Electronic intracavitary brachytherapy quality management based on risk analysis: The report of AAPM TG 182.

PURPOSE: The purpose of this study was to provide guidance on quality management for electronic brachytherapy. MATERIALS AND METHODS: The task group used the risk-assessment approach of Task Group 100 of the American Association of Physicists in Medicine. Because the quality management program for a device is intimately tied to the procedure in which it is used, the task group first designed quality interventions for intracavitary brachytherapy for both commercial electronic brachytherapy units in the setting of accelerated partial-breast irradiation. To demonstrate the methodology to extend an existing risk analysis for a different application, the task group modified the analysis for the case of post-hysterectomy, vaginal cuff irradiation for one of the devices. RESULTS: The analysis illustrated how the TG-100 methodology can lead to interventions to reduce risks and improve quality for each unit and procedure addressed. CONCLUSION: This report provides a model to guide facilities establishing a quality management program for electronic brachytherapy.

Lung cancer cell line screen links fanconi anemia/BRCA pathway defects to increased relative biological effectiveness of proton radiation.

PURPOSE: Growing knowledge of genomic heterogeneity in cancer, especially when it results in altered DNA damage responses, requires re-examination of the generic relative biological effectiveness (RBE) of 1.1 of protons. METHODS AND MATERIALS: For determination of cellular radiosensitivity, we irradiated 17 lung cancer cell lines at the mid-spread-out Bragg peak of a clinical proton beam (linear energy transfer, 2.5 keV/µm). For comparison, 250-kVp X rays and (137)Cs γ-rays were used. To estimate the RBE of protons relative to (60)Co (Co60eq), we assigned an RBE(Co60Eq) of 1.1 to X rays to correct the physical dose measured. Standard DNA repair foci assays were used to monitor damage responses. FANCD2 was depleted using RNA interference. RESULTS: Five lung cancer cell lines (29.4%) exhibited reduced clonogenic survival after proton irradiation compared with X-irradiation with the same physical doses. This was confirmed in a 3-dimensional sphere assay. Corresponding proton RBE(Co60Eq) estimates were statistically significantly different from 1.1 (P≤.05): 1.31 to 1.77 (for a survival fraction of 0.5). In 3 of these lines, increased RBE was correlated with alterations in the Fanconi anemia (FA)/BRCA pathway of DNA repair. In Calu-6 cells, the data pointed toward an FA pathway defect, leading to a previously unreported persistence of proton-induced RAD51 foci. The FA/BRCA-defective cells displayed a 25% increase in the size of subnuclear 53BP1 foci 18 hours after proton irradiation. CONCLUSIONS: Our cell line screen has revealed variations in proton RBE that are partly due to FA/BRCA pathway defects, suggesting that the use of a generic RBE for cancers should be revisited. We propose that functional biomarkers, such as size of residual 53BP1 foci, may be used to identify cancers with increased sensitivity to proton radiation.

Radiobiological intercomparison of the 160 MeV and 230 MeV proton therapy beams at the Harvard Cyclotron Laboratory and at Massachusetts General Hospital.

The purpose of this study was to determine the relative biological effectiveness (RBE) along the axis of two range-modulated proton beams (160 and 230 MeV). Both the depth and the dose dependence of RBE were investigated. Chinese hamster V79-WNRE cells, suspended in medium containing gelatin and cooled to 2 °C, were used to obtain complete survival curves at multiple positions throughout the entrance and 10 cm spread-out Bragg peak (SOBP). Simultaneous measurements of the survival response to (60)Co gamma rays served as the reference data for the proton RBE determinations. For both beams the RBE increased significantly with depth in the 10 cm SOBP, particularly in the distal half of the SOBP, then rose even more sharply at the distal edge, the most distal position measured. At a 4 Gy dose of gamma radiation (S = 0.34) the average RBE values for the entrance, proximal half, distal half and distal edge were 1.07 ± 0.01, 1.10 ± 0.01, 1.17 ± 0.01 and 1.21 ± 0.01, respectively, and essentially the same for both beams. At a 2 Gy dose of gamma radiation (S = 0.71) the average RBE values rose to 1.13 ± 0.03, 1.15 ± 0.02, 1.26 ± 0.02 and 1.30 ± 0.02, respectively, for the same four regions of the SOBP. The difference between the 4 Gy and 2 Gy RBE values reflects the dose dependence of RBE as measured in these V79-WNRE cells, which have a low α/ß value, as do other widely used cell lines that also show dose-dependent RBE values. Late-responding tissues are also characterized by low α/ß values, so it is possible that these cell lines may be predictive for the response of such tissues (e.g., spinal cord, optic nerve, kidney, liver, lung). However, in the very small number of studies of late-responding tissues performed to date there appears to be no evidence of an increased RBE for protons at low doses. Similarly, RBE measurements using early responding in vivo systems (mostly mouse jejunum, an early-responding tissue which has a large α/ß âˆ¼ 10 Gy) have generally shown little or no detectable dose dependence. It is useful to compare the RBE values reported here to the commonly used generic clinical RBE of 1.1, which assumes no dependence on depth or on dose. Our proximal RBEs obviously avoid the depth-related increase in RBE and for doses of 4 Gy or more, the low-dose increase in RBE is also minimized, as shown in this article. Thus the proximal RBE at a 4 Gy dose of 1.10 ± 0.01, quoted above, represents an interesting point of congruence with the clinical RBE for conditions where it could reasonably be expected in the measurements reported here. The depth dependence of RBE reported here is consistent with the majority of measurements, both in vitro and in vivo, by other investigators. The dose dependence of RBE, on the other hand, is tissue specific but has not yet been demonstrated for protons by RBE values in late-responding normal tissue systems. This indicates a need for additional RBE determination as function of dose, especially in late-responding tissues.

Outcomes in a multi-institutional cohort of patients treated with intraoperative radiation therapy for advanced or recurrent renal cell carcinoma.

PURPOSE/OBJECTIVE(S): This study aimed to analyze outcomes in a multi-institutional cohort of patients with advanced or recurrent renal cell carcinoma (RCC) who were treated with intraoperative radiation therapy (IORT). METHODS AND MATERIALS: Between 1985 and 2010, 98 patients received IORT for advanced or locally recurrent RCC at 9 institutions. The median follow-up time for surviving patients was 3.5 years. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were estimated with the Kaplan-Meier method. Chained imputation accounted for missing data, and multivariate Cox hazards regression tested significance. RESULTS: IORT was delivered during nephrectomy for advanced disease (28%) or during resection of locally recurrent RCC in the renal fossa (72%). Sixty-nine percent of the patients were male, and the median age was 58 years. At the time of primary resection, the T stages were as follows: 17% T1, 12% T2, 55% T3, and 16% T4. Eighty-seven percent of the patients had a visibly complete resection of tumor. Preoperative or postoperative external beam radiation therapy was administered to 27% and 35% of patients, respectively. The 5-year OS was 37% for advanced disease and 55% for locally recurrent disease. The respective 5-year DSS was 41% and 60%. The respective 5-year DFS was 39% and 52%. Initial nodal involvement (hazard ratio [HR] 2.9-3.6, P<.01), presence of sarcomatoid features (HR 3.7-6.9, P<.05), and higher IORT dose (HR 1.3, P<.001) were statistically significantly associated with decreased survival. Adjuvant systemic therapy was associated with decreased DSS (HR 2.4, P=.03). For locally recurrent tumors, positive margin status (HR 2.6, P=.01) was associated with decreased OS. CONCLUSIONS: We report the largest known cohort of patients with RCC managed by IORT and have identified several factors associated with survival. The outcomes for patients receiving IORT in the setting of local recurrence compare favorably to similar cohorts treated by local resection alone suggesting the potential for improved DFS with IORT.

The long view: 40 years of Marek's disease research and Avian Pathology.

Marek's disease (MD), named after the Hungarian veterinary pathologist over 100 years ago, is a major disease affecting poultry health worldwide. Research in the late 1960s that led to the identification of the causative herpesvirus and the development of a highly successful vaccine is undoubtedly one of the best success stories in veterinary medicine. As Avian Pathology is celebrating its 40th anniversary, we review the last four decades of MD research that has provided major advances in our understanding of the virus, the pathogenic mechanisms of the disease, methods of diagnosis and the control through different generations of vaccines. Particular attention has been paid to the contributions made by publications in Avian Pathology. Despite this tremendous progress, MD continues to pose major challenges particularly from increasing virulence and emergence of new pathotypes. Further research on the molecular mechanisms of the disease, genetic resistance, vaccine-induced protection and evolution of virulence will be needed to develop more sustainable control strategies in the coming years.

Do angles of obliquity apply to 30 degrees scattered radiation from megavoltage beams?

The angle of obliquity is used in radiation shielding calculations to account for the longer path length x rays will see when obliquely incident on the protective barrier. According to the National Council on Radiation Protection and Measurements (NCRP), use of the angle of obliquity is explicitly assumed for primary radiation, so that an angle of obliquity for secondary radiation is never addressed. However, in the example section of the latest report, it specifically recommends against using an angle of obliquity for scattered radiation. To check this assumption, the existence or not of an angle of obliquity for scattered radiation has been investigated for bremsstrahlung x-ray beams of 4, 6, 10, 15, and 18 MV and for barriers consisting of concrete, lead, and steel using a Monte Carlo approach. The MCNP Monte Carlo code, v4.2C, has been used to generate scattered radiation at 30 degrees from a water phantom and incident on a secondary barrier at the same angle relative to the normal to the barrier. The barrier thickness was increased from zero to a thickness sufficient to reduce the fluence (f4 tally) to <10(-3). A transmission curve was created for each energy-barrier material combination by normalizing to zero thickness. The results for the first tenth-value layer (TVL) in concrete (5 energies) show an average angle of obliquity of 21.7 degrees +/- 5.6 degrees , and for the first two TVLs averaged 29.7 degrees +/- 3.9 degrees . The results for the first TVL in lead (3 energies) show an average angle of obliquity of 27.7 degrees +/- 4.0 degrees , and for the first two TVLs averaged 20.5 degrees +/- 5.8 degrees . There are no data in the NCRP reports for 30 degrees scattered radiation attenuated by steel with which to make a comparison.

Measurement of the neutron leakage from a dedicated intraoperative radiation therapy electron linear accelerator and a conventional linear accelerator for 9, 12, 15(16), and 18(20) MeV electron energies.

The issue of neutron leakage has recently been raised in connection with dedicated electron-only linear accelerators used for intraoperative radiation therapy (IORT). In particular, concern has been expressed about the degree of neutron production at energies of 10 MeV and higher due to the need for additional, perhaps permanent, shielding in the room in which the device is operated. In particular, three mobile linear accelerators available commercially offer electron energies at or above the neutron threshold, one at 9 MeV, one at 10 MeV, and the third at 12 MeV. To investigate this problem, neutron leakage has been measured around the head of two types of electron accelerators at a distance of 1 m from the target at azimuthal angles of 0 degrees, 45 degrees, 90 degrees, 135 degrees, and 180 degrees. The first is a dedicated electron-only (nonmobile) machine with electron energies of 6 (not used here), 9, 12, 15, and 18 MeV and the second a conventional machine with electron energies of 6 (also not used here), 9, 12, 16, and 20 MeV. Measurements were made using neutron bubble detectors and track-etch detectors. For electron beams from a conventional accelerator, the neutron leakage in the forward direction in Sv/Gy is 2.1 x 10(-5) at 12 MeV, 1.3 x 10(-4) at 16 MeV, and 4.2 x 10(-4) at 20 MeV, assuming a quality factor (RBE) of 10. For azimuthal angles > 0 degrees, the leakage is almost angle independent [2 x 10(-6) at 12 MeV; (0.7-1.6) x 10(-5) at 16 MeV, and (1.6-2.9) x 10(-5) at 20 MeV]. For the electron-only machine, the neutron leakage was lower than for the conventional linac, but also independent of azimuthal angle for angles > 0 degrees: {[0 degrees: 7.7 x 10(-6) at 12 MeV; 3.0 x 10(-5) at 15 MeV; 1.0 x 10(-4) at 18 MeV]; [other angles: (2.6-5.9) x 10(-7) at 12 MeV; (1.4-2.2) x 10(-6) at 15 MeV; (2.7-4.7) x 10(-6) at 18 MeV]}. Using the upper limit of 6 x 10(-7) Sv/Gy at 12 MeV for the IORT machine for azimuthal angles > 0 degrees and assuming a workload of 200 Gy/wk and an inverse square factor of 10, the neutron dose equivalent is calculated to be 0.012 mSv/wk. For the primary beam at 12 MeV (0 degrees), the 10 x higher dose would be compensated by the attenuation of a primary beam stopper in a mobile linear accelerator. These neutron radiation levels are below regulatory values (National Council on Radiation Protection and Measurements, "Limitation of exposure to ionizing radiation," NCRP Report No. 116, NCRP Bethesda, MD, 1993).

Tenth value layers for 60Co gamma rays and for 4, 6, 10, 15, and 18 MV x rays in concrete for beams of cone angles between 0 degrees and 14 degrees calculated by Monte Carlo simulation.

The calculation of shielding barrier thicknesses for radiation therapy facilities according to the NCRP formalism is based on the use of broad beams (that is, the maximum possible field sizes). However, in practice, treatment fields used in radiation therapy are, on average, less than half the maximum size. Indeed, many contemporary treatment techniques call for reduced field sizes to reduce co-morbidity and the risk of second cancers. Therefore, published tenth value layers (TVLs) for shielding materials do not apply to these very small fields. There is, hence, a need to determine the TVLs for various beam modalities as a function of field size. The attenuation of (60)Co gamma rays and photons of 4, 6, 10, 15, and 18 MV bremsstrahlung x ray beams by concrete has been studied using the Monte Carlo technique (MCNP version 4C2) for beams of half-opening angles of 0 degrees , 3 degrees , 6 degrees , 9 degrees , 12 degrees , and 14 degrees . The distance between the x-ray source and the distal surface of the shielding wall was fixed at 600 cm, a distance that is typical for modern radiation therapy rooms. The maximum concrete thickness varied between 76.5 cm and 151.5 cm for (60)Co and 18 MV x rays, respectively. Detectors were placed at 630 cm, 700 cm, and 800 cm from the source. TVLs have been determined down to the third TVL. Energy spectra for 4, 6, 10, 15, and 18 MV x rays for 10 x 10 cm(2) and 40 x 40 cm(2) field sizes were used to generate depth dose curves in water that were compared with experimentally measured values.

Measurement of the leakage radiation from linear accelerators in the backward direction for 4, 6, 10, 15, and 18 MV x-ray energies.

The x-ray leakage from the housing of a therapy x-ray source is regulated to be <0.1% of the useful beam exposure at 1 m from the source. It is to be expected that the machine leakage in the backward direction would be less because the gantry and stand contain significant amounts of additional metal to attenuate the x rays. A reduction in head leakage in this direction will have a direct effect on the thickness of the shielding wall behind the linear accelerator. However, no reports have been published to date on measurements in this area. The x-ray leakage in the backward direction has been measured from linacs having energies of 4, 6, 10, 15, and 18 MV using a 100 cm ionization chamber and Al2O3 dosimeters. The leakage was measured at nine different positions over the rear wall using a 3 x 3 matrix with a 1-m separation between adjacent horizontal and vertical points with either the leftmost or rightmost column aligned with the target and isocenter. In general, the leakage is less than the canonical value, but the exact value depends on energy, gantry angle, and measurement position. There is significantly greater attenuation directly behind the gantry stand for all energies. Leakage at 10 MV for some positions exceeded 0.1%. Additionally, neutron leakage measurements were made for 10, 15, and 18 MV x-ray beams using track-etch detectors. The average neutron leakage was less than 0.1% except for 18 MV, where neutron leakage was more than 0.1% of the useful beam at some positions.

Intraoperative radiation therapy using mobile electron linear accelerators: report of AAPM Radiation Therapy Committee Task Group No. 72.

Intraoperative radiation therapy (IORT) has been customarily performed either in a shielded operating suite located in the operating room (OR) or in a shielded treatment room located within the Department of Radiation Oncology. In both cases, this cancer treatment modality uses stationary linear accelerators. With the development of new technology, mobile linear accelerators have recently become available for IORT. Mobility offers flexibility in treatment location and is leading to a renewed interest in IORT. These mobile accelerator units, which can be transported any day of use to almost any location within a hospital setting, are assembled in a nondedicated environment and used to deliver IORT. Numerous aspects of the design of these new units differ from that of conventional linear accelerators. The scope of this Task Group (TG-72) will focus on items that particularly apply to mobile IORT electron systems. More specifically, the charges to this Task Group are to (i) identify the key differences between stationary and mobile electron linear accelerators used for IORT, (ii) describe and recommend the implementation of an IORT program within the OR environment, (iii) present and discuss radiation protection issues and consequences of working within a nondedicated radiotherapy environment, (iv) describe and recommend the acceptance and machine commissioning of items that are specific to mobile electron linear accelerators, and (v) design and recommend an efficient quality assurance program for mobile systems.

Long term stability of a 50 kV X-ray unit for stereotactic irradiation.

A low-energy (50 kV) X-ray tube used for the stereotactic irradiation of intracranial lesions has been in use since 1999. The unit is calibrated prior to every procedure and during periodic quality assurance (QA) tests. The unit uses an internal and an external scintillation detector to monitor dose as well as a conventional timer. The records of these calibrations were reviewed to see whether a change in the output had occurred over that period. Using time as the reference, it was found that both the internal radiation monitor (IRM) and the beam output, determined with a parallel plate ionization chamber, dropped by variable amounts over the given period. The beam output dropped significantly more than the IRM, while the external radiation monitor (ERM) showed no significant deviation from its initial value. The beam output dropped to about 90% of its initial value after about 200 days but remained relatively constant thereafter. The IRM dropped steadily to about 96% to 97% of its initial value at 1000 days, but recovered to about 98% after that. Calibration prior to each procedure is strongly recommended.

Long-term results of intraoperative electron beam irradiation (IOERT) for patients with unresectable pancreatic cancer.

SUMMARY BACKGROUND DATA: To analyze the effects of a treatment program of intraoperative electron beam radiation therapy (IOERT) and external beam radiation therapy and chemotherapy on the outcome of patients with unresectable or locally advanced pancreatic cancer. METHODS: From 1978 to 2001, 150 patients with unresectable and nonmetastatic pancreatic cancer received IOERT combined with external beam radiation therapy and 5-fluorouracil-based chemotherapy for definitive treatment. RESULTS: The 1-, 2-, and 3-year actuarial survival rates of all 150 patients were 54%, 15%, and 7%, respectively. Median and mean survival rates were 13 and 17 months, respectively. Long-term survival has been observed in 8 patients. Five patients have survived beyond 5 years and 3 more between 3 and 4 years. There was a statistically significant correlation of survival to the diameter of treatment applicator (a surrogate for tumor size) used during IOERT. For 26 patients treated with a small-diameter applicator (5 cm or 6 cm), the 2- and 3-year actuarial survival rates were 27% and 17%, respectively. In contrast, none of the 11 patients treated with a 9-cm-diameter applicator survived beyond 18 months. Intermediate survival rates were seen for patients treated with a 7- or 8-cm-diameter applicator. Operative mortality was 0.6%, and postoperative and late complications were 20% and 15%, respectively. CONCLUSIONS: A treatment strategy employing IOERT has resulted in long-term survival in 8 of 150 patients with unresectable pancreatic cancer. Survival benefit was limited to patients with small tumors. Enrollment of selected patients with small tumors into innovative protocols employing this treatment approach is appropriate.