SECOND CANCER RISK FROM RADIATION THERAPY FOR COMMON SOLID TUMORS DIAGNOSED IN REPRODUCTIVE-AGED FEMALES

SECOND CANCER RISK FROM RADIATION THERAPY FOR COMMON SOLID TUMORS DIAGNOSED IN REPRODUCTIVE-AGED... Abstract This study provided second cancer risk estimates from radiation therapy for common solid tumors presented in reproductive-aged females. Three-dimensional treatment plans were generated for 10 patients with cervical, uterine, rectal, lung or breast carcinomas. The organ equivalent dose (OED) and the lifetime attributable risk (LAR) for carcinogenesis to organs receiving high doses were estimated for all study participants with a mechanistic model. This model accounts for cell-killing, tissue repair and dose fractionation effects. The patient- and organ-specific relative risk was assessed by using the LARs and the respective lifetime intrinsic cancer risks for unexposed population. The OED of the organs-at-risk varied from 17.3 to 1423.1 rad. The LAR range for bladder, colon, lung and breast cancer induction was 0.12–0.14%, 10.88–12.71%, 1.66–8.62% and 0.71–3.75%, respectively. The relative risk for the appearance of bladder, colon, lung and breast malignancies following radiotherapy was up to 1.12, 4.05, 2.42 and 1.31, respectively. INTRODUCTION Siegel et al.(1) reported that more than 850 000 new cancer cases are estimated to be presented in women of the United States of America in 2017. The recent improvements in cancer diagnosis and treatment have considerably increased the 5-year survival of female patients suffering from all malignant diseases from 55.6% in the decade of 70s to 69.1% nowadays(2). The 10-year survival rate has also been elevated to 61.6% from 48.7% 40 years ago(2). The 10% of the female cancer survivors are young with an age of <40 years old(3). Radiotherapy either alone or in combination with other anticancer therapeutic approaches such as surgery or chemotherapy is often employed for the management of malignant diseases in reproductive-aged females. It is well known that the patient’s exposure to high doses delivered by high-energy beams of ionizing radiation may increase the risk for the development of secondary cancers. Previous studies have reported data about the second cancer risk from radiation therapy of hematologic malignancies such as Hodgkin lymphoma in young adult females(4–6). Epidemiological data about the risk for carcinogenesis due to irradiation of young females with solid tumors have also been published(7–9). Chatuverdi et al.(7) found that the cumulative risks for the appearance of secondary malignancies in women irradiated for cervical cancer at ages below 50 years are higher than those observed for older females. Stovall et al.(9) also reported that radiotherapy for breast malignancies at ages smaller than 40 years old leads to an elevated contralateral breast cancer risk whereas no excess risk exists at older ages. Berrington de Gonzalez et al.(8) found that the probabilities for cancer induction at healthy tissues following breast irradiation are reduced with increasing patient’s age and year of exposure. It should be noted that the above data were collected from patients with solid malignant diseases irradiated before 2001(7–9) and included subjects treated up to 75 years ago(8). The process of treatment planning without the use of computed tomography (CT) images for many of these patients could lead to increased volumes of irradiated healthy tissues, and subsequently, to an elevated incidence of radiation effects(8). The treatment delivery might also differ considerably from the current irradiation techniques which are usually performed on linear accelerators equipped with multileaf collimators for the automatic and accurate conformation of the treatment fields to the target site. The purpose of this study was to estimate the second cancer risk at sites receiving high radiation doses attributable to photon-beam radiotherapy for common solid tumors diagnosed in reproductive-aged females. MATERIALS AND METHODS Patient selection The most common solid tumors presented in females of reproductive age are located in the cervix, uterus, ovaries, gastrointestinal tract, lungs and breasts(10). Chemotherapy is usually employed for patients with ovarian carcinoma(10). Radiation therapy plays a major role in the management of the cervical, uterine, colorectal, lung and breast cancer(11). Our study group consisted of reproductive-aged females who were referred in our department for external-beam radiotherapy with photon beams for the above five malignant diseases. Four patients with cervical cancer, one with uterine carcinoma, one with a malignant disease in the rectum, one with lung cancer and three with breast malignancies were included in this work. The patient’s age at the time of treatment was 34–47 years old. Patient’s irradiation All study participants initially underwent a treatment planning CT scanning on a 16-slice unit (Somatom Sensation 16, Siemens, Forcheim, Germany). The delineation both of the planning target volume (PTV) and the surrounding organs-at-risk was carried out by an experienced radiation oncologist. The 3D CT-based therapy plans were produced with the aid of XiO software (CMS Inc., St Louis, MO, USA). Each patient’s plan consisted of isocentric treatment fields shaped by multileaf collimators. All therapy plans were created with 6 MV photon beams emitted by a medical linear accelerator (Primus, Siemens, Germany). The total tumor dose, the tumor dose per fraction and the beam arrangement applied for radiotherapy of each malignancy are presented in Table 1. Table 1. Irradiation parameters used for treatment of female patients with various solid tumors. The beam arrangement, the total tumor dose and the fraction dose are presented. Patient no. Irradiation site Beam arrangement Total tumor dose (rad) Fraction dose (rad) 1, 2, 3, 4 Cervix 4-Field box 5040 180 5 Uterus 4-Field box 5040 180 6 Rectum 4-Field box 5040 180 7 Lung AP + 2 oblique fields 6480 180 8, 9, 10 Breast 2 Tangential fields 5000 200 Patient no. Irradiation site Beam arrangement Total tumor dose (rad) Fraction dose (rad) 1, 2, 3, 4 Cervix 4-Field box 5040 180 5 Uterus 4-Field box 5040 180 6 Rectum 4-Field box 5040 180 7 Lung AP + 2 oblique fields 6480 180 8, 9, 10 Breast 2 Tangential fields 5000 200 Table 1. Irradiation parameters used for treatment of female patients with various solid tumors. The beam arrangement, the total tumor dose and the fraction dose are presented. Patient no. Irradiation site Beam arrangement Total tumor dose (rad) Fraction dose (rad) 1, 2, 3, 4 Cervix 4-Field box 5040 180 5 Uterus 4-Field box 5040 180 6 Rectum 4-Field box 5040 180 7 Lung AP + 2 oblique fields 6480 180 8, 9, 10 Breast 2 Tangential fields 5000 200 Patient no. Irradiation site Beam arrangement Total tumor dose (rad) Fraction dose (rad) 1, 2, 3, 4 Cervix 4-Field box 5040 180 5 Uterus 4-Field box 5040 180 6 Rectum 4-Field box 5040 180 7 Lung AP + 2 oblique fields 6480 180 8, 9, 10 Breast 2 Tangential fields 5000 200 Organs-at-risk The linearity between the cancer risk and radiation dose in the high dose region exceeding 2.5 Gy is under question(12). In the current study, a non-linear mechanistic model proposed by Schneider et al.(13) was used for estimating the probability for carcinogenesis at specific sites exposed to high therapeutic doses. The model has already been applied for cancer risk assessments due to radiation therapy for both malignant(5, 14) and benign diseases(15). The dose–volume histograms obtained by the patients’ radiotherapy plans were used to define the critical organs receiving doses of more than 2.5 Gy for which Schneider et al.(13) provided the required data enabling the cancer risk assessment. Parts of the colon and bladder absorbed doses exceeding the above value in the irradiation for cervical, uterine and rectal cancer. Similar high doses were received by portions of the lungs and the contralateral breast during radiotherapy for breast malignancies. The contralateral healthy lung and breasts were also partly exposed to radiation doses above 2.5 Gy during radiation therapy for lung cancer. Second cancer risk estimates with a mechanistic model The model of Schneider et al.(13) is based on the use of the organ equivalent dose (OED) to each organ of interest. The quantity OED is directly proportional to the resultant cancer risk. The OED of the healthy organs referred in the previous section was calculated with the following formula: OED=1Vt∑iVDiexp(−ai′Di)−ai′R×[1−2R+R2exp(ai′Di)−(1−R)2exp(−ai′R1−RDi)] (1) where Vt is the whole organ volume, VDi is the organ volume receiving a dose equal to Di , R is the repopulation factor for each organ of interest and ai′ is the cell-killing parameter. The quantities Vt and VDi were determined by the differential dose–volume histograms derived from the patients’ 3D therapy plans. The radiation exposure of the rectum was taken into account in the estimation of the OED and the relevant cancer risk to colon. The organ-specific factor ai′ was calculated as follows: ai′=a+βDfDtDi (2) where a and β are the parameters for each organ-at-risk derived from the linear quadratic model, Df is the radiation dose to the tumor per fraction and Dt is the total tumor dose. The Df and Dt received by each tumor site are given in Table 1. The organ-dependent model parameters R, a and a/β, as provided by previously published reports(13, 16, 17), are summarized in Table 2. Table 2. Organ-dependent parameters employed for organ equivalent dose calculation and second cancer risk assessment with the mechanistic model. The presented values were derived from previously published studies(13, 16, 17). Organ a (Gy−1) a/β (Gy) R βEAR (104 PY Gy)−1 γe (y−1) γa (y−1) Colon 0.001 3 0.99 7.4 −0.056 6.9 Bladder 0.219 3 0.06 3.8 −0.024 2.38 Lung 0.061 3 0.84 8.0 0.002 4.23 Breast 0.067 3 0.62 8.2 −0.037 1.7 Organ a (Gy−1) a/β (Gy) R βEAR (104 PY Gy)−1 γe (y−1) γa (y−1) Colon 0.001 3 0.99 7.4 −0.056 6.9 Bladder 0.219 3 0.06 3.8 −0.024 2.38 Lung 0.061 3 0.84 8.0 0.002 4.23 Breast 0.067 3 0.62 8.2 −0.037 1.7 Table 2. Organ-dependent parameters employed for organ equivalent dose calculation and second cancer risk assessment with the mechanistic model. The presented values were derived from previously published studies(13, 16, 17). Organ a (Gy−1) a/β (Gy) R βEAR (104 PY Gy)−1 γe (y−1) γa (y−1) Colon 0.001 3 0.99 7.4 −0.056 6.9 Bladder 0.219 3 0.06 3.8 −0.024 2.38 Lung 0.061 3 0.84 8.0 0.002 4.23 Breast 0.067 3 0.62 8.2 −0.037 1.7 Organ a (Gy−1) a/β (Gy) R βEAR (104 PY Gy)−1 γe (y−1) γa (y−1) Colon 0.001 3 0.99 7.4 −0.056 6.9 Bladder 0.219 3 0.06 3.8 −0.024 2.38 Lung 0.061 3 0.84 8.0 0.002 4.23 Breast 0.067 3 0.62 8.2 −0.037 1.7 The OED calculations were used to assess the excess absolute risk (EAR) for second cancer induction to specific organs receiving high radiation doses from treatment of cervical, uterine, rectal, lung and breast cancer. The EAR per 10 000 persons per year was estimated with the following equation: EAR=βEAROEDexp[γe(agee−30)+γaln(agea70)] (3) where βEAR is the initial slope of the dose–response curve at low doses for a Western population, agee is the age of the female patient during external-beam radiotherapy, agea is the attained age of the irradiated patient and γe,γa are the age modifying parameters(13). Table 2 shows the previously reported values of βEAR,γe and γa for all organs-at-risk(13). The EARs were estimated by assuming a typical 40-year-old female irradiated for a solid tumor and a maximum attained age of 80 years. The lifetime attributable risk (LAR) for developing a secondary malignant disease in the critical organs due to photon-beam radiotherapy was estimated as follows: LAR=∑agee+L80EAR(Dt,agee,agea)S(agea)S(agee) (4) where L is a free-risk latent interval of 5 years following patient’s treatment and S(agea)/S(agee) is the probability of a female to survive from agee to agea. This survival probability was defined on the basis of the United States life tables(18). Each estimated organ-specific LAR was compared with the respective lifetime intrinsic risk (LIR) for unexposed and cancer-free females as provided by the most recent SEER Cancer Statistics Review 1975–2014(2). For 40-year-old healthy females, the LIR for developing colon, bladder, lung and breast cancer is 4.16, 1.14, 6.07 and 12.25%, respectively(2). The patient- and organ-specific relative risk (RR) for developing each malignancy was determined as the ratio of the sum of LIR and LAR to LIR. Second cancer risk estimates with plateau and bell-shaped models The probability of carcinogenesis following radiotherapy of women in reproductive age was also estimated with the aid of two different models. The bell-shaped model, which ignores the repopulation effects ( R = 0), was initially used. The OED was found with the following formula: OED=1Vt∑iVDiDiexp(−ai′Di) (5) The OED was then calculated on the basis of the plateau model, which assumes a full cell repopulation in the exposed tissues ( R = 1), as follows: OED=1Vt∑iVDiexp(−ai′Di)ai′ (6) The ai′ was determined with equation (2) presented in the previous subsection. The values of the quantity a for both bell-shaped and plateau models are listed in Table 3. The a/β ratio was taken equal to 3 for both models(13). The OED values as derived from the bell-shaped and plateau models were used to estimate the lifetime organ-dependent cancer risk with equation (4). Table 3. Values of the organ-specific parameter a used for organ equivalent dose calculation and second cancer risk assessment with the bell-shaped and plateau models. The values were obtained by a previous study of Schneider et al.(13). Organ a (Gy−1) Bell-shaped model Plateau model Colon 0.001 0.001 Bladder 0.213 0.633 Lung 0.022 0.056 Breast 0.041 0.115 Organ a (Gy−1) Bell-shaped model Plateau model Colon 0.001 0.001 Bladder 0.213 0.633 Lung 0.022 0.056 Breast 0.041 0.115 Table 3. Values of the organ-specific parameter a used for organ equivalent dose calculation and second cancer risk assessment with the bell-shaped and plateau models. The values were obtained by a previous study of Schneider et al.(13). Organ a (Gy−1) Bell-shaped model Plateau model Colon 0.001 0.001 Bladder 0.213 0.633 Lung 0.022 0.056 Breast 0.041 0.115 Organ a (Gy−1) Bell-shaped model Plateau model Colon 0.001 0.001 Bladder 0.213 0.633 Lung 0.022 0.056 Breast 0.041 0.115 RESULTS Second cancer risk estimates with a mechanistic model The OED calculations and the associated LARs for the appearance of secondary malignancies in critical healthy organs during radiotherapy of reproductive-aged females with cervical, uterine and rectal cancer are summarized in Table 4. The OED was up to a value of 1423.1 rad. The patient-specific probability for second cancer induction in the colon due to treatment of pelvic tumors was 10.88–12.71%. The lifetime risk range for developing bladder cancer was much lower and equal to 0.12–0.14%. Table 4. Patient-specific organ equivalent dose (OED) and lifetime attributable risk (LAR) for developing bladder or colon malignancies following radiotherapy for pelvic solid tumors in reproductive-aged females. Patient no. Treatment site Bladder Colon OED (rad) LAR (%) OED (rad) LAR (%) 1 Cervix 18.0 0.13 1293.6 11.55 2 Cervix 18.2 0.13 1260.2 11.25 3 Cervix 17.3 0.12 1423.1 12.71 4 Cervix 17.4 0.13 1321.0 11.80 5 Uterus 19.3 0.14 1346.8 12.03 6 Rectum 17.6 0.13 1218.3 10.88 Patient no. Treatment site Bladder Colon OED (rad) LAR (%) OED (rad) LAR (%) 1 Cervix 18.0 0.13 1293.6 11.55 2 Cervix 18.2 0.13 1260.2 11.25 3 Cervix 17.3 0.12 1423.1 12.71 4 Cervix 17.4 0.13 1321.0 11.80 5 Uterus 19.3 0.14 1346.8 12.03 6 Rectum 17.6 0.13 1218.3 10.88 Table 4. Patient-specific organ equivalent dose (OED) and lifetime attributable risk (LAR) for developing bladder or colon malignancies following radiotherapy for pelvic solid tumors in reproductive-aged females. Patient no. Treatment site Bladder Colon OED (rad) LAR (%) OED (rad) LAR (%) 1 Cervix 18.0 0.13 1293.6 11.55 2 Cervix 18.2 0.13 1260.2 11.25 3 Cervix 17.3 0.12 1423.1 12.71 4 Cervix 17.4 0.13 1321.0 11.80 5 Uterus 19.3 0.14 1346.8 12.03 6 Rectum 17.6 0.13 1218.3 10.88 Patient no. Treatment site Bladder Colon OED (rad) LAR (%) OED (rad) LAR (%) 1 Cervix 18.0 0.13 1293.6 11.55 2 Cervix 18.2 0.13 1260.2 11.25 3 Cervix 17.3 0.12 1423.1 12.71 4 Cervix 17.4 0.13 1321.0 11.80 5 Uterus 19.3 0.14 1346.8 12.03 6 Rectum 17.6 0.13 1218.3 10.88 The OEDs and the relevant lifetime second cancer risks from radiation therapy for solid tumors in the thoracic region are presented in Table 5. The OED values of the lung and breast varied from 48.1 to 480.3 rad. The patient-specific LARs related to the appearance of secondary breast malignancies were found to be 0.71–3.75%. For all patients, the corresponding lifetime probabilities for the induction of a lung malignant disease were more elevated than those related to breast cancer development. The LARs for developing a second lung cancer were 1.66–8.62%. Table 5. Patient-specific organ equivalent dose (OED) and lifetime attributable risk (LAR) for second cancer development following radiotherapy for thoracic solid tumors in reproductive-aged females. Patient no. Treatment site Organ-at-risk OED (rad) LAR (%) 7 Lung Breasts 254.3 3.75 Contralateral lung 480.3 8.62 8 Breast Contralateral breast 67.2 0.99 Lungs 92.6 1.66 9 Breast Contralateral breast 70.2 1.04 Lungs 115.0 2.06 10 Breast Contralateral breast 48.1 0.71 Lungs 158.2 2.84 Patient no. Treatment site Organ-at-risk OED (rad) LAR (%) 7 Lung Breasts 254.3 3.75 Contralateral lung 480.3 8.62 8 Breast Contralateral breast 67.2 0.99 Lungs 92.6 1.66 9 Breast Contralateral breast 70.2 1.04 Lungs 115.0 2.06 10 Breast Contralateral breast 48.1 0.71 Lungs 158.2 2.84 Table 5. Patient-specific organ equivalent dose (OED) and lifetime attributable risk (LAR) for second cancer development following radiotherapy for thoracic solid tumors in reproductive-aged females. Patient no. Treatment site Organ-at-risk OED (rad) LAR (%) 7 Lung Breasts 254.3 3.75 Contralateral lung 480.3 8.62 8 Breast Contralateral breast 67.2 0.99 Lungs 92.6 1.66 9 Breast Contralateral breast 70.2 1.04 Lungs 115.0 2.06 10 Breast Contralateral breast 48.1 0.71 Lungs 158.2 2.84 Patient no. Treatment site Organ-at-risk OED (rad) LAR (%) 7 Lung Breasts 254.3 3.75 Contralateral lung 480.3 8.62 8 Breast Contralateral breast 67.2 0.99 Lungs 92.6 1.66 9 Breast Contralateral breast 70.2 1.04 Lungs 115.0 2.06 10 Breast Contralateral breast 48.1 0.71 Lungs 158.2 2.84 The organ-dependent RRs for each irradiated female patient are presented in Figure 1. The range of the RR values associated with the colon and bladder cancer development following pelvic radiotherapy was 3.70–4.05 and 1.10–1.12, respectively. The RRs for the appearance of secondary breast and lung malignancies due to treatment of solid tumors in the thoracic region were found to be 1.06–1.31 and 1.27–2.42, respectively. Figure 1. View largeDownload slide Patient- and organ-specific relative risk for cancer development due to radiotherapy for solid tumors in reproductive-aged females. Figure 1. View largeDownload slide Patient- and organ-specific relative risk for cancer development due to radiotherapy for solid tumors in reproductive-aged females. Differences between the mechanistic and plateau or bell-shaped models The differences between the patient-specific lung cancer risks estimated with the mechanistic model and those derived from the use of bell-shaped and plateau models varied from 10.2 to 21.8% with a mean value of 14.4 ± 3.8%. The corresponding range of differences associated with the probabilities for developing radiation-induced colon and breast malignancies were 0.7–2.7% (mean difference: 1.5 ± 0.8%) and 1.2–7.5% (mean difference: 3.1 ± 2.1%), respectively. The bladder cancer risks as estimated by the plateau model were 5.6–5.8 times higher than the respective risks assessed with the aid of the mechanistic model. DISCUSSION Reported experience has recommended the use of organ-dependent dose data for the assessment of the radiotherapy-induced cancer risk at specific sites(19). In the current study, the probability for carcinogenesis due to radiotherapy was estimated with an advanced non-linear mechanistic model(13) based on the OEDs to critical organs exposed to high radiation doses. The model of Schneider et al.(13) adopted in this work takes into account the cell killing, dose fractionation and tissue repopulation effects. The organ-specific probabilities for carcinogenesis were also estimated with different models based either on the absence of repopulation during fractionated radiotherapy or on the full tissue repair. The colon, breast and lung cancer risks as estimated by the bell-shaped and plateau models were similar with those derived from the mechanistic model. The mean differences between the examined models varied from 1.5 to 14.4% by the organ under examination. The discrepancy between the plateau and mechanistic models for estimating the bladder cancer risk are consistent with previously published results presenting a large difference between the two models for bladder doses exceeding 20 Gy(13). A part of the urinary bladder of all study participants received such high radiation doses from pelvic radiotherapy. The mechanistic model was employed to determine the risk for developing a malignant disease in organs absorbing high doses during treatment of females of childbearing age and characterized by the strong disposition for radiation carcinogenesis. Diallo et al.(20) showed that most of the secondary malignant neoplasms following radiation therapy appear within a volume defined 2.5 cm inside and 5 cm outside the treatment field borders. However, radiotherapy inevitably exposes all critical tissues of the human body to ionizing radiation even if they are located at distant sites from the primarily irradiated area(21–23). These tissues are not depicted in the treatment planning CT scans. The cancer risk to these remote sites receiving low doses can be estimated through a different method based on the linear-no-threshold model and the average organ dose(15, 24). Radiation therapy for cervical, uterine and rectal cancer resulted in high LARs for developing secondary colon malignancies of more than 10.8%. A lower probability up to 0.14% was estimated for bladder cancer induction following pelvic irradiation. Radiotherapy for lung cancer led to a lifetime risk of 8.62% for the induction of a malignant disease in the contralateral healthy lung. The corresponding risk after treatment of breast carcinomas was up to 2.84%. The maximum probability for breast cancer appearance following irradiation of solid tumors in the thorax equaled to 3.75%. The LAR assessments were combined with the LIRs corresponding to unexposed people(2) in order to determine the patient- and organ-specific RR. The most elevated RR values up to 4.05 were found for colon cancer development. The corresponding maximum RR related to the incidence of bladder, breast and lung malignancies was 1.12, 1.31 and 2.42, respectively. The above organ-specific RR values show that photon-beam radiation therapy for solid tumors in reproductive-aged females may elevate the LIRs for cancer development The organ dose distribution as defined by a differential DVH derived from each patient’s radiotherapy plan was used to determine the OED and the subsequent organ-specific cancer risk. This distribution presented the organ volumes receiving low, medium and high radiation doses. Radiation dose calculations in the low dose region derived from commercial treatment planning systems may contain inaccuracies(25). The presented cancer risk assessments are mainly limited by the uncertainties of the non-linear models(13) used in this work. The organ-specific parameters of these models were defined from data obtained by the Japanese A-bomb and Hodgkin cohorts. Limitations in the process related to the determination of these parameters should be considered the small mean follow-up of 9 years of the Hodgkin lymphoma survivors and the low target dose given during treatment of this hematologic malignancy compared with that delivered for the management of several solid tumors. The genetic susceptibility, which underlies the above type of lymphoma(26), might also affect the development of any other malignant condition. The model-derived theoretical cancer risk assessments of patients irradiated for solid cancer may be more elevated than the real risks. Another source of uncertainty may arise by the assumption that the a/β ratio in all model calculations was considered constant and equal to 3 irrespective of the organ-at-risk. Schneider et al.(17) found that the variation of the breast cancer risk estimated with a/β values from 1 to 5 Gy is insignificant. To our knowledge, the effect of the magnitude of the a/β ratio on the probability for radiation-induced carcinogenesis of other critical tissues has not been investigated. CONCLUSION The lifetime second cancer risk estimates associated with photon-beam radiation therapy in reproductive-aged females varied widely by the irradiation site and the organ-at-risk. Radiotherapy of various primary solid tumors located in the pelvic and thoracic regions was found to elevate the LIRs related to the development of bladder, colon, lung and breast malignancies in unexposed population. The most pronounced increase was observed for colon cancer induction. The presented second cancer risks may be of value in the counseling and follow-up of the female cancer survivors. REFERENCES 1 Siegel , R. L. , Miller , K. D. and Jemal , A. Cancer statistics, 2017 . CA Cancer J. 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For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Protection Dosimetry Oxford University Press

SECOND CANCER RISK FROM RADIATION THERAPY FOR COMMON SOLID TUMORS DIAGNOSED IN REPRODUCTIVE-AGED FEMALES

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Abstract

Abstract This study provided second cancer risk estimates from radiation therapy for common solid tumors presented in reproductive-aged females. Three-dimensional treatment plans were generated for 10 patients with cervical, uterine, rectal, lung or breast carcinomas. The organ equivalent dose (OED) and the lifetime attributable risk (LAR) for carcinogenesis to organs receiving high doses were estimated for all study participants with a mechanistic model. This model accounts for cell-killing, tissue repair and dose fractionation effects. The patient- and organ-specific relative risk was assessed by using the LARs and the respective lifetime intrinsic cancer risks for unexposed population. The OED of the organs-at-risk varied from 17.3 to 1423.1 rad. The LAR range for bladder, colon, lung and breast cancer induction was 0.12–0.14%, 10.88–12.71%, 1.66–8.62% and 0.71–3.75%, respectively. The relative risk for the appearance of bladder, colon, lung and breast malignancies following radiotherapy was up to 1.12, 4.05, 2.42 and 1.31, respectively. INTRODUCTION Siegel et al.(1) reported that more than 850 000 new cancer cases are estimated to be presented in women of the United States of America in 2017. The recent improvements in cancer diagnosis and treatment have considerably increased the 5-year survival of female patients suffering from all malignant diseases from 55.6% in the decade of 70s to 69.1% nowadays(2). The 10-year survival rate has also been elevated to 61.6% from 48.7% 40 years ago(2). The 10% of the female cancer survivors are young with an age of <40 years old(3). Radiotherapy either alone or in combination with other anticancer therapeutic approaches such as surgery or chemotherapy is often employed for the management of malignant diseases in reproductive-aged females. It is well known that the patient’s exposure to high doses delivered by high-energy beams of ionizing radiation may increase the risk for the development of secondary cancers. Previous studies have reported data about the second cancer risk from radiation therapy of hematologic malignancies such as Hodgkin lymphoma in young adult females(4–6). Epidemiological data about the risk for carcinogenesis due to irradiation of young females with solid tumors have also been published(7–9). Chatuverdi et al.(7) found that the cumulative risks for the appearance of secondary malignancies in women irradiated for cervical cancer at ages below 50 years are higher than those observed for older females. Stovall et al.(9) also reported that radiotherapy for breast malignancies at ages smaller than 40 years old leads to an elevated contralateral breast cancer risk whereas no excess risk exists at older ages. Berrington de Gonzalez et al.(8) found that the probabilities for cancer induction at healthy tissues following breast irradiation are reduced with increasing patient’s age and year of exposure. It should be noted that the above data were collected from patients with solid malignant diseases irradiated before 2001(7–9) and included subjects treated up to 75 years ago(8). The process of treatment planning without the use of computed tomography (CT) images for many of these patients could lead to increased volumes of irradiated healthy tissues, and subsequently, to an elevated incidence of radiation effects(8). The treatment delivery might also differ considerably from the current irradiation techniques which are usually performed on linear accelerators equipped with multileaf collimators for the automatic and accurate conformation of the treatment fields to the target site. The purpose of this study was to estimate the second cancer risk at sites receiving high radiation doses attributable to photon-beam radiotherapy for common solid tumors diagnosed in reproductive-aged females. MATERIALS AND METHODS Patient selection The most common solid tumors presented in females of reproductive age are located in the cervix, uterus, ovaries, gastrointestinal tract, lungs and breasts(10). Chemotherapy is usually employed for patients with ovarian carcinoma(10). Radiation therapy plays a major role in the management of the cervical, uterine, colorectal, lung and breast cancer(11). Our study group consisted of reproductive-aged females who were referred in our department for external-beam radiotherapy with photon beams for the above five malignant diseases. Four patients with cervical cancer, one with uterine carcinoma, one with a malignant disease in the rectum, one with lung cancer and three with breast malignancies were included in this work. The patient’s age at the time of treatment was 34–47 years old. Patient’s irradiation All study participants initially underwent a treatment planning CT scanning on a 16-slice unit (Somatom Sensation 16, Siemens, Forcheim, Germany). The delineation both of the planning target volume (PTV) and the surrounding organs-at-risk was carried out by an experienced radiation oncologist. The 3D CT-based therapy plans were produced with the aid of XiO software (CMS Inc., St Louis, MO, USA). Each patient’s plan consisted of isocentric treatment fields shaped by multileaf collimators. All therapy plans were created with 6 MV photon beams emitted by a medical linear accelerator (Primus, Siemens, Germany). The total tumor dose, the tumor dose per fraction and the beam arrangement applied for radiotherapy of each malignancy are presented in Table 1. Table 1. Irradiation parameters used for treatment of female patients with various solid tumors. The beam arrangement, the total tumor dose and the fraction dose are presented. Patient no. Irradiation site Beam arrangement Total tumor dose (rad) Fraction dose (rad) 1, 2, 3, 4 Cervix 4-Field box 5040 180 5 Uterus 4-Field box 5040 180 6 Rectum 4-Field box 5040 180 7 Lung AP + 2 oblique fields 6480 180 8, 9, 10 Breast 2 Tangential fields 5000 200 Patient no. Irradiation site Beam arrangement Total tumor dose (rad) Fraction dose (rad) 1, 2, 3, 4 Cervix 4-Field box 5040 180 5 Uterus 4-Field box 5040 180 6 Rectum 4-Field box 5040 180 7 Lung AP + 2 oblique fields 6480 180 8, 9, 10 Breast 2 Tangential fields 5000 200 Table 1. Irradiation parameters used for treatment of female patients with various solid tumors. The beam arrangement, the total tumor dose and the fraction dose are presented. Patient no. Irradiation site Beam arrangement Total tumor dose (rad) Fraction dose (rad) 1, 2, 3, 4 Cervix 4-Field box 5040 180 5 Uterus 4-Field box 5040 180 6 Rectum 4-Field box 5040 180 7 Lung AP + 2 oblique fields 6480 180 8, 9, 10 Breast 2 Tangential fields 5000 200 Patient no. Irradiation site Beam arrangement Total tumor dose (rad) Fraction dose (rad) 1, 2, 3, 4 Cervix 4-Field box 5040 180 5 Uterus 4-Field box 5040 180 6 Rectum 4-Field box 5040 180 7 Lung AP + 2 oblique fields 6480 180 8, 9, 10 Breast 2 Tangential fields 5000 200 Organs-at-risk The linearity between the cancer risk and radiation dose in the high dose region exceeding 2.5 Gy is under question(12). In the current study, a non-linear mechanistic model proposed by Schneider et al.(13) was used for estimating the probability for carcinogenesis at specific sites exposed to high therapeutic doses. The model has already been applied for cancer risk assessments due to radiation therapy for both malignant(5, 14) and benign diseases(15). The dose–volume histograms obtained by the patients’ radiotherapy plans were used to define the critical organs receiving doses of more than 2.5 Gy for which Schneider et al.(13) provided the required data enabling the cancer risk assessment. Parts of the colon and bladder absorbed doses exceeding the above value in the irradiation for cervical, uterine and rectal cancer. Similar high doses were received by portions of the lungs and the contralateral breast during radiotherapy for breast malignancies. The contralateral healthy lung and breasts were also partly exposed to radiation doses above 2.5 Gy during radiation therapy for lung cancer. Second cancer risk estimates with a mechanistic model The model of Schneider et al.(13) is based on the use of the organ equivalent dose (OED) to each organ of interest. The quantity OED is directly proportional to the resultant cancer risk. The OED of the healthy organs referred in the previous section was calculated with the following formula: OED=1Vt∑iVDiexp(−ai′Di)−ai′R×[1−2R+R2exp(ai′Di)−(1−R)2exp(−ai′R1−RDi)] (1) where Vt is the whole organ volume, VDi is the organ volume receiving a dose equal to Di , R is the repopulation factor for each organ of interest and ai′ is the cell-killing parameter. The quantities Vt and VDi were determined by the differential dose–volume histograms derived from the patients’ 3D therapy plans. The radiation exposure of the rectum was taken into account in the estimation of the OED and the relevant cancer risk to colon. The organ-specific factor ai′ was calculated as follows: ai′=a+βDfDtDi (2) where a and β are the parameters for each organ-at-risk derived from the linear quadratic model, Df is the radiation dose to the tumor per fraction and Dt is the total tumor dose. The Df and Dt received by each tumor site are given in Table 1. The organ-dependent model parameters R, a and a/β, as provided by previously published reports(13, 16, 17), are summarized in Table 2. Table 2. Organ-dependent parameters employed for organ equivalent dose calculation and second cancer risk assessment with the mechanistic model. The presented values were derived from previously published studies(13, 16, 17). Organ a (Gy−1) a/β (Gy) R βEAR (104 PY Gy)−1 γe (y−1) γa (y−1) Colon 0.001 3 0.99 7.4 −0.056 6.9 Bladder 0.219 3 0.06 3.8 −0.024 2.38 Lung 0.061 3 0.84 8.0 0.002 4.23 Breast 0.067 3 0.62 8.2 −0.037 1.7 Organ a (Gy−1) a/β (Gy) R βEAR (104 PY Gy)−1 γe (y−1) γa (y−1) Colon 0.001 3 0.99 7.4 −0.056 6.9 Bladder 0.219 3 0.06 3.8 −0.024 2.38 Lung 0.061 3 0.84 8.0 0.002 4.23 Breast 0.067 3 0.62 8.2 −0.037 1.7 Table 2. Organ-dependent parameters employed for organ equivalent dose calculation and second cancer risk assessment with the mechanistic model. The presented values were derived from previously published studies(13, 16, 17). Organ a (Gy−1) a/β (Gy) R βEAR (104 PY Gy)−1 γe (y−1) γa (y−1) Colon 0.001 3 0.99 7.4 −0.056 6.9 Bladder 0.219 3 0.06 3.8 −0.024 2.38 Lung 0.061 3 0.84 8.0 0.002 4.23 Breast 0.067 3 0.62 8.2 −0.037 1.7 Organ a (Gy−1) a/β (Gy) R βEAR (104 PY Gy)−1 γe (y−1) γa (y−1) Colon 0.001 3 0.99 7.4 −0.056 6.9 Bladder 0.219 3 0.06 3.8 −0.024 2.38 Lung 0.061 3 0.84 8.0 0.002 4.23 Breast 0.067 3 0.62 8.2 −0.037 1.7 The OED calculations were used to assess the excess absolute risk (EAR) for second cancer induction to specific organs receiving high radiation doses from treatment of cervical, uterine, rectal, lung and breast cancer. The EAR per 10 000 persons per year was estimated with the following equation: EAR=βEAROEDexp[γe(agee−30)+γaln(agea70)] (3) where βEAR is the initial slope of the dose–response curve at low doses for a Western population, agee is the age of the female patient during external-beam radiotherapy, agea is the attained age of the irradiated patient and γe,γa are the age modifying parameters(13). Table 2 shows the previously reported values of βEAR,γe and γa for all organs-at-risk(13). The EARs were estimated by assuming a typical 40-year-old female irradiated for a solid tumor and a maximum attained age of 80 years. The lifetime attributable risk (LAR) for developing a secondary malignant disease in the critical organs due to photon-beam radiotherapy was estimated as follows: LAR=∑agee+L80EAR(Dt,agee,agea)S(agea)S(agee) (4) where L is a free-risk latent interval of 5 years following patient’s treatment and S(agea)/S(agee) is the probability of a female to survive from agee to agea. This survival probability was defined on the basis of the United States life tables(18). Each estimated organ-specific LAR was compared with the respective lifetime intrinsic risk (LIR) for unexposed and cancer-free females as provided by the most recent SEER Cancer Statistics Review 1975–2014(2). For 40-year-old healthy females, the LIR for developing colon, bladder, lung and breast cancer is 4.16, 1.14, 6.07 and 12.25%, respectively(2). The patient- and organ-specific relative risk (RR) for developing each malignancy was determined as the ratio of the sum of LIR and LAR to LIR. Second cancer risk estimates with plateau and bell-shaped models The probability of carcinogenesis following radiotherapy of women in reproductive age was also estimated with the aid of two different models. The bell-shaped model, which ignores the repopulation effects ( R = 0), was initially used. The OED was found with the following formula: OED=1Vt∑iVDiDiexp(−ai′Di) (5) The OED was then calculated on the basis of the plateau model, which assumes a full cell repopulation in the exposed tissues ( R = 1), as follows: OED=1Vt∑iVDiexp(−ai′Di)ai′ (6) The ai′ was determined with equation (2) presented in the previous subsection. The values of the quantity a for both bell-shaped and plateau models are listed in Table 3. The a/β ratio was taken equal to 3 for both models(13). The OED values as derived from the bell-shaped and plateau models were used to estimate the lifetime organ-dependent cancer risk with equation (4). Table 3. Values of the organ-specific parameter a used for organ equivalent dose calculation and second cancer risk assessment with the bell-shaped and plateau models. The values were obtained by a previous study of Schneider et al.(13). Organ a (Gy−1) Bell-shaped model Plateau model Colon 0.001 0.001 Bladder 0.213 0.633 Lung 0.022 0.056 Breast 0.041 0.115 Organ a (Gy−1) Bell-shaped model Plateau model Colon 0.001 0.001 Bladder 0.213 0.633 Lung 0.022 0.056 Breast 0.041 0.115 Table 3. Values of the organ-specific parameter a used for organ equivalent dose calculation and second cancer risk assessment with the bell-shaped and plateau models. The values were obtained by a previous study of Schneider et al.(13). Organ a (Gy−1) Bell-shaped model Plateau model Colon 0.001 0.001 Bladder 0.213 0.633 Lung 0.022 0.056 Breast 0.041 0.115 Organ a (Gy−1) Bell-shaped model Plateau model Colon 0.001 0.001 Bladder 0.213 0.633 Lung 0.022 0.056 Breast 0.041 0.115 RESULTS Second cancer risk estimates with a mechanistic model The OED calculations and the associated LARs for the appearance of secondary malignancies in critical healthy organs during radiotherapy of reproductive-aged females with cervical, uterine and rectal cancer are summarized in Table 4. The OED was up to a value of 1423.1 rad. The patient-specific probability for second cancer induction in the colon due to treatment of pelvic tumors was 10.88–12.71%. The lifetime risk range for developing bladder cancer was much lower and equal to 0.12–0.14%. Table 4. Patient-specific organ equivalent dose (OED) and lifetime attributable risk (LAR) for developing bladder or colon malignancies following radiotherapy for pelvic solid tumors in reproductive-aged females. Patient no. Treatment site Bladder Colon OED (rad) LAR (%) OED (rad) LAR (%) 1 Cervix 18.0 0.13 1293.6 11.55 2 Cervix 18.2 0.13 1260.2 11.25 3 Cervix 17.3 0.12 1423.1 12.71 4 Cervix 17.4 0.13 1321.0 11.80 5 Uterus 19.3 0.14 1346.8 12.03 6 Rectum 17.6 0.13 1218.3 10.88 Patient no. Treatment site Bladder Colon OED (rad) LAR (%) OED (rad) LAR (%) 1 Cervix 18.0 0.13 1293.6 11.55 2 Cervix 18.2 0.13 1260.2 11.25 3 Cervix 17.3 0.12 1423.1 12.71 4 Cervix 17.4 0.13 1321.0 11.80 5 Uterus 19.3 0.14 1346.8 12.03 6 Rectum 17.6 0.13 1218.3 10.88 Table 4. Patient-specific organ equivalent dose (OED) and lifetime attributable risk (LAR) for developing bladder or colon malignancies following radiotherapy for pelvic solid tumors in reproductive-aged females. Patient no. Treatment site Bladder Colon OED (rad) LAR (%) OED (rad) LAR (%) 1 Cervix 18.0 0.13 1293.6 11.55 2 Cervix 18.2 0.13 1260.2 11.25 3 Cervix 17.3 0.12 1423.1 12.71 4 Cervix 17.4 0.13 1321.0 11.80 5 Uterus 19.3 0.14 1346.8 12.03 6 Rectum 17.6 0.13 1218.3 10.88 Patient no. Treatment site Bladder Colon OED (rad) LAR (%) OED (rad) LAR (%) 1 Cervix 18.0 0.13 1293.6 11.55 2 Cervix 18.2 0.13 1260.2 11.25 3 Cervix 17.3 0.12 1423.1 12.71 4 Cervix 17.4 0.13 1321.0 11.80 5 Uterus 19.3 0.14 1346.8 12.03 6 Rectum 17.6 0.13 1218.3 10.88 The OEDs and the relevant lifetime second cancer risks from radiation therapy for solid tumors in the thoracic region are presented in Table 5. The OED values of the lung and breast varied from 48.1 to 480.3 rad. The patient-specific LARs related to the appearance of secondary breast malignancies were found to be 0.71–3.75%. For all patients, the corresponding lifetime probabilities for the induction of a lung malignant disease were more elevated than those related to breast cancer development. The LARs for developing a second lung cancer were 1.66–8.62%. Table 5. Patient-specific organ equivalent dose (OED) and lifetime attributable risk (LAR) for second cancer development following radiotherapy for thoracic solid tumors in reproductive-aged females. Patient no. Treatment site Organ-at-risk OED (rad) LAR (%) 7 Lung Breasts 254.3 3.75 Contralateral lung 480.3 8.62 8 Breast Contralateral breast 67.2 0.99 Lungs 92.6 1.66 9 Breast Contralateral breast 70.2 1.04 Lungs 115.0 2.06 10 Breast Contralateral breast 48.1 0.71 Lungs 158.2 2.84 Patient no. Treatment site Organ-at-risk OED (rad) LAR (%) 7 Lung Breasts 254.3 3.75 Contralateral lung 480.3 8.62 8 Breast Contralateral breast 67.2 0.99 Lungs 92.6 1.66 9 Breast Contralateral breast 70.2 1.04 Lungs 115.0 2.06 10 Breast Contralateral breast 48.1 0.71 Lungs 158.2 2.84 Table 5. Patient-specific organ equivalent dose (OED) and lifetime attributable risk (LAR) for second cancer development following radiotherapy for thoracic solid tumors in reproductive-aged females. Patient no. Treatment site Organ-at-risk OED (rad) LAR (%) 7 Lung Breasts 254.3 3.75 Contralateral lung 480.3 8.62 8 Breast Contralateral breast 67.2 0.99 Lungs 92.6 1.66 9 Breast Contralateral breast 70.2 1.04 Lungs 115.0 2.06 10 Breast Contralateral breast 48.1 0.71 Lungs 158.2 2.84 Patient no. Treatment site Organ-at-risk OED (rad) LAR (%) 7 Lung Breasts 254.3 3.75 Contralateral lung 480.3 8.62 8 Breast Contralateral breast 67.2 0.99 Lungs 92.6 1.66 9 Breast Contralateral breast 70.2 1.04 Lungs 115.0 2.06 10 Breast Contralateral breast 48.1 0.71 Lungs 158.2 2.84 The organ-dependent RRs for each irradiated female patient are presented in Figure 1. The range of the RR values associated with the colon and bladder cancer development following pelvic radiotherapy was 3.70–4.05 and 1.10–1.12, respectively. The RRs for the appearance of secondary breast and lung malignancies due to treatment of solid tumors in the thoracic region were found to be 1.06–1.31 and 1.27–2.42, respectively. Figure 1. View largeDownload slide Patient- and organ-specific relative risk for cancer development due to radiotherapy for solid tumors in reproductive-aged females. Figure 1. View largeDownload slide Patient- and organ-specific relative risk for cancer development due to radiotherapy for solid tumors in reproductive-aged females. Differences between the mechanistic and plateau or bell-shaped models The differences between the patient-specific lung cancer risks estimated with the mechanistic model and those derived from the use of bell-shaped and plateau models varied from 10.2 to 21.8% with a mean value of 14.4 ± 3.8%. The corresponding range of differences associated with the probabilities for developing radiation-induced colon and breast malignancies were 0.7–2.7% (mean difference: 1.5 ± 0.8%) and 1.2–7.5% (mean difference: 3.1 ± 2.1%), respectively. The bladder cancer risks as estimated by the plateau model were 5.6–5.8 times higher than the respective risks assessed with the aid of the mechanistic model. DISCUSSION Reported experience has recommended the use of organ-dependent dose data for the assessment of the radiotherapy-induced cancer risk at specific sites(19). In the current study, the probability for carcinogenesis due to radiotherapy was estimated with an advanced non-linear mechanistic model(13) based on the OEDs to critical organs exposed to high radiation doses. The model of Schneider et al.(13) adopted in this work takes into account the cell killing, dose fractionation and tissue repopulation effects. The organ-specific probabilities for carcinogenesis were also estimated with different models based either on the absence of repopulation during fractionated radiotherapy or on the full tissue repair. The colon, breast and lung cancer risks as estimated by the bell-shaped and plateau models were similar with those derived from the mechanistic model. The mean differences between the examined models varied from 1.5 to 14.4% by the organ under examination. The discrepancy between the plateau and mechanistic models for estimating the bladder cancer risk are consistent with previously published results presenting a large difference between the two models for bladder doses exceeding 20 Gy(13). A part of the urinary bladder of all study participants received such high radiation doses from pelvic radiotherapy. The mechanistic model was employed to determine the risk for developing a malignant disease in organs absorbing high doses during treatment of females of childbearing age and characterized by the strong disposition for radiation carcinogenesis. Diallo et al.(20) showed that most of the secondary malignant neoplasms following radiation therapy appear within a volume defined 2.5 cm inside and 5 cm outside the treatment field borders. However, radiotherapy inevitably exposes all critical tissues of the human body to ionizing radiation even if they are located at distant sites from the primarily irradiated area(21–23). These tissues are not depicted in the treatment planning CT scans. The cancer risk to these remote sites receiving low doses can be estimated through a different method based on the linear-no-threshold model and the average organ dose(15, 24). Radiation therapy for cervical, uterine and rectal cancer resulted in high LARs for developing secondary colon malignancies of more than 10.8%. A lower probability up to 0.14% was estimated for bladder cancer induction following pelvic irradiation. Radiotherapy for lung cancer led to a lifetime risk of 8.62% for the induction of a malignant disease in the contralateral healthy lung. The corresponding risk after treatment of breast carcinomas was up to 2.84%. The maximum probability for breast cancer appearance following irradiation of solid tumors in the thorax equaled to 3.75%. The LAR assessments were combined with the LIRs corresponding to unexposed people(2) in order to determine the patient- and organ-specific RR. The most elevated RR values up to 4.05 were found for colon cancer development. The corresponding maximum RR related to the incidence of bladder, breast and lung malignancies was 1.12, 1.31 and 2.42, respectively. The above organ-specific RR values show that photon-beam radiation therapy for solid tumors in reproductive-aged females may elevate the LIRs for cancer development The organ dose distribution as defined by a differential DVH derived from each patient’s radiotherapy plan was used to determine the OED and the subsequent organ-specific cancer risk. This distribution presented the organ volumes receiving low, medium and high radiation doses. Radiation dose calculations in the low dose region derived from commercial treatment planning systems may contain inaccuracies(25). The presented cancer risk assessments are mainly limited by the uncertainties of the non-linear models(13) used in this work. The organ-specific parameters of these models were defined from data obtained by the Japanese A-bomb and Hodgkin cohorts. Limitations in the process related to the determination of these parameters should be considered the small mean follow-up of 9 years of the Hodgkin lymphoma survivors and the low target dose given during treatment of this hematologic malignancy compared with that delivered for the management of several solid tumors. The genetic susceptibility, which underlies the above type of lymphoma(26), might also affect the development of any other malignant condition. The model-derived theoretical cancer risk assessments of patients irradiated for solid cancer may be more elevated than the real risks. Another source of uncertainty may arise by the assumption that the a/β ratio in all model calculations was considered constant and equal to 3 irrespective of the organ-at-risk. Schneider et al.(17) found that the variation of the breast cancer risk estimated with a/β values from 1 to 5 Gy is insignificant. To our knowledge, the effect of the magnitude of the a/β ratio on the probability for radiation-induced carcinogenesis of other critical tissues has not been investigated. CONCLUSION The lifetime second cancer risk estimates associated with photon-beam radiation therapy in reproductive-aged females varied widely by the irradiation site and the organ-at-risk. Radiotherapy of various primary solid tumors located in the pelvic and thoracic regions was found to elevate the LIRs related to the development of bladder, colon, lung and breast malignancies in unexposed population. The most pronounced increase was observed for colon cancer induction. The presented second cancer risks may be of value in the counseling and follow-up of the female cancer survivors. REFERENCES 1 Siegel , R. L. , Miller , K. D. and Jemal , A. Cancer statistics, 2017 . CA Cancer J. 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Radiation Protection DosimetryOxford University Press

Published: Mar 28, 2018

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