Enhancement of IUdR Radiosensitization by Low-Energy Photons Results from Increased and Persistent DNA Damage.

Low-energy X-rays induce Auger cascades by photoelectric absorption in iodine present in the DNA of cells labeled with 5-iodo-2'-deoxyuridine (IUdR). This photoactivation therapy results in enhanced cellular sensitivity to radiation which reaches its maximum with 50 keV photons. Synchrotron core facilities are the only way to generate such monochromatic beams. However, these structures are not adapted for the routine treatment of patients. In this study, we generated two beams emitting photon energy means of 42 and 50 keV respectively, from a conventional 225 kV X-ray source. Viability assays performed after pre-exposure to 10 µM of IUdR for 48h suggest that complex lethal damage is generated after low energy photons irradiation compared to 137Cs irradiation (662KeV). To further decipher the molecular mechanisms leading to IUdR-mediated radiosensitization, we analyzed the content of DNA damage-induced foci in two glioblastoma cell lines and showed that the decrease in survival under these conditions was correlated with an increase in the content of DNA damage-induced foci in cell lines. Moreover, the follow-up of repair kinetics of the induced double-strand breaks showed the maximum delay in cells labeled with IUdR and exposed to X-ray irradiation. Thus, there appears to be a direct relationship between the reduction of radiation survival parameters and the production of DNA damage with impaired repair of these breaks. These results further support the clinical potential use of a halogenated pyrimidine analog combined with low-energy X-ray therapy.

Cardiac Diseases Following Childhood Cancer Treatment: Cohort Study.

BACKGROUND: Cardiac disease (CD) is one of the major side effects of childhood cancer therapy, but until now little has been known about the relationship between the heart radiation dose (HRD) received during childhood and the risk of CD. METHODS AND RESULTS: The cohort comprised 3162 5-year survivors of childhood cancer. Chemotherapy information was collected and HRD was estimated. There were 347 CDs in 234 patients, 156 of them were rated grade ≥3. Cox and Poisson regression models were used. The cumulative incidence of any type of CD at 40 years of age was 11.0% (95% confidence interval [CI], 9.5-12.7) and 7·4% (95% CI, 6.2-8.9) when only the CDs of grade ≥3 were considered. In comparison with patients who received no anthracycline and either no radiotherapy or an HRD<0·1Gy, the risk was multiplied by 18·4 (95% CI, 7.1-48.0) in patients who had received anthracycline and no radiotherapy or a HRD <0.1Gy, by 60.4 (95% CI, 22.4-163.0) in those who had received no anthracycline and an HRD≥30Gy, and 61.5 (95% CI, 19.6-192.8) in those who had received both anthracycline and an HRD≥30Gy. CONCLUSIONS: Survivors of childhood cancers treated with radiotherapy and anthracycline run a high dose-dependent risk of developing CD. CDs develop earlier in patients treated with anthracycline than in those treated without it.

Epac contributes to cardiac hypertrophy and amyloidosis induced by radiotherapy but not fibrosis.

BACKGROUND: Cardiac toxicity is a side-effect of anti-cancer treatment including radiotherapy and this translational study was initiated to characterize radiation-induced cardiac side effects in a population of breast cancer patients and in experimental models in order to identify novel therapeutic target. METHODS: The size of the heart was evaluated in CO-HO-RT patients by measuring the Cardiac-Contact-Distance before and after radiotherapy (48months of follow-up). In parallel, fibrogenic signals were studied in a severe case of human radiation-induced pericarditis. Lastly, radiation-induced cardiac damage was studied in mice and in rat neonatal cardiac cardiomyocytes. RESULTS: In patients, time dependent enhancement of the CCD was measured suggesting occurrence of cardiac hypertrophy. In the case of human radiation-induced pericarditis, we measured the activation of fibrogenic (CTGF, RhoA) and remodeling (MMP2) signals. In irradiated mice, we documented decreased contractile function, enlargement of the ventricular cavity and long-term modification of the time constant of decay of Ca(2+) transients. Both hypertrophy and amyloid deposition were correlated with the induction of Epac-1; whereas radiation-induced fibrosis correlated with Rho/CTGF activation. Transactivation studies support Epac contribution in hypertrophy stimulation and showed that radiotherapy and Epac displayed specific and synergistic signals. CONCLUSION: Epac-1 has been identified as a novel regulator of radiation-induced hypertrophy and amyloidosis but not fibrosis in the heart.

A multi-plane source model for out-of-field head scatter dose calculations in external beam photon therapy.

Our purpose was to assess the out-of-field dose component related to head scatter radiation in high-energy photon therapy beams and then derive a multisource model for this dose component. For scattered photons, several planar sources have been defined, with number, location and tilt depending on the complexity of the field shape. In the absence of precise knowledge of out-of-field scattering characteristics, several assumptions are made to derive emission spectra and radiation intensity from measurements. Among these, the Compton formula is used to evaluate scattered photon energy and the Henyey-Greenstein phase function is used to evaluate the scattered photon angular distribution. For measured doses under out-of-field conditions, the average local difference between the calculated and measured photon dose is 10%, including doses as low as 0.01% of the maximum dose on the beam axis. This study demonstrates that the multi-plane source approach is suitable for accurate analytical modeling of the out-of-field dose component related to head scatter radiation. These results should be taken into account when evaluating doses to the remaining volume at risk in external beam radiotherapy planning.

Thyroid adenomas after solid cancer in childhood.

PURPOSE: Very few childhood cancer survivor studies have been devoted to thyroid adenomas. We assessed the role of chemotherapy and the radiation dose to the thyroid in the risk of thyroid adenoma after childhood cancer. METHODS AND MATERIALS: A cohort of 3254 2-year survivors of a solid childhood cancer treated in 5 French centers before 1986 was established. The dose received by the isthmus and the 2 lobes of the thyroid gland during each course of radiation therapy was estimated after reconstruction of the actual radiation therapy conditions in which each child was treated as well as the dose received at other anatomical sites of interest. RESULTS: After a median follow-up of 25 years, 71 patients had developed a thyroid adenoma. The risk strongly increased with the radiation dose to the thyroid up to a few Gray, plateaued, and declined for high doses. Chemotherapy slightly increased the risk when administered alone but also lowered the slope of the dose-response curve for the radiation dose to the thyroid. Overall, for doses up to a few Gray, the excess relative risk of thyroid adenoma per Gray was 2.8 (90% CI: 1.2-6.9), but it was 5.5 (90% CI: 1.9-25.9) in patients who had not received chemotherapy or who had received only 1 drug, and 1.1 (90% CI: 0.4-3.4) in the children who had received more than 1 drug (P=.06, for the difference). The excess relative risk per Gray was also higher for younger children at the time of radiation therapy than for their older counterparts and was higher before attaining 40 years of age than subsequently. CONCLUSIONS: The overall pattern of thyroid adenoma after radiation therapy for a childhood cancer appears to be similar to that observed for thyroid carcinoma.

Total heart volume as a function of clinical and anthropometric parameters in a population of external beam radiation therapy patients.

The aim of this paper was to determine anthropometric parameters leading to the least uncertain estimate of heart size when connecting a computational phantom to an external beam radiation therapy (EBRT) patient. From computed tomography images, we segmented the heart and calculated its total volume (THV) in a population of 270 EBRT patients of both sexes, aged 0.7­83 years. Our data were fitted using logistic growth functions. The patient age, height, weight, body mass index and body surface area (BSA)were used as explanatory variables. For both genders, good fits were obtained with both weight (R2 = 0.89 formales and 0.83 for females) and BSA (R2=0.90 formales and 0.84 for females). These results demonstrate that, among anthropometric parameters, weight plays an important role in predicting THV. These findings should be taken into account when assigning a computational phantom to a patient.

Radiation therapy and late mortality from second sarcoma, carcinoma, and hematological malignancies after a solid cancer in childhood.

PURPOSE: To compare patterns of long-term deaths due to secondary carcinomas, sarcomas, and hematological malignancies occurring after childhood cancer in a cohort of patients followed over a median of 28 years. METHODS AND MATERIALS: The study included 4,230 patients treated at eight institutions, who were at least 5-year survivors of a first cancer, representing 105,670 person-years of observation. Complete clinical, chemotherapeutic, and radiotherapeutic data were recorded, and the integral radiation dose was estimated for 2,701 of the 2,948 patients who had received radiotherapy. The integral dose was estimated for the volume inside the beam edges. The causes of death obtained from death certificates were validated. RESULTS: In total, 134 events were due to second malignant neoplasm(s) (SMN). We found that the standardized mortality ratio decreased with increasing follow-up for second carcinomas and sarcomas, whereas the absolute excess risk (AER) increased for a second carcinoma but decreased for second sarcomas. There was no clear variation in SMN and AER for hematological malignancies. We found a significant dose-response relationship between the radiation dose received and the mortality rate due to a second sarcoma and carcinoma. The risk of death due to carcinoma and sarcoma as SMN was 5.2-fold and 12.5-fold higher, respectively, in patients who had received a radiation dose exceeding 150 joules. CONCLUSIONS: Among patients who had received radiotherapy, only those having received the highest integral radiation dose actually had a higher risk of dying of a second carcinoma or sarcoma.

Comparison of dose contribution to normal pelvic tissues among conventional, conformal and intensity-modulated radiotherapy techniques in prostate cancer.

High-energy external radiotherapy has become one of the most common treatment in localized prostate cancer. We compared the difference of dose distribution, mainly at the 5-30 Gy dose level, in the irradiated pelvic volume among three modalities of radiotherapy for patients with prostate cancer: conventional, conformal and intensity-modulated radiotherapy (IMRT). We selected six patients with prostate cancer treated by conformal radiotherapy at the doses of 46 Gy to PTVN (prostate and seminal vesicles), and 70 Gy to PTV-T (prostate). The conventional technique": an 8-field arrangement was used; the conformal technique 4 fields with a boost through 6 fields. For IMRT, a five-beam arrangement was used. Dose-volume histograms (DVH) were analyzed and compared among the three techniques. The IMRT technique significantly increased the pelvic volume covered by the isodose surfaces below 15 Gy as compared with the conventional and conformal techniques. The mean absolute increase for the pelvic volume included between 5-30 Gy for the IMRT technique, was about 2 900 ml as compared with the conventional technique. However, IMRT significantly reduced the irradiated volume of the rectum in the dose range of 5 to 40 Gy, also significantly reduced the irradiated volume of bladder and femoral heads, and obtained a similar or improved isodose distribution in the PTVs. In addition, the use of IMRT slightly increased the relative dose delivered to the body volume outside the pelvis, as estimated by the use of specific software. A long-term follow-up will be needed to evaluate potential late treatment complications related to the use of IMRT and the low or moderate irradiation dose level obtained in the pelvis and in the whole body.

Development of a TLD mailed system for remote dosimetry audit for (192)Ir HDR and PDR sources.

BACKGROUND AND PURPOSE: In the framework of an ESTRO ESQUIRE project, the BRAPHYQS Physics Network and the EQUAL-ESTRO laboratory have developed a procedure for checking the absorbed dose to water in the vicinity of HDR or PDR sources using a mailed TLD system. The methodology and the materials used in the procedure are based on the existing EQUAL-ESTRO external radiotherapy dose checks. MATERIALS AND METHODS: A phantom for TLD postal dose assurance service, adapted to accept catheters from different HDR afterloaders, has been developed. The phantom consists of three PMMA tubes supporting catheters placed at 120 degrees around a central TLD holder. A study on the use of LiF powder type DTL 937 (Philitech) has been performed in order to establish the TLD calibration in dose-to-water at a given distance from (192)Ir source, as well as to determine all correction factors to convert the TLD reading into absorbed dose to water. The dosimetric audit is based on the comparison between the dose to water measured with the TL dosimeter and the dose calculated by the clinical TPS. Results of the audits are classified in four different levels depending on the ratio of the measured dose to the stated dose. The total uncertainty budget in the measurement of the absorbed dose to water using TLD near an (192)Ir HDR source, including TLD reading, correction factors and TLD calibration coefficient, is determined as 3.27% (1s). RESULTS: To validate the procedures, the external audit was first tested among the members of the BRAPHYQS Network. Since November 2004, the test has been made available for use by all European brachytherapy centres. To date, 11 centres have participated in the checks and the results obtained are very encouraging. Nevertheless, one error detected has shown the usefulness of this audit. CONCLUSION: A method of absorbed dose to water determination in the vicinity of an (192)Ir brachytherapy source was developed for the purpose of a mailed TL dosimetry system. The accuracy of the procedure was determined. This method allows a check of the whole dosimetry chain for this type of brachytherapy afterloading system and can easily be performed by mail to any institution in the European area and elsewhere. Such an external audit can be an efficient QC method complementary to internal quality control as it can reveal some errors which are not observable by other means.