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The purpose of this study was to measure the scattered dose to out-of-field organs from head and neck radiotherapy in pediatric patients and to estimate the risk for second cancer induction to individual organs. Radiotherapy for thalamic tumor, brain tumor, acute leukemia and Hodgkin's disease in the neck region was simulated on 5 and 10-year-old pediatric phantoms with a 6 MV photon beam. The radiation dose to thyroid, breast, lung, stomach, ovaries, bladder, liver, uterus, prostate and colon was measured using thermoluminescent dosimeters. The methodology, provided by the BEIR VII report was used for the second cancer risk estimations. Peripheral dose range for a simulated 5-year-old patient was 0.019%–1.572% of the given tumor dose. The corresponding range at the advanced patient age was reduced to 0.018%–1.468%. The second cancer risk per fraction for male patients varied from 3 to 215 per 1,000,000 patients depending upon the age at the time of exposure, primary cancer site and organ scattered dose. The corresponding risk for females was 1–1186 per 1,000,000 patients. The higher risk values were found for breast, thyroid and lung cancer development. The current data concerning the risk magnitude for developing subsequent neoplasms to various out-of-field organs may be of value for health care professionals in the follow-up studies of childhood cancer survivors.
Improvement in childhood cancer treatment over the last years has resulted in longer survival. In the United States nearly 75% of children with cancer survive to adulthood [
Ries LAG, Melbert D, Krapcho M, Stinchcomb DG, Howlander N, Horner MJ et al, SEER cancer statistics review 1975-2005, Available from: http://seer.cancer.gov/csr/1975_2005/.
]. Radiotherapy plays a major role in the treatment of the above pediatric malignancies. Nevertheless, therapeutic external irradiation may always expose the organs-at-risk to ionizing radiation even if they are located outside the collimated field [
]. Water phantoms are currently unable to simulate both the shape of pediatric patient and the tissue inhomogeneities. Out-of-field dose values are usually obtained using open square fields at a gantry angle of 0°, which cannot simulate the real conditions of head and neck radiotherapy. The use of water phantom measurements may introduce errors in the assessment of out-of-field doses presented in pediatric patients [
]. The purpose of the current study was to measure the scattered dose to out-of-field organs from head and neck irradiations and to estimate the risk of developing second cancer for 5- and 10-year old male and female patients.
Materials and methods
Pediatric phantoms
Two anthropomorphic phantoms (ATOM Ltd, Norfolk, VA, USA), constructed from tissue equivalent material were used in this study. The phantoms simulated an average child of 5 and 10-year-old with a weight of 19 kg and 32 kg, respectively. The height of the simulated children was 110 cm and 120 cm, respectively. The phantoms representing 5- and 10-year-old patients are divided into 26 and 32 slices, respectively. The thickness of each slice is 2.5 cm. All slices have a grid of 5 mm diameter hole for TLD accommodation. The positions of radiosensitive organs, which show strong predilection for carcinogenesis according to BEIR VII report [
], were determined in pediatric phantoms with the aid of a radiotherapist. The location of the center of each organ-at-risk in both pediatric phantoms is presented in Table 1.
Table 1Organ positions: Phantom's slice no where the center of each organ is lying and depth between organ center and phantom's anterior surface.
Lithium fluoride thermoluminescent dosimeters (TLD-100, Harshaw, Solon, OH, USA), of dimensions 3.0 × 3.0 × 0.9 mm3, were used for organ dose measurements. The dosimeters were read in a Harshaw Bicron 3500 automatic TLD reader (Solon, Ohio, USA). They were annealed before each exposure for 1 h at 400 °C and 20 h at 80 °C. Calibration of TLDs was performed with a 6 MV photon beam on the same linear accelerator (Primus Siemens, Erlangen, Germany) with that employed for all dosimetric measurements presented in this study. The crystals were placed at a depth of 5.5 cm from the anterior surface of a solid water phantom (SP34, Wellhofer, Uppsala, Sweden). They were irradiated with a 15 × 15 cm2 radiation field using an SSD of 100 cm. A cylindrical ionization chamber 0.3 cm3 (PTW 31003, Freiburg, Germany) was used as a dosimetric reference unit. The background signal was subtracted from TLDs signal. The sensitivity factor of each TLD crystal was initially determined and, then, the TLDs were divided into three batches each having similar sensitivity. The standard deviation of sensitivity factors within each batch was less than 4%. For each batch, the mean sensitivity factor was adopted for scattered dose measurements. Two dosimeters were placed at a position corresponding to the center of each organ-at-risk. The average value of the two TLD readings was considered as the organ absorbed-dose.
Phantom irradiations
Out-of-field dose measurements were performed for the most common pediatric malignances requiring head or neck irradiation. Treatment planning procedure was performed in the simulator (SIEMVIEW NT, Siemens, Erlangen, Germany) of our department by a radiotherapist experienced in the management of pediatric tumors. Therapeutic irradiation of brain tumors and thalamic lesions was simulated with two lateral and opposed treatment fields. A similar field configuration was employed to simulate prophylactic cranial irradiation applied for treatment of acute lymphoblastic leukemia. Anteroposterior (AP) and posteroanterior (PA) field irradiations were used to represent the real conditions of radiotherapy of Hodgkin's disease in the neck region.
All treatments were performed isocentrically with 6 MV X-rays. An isocentric dose of 1300 cGy was delivered during each field treatment to ensure significant TLDs readings. For irradiation of brain and thalamic tumors, the collimator was properly angled to protect the eye lens and surrounding healthy tissues. Regarding the acute leukemia disease, multileaf collimators (MLCs) were used to shield the eye globes and surrounding healthy facial structures. For radiotherapy of HD in the region of neck, the MLCs were used to protect the thyroid gland and spinal cord. In our linear accelerator, the MLCs behave as a pair of x-jaws. The dimensions of the rectangular fields before the required MLC insertion for field shaping are presented in Table 2. The field sizes and the distances separating the organs-at-risk from the field edge are presented in Table 2, Table 3, respectively. The thyroid gland was partly included in the treatment field used for cervical node irradiation and, therefore, no scattered dose measurements were carried out.
The tumor dose per fraction during head radiotherapy was 180 cGy whereas the respective dose for cervical node irradiation was 150 cGy. To estimate the risk per fraction for developing subsequent neoplasms to individual organs, the organ doses per fraction were multiplied by the appropriate risk factors. The National Academies committee on Biological Effects of Ionizing Radiation (BEIR) report VII has provided sex-, age-, and organ-specific risk coefficients to assess the lifetime attributable risk (LAR) of radiation induced cancer [
]. These coefficients have been adjusted by the dose and dose rate effectiveness factor of 1.5 and, therefore, the effect of dose fractionation on the risk estimates has already been taken into account [
]. For each malignant disease, the LAR was calculated for male and female pediatric patients irradiated at the age of 5 and 10-year-old. The projected LAR for any childhood cancer survivor refers to the risk of developing malignancies to any specific radiosensitive organ at any time after radiotherapy. The above described risk calculation method has been widely adopted by many previous studies referring to radiotherapy-induced cancer to out-of-field organs [
A comparative study on the risk of second primary cancers in out-of-field organs associated with radiotherapy of localized prostate carcinoma using Monte Carlo-based accelerator and patient models.
Out-of-field organ doses from radiotherapy of 5 and 10-year-old patients are presented in Table 4. Dose values are given as a percentage of the radiation dose delivered to the tumor site. The LAR for 5 and 10-year-old patient is presented in Figure 1, Figure 2, respectively. For a pediatric patient at the age of 5-year-old, peripheral doses varied from 0.019% to 1.572%, depending upon the primary cancer site. The respective dose range at the advanced pediatric patient age was from 0.018% to 1.468%.
Table 4Out-of-field organ doses for 5- and 10-year-old patients.
Figure 1Lifetime Attributable Risk (LAR) per fraction for out-of-field organs of a 5-year-old patient from radiotherapy for (a) thalamic tumor, (b) brain tumor, (c) leukemia and (d) Hodgkin's disease in the neck region.
Figure 2Lifetime Attributable Risk (LAR) per fraction for out-of-field organs of a 10-year-old patient from radiotherapy for (a) thalamic tumor, (b) brain tumor, (c) leukemia and (d) Hodgkin's disease in the neck region.
The thyroid gland absorbed the highest amount of scattered radiation during head irradiation. For radiotherapy of brain malignancy, thalamic lesion and leukemia at the age of 5-year-old, the thyroid dose was 0.412%, 0.480% and 1.572% of the prescribed tumor dose, respectively. The corresponding scattered doses for the 10-year-old pediatric phantom were 0.382%, 0.433% and 1.468%. The breast tissue received the highest radiation dose for cervical node irradiation. Breast dose was equal to 0.648% and 0.510% of the delivered tumor dose during treatment at the age of 5 and 10-year-old, respectively. As expected, organs below the diaphragm received the lowest amount of scattered radiation. The scattered dose to abdominopelvic organs was below 0.20% of the prescribed tumor dose irrespectively of the patient age.
The second cancer risk per fraction for 5-year-old male patients was (3–215) × 10−6 depending upon the scattered dose to individual organs and the second cancer site. The respective risk at the advanced patient age was (3–132) × 10−6. The second cancer risk range for 5 and 10-year-old female patients was (1–1186) × 10−6 and (1–726) × 10−6, respectively. Brain and thalamic radiotherapy to a typical total tumor dose of 5580 cGy may result in a maximum risk value for organ cancer induction of 1124 × 10−5 and 963 × 10−5, respectively. Cervical node irradiation with a dose of 2400 cGy is associated with a maximum cancer risk to an individual organ of 1417 × 10−5. The corresponding risk for leukemia treatment with a typical cranial dose of 1800 cGy is 1186 × 10−5. For male patients, the total LAR of all solid cancers from the entire radiotherapy course was (231–348) × 10−5. The corresponding risk for female patients was (1208–1764) × 10−5.
Discussion
In the current study 5 and 10-year old pediatric phantoms were used to measure out-of-field organ doses and then to calculate the second cancer risk associated with head and neck irradiations. The out-of-field doses varied considerably depending upon the location of the organ-at-risk relative to the primary cancer site. As expected, organs located at the most distant positions from the head and neck region received the lowest amount of radiation. The associated second cancer risk was strongly dependent upon the organ dose, gender and age at the time of treatment. Head irradiations resulted in out-of-field organ doses up to 28.3 cGy. The above thyroid gland dose is much lower than the value of 2500 cGy which may be associated with thyroid dysfunction [
] has reported that thyroid doses as low as 10 cGy can cause secondary malignancies. The highest scattered dose during treatment of HD in the neck region was observed in the breast due to the close proximity of this tissue to the treatment volume. Breast radiation doses up to 15.5 cGy were measured.
Several studies have focused on the second cancer risk after therapeutic irradiation of pediatric malignant diseases [
Radiation dose and relapse are predictors for development of second malignant solid tumors after cancer in childhood and adolescence: a population-based case-control study in the five Nordic countries.
]. The majority of the subsequent neoplasms appear within the primary radiation field or in a region bordering the treatment volume. Svahn-Tapper et al [
Radiation dose and relapse are predictors for development of second malignant solid tumors after cancer in childhood and adolescence: a population-based case-control study in the five Nordic countries.
] showed that 22% of subsequent neoplasms occur 5 cm away from the treatment fields. These reports clearly reveal that the risk for secondary cancer induction at distant locations from the irradiated area may be relatively small but not trivial. The higher cancer risk values presented in our study were found for organs located at small distances from the field edge.
In the present study the highest second cancer risk from head irradiations for male and female patients was noticed for thyroid cancer. The thyroid cancer risk for females was 5.5 times higher than the thyroid cancer risk for male patients. Furthermore, an elevated lung cancer risk was observed for male and a high breast cancer risk for female patients. Regarding neck irradiations, breast cancer was the most probable detriment for female patients. For female patients, the risk for developing breast carcinomas was one per one hundred children treated for HD in the neck region. The corresponding detrimental effect for male patient was lung cancer. Nevertheless, females had 2.3 times higher lung cancer risk than males.
There are few publications which have estimated out-of-field organ doses for pediatric head and neck irradiations [
] reported thyroid dose up to 1.40% and 1.58%, respectively, of the prescribed tumor dose from treatment of acute lymphoblastic leukemia. These results are similar with the values of 1.47%–1.57% presented here. For similar field sizes and distances from treatment volume, our thyroid dose measurements were comparable with the values of about 0.70% obtained by Mazonakis et al. [
] because of the different irradiation technique used.
Sources of error in out-of-field organ dose measurements are mainly caused by the uncertainty of TLDs. Our measurements were derived by using anthropomorphic phantoms representing average pediatric patients. Abnormal patient sizes may result in different distances from treatment volume and, therefore, they may introduce errors in out-of-field organ dose assessment. Moreover, the current study provides information about the dose at the center of each organ where the TLDs were placed. Regarding the energy dependence in dosimetric data acquisitions using 6 MV X-rays, previously reported Monte Carlo simulations have shown that the average photon energy on central axis at dmax is 1.50 MeV [
]. The above imply a limited energy dependence. The dosimetric results of this study refer to common radiotherapy techniques with 6 MV X-rays on a Siemens Primus linear accelerator. Patient's irradiation with different therapy machines or techniques might result in different out-of-field dose values than those presented here.
It is well known that the models used for the estimation of the radiation induced cancer risk based on organ dose measurements may contain considerable uncertainties especially in the low dose regions. Athar et al. [
] have reported that the uncertainty of the methodology introduced by the BEIR VII report might introduce an error up to 50%. The BEIR is predicated on the linear no-threshold model. This model assumes that the second cancer risk at low-dose exposures to radiation can be extrapolated from linear fits to the second cancer risk at high-dose exposure. Despite these uncertainties, the analytical data of the projected LAR values presented here may constitute a useful guide for clinicians and radiotherapists to obtain rough estimations of second cancer risk.
Conclusion
The present study provides out-of-field doses and the risk for second cancer to various organs attributable to head and neck irradiation during childhood. The presented dosimetric results show that the risk for developing subsequent neoplasms in abdominopelvic organs is low or even negligible. The thyroid gland, lung and breast have increased risk for second cancer induction due to the close proximity to the applied treatment fields. Follow-up studies concerning the diagnosis of thyroid gland, breast and lung carcinomas might be of value in these childhood cancer survivors.
References
Ries LAG, Melbert D, Krapcho M, Stinchcomb DG, Howlander N, Horner MJ et al, SEER cancer statistics review 1975-2005, Available from: http://seer.cancer.gov/csr/1975_2005/.
A comparative study on the risk of second primary cancers in out-of-field organs associated with radiotherapy of localized prostate carcinoma using Monte Carlo-based accelerator and patient models.
Radiation dose and relapse are predictors for development of second malignant solid tumors after cancer in childhood and adolescence: a population-based case-control study in the five Nordic countries.
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