Subsequent primary neoplasms after childhood cancer therapy - design and description of the German nested case-control study STATT-SCAR.

BACKGROUND: Subsequent primary neoplasms (SPN) are among the most severe late effects and the second most frequent cause of death in childhood cancer patients. In this paper we introduce method and properties of the STATT-SCAR study (Second Tumor After Tumor Therapy, Second Cancer After Radiotherapy), which is a joint nested matched case-control study to evaluate the impact of chemotherapy (STATT) as well as radiotherapy (SCAR) on the risk of developing a SPN. METHODS: Based on the cohort of the German childhood cancer registry (GCCR), we selected patients diagnosed with a first neoplasm before age 15 or younger between 1980 and 2014. We selected those with a SPN at least half a year after the first neoplasm, and matched up to four controls to each case. Therapy data were acquired from various sources, including clinical study centers and treating hospitals. To analyze the impact of radiotherapy, organ doses were estimated by using reconstructed treatment plans. The effect of chemotherapy was analyzed using substance groups summarized after isotoxic dose conversion. RESULTS: 1244 cases with a SPN were identified and matched with 4976 controls. Treatment data were acquired for 83% of all match groups (one case and at least one control). Based on preliminary analyses, 98% of all patients received chemotherapy and 54% of all patients were treated with radiotherapy. CONCLUSIONS: Based on our data, detailed analyses of dose response relationships and treatment element combinations are possible, leading to a deeper insight into SPN risks after cancer treatments. TRIAL REGISTRATION: The study is registered at the German clinical trial register (DRKS) under number DRKS00017847 [45].

Heart atlas for retrospective cardiac dosimetry: a multi-institutional study on interobserver contouring variations and their dosimetric impact.

PURPOSE: Cardiac effects after breast cancer radiation therapy potentially affect more patients as survival improves. The heart's heterogeneous radiation exposure and composition of functional structures call for establishing individual relationships between structure dose and specific late effects. However, valid dosimetry requires reliable contouring which is challenging for small volumes based on older, lower-quality computed tomography imaging. We developed a heart atlas for robust heart contouring in retrospective epidemiologic studies. METHODS AND MATERIALS: The atlas defined the complete heart and geometric surrogate volumes for six cardiac structures: aortic valve, pulmonary valve, all deeper structures combined, myocardium, left anterior myocardium, and right anterior myocardium. We collected treatment planning records from 16 patients from 4 hospitals including dose calculations for 3D conformal tangential field radiation therapy for left-sided breast cancer. Six observers each contoured all patients. We assessed spatial contouring agreement and corresponding dosimetric variability. RESULTS: Contouring agreement for the complete heart was high with a mean Jaccard similarity coefficient (JSC) of 89%, a volume coefficient of variation (CV) of 5.2%, and a mean dose CV of 4.2%. The left (right) anterior myocardium had acceptable agreement with 63% (58%) JSC, 9.8% (11.5%) volume CV, and 11.9% (8.0%) mean dose CV. Dosimetric agreement for the deep structures and aortic valve was good despite higher spatial variation. Low spatial agreement for the pulmonary valve translated to poor dosimetric agreement. CONCLUSIONS: For the purpose of retrospective dosimetry based on older imaging, geometric surrogate volumes for cardiac organs at risk can yield better contouring agreement than anatomical definitions, but retain limitations for small structures like the pulmonary valve.

Pediatric craniospinal irradiation with a short partial-arc VMAT technique for medulloblastoma tumors in dosimetric comparison.

BACKGROUND: This study aimed to contrast four different irradiation methods for pediatric medulloblastoma tumors in a dosimetric comparison regarding planning target volume (PTV) coverage and sparing of organs at risk (OARs). METHODS: In sum 24 treatment plans for 6 pediatric patients were realized. Besides the clinical standard of a 3D-conformal radiotherapy (3D-CRT) treatment plan taken as a reference, volumetric modulated arc therapy (VMAT) treatment plans ("VMAT_AVD" vs. "noAVD" vs. "FullArc") were optimized and calculated for each patient. For the thoracic and abdominal region, the short partial-arc VMAT_AVD technique uses an arc setup with reduced arc-length by 100°, using posterior and lateral beam entries. The noAVD uses a half 180° (posterior to lateral directions) and the FullArc uses a full 360° arc setup arrangement. The prescription dose was set to 35.2 Gy. RESULTS: We identified a more conformal dose coverage for PTVs and a better sparing of OARs with used VMAT methods. For VMAT_AVD mean dose reductions in organs at risk can be realized, from 16 to 6.6 Gy, from 27.1 to 8.7 Gy and from 8.0 to 1.9 Gy for the heart, the thyroid and the gonads respectively, compared to the 3D-CRT treatment method. In addition we have found out a superiority of VMAT_AVD compared to the noAVD and FullArc trials with lower exposure to low-dose radiation to the lungs and breasts. CONCLUSIONS: With the short partial-arc VMAT_AVD technique, dose exposures to radiosensitive OARS like the heart, the thyroid or the gonads can be reduced and therefore, maybe the occurrence of late sequelae is less likely. Furthermore the PTV conformity is increased. The advantages of the VMAT_AVD have to be weighed against the potentially risks induced by an increased low dose exposure compared to the 3D-CRT method.

Radiation-induced DNA double-strand breaks in peripheral leukocytes and therapeutic response of heel spur patients treated by orthovoltage X-rays or a linear accelerator.

PURPOSE: Biodosimetric assessment and comparison of radiation-induced deoxyribonucleic acid (DNA) double-strand breaks (DSBs) by γH2AX immunostaining in peripheral leukocytes of patients with painful heel spur after radiation therapy (RT) with orthovoltage X­rays or a 6-MV linear accelerator (linac). The treatment response for each RT technique was monitored as a secondary endpoint. PATIENTS AND METHODS: 22 patients were treated either with 140-kV orthovoltage X­rays (n = 11) or a 6-MV linac (n = 11) with two weekly fractions of 0.5 Gy for 3 weeks. In both scenarios, the dose was prescribed to the International Commission on Radiation Units and Measurements (ICRU) dose reference point. Blood samples were obtained before and 30 min after the first RT session. γH2AX foci were quantified by immunofluorescence microscopy to assess the yield of DSBs at the basal level and after radiation exposure ex vivo or in vivo. The treatment response was assessed before and 3 months after RT using a five-level functional calcaneodynia score. RESULTS: RT for painful heel spurs induced a very mild but significant increase of γH2AX foci in patients' leukocytes. No difference between the RT techniques was observed. High and comparable therapeutic responses were documented for both treatment modalities. This trial was terminated preliminarily after an interim analysis (22 patients randomized). CONCLUSION: Low-dose RT for painful heel spurs with orthovoltage X­rays or a 6-MV linac is an effective treatment option associated with a very low and comparable radiation burden to the patient, as confirmed by biodosimetric measurements.

Influence of a Commercial Lead Apron on Patient Skin Dose Delivered During Oral and Maxillofacial Examinations under Cone Beam Computed Tomography (CBCT).

The purpose of this paper is to investigate the impact of a commercial lead apron on patient skin dose delivered during maxillofacial CBCT in five critical regions by means of solid-state-dosimetry. Five anatomical regions (thyroid gland, left and right breast, gonads, back of the phantom torso) in an adult female anthropomorphic phantom were selected for dose measurement by means of the highly sensitive solid-state dosimeter QUART didoSVM. Ten repeated single exposures were assessed for each patient body region for a total of five commercial CBCT devices with and without a lead apron present. Shielded and non-shielded exposures were compared under the paired Wilcoxon test, with absolute and relative differences computed. Reproducibility was expressed as the coefficient of variation (CV) between the 10 repeated assessments. The highest doses observed at skin level were found at the thyroid (mean shielded ± SD: 450.5 ± 346.7 µGy; non-shielded: 339.2 ± 348.8 µGy, p = 0.4922). Shielding resulted in a highly significant (p < 0.001) 93% dose reduction in skin dose in the female breast region with a mean non-shielded dose of approximately 35 µGy. Dose reduction was also significantly lower for the back-region (mean: -65%, p < 0.0001) as well as for the gonad-region (mean: -98%, p < 0.0001) in the shielded situation. Reproducibility was inversely correlated to skin dose (Rspearman = -0.748, p < 0.0001) with a mean CV of 10.45% (SD: 24.53 %). Skin dose in the thyroid region of the simulated patient was relatively high and not influenced by the lead apron, which did not shield this region. Dose reduction by means of a commercial lead apron was significant in all other regions, particularly in the region of the female breast.

Predicting Heart Dose in Breast Cancer Patients Who Received 3D Conformal Radiation Therapy.

Cardiac late effects are a major health concern for long-term survivors after radiotherapy for breast cancer. Large cohort studies to better understand the exact dose-response relationship require individual estimates of radiation dose to the heart. To predict individual cardiac dose from information that is typically available for all members of a retrospective epidemiological cohort study, 774 female breast cancer patients treated with megavoltage tangential field radiotherapy in 1998-2008 were examined. All dose distributions were calculated using Eclipse with the anisotropic analytical algorithm (AAA) for photon fields and the electron Monte Carlo algorithm for electron boost fields. Based on individual dose volume histograms, the authors calculated absorbed dose in the complete heart as well as in six functional substructures. Statistical models were developed to predict absorbed dose using only covariate information from patients' clinical records on tumor location, patient anatomy and radiotherapy prescription. The out-of-sample prediction error for mean heart dose was 54% (coefficient of variation). The prediction error in functional substructures ranged from 49-68% for mean dose and from 52-86% for extreme dose. The authors conclude that based on a patient sample with exact heart dosimetry, it is possible to use clinical information alone to predict absorbed heart dose in the remaining cohort with a quantified error suitable for dose-response analyses of cardiac late effects.

Skin entrance dose with and without lead apron in digital panoramic radiography for selected sensitive body regions.

PURPOSE: The aim of this study was to compare the dose at skin level at five significant anatomical regions for panoramic radiography devices with and without lead apron by means of a highly sensitive dosimeter. MATERIALS AND METHODS: A female RANDO-phantom was exposed in five different digital panoramic radiography systems, and the dose at skin level was assessed tenfold for each measurement region by means of a highly sensitive solid-state-dosimeter. The five measurement regions selected were the thyroid, both female breasts, the gonads, and a central region in the back of the phantom. For each panoramic machine, the measurements were performed in two modes: with and without a commercial lead apron specifically designed for panoramic radiography. Reproducibility of the measurements was expressed by absolute differences and the coefficient of variation. Values between shielded and unshielded doses were pooled for each region and compared by means of the paired Wilcoxon tests (p ≤ 0.05). RESULTS: Reproducibility as represented by the mean CV was 22 ± 52 % (median 2.3 %) with larger variations for small dose values. Doses at skin level ranged between 0.00 µGy at the gonads and 85.39 µGy at the unshielded thyroid (mean ± SD 15 ± 24 µGy). Except for the gonads, the dose in all the other regions was significantly lower (p < 0.001) when a lead apron was applied. Unshielded doses were between 1.02-fold (thyroid) and 112-fold (at the right breast) higher than those with lead apron shielding (mean: 14-fold ± 18-fold). CONCLUSION: Although the doses were entirely very low, we observed a significant increase in dose in the radiation-sensitive female breast region when no lead apron was used. Future discussions on shielding requirements for panoramic radiography should focus on these differences in the light of the linear non-threshold (LNT) theory which is generally adopted in medical imaging.

Quantification of Radiation Biomarkers in Leukocytes of Breast Cancer Patients Treated with Different Modalities of 3D-CRT or IMRT.

The goal of this study was to determine whether the quantification of radiation biomarkers in peripheral leukocytes of 111 breast cancer patients after adjuvant treatment with different modalities of three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) revealed any difference in the patients' radiation burden by out-of-field doses and an associated risk of second malignancies. Whole-breast radiation therapy was performed by 3D-CRT using either a hard wedge (n = 32) or a virtual wedge (n = 49) at dose rates of 3 and 6 Gy per min each. Patients receiving additional radiotherapy to lymph nodes were treated by 3D-CRT (n = 21) or IMRT (n = 9). DNA damage was measured as γ-H2AX foci (n = 111) and as unstable chromosomal aberrations (n = 15) in leukocytes drawn 30 min and 24 h after the first radiation fraction, respectively. The individual basal yield and radiation sensitivity ex vivo were assessed in leukocytes obtained before the first treatment. After radiation therapy, the average rate of γ-H2AX foci and chromosomal aberrations per leukocyte were dependent on multiple parameters of irradiation: the treatment volume, the administered equivalent whole-body dose, the number of monitor units and the beam-on time. Different modalities of radiation therapy caused significant variations in the levels of both radiation biomarkers irrespective of the treatment volume and administered dose, and in particular, a twofold higher rate after IMRT compared to 3D-CRT. Any deviation in biomarker response between radiation therapy techniques was directed by a linear dependence on the absolute beam-on time. However, the dispersion of γ-H2AX foci in peripheral leukocytes after radiation therapy correlated very well with the relative distribution of dose in the whole-body volume for each radiation therapy technique. In conclusion, the induction of radiation biomarkers in leukocytes of breast cancer patients by different radiotherapy modalities is dominated by general variables of irradiation. There was no significant difference in peripheral dose exposure observed in the investigated radiation therapy techniques. Radiotherapy techniques with prolonged absolute beam-on time increase the fraction of exposed leukocytes with pronounced risks for hematologic toxicities or immunosuppressive side effects.

Radiation dose distribution in functional heart regions from tangential breast cancer radiotherapy.

BACKGROUND AND PURPOSE: To analyze the distribution of individually-determined radiation dose to the heart and its functional sub-structures after radiotherapy in breast cancer patients treated in Germany during 1998-2008. MATERIAL AND METHODS: We obtained electronic treatment planning records for 769 female breast cancer patients treated with megavoltage tangential field radiotherapy. All dose distributions were re-calculated using Eclipse with the anisotropic analytical algorithm (AAA) for photon fields, and the electron Monte Carlo algorithm for electron boost fields. Based on individual dose volume histograms for the complete heart and several functional sub-structures, we estimated various dose measures in patient groups. RESULTS: Mean heart dose spanned a range of 0.9-19.1Gy for left-sided radiotherapy and 0.3-11.6Gy for right-sided radiotherapy. Average (median) mean heart dose was 4.6Gy (3.7Gy) for left-sided radiotherapy, and 1.7Gy (1.4Gy) for right-sided RT. With left-sided radiotherapy, 66% of the patients had 2cm(3) of the complete heart exposed to at least 40Gy. Younger age, higher body mass index, tumor location in a medial quadrant, and presence of a parasternal field were also associated with higher heart dose. CONCLUSION: Tumor location and treatment choices influence cardiac dose with complex interactions. There is considerable variability in heart dose, with dose metrics of different cardiac sub-structures showing different patterns in their dependency on external influences. Dose-response analysis of late cardiac effects after radiotherapy requires detailed individual dosimetry.

Investigation of correction factors for non-reference conditions in ion chamber photon dosimetry with Monte-Carlo simulations.

Current dosimetry protocols require geometrical reference conditions for the determination of absorbed dose in external radiotherapy. Whenever these geometrical conditions cannot be maintained the application of additional corrections becomes necessary, in principle. The current DIN6800-2 protocol includes a corresponding factor k(NR), but numerical values are lacking and no definite information about the magnitude of this correction is available yet. This study presents Monte-Carlo based calculations within the 6 MV-X photon field of a linear accelerator for a common used ion chamber (PTW31010) employing the EGSnrc code system. The linear accelerator model was matched to measurements, showing good agreement and is used as a realistic source. The individual perturbation correction factors as well as the resulting correction factor k(NR) were calculated as a function of depth for three field sizes, as a function of central axis distance for the largest field and within the build-up region. The behaviour of the ion chamber was further investigated for an idealized hypothetical field boundary. Within the field of the linear accelerator where charged particle equilibrium is achieved the factor k(NR) was generally below approximately 0.5%. In the build-up region a depth dependent correction of up to 2% was calculated when positioning the chamber according to DIN6800-2. Minimizing the depth dependence of the corrections in the build-up region lead to a slightly different positioning of the ion chamber as currently recommended. In regions of the hypothetical field boundary with missing charged particle equilibrium and high dose gradients, the ion chamber response changed by up to approximately 40%, caused by the comparatively large volume (0.125 cm(3)) of the investigated chamber.

Verification of a commercial implementation of the Macro-Monte-Carlo electron dose calculation algorithm using the virtual accelerator approach.

In this work, the accuracy of the implementation of the Macro Monte Carlo electron dose calculation algorithm into the radiation therapy treatment planning system Eclipse is evaluated. This implementation - called eMC - uses a particle source based on the Rotterdam Initial Phase-Space model. A three-dimensional comparison of eMC calculated dose to dose distributions resulting from full treatment head simulations with the Monte Carlo code package EGSnrc is performed using the 'virtual accelerator' approach. Calculated dose distributions are compared for a homogeneous tissue equivalent phantom and a water phantom with air and bone inhomogeneities. The performance of the eMC algorithm in both phantoms can be considered acceptable within the 2%/2 mm Gamma index criterion. A systematic underestimation of dose by the eMC algorithm within the air inhomogeneity is found.