Independent external validation using the EORTC HNCG-ROG 1219 DAHANCA trial data of NTCP models for acute oral mucositis.

PURPOSE: To externally validate previously published Normal Tissue Complication Probability (NTCP) models developed by separate teams for grade 3 oral mucositis (g3OM). MATERIALS AND METHODS: Two models were validated: a logistic model, based on 144 head and neck cancer (HNC) patients receiving induction chemotherapy followed by chemo-IMRT; a multivariable logistic model for prediction of g3OM for 253 patients receiving radical treatment for the head and neck squamous cell carcinoma (HNSCC). The EORTC HNCG-ROG 1219 DAHANCA trial dataset, consisting of 169 patients was used as the validation cohort. This cohort was treated with accelerated fractionated chemo-IMRT, with/without the hypoxic radiosensitizer Nimorazole for HNSCC. External validity was assessed using the scaled Brier score. Calibration was assessed in terms of calibration curves as well as measures of mean and weak calibration. Hosmer-Lemeshow was used for goodness-of-fit test. Discrimination was calculated using the area under the receiver operating curve (AUC-ROC). RESULTS: The prevalence of g3OM in the validation cohort (35.5%) was similar to that of two development cohorts, i.e. 38.7% and 31.9% for Bhide logistic and Otter multivariable logistic models respectively. The scaled Brier scores showed good overall model performance. Perfect calibration was observed in the prevalence range of 20% to 40%. AUC-ROC was acceptable in external validation (0.67). The Hosmer-Lemeshow test showed good agreement between predicted and observed outcomes for two models. CONCLUSION: The NTCP models were validated and lead to valid predictions in a wide range of diverse treatment techniques and patient characteristics, also when Nimorazole is added as hypoxic radiosensitizer.

A comprehensive evaluation of treatment accuracy, including end-to-end tests and clinical data, applied to intracranial stereotactic radiotherapy.

BACKGROUND AND PURPOSE: A methodology is presented to quantify the uncertainty associated with linear accelerator-based frameless intracranial stereotactic radiotherapy (SRT) combining end-to-end phantom tests and clinical data. METHODS AND MATERIALS: The following steps of the SRT chain were analysed: planning computed tomography (CT) and magnetic resonance (MR) scans registration, target volume delineation, CT and cone beam CT (CBCT) registration and intrafraction-patient displacement. The overall accuracy was established with an end-to-end test. The measured uncertainties were combined, deriving the total systematic (ΣT) and random (σT) error components, to estimate the GTV-PTV margin. RESULTS: The uncertainty in the MR-CT registration was on average 0.40mm (averaged over AP, CC and LR directions). Rotational variations were smaller than 0.5° in all directions. Interobser variation in GTV delineation was on average 0.29mm. The uncertainty in the CBCT-CT registration was on average 0.15mm. Again, rotational variations were smaller than 0.5° in all directions. The systematic and random intrafraction displacement errors were on average 0.55mm and 0.45mm, respectively. The systematic and random positional errors from the end-to-end test were on average 0.49mm and 0.53mm, respectively. Combining these uncertainties resulted in an average ΣT=0.9mm and σT=0.7mm and an average GTV-PTV margin of 2.8mm. CONCLUSION: This comprehensive methodology including end-to-end tests enabled a GTV-PTV margin calculation considering all sources of uncertainties. This generic method can also be used for other treatment sites.

LungTech, an EORTC Phase II trial of stereotactic body radiotherapy for centrally located lung tumours: a clinical perspective.

Evidence supports stereotactic body radiotherapy (SBRT) as a curative treatment option for inoperable early stage non-small-cell lung cancer (NSCLC) resulting in high rates of tumour control and low risk of toxicity. However, promising results are mainly derived from SBRT of peripheral pulmonary lesions, whereas SBRT for the central tumours can lead to severe radiation sequelae owing to the spatial proximity to the serial organs at risk. Robust data on the tolerance of mediastinal structures to high-dose hypofractionated radiation are limited; furthermore, there are many open questions regarding the efficiency, safety and response assessment of SBRT in inoperable, centrally located early stage NSCLC, which are addressed in a prospective multicentre study [sponsored by the European Organization for Research and Treatment of Cancer (EORTC 22113-08113-LungTech)]. In this review, we summarize the current status regarding SBRT for centrally located early stage NSCLC that leads to the rationale of the LungTech trial. Outline and some essential features of the study with focus on a summary of current experiences in dose/fraction-toxicity coherences after SBRT to the mediastinal structures that lead to LungTech normal tissue constraints are provided.

Do results of the EORTC dummy run predict quality of radiotherapy delivered within multicentre clinical trials?

OBJECTIVE: The European Organisation for the Research and Treatment of Cancer (EORTC) Radiation Oncology Group (ROG) has performed radiotherapy quality assurance (QA) in clinical trials, including dummy runs (DR) and individual case reviews (ICR), since 1991. We investigated the influence of DR results on subsequent QA and patient outcomes. METHODS: EORTC ROG studies were reviewed for DR inclusion, QA and mature clinical outcomes. A DR was classified as a failure if corrections necessitated re-submission. ICR were graded as acceptable, minor or major deviation overall. Fisher's exact test characterised potential correlations and the Mantel-Haenszel statistic quantified pooled odds ratios (OR). RESULTS: DR and ICR data were available from 12 and 3 protocols, respectively. The proportion of institutions successful at first DR attempt varied per trial from 5.6% to 68.8%. Participants were 3.2 times more likely to pass at first attempt after previous DR participation (p=0.0002). Pooled OR for an acceptable ICR was 1.69 (p=0.06) for institutions successful at DR first attempt. The effect of DR participation was not significantly correlated with patient outcome in the trial available for analysis. CONCLUSIONS: Implementing QA measures in ROG clinical trials should ensure optimal radiotherapy delivery. Centres which previously participated in a DR were significantly more likely to be successful at subsequent QA procedures.

Development of clinical trial protocols involving advanced radiation therapy techniques: the European Organisation for Research and Treatment of Cancer Radiation Oncology Group approach.

The European Organisation for Research and Treatment of Cancer (EORTC) Master Protocol for phase III radiation therapy (RT) studies was published in 1995 to define in a consistent sequence the parameters which must be addressed when designing a phase III trial 'from the rationale to the references'. This was originally implemented to assist study investigators and writing committees, and to increase homogeneity within Radiation Oncology Group (ROG) study protocols. However, RT planning, delivery, treatment verification and quality assurance (QA) have evolved significantly over the last 15 years and clinical trial protocols must reflect these developments. The goal of this update is to describe the incorporation of these developments into the EORTC-ROG protocol template. Implementation of QA procedures for advanced RT trials is also briefly described as these essential elements must also be clearly articulated. This guide may assist both investigators participating in current ROG trials and others involved in writing an advanced RT trial protocol.

WE-G-218-03: Management of RT Patients with Implanted Cardiac Devices: From Recommendation to Practical Implementation.

Guidelines for the management of patients with an internal cardiac pacemaker (ICP) or internal cardiac defibrillator (ICD) referred for radiotherapy exist but are outdated, as both ICP and ICD technology and radiation therapy techniques have evolved. (ICPs and ICDs are both CIEDs). Furthermore, the clinical practice of patient management varies widely and the number of patient with a ICP or ICD referred for radiation therapy is increasing. There is thus a clear need for updated guidelines, which are currently developed by the new AAPM TG 203.An overview of the literature, existing recommendations and dose measurement methods has been given the previous speakers of this session. In this presentation, the focus will be more on the management aspects. Which questions need to be answered to decide if a patient can receive radiation therapy? How can this be weighted against e.g. CIED relocation or replacement? It is clear that good communication between the patient, the treating cardiologist and radiation therapy department is of importance to come to the best multidisciplinary treatment approach. When radiotherapy is given, the practical measures that need to be taken should preferably be categorised based on the chance on CIED failure combined with the consequence for the patient in case of such failure. Thus, an important distinction may be made between pacing dependent and pacing independent patients. Examples of such risk classifications with corresponding practical implications will be presented, including the new Dutch national guideline recently authorised by the national cardiology, pacemaker technologists, medical physics and radiation oncology societies. LEARNING OBJECTIVES: 1. Understand and list the questions that need to be answered to tailor the treatment to the individual patient and whom should be involved in this process. 2. Appreciate the reasons why only a crude categorisation of risks can be given. 3. Know how to interpret new CIED guidelines, their strengths and weaknesses and have sufficient knowledge to translate and incorporate these guidelines into your own institution.

Interference detection in implantable defibrillators induced by therapeutic radiation therapy.

BACKGROUND: Electromagnetic fields and ionising radiation during radiotherapy can influence the functioning of ICDs. Guidelines for radiotherapy treatment were published in 1994, but only based on experience with pacemakers. Data on the influence of radiotherapy on ICDs is limited. OBJECTIVES: We determined the risk to ICDs of interference detection induced by radiotherapy. METHODS: In our study we irradiated 11 ICDs. The irradiation was performed with a 6 megavolt photon beam. In each individual device test, a total of 20 Gray was delivered in a fractionated fashion. During each irradiation the output stimulation rate was monitored and electrogram storage was activated. In case of interference the test was repeated with the ICD outside and the lead(s) inside and outside the irradiation field. RESULTS: With the ICD inside the irradiation field, interference detection was observed in all ICDs. This caused pacing inhibition or rapid ventricular pacing. Ventricular tachycardia (VT) or ventricular fibrillation (VF) detection occurred, which would have caused tachycardia-terminating therapy. If the ICD was placed outside the irradiation field, no interference was observed. CONCLUSION: Interference by ionising radiation on the ICDs is demonstrated both on bradycardia and tachycardia therapy. This can have consequences for patients. Recommendations for radiotherapy are presented in this article.

Quality assurance of EORTC trial 22922/10925 investigating the role of internal mammary--medial supraclavicular irradiation in stage I-III breast cancer: the individual case review.

To assess consistency among participants in an European Organisation for Research and Treatment of Cancer (EORTC) phase III trial randomising between irradiation and no irradiation of the internal mammary and medial supraclavicular (IM-MS) lymph nodes, all participating institutes were invited to send data from 3 patients in each arm as soon as they started accrual. The evaluation focused on eligibility, compliance with the radiotherapy guidelines, treatment techniques and dose prescription to the IM-MS region. Nineteen radiotherapy departments provided a total of 111 cases, all being eligible. Minor discrepancies were found in the surgery and pathology data in almost half the patients. Major radiotherapy protocol deviations were very limited: 2 cases of unwarranted irradiation of the supraclavicular region and a significant dose deviation to the internal mammary region in 5 patients. The most frequently observed minor protocol deviation was the absence of delineation of the target volumes in 80% of the patients. By detecting systematic protocol deviations in an early phase of the trial, recommendations made to all the participating institutes should improve the interinstitutional consistency and promote a high-quality treatment.

Implementation of a forearm support to reduce the amount of irradiated lung and heart in radiation therapy of the breast.

We compared simulator images of medial tangential fields taken in two positions: (1) with the ipsilateral arm abducted, holding a 'L-bar' armrest and (2) with both arms extended above the head in a forearm support. The average maximum heart distance as well as the central lung distance decreased significantly by 3.4 (SE 0.9) and 4.7 (SE 1.1) mm, respectively, when the new forearm support was used. The estimated normal tissue complication probability for excess cardiac mortality decreased by on average 3.1% (SE 1.3%). For some patients, a greater amount of the axilla was included in the field. We recommend the use of the forearm support during breast cancer treatment with tangential fields to decrease the amount of heart and lung inside the fields.

Variability in target volume delineation on CT scans of the breast.

PURPOSE: To determine the intra- and interobserver variation in delineation of the target volume of breast tumors on computed tomography (CT) scans in order to perform conformal radiotherapy. MATERIALS AND METHODS: The clinical target volume (CTV) of the breast was delineated in CT slices by four radiation oncologists on our clinically used delineation system. The palpable glandular breast tissue was marked with a lead wire on 6 patients before CT scanning, whereas 4 patients were scanned without a lead wire. The CTV was drawn by each observer on three separate occasions. Planning target volumes (PTVs) were constructed by expanding the CTV by 7 mm in each direction, except toward the skin. The deviation in the PTV extent from the average extent was quantified in each orthogonal direction for each patient to find a possible directional dependence in the observer variations. In addition, the standard deviation of the intra- and interobserver variation in the PTV volume was quantified. For each patient, the common volumes delineated by all observers and the smallest volume encompassing all PTVs were also calculated. RESULTS: The patient-averaged deviations in PTV extent were larger in the posterior (42 mm), cranial (28 mm), and medial (24 mm) directions than in the anterior (6 mm), caudal (15 mm), and lateral (8 mm) directions. The mean intraobserver variation in volume percentage (5.5%, 1 SD) was much smaller than the interobserver variation (17.5%, 1 SD). The average ratio between the common and encompassing volume for the four observers separately was 0.82, 0.74, 0.82, and 0.80. A much lower combined average ratio of 0.43 was found because of the large interobserver variations. For the observer who placed the lead wire, the intraobserver variation in volume was decreased by a factor of 4 on scans made with a lead wire in comparison to scans made without a lead wire. For the other observers, no improvement was seen. Based on these results, an improved delineation protocol was designed. CONCLUSIONS: Intra- and especially interobserver variation in the delineation of breast target volume on CT scans can be rather large. A detailed delineation protocol making use of CT scans with lead wires placed on the skin around the palpable breast by the delineating observer reduces the intraobserver variation. To reduce the interobserver variation, better imaging techniques and pathology studies relating glandular breast tissue to imaging may be needed to provide more information on the extent of the clinical target volume.

The potential impact of treatment variations on the results of radiotherapy of the internal mammary lymph node chain: a quality-assurance report on the dummy run of EORTC Phase III randomized trial 22922/10925 in Stage I--III breast cancer(1).

PURPOSE: To present the results of the dummy run of the European Organization for Research and Treatment of Cancer (EORTC) trial investigating the role of adjuvant internal mammary and medial supraclavicular (IM-MS) irradiation in Stage I--III breast cancer. METHODS AND MATERIALS: All participating institutions were asked to produce a treatment plan without (Arm 1) and with (Arm 2) simultaneous IM-MS irradiation of 1 patient after mastectomy and of 1 patient after lumpectomy. Thirty-two dummy runs have been evaluated for compliance to protocol guidelines, with respect to treatment technique and dose prescription. RESULTS: A number of more or less important deviations in treatment setup and prescription have been found. The dose in the IM-MS region deviated significantly from the prescribed dose in 10% of the cases for Arm 1, and in 21% for Arm 2. Assuming a true 5% 10-year survival benefit from optimal IM-MS irradiation, an increase of only 3.8% will be found due to this suboptimal dose distribution. CONCLUSION: In the dummy run, a number of potential systematic protocol deviations that might lead to false-negative results were detected. By providing recommendations to the participating institutions, we expect to improve the interinstitutional consistency and to promote a high quality irradiation in all institutions participating in the trial.

Set-up verification using portal imaging; review of current clinical practice.

In this review of current clinical practice of set-up error verification by means of portal imaging, we firstly define the various types of set-up errors using a consistent nomenclature. The different causes of set-up errors are then summarized. Next, the results of a large number of studies regarding patient set-up verification are presented for treatments of patients with head and neck, prostate, pelvis, lung and breast cancer, as well as for mantle field/total body treatments. This review focuses on the more recent studies in order to assess the criteria for good clinical practice in patient positioning. The reported set-up accuracy varies widely, depending on the treatment site, method of immobilization and institution. The standard deviation (1 SD, mm) of the systematic and random errors for currently applied treatment techniques, separately measured along the three principle axes, ranges from 1.6-4.6 and 1.1-2.5 (head and neck), 1.0-3.8 and 1.2-3.5 (prostate), 1.1-4.7 and 1.1-4.9 (pelvis), 1.8-5.1 and 2.2-5.4 (lung), and 1.0-4.7 and 1.7-14.4 (breast), respectively. Recommendations for procedures to quantify, report and reduce patient set-up errors are given based on the studies described in this review. Using these recommendations, the systematic and random set-up errors that can be achieved in routine clinical practice can be less than 2.0 mm (1 SD) for head and neck, 2.5 mm (1 SD) for prostate, 3.0 mm (1 SD) for general pelvic and 3.5 mm (1 SD) for lung cancer treatment techniques.

An improved technique for breast cancer irradiation including the locoregional lymph nodes.

PURPOSE: To find an irradiation technique for locoregional irradiation of breast cancer patients which, compared with a standard technique, improves the dose distribution to the internal mammary-medial supraclavicular (IM-MS) lymph nodes. The improved technique is intended to minimize the lung dose and reduce the dose to the heart. METHODS AND MATERIALS: The standard technique consists of an anterior mixed electron/photon IM-MS field. In the improved technique, an oblique electron and an oblique asymmetric photon field are combined to irradiate the IM lymph nodes. To irradiate the MS lymph nodes, a combination of an anterior electron and an anterior asymmetric photon field is used. For both the standard and the improved technique, tangential photon fields are used to irradiate the breast. Three-dimensional (3D) treatment planning was performed for 8 patients with various breast sizes for these two techniques. Dose-volume histograms (DVHs) and normal tissue complication probabilities (NTCPs) were compared for both techniques. The field dimensions and energy of the standard technique were determined at simulation, whereas for the improved technique the fields were designed by CT-based treatment planning. RESULTS: The dose in the breast planning target volume was essentially the same for both techniques. For the improved technique, combined with 3D localization information, an improvement in the IM-MS planning target coverage is seen. The volume within the 95% isodose surface was on average 25% (range, 0-64%) and 74% (range, 43-90%) for the standard and improved technique, respectively. The heart generally receives less dose with the improved technique. However, sometimes a small but acceptable increase in lung dose is found. CONCLUSION: The improved technique, combined with localization information of the IM-MS lymph nodes, greatly improves the dose distribution in the planning target volume for a large group of patients without significantly increasing the dose to organs at risk.

Cardiac and lung complication probabilities after breast cancer irradiation.

PURPOSE: To assess for locoregional irradiation of breast cancer patients, the dependence of cardiac (cardiac mortality) and lung (radiation pneumonitis) complications on treatment technique and individual patient anatomy. MATERIALS AND METHODS: Three-dimensional treatment planning was performed for 30 patients with left-sided breast cancer and various breast sizes. Two locoregional techniques (Techniques A and B) and a tangential field technique, including only the breast in the target volume, were planned and evaluated for each patient. In both locoregional techniques tangential photon fields were used to irradiate the breast. The internal mammary (IM)-medial supraclavicular (MS) lymph nodes were treated with an anterior mixed electron/photon field (Technique A) or with an obliquely incident mixed electron/photon IM field and an anterior electron/photon MS field (Technique B). The optimal IM and MS electron field dimensions and energies were chosen on the basis of the IM-MS lymph node target volume as delineated on CT-slices. The position of the tangential fields was adapted to match the IM-MS fields. Dose-volume histograms (DVHs) and normal tissue complication probabilities (NTCPs) for the heart and lung were compared for the three techniques. In the beam's eye view of the medial tangential fields the maximum distance of the heart contour to the posterior field border was measured; this value was scored as the Maximum Heart Distance. RESULTS: The lymph node target volume receiving more than 85% of the prescribed dose was on average 99% for both locoregional irradiation techniques. The breast PTV receiving more than 95% of the prescribed dose was generally smaller using Technique A (mean: 90%, range: 69-99%) than using Technique B (mean: 98%, range: 82-100%) or for the tangential field technique (mean: 98%, range: 91-100%). NTCP values for excess cardiac mortality due to acute myocardial ischemia varied considerably between patients, with minimum and maximum values of 0.1 and 7.5% (Technique A), 0.1 and 5.8% (Technique B) and 0.0 and 6.1% (tangential tech.). The NTCP values were on average significantly higher (P<0.001) by 1.7% (Technique A) and 1.0% (Technique B) when locoregional breast irradiation was given, compared with irradiation of the left breast only. The NTCP values for the tangential field technique could be estimated using the Maximum Heart Distance. NTCP values for radiation pneumonitis were very low for all techniques; between 0.0 and 1.0%. CONCLUSIONS: Technique B results in a good coverage of the breast and locoregional lymph nodes, while Technique A sometimes results in an underdosage of part of the target volume. Both techniques result in a higher probability of heart complications compared with tangential irradiation of the breast only. Irradiation toxicity for the lung is low in all techniques. The Maximum Heart Distance is a simple and useful parameter to estimate the NTCP values for cardiac mortality for tangential breast irradiation.

Dosimetric verification of open asymmetric photon fields calculated with a treatment planning system based on dose-to-energy-fluence concepts.

Output normalized dose profiles for asymmetric open photon fields has been calculated using a commercial treatment planning system (TPS) based on a dose-to-energy-fluence concept. The model does not require any additional measurements for off-axis fields. Calculations are compared with measurements for quadratic fields of 5 cm x 5 cm up to 20 cm x 20 cm, with their geometric field centre positioned 10 cm off-axis in the in-plane direction. The measurements include depth doses and profiles in-plane as well as cross-plane for nominal photon energies of 4, 6 and 18 MV x-rays. Both calculated and measured doses are normalized with respect to a 10 cm x 10 cm reference field, therefore making it possible to compare not only the relative distributions but also the absolute dose levels; that is, calculation of monitor units is included. The calculated depth-dose curves are generally in good agreement with measured data with an accuracy at the absolute dose level of 2% at depths beyond the dose maximum. The cross-plane profiles are calculated with an accuracy better than 3% within the field. The 'tilt' towards the collimator central axis of the in-plane profiles is predicted by the model, but is somewhat overestimated at large depths. The system provides the possibility to separate the primary and scattered parts of the dose and the cause of this tilting was studied by comparing calculated phantom-scattering and head-scattering dose profiles for a symmetric 40 cm x 20 cm field to dose profiles for an asymmetric 20 cm x 20 cm field. The tilting is shown to originate from a change both in phantom scattering and in head scattering compared to the case of symmetrical fields. The results indicate that the investigated TPS can calculate dose distributions in open asymmetric fields with a high degree of accuracy, typically better than 2-3%.

Limitations of a pencil beam approach to photon dose calculations in the head and neck region.

The inherent limitations of a specific pencil beam model have been studied when applied to a cylindrical geometry simulating the neck region. A comparison is made between measured and calculated absorbed dose in a cylindrical phantom. The goal is to quantify the deviations in the absorbed dose level, i.e., the dose per monitor unit, when photons are used for the treatment of head and neck tumours. Square fields ranging from 5 x 5 up to 30 x 30 cm2 are studied for photon beam energies of 60Co, 4, 6 and 18 MV. Ionisation chamber measurements have been performed in the cylinder as well as in two other configurations in order to trace the origin of possible deviations. For 18 MV no significant deviations are found between measurement and calculation in the cylindrical configuration. For the lower energies, an overestimation of the calculated dose in the cylindrical configuration up to about 6% for a 20 x 20-cm2 60Co field has been found. These deviations have been traced to the basic approximation for the integration volume for phantom scatter calculations inherent in this pencil beam implementation.

Calculation and measurement of the dose to points outside the primary beam for CO-60 gamma radiation.

PURPOSE: In radiation therapy one sometimes needs to estimate the dose to points in the body outside the primary beam. Therefore a generalized model is developed to calculate this dose with reasonable accuracy. METHODS AND MATERIALS: Measurements were made for a cobalt beam to determine separately the contribution of leakage radiation, radiation scattered from the collimator, scattered from the floor and radiation scattered inside the patient. RESULTS: The radiation scattered in the patient shows a strong dependence on field size and distance to the beam axis and is predominant only at short distances. The radiation scattered from the collimator also depends strongly on distance and field size and is more important than the leakage radiation. With appropriate factors, correcting for patient dimensions and field shape, the total dose outside the primary beam can be calculated with an accuracy better than +/- 30%. The results are in accordance with published data. CONCLUSION: Using the measured data it is possible to calculate the dose at any point of the body outside the primary beam for Co-60 gamma radiation. The accuracy is considered to be adequate for risk assessment. Gonadal dose, Radiation therapy, Risk assessment.