British Journal of Radiology (2004) 77, 847-850
© 2004 British Institute of Radiology
doi: 10.1259/bjr/88840344
Therapeutic external irradiation in women of reproductive age: risk estimation of hereditary effects
M Mazonakis, MSc, PhD
1
J Damilakis, MSc, PhD
1
H Varveris, MD, PhD
2 and
N Gourtsoyiannis, MD, PhD
3
Departments of 1 Medical Physics, 2 Radiotherapy & Oncology and 3 Radiology, University Hospital of Iraklion, PO Box 1352, 71110 Iraklion, Crete, Greece
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Abstract
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Exposure of women of childbearing age to ionizing radiation may result in induction of genetic disorders in future generations. This study aims to estimate the risk of hereditary effects attributable to therapeutic external irradiation in women. An anthropomorphic phantom was used to simulate radiotherapy in female patients and ovarian dose was measured for irradiation of brain, breast and lung cancer, and for treatment of Hodgkin's disease. These malignancies are among the most common tumours presenting in women of reproductive age. Dose measurements were undertaken using thermoluminescent dosemeters and all exposures were made with 6 MV X-ray beams. The dose to ovaries was found to be 2–3 cGy, 8–11 cGy and 11–15 cGy depending on the distance from the primary irradiation field during radiotherapy of brain, breast and lung cancer, respectively. The corresponding ovarian dose resulting from treatment of supradiaphragmatic and infradiaphragmatic Hodgkin's disease was 18–25 cGy and 128–356 cGy, respectively. A small excess risk of genetic diseases of (1–15) x 10–4 was estimated for radiotherapy above the diaphragm. Pelvic irradiation resulted in an increased risk of hereditary effects of (77–214) x 10–4.
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Introduction
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Radiotherapy plays a major role in the curative and palliative treatment of malignant diseases. However, therapeutic external irradiation will result in an unavoidable exposure of out-of-beam structures characterized by low dose tolerances. Ovaries are among the more radiosensitive anatomical structures, as ovarian exposure to ionizing radiation may cause harmful effects on gonadal function. The issues of radiation induced sterility and the induction of genetic effects in future generations are strongly associated with quality of life. Continued therapeutic advances have substantially improved the survival of adolescents and young cancer patients [1, 2], and it is important to ensure, in as far as it is possible to do so, that all these patients can safely give birth to children and that their offspring will be free of problems related to the parental irradiation. To our knowledge, the risk of genetic effects in future generations associated with therapeutic irradiation in women of reproductive age has not been evaluated. Niroomand-Rad and Cumberlin [3] determined the genetically significant dose resulting from radiotherapy. However, their study was limited to treatment of Hodgkin's disease and young female patients may present with a wide variety of tumours.
This study aims to estimate the risk of hereditary effects resulting from therapeutic external irradiation of malignant diseases appearing in women of reproductive age.
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Materials and methods
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Irradiation techniques
The radiation dose to ovaries was measured for radiotherapy of brain, breast and lung cancer, and for treatment of Hodgkin's disease. A retrospective review in the records of our radiation oncology department showed that 80% of female patients of reproductive age treated for non-gynaecological cancers between 1999 and 2002 presented with a malignancy in one of the above sites. For each of the treatments studied, the most common irradiation technique was applied [4]. The treatment planning procedure was performed by a senior radiotherapist and large field sizes were applied in order not to underestimate ovarian dose. The source to skin distance was 100 cm for all the irradiation fields planned. Treatment parameters including the fields used, the field sizes and directions and the dose delivered to the tumour site during the entire treatment course are shown in Table 1
. For all the above, opposed coaxial beams were applied with equally weighted contributions.
For radiotherapy of lung cancer, a tumour lying in the mediastinum was assumed. To simulate breast irradiation, a phantom representing the shape of the breast was placed on an anthropomorphic phantom. The breast phantom was made of wax, which simulates the density of the breast tissue [5]. Radiotherapy of Hodgkin's disease was performed using the mantle and the inverted Y technique, which are currently applied for treatment of supradiaphragmatic or infradiaphragmatic nodal disease, respectively. Mantle irradiation was generated by shielding the lungs and both humeral heads with lead blocks and a laryngeal shield was also placed in the anterior field. For the inverted Y technique, lead blocks were used to shield the kidneys and a central lead block with a thickness of 10 cm was placed in the region of the pelvis to shield the ovaries. All irradiations of this study were performed using a 6 MV linear accelerator (Philips SL 75/5, The Netherlands).
Ovarian dose measurements
Thermoluminescent dosemeters containing calcium fluoride (TLD–200; Harshaw, Solon, OH) were used to measure the radiation dose to ovaries. The crystals were calibrated against a thimble ionization chamber (No. M31003; PTW, Freiburg) with a sensitive volume of 0.3 cm3. The TLDs were placed in a commercially available Rando humanoid phantom (Alderson Research Labs, Stanford, CA) that has been extensively used for radiation dose measurements in radiotherapy [3, 6–10]. The phantom is manufactured from tissue equivalent material and consists of 36 separate sections numbered 0–35. It contains both a skeleton and lungs. Each section has a matrix of holes permitting TLD positioning. Ovarian dose was measured in phantom section 31 corresponding to the most likely ovarian location [11] and also in sections 30 and 32, which may represent ovary positions in patients whose sizes differ from that of the phantom. Four TLDs were placed in two holes of each section, i.e. two TLDs were placed in each hole. The holes were located 3 cm from the median plane of the pelvic sections and 10.5 cm from the anterior phantom surface. For each section, the average reading of the four TLDs was taken as the ovarian dose at this level.
Oophoropexy is currently used to protect the ovaries in patients undergoing radiotherapy of Hodgkin's disease using the inverted Y technique. The ovaries may be transposed either medially or laterally [12] and locations of the TLDs were adjusted to account for this. For medial ovarian transposition, two TLDs were placed at the centre of the part of the beam intercepted by the 10 cm thick lead block, and for lateral transposition, eight TLDs were placed at holes located 9 cm and 12 cm on either side of the midline of the irradiation field. Thus, for lateral transposition, the measurement points were at a distance of 2 cm and 5 cm from the lateral field edges. Two TLDs were again positioned in each hole. Dose measurements were performed at two different distances from the field edge to take into account possible variations in the location of the transposed ovaries.
Dependence of ovarian dose upon the beam modifiers
Beam modifiers such as wedges or blocks might be used during external irradiation of brain, breast and lung cancer to achieve the desired dose distributions, and so additional measurements were carried out to study the influence of these on the dose to ovaries. Ovarian dose was again measured at the phantom section 31. These measurements were performed using the universal 60° wedge filter.
Risk estimation of hereditary effects
The International Commission on Radiological Protection has suggested a risk coefficient of 0.6% per Gy for induction of hereditary effects in the working age population [13] and this has been used to convert our ovarian dose measurements to an estimate of the risk. All risk estimations express the expected increase in the frequency of genetic disorders in future generations over those occurring naturally in the population. For breast radiotherapy, the risk was estimated assuming a treatment course combining two tangential fields with a supraclavicular field.
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Results
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Ovarian dose measurements
Ovarian dose measurements and the distances from the field edge to the point of measurement are presented in Table 2. All radiation dose values are expressed as a percentage of the prescribed tumour dose. The radiation dose to medially transposed ovaries during the inverted Y field irradiation was found to be 9% of the dose delivered to the tumour site. All values will indicate the maximum ovarian dose since they have been derived from phantom exposures using large field sizes.
Dependence of ovarian dose upon the beam modifiers
The presence of beam modifiers in the primary beam resulted in a considerable increase of the dose to the ovaries. For brain radiotherapy, the introduction of a lead block or a wedge increased the ovarian dose by a factor of 1.4 and 2.2, respectively. The use of wedged lateral beams during lung irradiation produced an ovarian dose that was 2.3 times higher than that obtained using open beams. For breast radiotherapy, the insertion of a wedge into tangential fields caused an increase in the ovarian dose by a factor of 1.8. All the above dose measurements were obtained using the maximum available wedge angle of 60°, but in every day clinical practice, smaller wedge angles are more common. In such cases there would be a smaller increase in the ovarian dose than that reported in this study.
Risk estimation of hereditary effects
The risk of radiation induced hereditary effects associated with radiotherapy in women of reproductive age is presented in Table 3. For radiotherapy of brain, breast and lung cancer and for mantle treatment the range of ovarian dose values is that between the minimum and the maximum dose corresponding to the most distant and the most proximal ovarian location relative to the inferior field edge. The total radiation dose received by medially or laterally transposed ovaries and the associated risks of hereditary effects resulting from the inverted Y field irradiation are also presented.
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Discussion
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The treatment site is the most important factor determining the distance between the ovaries and the primary irradiation field; the smaller the distance the higher the ovarian dose. The introduction of wedges and shielding blocks into the primary beam may increase the ovarian dose considerably. The presence of a wedge resulted in elevated scattered radiation emanating from the beam modifier and in elevated head leakage associated with the increase of monitor units required. The use of lead blocks led to an increase of the scattered radiation from the block and the support tray.
Ovarian doses of 250–500 cGy in female patients aged 15–40 years may result in a 60% incidence of sterility and may cause a 100% sterility in women aged above 40 years [14]. Temporary sterility may also result from an ovarian dose of 200 cGy [15]. For radiotherapy of brain, breast and lung cancer, and for mantle treatment, our measurements showed that the ovarian dose is much lower than that associated with radiation induced infertility. However, ovarian doses as low as 10 cGy may cause a delay or a suppression of menstruation [15]. Our measurements show that treatments of breast cancer, lung tumours and supradiaphragmatic nodal disease may result in ovarian doses of 8–25 cGy, and therefore, may be associated with the induction of menstrual irregularities.
Pelvic irradiation, without transposition of the ovaries, may result in very high ovarian doses. For inverted Y field irradiation, the ovaries may receive a primary radiation dose of 40 Gy, which may be expected to lead to ovarian failure [16]. Therefore, transposition of the ovaries during treatment of infradiaphragmatic Hodgkin's disease could be of vital importance in maintaining the ovarian function. The radiation dose to medially transposed ovaries was similar to that required to induce sterility, but the use of lateral transposition reduced the ovarian dose considerably. The reduction is attributed to the ovarian position in respect to the treatment field. The laterally transposed ovaries are lying outside the primary irradiation field whereas the medially transposed ovaries are surrounded by the treatment volume. Hence, lateral ovarian transposition is the preferred approach to achieve the maximum protection of the ovaries during radiotherapy with the inverted Y technique.
The excess risk of hereditary effects from treatment of brain, breast and lung cancer and from mantle irradiation, may be regarded as very low when taking into account that the current incidence of serious birth defects in humans has been estimated as 6% [17]. The risk of genetic disorders may be increased whenever wedges or lead blocks are used during treatment of brain, breast and lung cancer, but should still be regarded as low compared with the risk of naturally occurring hereditary effects. On the other hand, the use of the inverted Y technique for the management of infradiaphragmatic nodal disease may be associated with an increased risk of genetic disorders.
Inaccuracies in ovarian dose measurements may be associated with the use of TLDs. To reduce the uncertainty of TLD readings, the calibration of the crystals was performed with the same radiation modality used for ovarian dose measurements and the individual sensitivity of each crystal was applied. The overall uncertainty in TLD measurements was estimated to be less than 8%. Moreover, possible variations either in the distance between the ovaries and the median pelvic plane or in the ovarian depth from the average may result in inaccuracies in ovarian dose estimation. Phantom measurements at different section levels accounted for the variations in the distance separating the ovaries from the primary irradiation field, and so dose data from this study may be applied to women of different heights. It should be stressed that the current knowledge of the harmful effects of radiation is from patients who received radiotherapy, from the follow-up of atomic bomb survivors and from animal studies. Thus, all risk estimates might contain considerable uncertainty especially at low dose levels.
Ovarian dose measurements presented in this study are similar to those previously reported for treatment of supradiaphragmatic or infradiaphragmatic Hodgkin's disease [3, 6, 18, 19]. Regarding the medial ovarian transposition applied during the inverted Y irradiation, a difference may be observed when our dose measurements are compared with those of Sharma et al [6]. They found that the radiation dose to ovaries may be 15% of the given tumour dose, while our phantom measurements suggested a lower ovarian dose of 9%. This difference may be due to the larger shielded region and to the thicker block used in the current study. Moreover, no considerable difference was observed between our dosimetric results and fetal dose measurements performed in early pregnancy for radiotherapy of brain tumours [7], for tangential breast irradiation [20, 21] and for mantle treatment [9, 22]. This may be attributed to the very close anatomical positions that characterize a fetus in the first post-conception weeks and the ovaries.
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Conclusions
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The current study provides radiation dose measurements to ovaries and risk estimates resulting from therapeutic external irradiation in female patients of reproductive age. The measurements revealed that the risk of radiation-induced hereditary effects may be considered as low whenever the treatment fields exclude the pelvic region. Of the sites studied only the treatment of infradiaphragmatic Hodgkin's disease revealed an increased risk that might not be regarded as low when compared with the naturally occurring incidence of genetic effects.
Received for publication September 29, 2003.
Revision received April 5, 2004.
Accepted for publication April 23, 2004.
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Abstract
Introduction
