Risk for second bladder and rectal malignancies from cervical cancer irradiation

Abstract The objective of this study was to estimate the risk of developing second malignancies to partially in‐field organs from volumetric modulated arc therapy (VMAT) of cervical cancer and to compare the above risks with those from the conventional three‐dimensional conformal radiotherapy (3D‐CRT). Seventeen consecutive patients with uterine cervix carcinoma were selected. VMAT and 3D‐CRT plans were generated with 6 and 10 MV photons, respectively. The prescribed tumor dose was 45 Gy given in 25 fractions. Differential dose‐volume histogram data from the treatment plans were obtained for the partially in‐field organs such as bladder and rectum. These data were used to estimate the patient‐specific lifetime attributable risk (LAR) for bladder and rectal cancer induction with a non‐linear model based on a mixture of plateau and bell‐shaped dose–response relationships. The estimated risks per 10000 people were compared with the baseline risks for unexposed population. The patient‐specific rectal cancer risk estimates from VMAT were significantly lower than those from 3D‐CRT (P = 0.0144). The LARs for developing bladder malignancies from VMAT were significantly high compared to those from conventional irradiation (P = 0.0003). The mean difference between the patient‐specific LARs for radiation‐induced bladder and rectal malignancies as derived from 3D‐CRT and VMAT plans was 6.6% and 2.0%, respectively. The average LAR for developing bladder and rectal malignant diseases due to VMAT was 9.2 × 10‐4 and 43.7 × 10‐4, respectively. The corresponding risks following 3D‐CRT were 8.6 × 10‐4 and 44.6 × 10‐4. These average risks showed that pelvic irradiation increases the baseline probability for cancer induction by 12.6‐19.1%. The differences in the second cancer risks associated with the VMAT and 3D‐CRT for cervical cancer were found to be small. Both treatment techniques resulted in considerable increased probabilities for developing bladder and rectal malignancies relative to those of unirradiated population.


2.A | CT scanning and contouring
Seventeen consecutive patients with localized carcinoma of the uterine cervix were included in this work. The patient's age ranged from 40 to 68 yrs old with a mean age of 53.1 AE 9.2 yrs (Fig. 1).
The study participants underwent a planning computed tomography (CT) examination in supine treatment position. The CT slice thickness was 5 mm without a gap. All CT datasets were transferred to Monaco system (Elekta AB, Stockholm, Sweden) for contouring and planning. The RTOG-0418 guidelines 14

2.B | 3D-CRT and VMAT planning
For each patient, treatment plans were generated with 3D-CRT and VMAT for delivery on a medical linear accelerator (Infinity, Elekta AB, Stockholm, Sweden) emitting 6 and 10 MV photons. The PTV prescribed dose was 45 Gy given in 25 daily fractions of 1.8 Gy. The 3D-CRT plans involved 10 MV photon beams. The beam arrangement consisted of an anteroposterior, a posteroantrior and two lateral opposed treatment fields at the following gantry angles: of 0°, 90°, 180°, and 270°. The beam weight was optimized for each separate plan in order to achieve a homogeneous dose distribution within the PTV and reduce the radiation dose to surrounding structures.
The planning aim was to cover at least 95% of the PTV with the 95% of the prescribed dose.
The VMAT plans were created with 6 MV photons. Two coplanar full arcs rotating in clockwise and anticlockwise directions were used. The segment width was set to 1.0 cm 15 and the increment of gantry was 30°. 16 All VMAT plans were designed to satisfy the dose constraints introduced by the RTOG 0418 for modulated radiotherapy. 17 These constraints are summarized in Table 1. Furthermore, the maximum PTV dose was kept below 49.5 Gy whereas less than 1% of the target volume received a dose smaller than 93% of the prescribed dose. No more than 1% or 1 cm 3 (whichever is lower) of the healthy tissues outside PTV absorbed a radiation dose exceeding 110% of the tumor dose.

2.C | Estimation of the patient-specific cancer risk
Pelvic radiation therapy for gynecological carcinomas may result in second bladder and rectal malignant diseases. [4][5][6]10 The above structures were characterized as partially in-field organs in accordance with a previous study of Howell et al. 18 The above OARs were adjacent to the target volume and they received an inhomogeneous dose distribution in the 3D-CRT and VMAT plans of all study participants.
Parts of both rectum and urinary bladder absorbed radiation doses up to that of the PTV.
Hall 19 reported that the risk of radiation carcinogenesis is linearly related to the absorbed dose for a dose range of 0.1-2.5 Gy. Dasu and Toma-Dasu 20 also stated that the linear relationship exists up to doses of 1-2 Gy. The extrapolation of the linear-no-threshold approach to doses exceeding the above levels is not recommended. 21 There are several non-linear models in the literature which ignore either the fractionation or the cell proliferation effects occurring during radiotherapy. 20 Schneider et al. 22 introduced a mechanistic model providing site-specific dose response relations using data obtained by A-bomb survivors and irradiated Hodgkin's disease patients. This mechanistic model is based on a mixture of plateau and bell-shaped dose response relationships. The modelbased cancer risk estimates account for the tumor dose fractionation and the interfraction repair of the exposed tissues.
The above non-linear mechanistic model was applied to estimate the cancer risk to bladder and rectum from radiation therapy for cervical cancer. The probability of carcinogenesis to critical organs has been previously assessed with this model for patients irradiated for carcinomas [23][24][25] and benign disorders. 26 The application of the mechanistic model required the knowledge of the organ equivalent dose (OED) of each OAR. Differential dose-volume histograms were used to calculate the OED of the bladder or rectum from the 3D-CRT and VMAT plans of each patient as follows: where V t is the total organ volume, V Di is the organ volume receiving a dose equal to D i , R is a factor associated with the organdependent repopulation and a 0 i is the cell killing factor. The a 0 i was calculated using the formula: where a and β are the linear quatradic parameters, D f is the PTV dose of 1.8 Gy delivered in each fraction and D t is the total target dose of 45 Gy.
The patient-dependent excess absolute risk (EAR) for the appearance of radiation-induced bladder or rectal malignancies due to 3D-CRT or VMAT for cervical cancer was estimated as follows: where β EAR is the initial slope at low doses of the dose-response curve for a Western population, γ e and γ a are the age modifying parameters for each organ of interest, age e is the age of the female patient during radiation therapy and age a is the attained age. The lifetime attributable risk (LAR) for second cancer induction was estimated with the formula: The parameters, R, a, γ e , γ a and β EAR for the bladder were taken from the literature and they were 0.06, 0.219 Gy -1 , −0.024, 2.38, and 3.8/(10 4 PY Gy), respectively. 22 The corresponding parameters for the rectum were 0.56, 0.033 Gy -1 , −0.056, 6.9 and 0.73/(10 4 PY Gy). 22,23 The LAR estimates were expressed as the risk per 10000 people.

2.D | Estimation of the average cancer risk
The average OED av of bladder and rectum was found from the 3D-CRT and VMAT plans of all patients. The calculated OED av was employed to estimate the respective average lifetime risk (LAR av ) for the appearance of radiotherapy-induced bladder and rectal malignancies using the equations of the previous subsection. The LAR av was estimated for a typical 50-year-old patient at the time of irradiation and an attained age of 80 yrs. The LAR av was combined with the baseline risk (BR) to estimate the average relative risk (RR av ) of carcinogenesis as follows: Based on SEER data, 2 the BR of a 50-year-old healthy female to be diagnosed with bladder and rectal malignancies in 30 yrs is 0.68% and 2.33%, respectively.

2.E | Statistics
The patient-specific second cancer risk estimates related to 3D-CRT for cervical carcinoma were compared with the assessments derived T A B L E 1 Dosimetric constraints of the planning target volume (PTV) and surrounding critical organs applied for VMAT planning.
The V i corresponds to the structure volume absorbing a radiation dose of i Gy.

3.A | Patient-specific cancer risk estimates
The OED calculations are presented in Figs  The LARs for second cancer induction from 3D-CRT were significantly different from those related to VMAT for cervical cancer (Bladder: P = 0.0003; Rectum: P = 0.0144). The use of 3D-CRT resulted in lower bladder cancer risks than VMAT for all patients examined (Table 2). Conventional treatment led to an increased rectal cancer risk compared to that from VMAT in 14 of 17 study participants ( Table 2). The Bland-Altman scatter plots are shown in Fig. 4. The MD between the bladder cancer risk estimates associated with 3D-CRT and VMAT was −6.6 AE 3.4% with 95% confidence intervals of 0.1% to −13.3%. The corresponding MD in the assessment of the probability for rectal cancer development was 2.0 AE 2.1%. The 95% limits of agreement were equal to −2.1% and 6.1%.

3.B | Average cancer risk estimates
The OED av of bladder attributable to 3D-CRT and VMAT for cervical carcinoma was 17.7 and 18.9 cGy, respectively. The corresponding quantity for the rectum was 909.2 and 890.4 cGy. The average risks are presented in Table 3.

| DISCUSSION
The unavoidable exposure of healthy tissues to ionizing radiation during external-beam radiotherapy of primary neoplasms may elevate the risk for subsequent carcinogenesis. The appearance of second tumors at distant sites from the primarily irradiated area is relatively rare. Dorr and Hermann 29 found that almost 50% of the second tumors appear in the margin area of the treatment volume and less than 10% within the radiation fields. Welte et al. 30 showed that 69% of the total number of second malignancies are presented at the field margins or inside the primarily irradiated region. The current study was focused on the assessment of the second cancer risk to the partially in-field bladder and rectum due to radiation therapy for uterine cervix carcinoma. These organs, which are characterized by the high susceptibility for radiation carcinogenesis, were partly exposed to primary radiation due to their adjacent location to the treatment volume.
The probabilities for the appearance of second malignancies were estimated for 3D-CRT with 10 MV photons and 6 MV VMAT of cervical carcinoma. The above photon energies are usually employed in our department for non-modulated and modulated treatment of primary pelvic tumors. The neutron contribution to the exposure of critical sites due to irradiation with 10 MV X-rays was considered as minimal. 31 The second bladder and rectal cancer risks varied considerably by the patient's age during treatment. Based on the risks shown in Table 2, the LAR for developing second bladder malignancies due to irradiation of a 40-year-old female (patient no. 7) was 5.5 times higher than that for patient no. 5 who was 68- year-old at the time of treatment. The corresponding ratio related to the second rectal cancer was about 8.0. The use of 3D-CRT resulted F I G . 4. Scatter plots presenting the differences between the patient-specific risks for developing bladder cancer (a), and rectal cancer (b) as estimated by the 3D-CRT and VMAT plans of patients with primary carcinoma of the uterine cervix against the average risk value. The dotted lines illustrate the 95% confidence intervals and the solid line is the mean% risk difference.
T A B L E 3 Average lifetime attributable risk (LAR av ) and average relative risk (RR av ) for the development of second bladder and rectal malignancies following 3D-CRT and VMAT of a 50-year-old cervical cancer patient. 3 Gy for all tissues under investigation in accordance with the recommendation of Schneider et al. 22 Reported experience has shown an insignificant change of the breast cancer risk with a=β values from 1 to 5 Gy. 34 It has to be mentioned that the estimated probabilities for radiation-induced bladder and rectal malignancies presented here solely referred to therapeutic doses. The use of image guidance procedures in clinical practice may result in small absorbed doses to these critical organs compared to those from radiation therapy. 35 Further research is required to evaluate whether these imaging doses have an impact on the second cancer risk magnitude.

| CONCLUSION S
The use of VMAT for cervical cancer significantly reduced the probability for developing second rectal malignancies than 3D-CRT.
The bladder cancer risk from VMAT was significantly high compared to that from the conventional irradiation. However, the absolute differences in the patient-specific probabilities for the appearance of second malignancies due to VMAT and 3D-CRT were found to be small. Both delivery techniques led to noticeable elevated second cancer risks compared to those for unirradiated population.

ACKNOWLEDG EMENTS
This study was funded by the Research Committee of the University of Crete (Code: 10599).

CONFLI CT OF INTEREST
The authors declare that there is no conflict of interest regarding the publication of this article.

D A T A A V A I L A B I L I T Y S T A T E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.