Primary Treatment Field Research Articles

Method to quickly and accurately calculate absorbed dose from therapeutic and stray photon exposures throughout the entire body in individual patients

Photon radiotherapy techniques typically devote considerable attention to limiting the exposure of healthy tissues outside of the target volume. Numerous studies have shown, however, that commercial treatment planning systems (TPSs) significantly underestimate the absorbed dose outside of the treatment field. The purpose of this study was to test the feasibility of quickly and accurately calculating the total absorbed dose to the whole body from photon radiotherapy in individual patients. We created an extended TPS by implementing a physics-based analytical model for the absorbed dose from stray photons during photon therapy into a research TPS. We configured and validated the extended TPS using measurements of 6- and 15-MV photon beams in water-box and anthropomorphic phantoms. We characterized the additional computation time required for therapeutic and stray dose calculations in a 44×30×180cm3 water-box phantom. The extended TPS achieved superior dosimetric accuracy comparedto the research TPS in both water and anthropomorphic phantoms, especially outside of the primary treatment field. In the anthropomorphic phantom, the extended TPS increased the generalized gamma index passing rate by a factor of 10 and decreased the median dosimetric discrepancy in the out-of-field region by a factor of 26. The extended TPS achieved an average discrepancy <1% in and near the treatment field and <1mGy/Gy far from the treatment field in the anthropomorphic phantom. Characterization of computation time revealed that on average, the extended TPS only required 7% longer than the research TPS to calculate the total absorbed dose. The results of this work suggest that it is feasible to quickly and accurately calculate whole-body doses inside and outside of the therapeutic treatment field in individual patients on a routine basis using physics-based analytical dose models. This additional capability enables a more personalized approach to minimizing the risk of radiogenic late effects, such as second cancer and cardiac toxicity, as part of the treatment planning process.

DNA Damage and Cytokine Production in Non-Target Irradiated Lymphocytes.

In advanced radiotherapy, treatment of the tumor with high-intensity modulated fields is balanced with normal tissue sparing. However, the non-target dose delivered to surrounding healthy tissue within the irradiated volume is a potential cause for concern. Whether the effects observed are caused after exposure to out-of-field radiation or bystander effects through neighboring irradiated cells is not fully understood. The goal of this study was to determine the effect of exposure to out-of-field radiation in lymphocyte cell lines and primary blood cells. The role of cellular radiosensitivity in altering bystander responses in out-of-field exposed cells was also investigated. Target cells were positioned in a phantom in the center of the radiation field (in-field dose) and exposed to 2 Gy irradiation. Lymphocyte cell lines (C1, AT3ABR, Jurkat, THP-1, AT2Bi and AT3Bi) and peripheral blood were placed 1 cm away from the radiation field edge (out-of-field dose) and received an average dose of 10.8 ± 4.2 cGy. Double-stranded DNA damage, cell growth and gene expression were measured in the out-of-field cells. Radiosensitive AT3ABR and primary blood cells demonstrated the largest increase in γ-H2AX foci after irradiation. Exposure of normal cells to bystander factors from irradiated radiosensitive cell lines also increased DNA damage. Expression of IL-1, IL-6, TNFα and TGFβ after addition of bystander factors from radiosensitive cells showed differential effects in normally responding cells, with some evidence of an adaptive response observed. Exposure to out-of-field radiation induces DNA damage and reduces growth in radiosensitive cells. Bystander factors produced by directly irradiated cells in combination with out-of-field exposure may upregulate pro- and anti-inflammatory genes in responding cells of different radiosensitivities, with the potential of affecting the tumor microenvironment. A greater understanding of the radio-biological response in normal cells outside the primary treatment field would assist in radiation treatment planning and in reducing early and late toxicities.

Neutron dose in and out of 18 MV photon fields

In radiation therapy, neutron contamination is an undesirable side effect of using high energy photons to treat patients. Neutron contamination requires adjustments to the shielding requirements of the linear accelerator vault and contributes to the risk of secondary malignancies in patients by delivering dose outside of the primary treatment field. Using MCNPX, an established Monte Carlo code, manufacturer blueprints, and the most up to date ICRP neutron dose conversion factors, the neutron spectra, neutron/photon dose ratio, and the neutron capture gamma ray dose were calculated at different depths and off axis distances in a tissue equivalent phantom. Results demonstrated that the neutron spectra and dose are dependent on field size, depth in the phantom, and off-axis distance. Simulations showed that because of the low neutron absorption cross section of the linear accelerator head materials, the contribution to overall patient dose from neutrons can be up to 1000 times the photon dose out of the treatment field and is also dependent on field size and depth. Beyond 45cm off-axis, the dependence of the neutron dose on field size is minimal. Neutron capture gamma ray dose is also field size dependent and is at a maximum at a depth of about 7cm. It is important to remember that when treating with high energy photons, the dose from contamination neutrons must be considered as it is much greater than the photon dose.

Immune modulation in advanced radiotherapies: Targeting out-of-field effects

By virtue of being a localized treatment modality, radiotherapy is unable to deliver a tumoricidal radiation dose to tissues outside of the irradiated field. Nevertheless, ionizing radiation may result in radiation damage mediated by a bystander like effect away from the irradiated field, but this response is likely to be modest when radiotherapy is the sole treatment modality. Over the last decade there has been a re-emergence of immune modulating therapies as anti-cancer treatment modalities. Clinical trials on vaccines have on the whole been largely disappointing, but greater response rates have been observed from the immune checkpoint modulators. A clinical benefit of using such agents has been shown in disease sites such as melanoma and non-small cell lung cancer. There is growing pre-clinical data and a number of case reports which suggest the presence of abscopal effects when radiotherapy is co-administered with immune checkpoint inhibitors, suggesting that this combination may lead to an enhanced tumour response outside of the primary treatment field. In this review, the mechanisms of such an enhanced out-of-field tumour response, the potential clinical utilities, the optimal radiotherapy delivery and considerations for clinical follow-up following treatment are discussed.

SU-E-T-219: Investigation of IMRT Out-Of-Field Dose Calculation Accuracy for a Commercial Treatment Planning System

Medical PhysicsVolume 41, Issue 6Part14 p. 273-273 Fifty-sixth annual meeting of the American association of physicists in medicine SU-E-T-219: Investigation of IMRT Out-Of-Field Dose Calculation Accuracy for a Commercial Treatment Planning System First published: 29 May 2014 https://doi.org/10.1118/1.4888549 Vanderbilt University, Nashville, TN About ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Purpose: Inaccuracies in out-of-field calculations could lead to underestimation of dose to organs-at-risk. This study evaluates the dose calculation accuracy of a model-based calculation algorithm at points outside the primary treatment field for an intensity modulated radiation therapy (IMRT) plan using experimental measurements. Methods: The treatment planning system investigated is Varian Eclipse V.10 with Analytical Anisotropic Algorithm (AAA). The IMRT fields investigated are from real patient treatment plans. The doses from a dynamic (DMLC) IMRT brain plan were calculated and compared with measured doses at locations outside the primary treatment fields. Measurements were performed with a MatriXX system (2-D chamber array) placed in solid water. All fields were set vertically incident on the phantom and were 9 cm × 6 cm or smaller. The dose was normalized to the central axis for points up to 15 cm off isocenter. The comparisons were performed at depths of 2, 10, 15, and 20 cm Results: The measurements have shown that AAA calculations underestimate doses at points outside the primary treatment field. The underestimation occurs at 2 cm depth and decreases down to a factor of 2 as depth increases to 20 cm. In low dose (<2% of target dose) regions outside the primary fields the local dose underestimations can be >200% compared to measured doses. Relative to the plan target dose, the measured doses to points outside the field were less than 1% at shallow depths and less than 2% at greater depths. Conclusion: Compared to measurements, the AAA algorithm underestimated the dose at points outside the treatment field with the greatest differences observed at shallow depths. Despite large local dose uncertainties predicted by the treatment planning system, the impact of these uncertainties is expected to be insignificant as doses at these points were less than 1-2% of the prescribed treatment dose. Volume41, Issue6Part14June 2014Pages 273-273 RelatedInformation

Quantitative analysis of the factors which affect the interpatient organ‐at‐risk dose sparing variation in IMRT plans

The authors present an evidence-based approach to quantify the effects of an array of patient anatomical features of the planning target volumes (PTVs) and organs-at-risk (OARs) and their spatial relationships on the interpatient OAR dose sparing variation in intensity modulated radiation therapy (IMRT) plans by learning from a database of high-quality prior plans. The authors formulized the dependence of OAR dose volume histograms (DVHs) on patient anatomical factors into feature models which were learned from prior plans by a stepwise multiple regression method. IMRT plans for 64 prostate, 82 head-and-neck (HN) treatments were used to train the models. Two major groups of anatomical features were considered in this study: the volumetric information and the spatial information. The geometry of OARs relative to PTV is represented by the distance-to-target histogram, DTH. Important anatomical and dosimetric features were extracted from DTH and DVH by principal component analysis. The final models were tested by additional 24 prostate and 24 HN plans. Significant patient anatomical factors contributing to OAR dose sparing in prostate and HN IMRT plans have been analyzed and identified. They are: the median distance between OAR and PTV, the portion of OAR volume within an OAR specific distance range, and the volumetric factors: the fraction of OAR volume which overlaps with PTV and the portion of OAR volume outside the primary treatment field. Overall, the determination coefficients R(2) for predicting the first principal component score (PCS1) of the OAR DVH by the above factors are above 0.68 for all the OARs and they are more than 0.53 for predicting the second principal component score (PCS2) of the OAR DVHs except brainstem and spinal cord. Thus, the above set of anatomical features combined has captured significant portions of the DVH variations for the OARs in prostate and HN plans. To test how well these features capture the interpatient organ dose sparing variations in general, the DVHs and specific dose-volume indices calculated from the regression models were compared with the actual DVHs and dose-volume indices from each patient's plan in the validation dataset. The dose-volume indices compared were V99%, V85%, and V50% for bladder and rectum in prostate plans and parotids median dose in HN plans. The authors found that for the bladder and rectum models, 17 out of 24 plans (71%) were within 6% OAR volume error and 21 plans (85%) were within 10% error; For the parotids model, the median dose values for 30 parotids out of 48 (63%) were within 6% prescription dose error and the values in 40 parotids (83%) were within 10% error. Quantitative analysis of patient anatomical features and their correlation with OAR dose sparing has identified a number of important factors that explain significant amount of interpatient DVH variations in OARs. These factors can be incorporated into evidence-based learning models as effective features to provide patient-specific OAR dose sparing goals.

DNA Damage Responses following Exposure to Modulated Radiation Fields

During the delivery of advanced radiotherapy treatment techniques modulated beams are utilised to increase dose conformity across the target volume. Recent investigations have highlighted differential cellular responses to modulated radiation fields particularly in areas outside the primary treatment field that cannot be accounted for by scattered dose alone. In the present study, we determined the DNA damage response within the normal human fibroblast AG0-1522B and the prostate cancer cell line DU-145 utilising the DNA damage assay. Cells plated in slide flasks were exposed to 1 Gy uniform or modulated radiation fields. Modulated fields were delivered by shielding 25%, 50% or 75% of the flask during irradiation. The average number of 53BP1 or γH2AX foci was measured in 2 mm intervals across the slide area. Following 30 minutes after modulated radiation field exposure an increase in the average number of foci out-of-field was observed when compared to non-irradiated controls. In-field, a non-uniform response was observed with a significant decrease in the average number of foci compared to uniformly irradiated cells. Following 24 hrs after exposure there is evidence for two populations of responding cells to bystander signals in-and out-of-field. There was no significant difference in DNA damage response between 25%, 50% or 75% modulated fields. The response was dependent on cellular secreted intercellular signalling as physical inhibition of intercellular communication abrogated the observed response. Elevated residual DNA damage observed within out-of-field regions decreased following addition of an inducible nitric oxide synthase inhibitor (Aminoguanidine). These data show, for the first time, differential DNA damage responses in-and out-of-field following modulated radiation field delivery. This study provides further evidence for a role of intercellular communication in mediating cellular radiobiological response to modulated radiation fields and may inform the refinement of existing radiobiological models for the optimization of advanced radiotherapy treatment plans.

MO-D-BRB-10: Modeling Inter-Patient Variation of Organ-At-Risk Sparing in IMRT Plans: An Evidence-Based Plan Quality Evaluation.

To develop a predictive model to assess the quality of critical organ dose sparing in IMRT plans by providing patient specific dose sparing references, based on an array of patient anatomical features and prior planning experience. Contributions of various patient anatomical features to the inter-patient OAR dose sparing variation in IMRT planning were systematically studied using machine learning method based on high quality prior plans. The dependence of anatomical factor on OAR dosimetric parameters is formulated into predictive models. The OAR dosimetric parameters generated by these predictive models represent the "best feasible" clinical outcomes based on past planning experiences. IMRT plans of 88 prostate, 106 head-and-neck (HN) and 21 spine SBRT treatments were used to train the models. The final models were tested by additional 24 prostate and 48 HN plans. The model for spine SBRT was tested by the leave-one-out method. For HN and prostate planning, the significant patient anatomical features that affect OAR sparing are: the distance between OAR and PTV, the portion of OAR volume within an OAR specific distance range, the overlap volume between OAR and PTV, and the portion of OAR volume outside the primary treatment field. For spine SBRT planning, the most significant patient anatomical feature that affects cord sparing is the tightness of the geometric enclosure of PTV surrounding the cord and the homogeneity of PTV dose coverage. The dosimetric parameters predicted for the test patient cases using the models were in agreement with those from the clinical plans in more than 75% of the cases. The developed predictive models indicated substantial correlation between some important patient anatomical features and OAR dose sparing based on expert experiences. These models can be used as effective tools for evaluating the quality of treatment plans customized to individual patient's anatomy. Partially supported by a master research agreement with Varian Medical System, Inc.

A Computational Model of Cellular Response to Modulated Radiation Fields

To develop a model to describe the response of cell populations to spatially modulated radiation exposures of relevance to advanced radiotherapies. A Monte Carlo model of cellular radiation response was developed. This model incorporated damage from both direct radiation and intercellular communication including bystander signaling. The predictions of this model were compared to previously measured survival curves for a normal human fibroblast line (AGO1522) and prostate tumor cells (DU145) exposed to spatially modulated fields. The model was found to be able to accurately reproduce cell survival both in populations which were directly exposed to radiation and those which were outside the primary treatment field. The model predicts that the bystander effect makes a significant contribution to cell killing even in uniformly irradiated cells. The bystander effect contribution varies strongly with dose, falling from a high of 80% at low doses to 25% and 50% at 4 Gy for AGO1522 and DU145 cells, respectively. This was verified using the inducible nitric oxide synthase inhibitor aminoguanidine to inhibit the bystander effect in cells exposed to different doses, which showed significantly larger reductions in cell killing at lower doses. The model presented in this work accurately reproduces cell survival following modulated radiation exposures, both in and out of the primary treatment field, by incorporating a bystander component. In addition, the model suggests that the bystander effect is responsible for a significant portion of cell killing in uniformly irradiated cells, 50% and 70% at doses of 2Gy in AGO1522 and DU145 cells, respectively. This description is a significant departure from accepted radiobiological models and may have a significant impact on optimization of treatment planning approaches if proven to be applicable invivo.

Cell Survival Responses after Exposure to Modulated Radiation Fields

In the present study survival responses were determined in cells with differing radiosensitivity, specifically primary fibroblast (AG0-1522B), human breast cancer (MDA-MB-231), human prostate cancer (DU-145) and human glioma (T98G) cells, after exposure to modulated radiation fields delivered by shielding 50% of the tissue culture flask. A significant decrease (P < 0.05) in cell survival was observed in the shielded area, outside the primary treatment field (out-of-field), that was lower than predicted when compared to uniform exposures fitted to the linear-quadratic model. Cellular radiosensitivity was demonstrated to be an important factor in the level of response for both the in- and out-of-field regions. These responses were shown to be dependent on secretion-mediated intercellular communication, because inhibition of cellular secreted factors between the in- and out-of-field regions abrogated the response. Out-of-field cell survival was shown to increase after pretreatment of cells with agents known to inhibit factors involved in mediating radiation-induced bystander signaling (aminoguanidine, DMSO or cPTIO). These data illustrate a significant decrease in survival out-of-field, dependent upon intercellular communication, in several cell lines with varying radiosensitivity after exposure to a modulated radiation field. This study provides further evidence for the importance of intercellular signaling in modulated exposures, where dose gradients are present, and may inform the refinement of established radiobiological models to facilitate the optimization of advanced radiotherapy treatment plans.

MO‐A‐350‐01: Out‐Of‐Field Dosimetry for Secondary Cancer Studies: Past Experience and Future Needs

Patients treated with ionizing radiation carry a risk of developing second cancers in their life times. Factors contributing to the recently renewed concern about this risk include improved cancer survival rates, younger patient pool, as well as emerging treatment modalities such as IMRT and proton therapy that can potentially prolong secondary exposures to healthy tissues or expose patients to neutrons. In the past 20 years, external beam treatment technologies have evolved significantly, and there is an overwhelming amount of data on both dosimetry and epidemiological studies. This lecture reviews historical studies related to the assessment of scatter and leakage radiation from classical radiation therapy, 3D‐Conformal x‐ray therapy, intensity‐modulated x‐ray therapy (IMRT and tomotherapy), and proton therapy. The concept of high‐, intermediate‐ and low‐dose regions outside the primary treatment field is introduced. Terms such as “secondary cancers,” “organ‐average equivalent dose,” “out‐of‐field,” and “peripheral dose” are reviewed. Comparison of secondary doses from different treatment modalities, make/energy of accelerator and for adult and pediatric treatments is also made. Concomitant dose from IGRT localization and verification procedures involving cone‐beam CT is briefly discussed. This is followed by a detailed review on methods of performing measurements in physical phantoms using different types of radiation detectors, as well as Monte Carlo simulations using gender‐ and age‐specific “virtual patient” computational models. Finally future needs on dosimetry and epidemiological studies are discussed.Educational Objectives:1. Understand the importance of secondary cancer risk in radiation treatment.2. Understand basic concepts in radiation dosimetry associated with secondary cancer studies.3. Understand practical methods of measurement and Monte Carlo simulation for the assessment of organ‐average equivalent doses for various treatment modalities.

Patterns of failure in squamous cell carcinoma of the vagina treated with definitive radiotherapy alone: what is the appropriate treatment volume?

The purpose of this study was to review treatment results, sites of failure, and complications in relation to the irradiation volume for carcinoma of the vagina treated with radiotherapy alone. A retrospective review of 65 patients with histologically confirmed squamous cell carcinoma of the vagina who received definitive radiotherapy was undertaken. The 5-year cause-specific survival rates were as follows: Stage I, 91%; Stage IIA (paravaginal extension), 90%; Stage IIB, 55%; Stage III, 89%; and Stage IVA, 62%. The pelvic disease control rates at 5 years were as follows: Stage I, 74%; Stage IIA, 90%; Stage IIB, 79%; Stage III, 89%; and Stage IVA, 67%. Recurrence in the pelvis occurred in 22% of patients. Eighty-five percent of pelvis recurrences were in the primary treatment field. Although pelvic control rates were not increased by use of larger treatment fields (>2,700 cm(3)), moderate acute and late effects were increased with these fields. Carcinoma of the vagina appears to have a different failure pattern than carcinoma of the cervix. The primary failure sites are the vagina and the paracolpal tissues and the inguinal nodes. Because of this, the superior edge of the pelvic fields does not have to extend above the bottom of the sacroiliac joints except with advanced lesions.

Dosimetric Aspects of Exposure of the Population to Ionizing Radiation

Radiation carcinogenesis is generally considered to be the most important detrimental effect of exposure to ionizing radiation. The collective effective dose-equivalent values due to medical procedures amount to values between 10 and 20 per cent of the doses received from natural radiation. Risk factors have been derived up to the present from three large epidemiological studies, notably atomic bomb survivors, spondylitis patients and female patients treated for cancer of the cervix. The assessment of the absorbed doses received by the inhabitants of Hiroshima and Nagasaki has received continuous attention and the latest estimates are summarized. On the basis of original radiotherapy records the absorbed doses in organs adjacent to the primary treatment field can be derived from computerized dosimetry and this source of information should be further exploited. European co-operation has been established to investigate dosimetric problems for medical applications and radiation protection. The risk factors obtained up to the present are derived at relatively high dose levels (in excess of 0.3 Gy). The uncertainties in the extrapolation of these values to the area of low doses administered at low dose rates are discussed.