Ann Surg Oncol (2009) 16:100–105 DOI 10.1245/s10434-008-0172-z
ORIGINAL ARTICLE – BREAST ONCOLOGY
Is Electron Beam Intraoperative Radiotherapy (ELIOT) Safe in Pregnant Women with Early Breast Cancer? In Vivo Dosimetry to Assess Fetal Dose Viviana Galimberti1, Mario Ciocca2, Maria Cristina Leonardi3, Vanna Zanagnolo4, Baratella Paola1, Sargenti Manuela1, Rafaela Cecilio Sahium1, Roberta Lazzari3, Oreste Gentilini1, Fedro Peccatori5, Umberto Veronesi1, and Roberto Orecchia3,6 1 Unit of Molecular Senology, Senology Department, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy; 2Department of Medical Physics, European Institute of Oncology, Milan, Italy; 3Department of Radiotherapy, European Institute of Oncology, Milan, Italy; 4Department of Gynecology, European Institute of Oncology, Milan, Italy; 5 Unit of Allogenic Transplantation, European Institute of Oncology, Milan, Italy; 6University of Milan, Milan, Italy
ABSTRACT Electron beam intraoperative radiotherapy (ELIOT) is a new technique permitting breast radiotherapy to be completed in a single session. Since ELIOT is associated with much reduced irradiation to nontarget tissues, we carried out a study on nonpregnant breast cancer patients to estimate doses to the uterus during ELIOT to better evaluate the possible use of ELIOT in pregnant breast cancer patients. We performed in vivo dosimetry with thermoluminescence radiation detectors (TLDs) in 15 premenopausal patients receiving ELIOT to the breast (prescribed dose 21 Gy) using two mobile linear accelerators. The TLDs were positioned subdiaphragmatically on the irradiated side, at the medial pubic position, and within the uterus. A shielding apron (2 mm lead equivalent) was placed over the viscera from the subcostal to the subpubic region. TLDs showed mean doses of 3.7 mGy (range 1–8.5 mGy) at subdiaphragm, 0.9 mGy (range 0.3–2 mGy) pubic, and 1.7 mGy (range 0.6–3.2 mGy) in utero, for beam energies in the range 5–9 MeV. These findings indicate that ELIOT with a mobile linear accelerator and shielding apron would be safe for the fetus, as doses of a few mGy are not associated with measurable increased risk of fetal damage, and the threshold dose for deterministic effects is estimated at 100–200 mGy. We conclude that studies on the use of ELIOT in pregnant women treated with conservative breast surgery are justified.
Ó Society of Surgical Oncology 2008 First Received: 30 May 2008; Published Online: 21 October 2008 V. Galimberti e-mail:
[email protected]
Although breast cancer is rarely diagnosed in pregnancy (about 1 per 1000), the event has a major, sometimes devastating, emotional impact on the woman. In such cases, mastectomy is the usual treatment, since the cancer is typically at a locally advanced stage because physiological changes within the breast and restrictions on the use of diagnostic procedures make early diagnosis difficult.1–3 It has been shown that surgery can be performed at any time during pregnancy with low risk (1–2%) of spontaneous abortion during the first 3 months and low (range 1.5–2.0) relative risk of premature birth in subsequent trimesters.4 Complete axillary dissection is also a common procedure in pregnant women, because the axilla is usually involved and even for small tumors sentinel node biopsy is not performed because of the perceived risk to the fetus associated with radiotracer use. However, a recently published dosimetry study of sentinel node biopsy with radioactive tracer showed that doses to different areas of the abdomen, indicative of the absorbed dose to the fetus at each trimester, were so low as to constitute no increased risk of fetal harm, and suggesting that sentinel node biopsy should have the same indications in pregnant as in nonpregnant women.5,6 Furthermore, most pregnant women with early breast cancer are not usually offered conservative surgery, because the postoperative radiotherapy (RT) must be delayed until after parturition. Although for cases diagnosed in late pregnancy RT can start without delay following induced birth as soon as fetal maturation is complete (32–34 weeks).7–10 A number of studies have assessed fetal dose in women undergoing RT for various malignancies including brain cancers, head and neck cancers, and Hodgkin’s disease.11 For breast cancer, several estimates of the peripheral dose
ELIOT in Pregnant Women with Early Breast Cancer
to the uterus from external tangential photon fields have been published; for example, Antypas et al. reported a fetal dose of 39 mGy after 46 Gy had been given over 4 weeks in 20 fractions to the breast of a woman in early pregnancy (2–6 weeks), when the distance between the uterine fundus and radiation fields was at its greatest.12 Ngu et al. estimated a dose of 210 mGy to the unshielded fetus and 140–180 mGy to the shielded fetus for 50 Gy total dose prescribed to the breast in a patient irradiated in late pregnancy, when the uterine fundus was close to the edge of the radiation fields.13 Antolak et al. used an anthropomorphic phantom to estimate the fetal dose to a woman undergoing RT for chest wall recurrence.14 The measured dose to an unshielded fetus was 53 mGy, but could be reduced to less than 15 mGy using abdominal shielding (6.6 cm of lead). A further 30% dose reduction could be achieved using the lower (instead of upper) variable trimmer bars to define the field edge closest to the fetus. For conventional breast cancer with RT dose prescription of 50 Gy in 25 daily fractions to the whole breast, the fetal dose from high-energy photon beams in early pregnancy (up to 24 weeks) has been estimated in the range 20– 240 mGy, increasing to 2,000 mGy in late pregnancy.15–17 The International Commission on Radiological Protection (ICRP) considers a fetal dose of less than 1 mGy to be insignificant, and that doses of a few mGy are acceptable as they are associated with no measurable increased risk of fetal damage.18 The threshold dose for deterministic effects, such as organ malformation, mental impairment and growth retardation, is estimated at about 100–200 mGy.19 Thus, in view of fetal dose estimates of 20–240 mGy up to the 24th week, increasing to 2000 mGy and beyond in late pregnancy, external beam RT should not be given during pregnancy.19 The interpretation of the association of in utero exposure with the subsequent risk of childhood cancer (stochastic effects) is controversial as regards the existence of a threshold dose below which there is no excess risk.20–24 Intraoperative RT with electrons (ELIOT) after breastconserving surgery at full dose (21 Gy prescribed at 90% isodose, delivered in single fraction) has been introduced at our institute for postmenopausal women in the context of partial breast irradiation, with encouraging clinical results.25,26 The procedure eliminates the need for a long course of postoperative RT, drastically reduces the radiation dose to normal tissues and organs, and improves targeting to the tumor bed that is under direct visual control. In view of this promising experience of ELIOT for breast cancer, we decided to perform a study to provide dosimetric data pertinent to the safety of this procedure in pregnant women. We performed in vivo dose measurements on nonpregnant premenopausal patients undergoing ELIOT.
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MATERIALS AND METHODS Treatment Units ELIOT to the breast tumor bed following quadrantectomy, wide excision or nipple-sparing mastectomy is given with a mobile linear accelerator (either a Novac7, Hitesys, Aprilia, Italy, or a Liac, Info & Tech, Rome, Italy) installed in an operating room. The machines produce electron beams at four selectable energy levels (Novac7: 3, 5, 7 or 9 MeV; Liac: 4, 6, 8 or 10 MeV) and high dose rate (around 10–20 Gy per min, depending on beam energy and applicator size), so that irradiation time is 1–2 min for typical doses.27 The beam is collimated by sterile cylindrical Perspex applicators of thickness 5 mm and diameter between 3 and 12 cm. For breast cancer, the applicator chosen is typically 4–6 cm in diameter, and depending on the breast being irradiated the applicator base may be flat or beveled (at 15–22.5°) to facilitate docking to the machine. Source to skin distance is 80 cm for the Novac7 and 60 cm for the Liac. Aluminum and lead discs of diameter 5–8 cm (6–8 mm thickness) are placed between the residual breast and chest wall as internal shielding to protect the underlying tissues. Mobile vertical lead shields and a primary beam stopper are positioned in the operating room (not purpose built for intraoperative irradiation) to keep radiation levels outside the operating room below statutory limits. In Vivo Dosimetry Between January and April 2008, we performed in vivo dosimetry on 15 nonpregnant premenopausal patients undergoing ELIOT for breast cancer, either as only irradiation treatment (nine patients at dose 21 Gy; three patients undergoing nipple-sparing mastectomy who received 16 Gy to the nipple–areola complex) or as boost prior to conventional radiotherapy to the whole breast (three patients, dose 12 Gy). One woman received ELIOT to both breasts for simultaneous bilateral cancer. ELIOT beam energies were in the range 5–9 MeV; applicator diameters were either 4 cm or 5 cm; applicator ends were flat in 12 instances and beveled in 4 instances. The Novac7 was used in seven patients and the Liac was used in eight patients. The detectors used were thermoluminescence radiation detectors (TLDs) in the form of microrods (TLD 100, Harshaw, USA). TLDs were placed in a thin plastic envelope at two sites on the skin of each patient: subdiaphragmatically on the side being irradiated (10–15 cm from the applicator) and at the medial suprapubic position (about 30–40 cm from the applicator). For uterine insertion, the TLDs were placed in the tip of a sterile thin
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flexible close-ended catheter (length 30 cm, external diameter 2 mm). The catheter was introduced into the uterus by a gynecologist when the patient was under general anesthesia, immediately prior to breast surgery. Written informed consent for this procedure was obtained for each patient. A shielding apron (2 mm lead equivalent) was placed on the patient’s abdomen so as to block most of the electron scatter from the machine. Two microrod detectors were placed at each location and average values recorded. The TLDs were from a batch calibrated in terms of absorbed dose to water under 6 MeV electron beams generated by a conventional linear accelerator (Cl2100, Varian, USA). Twenty-four to 48 h after irradiation, the detectors were analyzed with a manual TLD reader and commercial software (Model 3500 reader and WinREMS SW, SaintGobain Crystals and Detectors, USA). The readout was converted to absorbed dose using an appropriate calibration factor. Postirradiation TLD annealing consisted of heating 1 h at 400°C followed by 16 h at 80°C. The overall uncertainty of the measurements was estimated at around ±15% (one standard deviation). Reported data were rescaled to the prescription dose of 21 Gy, thus for patients receiving ELIOT as boost the data were scaled by a factor of 21/12, and for women receiving nipple-sparing mastectomy the data were scaled by a factor of 21/16. For the bilateral ELIOT, reported peripheral dose was halved. The dose to the uterus from radioactive tracer used in sentinel node biopsy was neglected since a previous study had shown that doses were very low and well below the uncertainty of dose measurements by TLDs during ELIOT.5 RESULTS The results for each patient are shown in Table 1 and comprise the doses to the three body areas, the linear accelerator used, beam energy, applicator size, breast area irradiated, and prescribed dose. The mean dose to the subdiaphragmatic skin was 3.7 mGy, standard deviation (SD) 2.4 mGy, range 1–8.5 mGy. The mean dose to the suprapubic skin was 0.9 mGy, SD 0.5 mGy, range 0.3– 2 mGy. Mean intrauterine dose was 1.7 mGy, SD 0.8 mGy, range 0.6–3.2 mGy. The mean ratio of intrauterine dose to subdiaphragmatic surface dose was 0.6, SD 0.4, range 0.16–1.58, and in two cases (13%) the intrauterine dose was slightly higher than the subdiaphragmatic surface dose. The mean ratio of intrauterine dose to suprapubic surface dose was 2.08, SD 1.1, range 0.8–3.88, with intrauterine dose slightly lower than suprapubic surface dose in two women. On average, therefore, the intrauterine dose was about half that of the most cranial surface dose (closest to the irradiation field) and about twice that of the most caudal surface dose. These
V. Galimberti et al.
findings suggest that one may consider surface dose measured at the subdiaphragmatic level as the upper limit of the dose absorbed by the fetus. Overall the measured doses appeared independent of applicator size, beam energy, and breast quadrant irradiated. However, mean peripheral doses measured with Novac7 were lower than with Liac even though the mean energy delivered by the two instruments (7.6 MeV Novac7; 7.5 MeV Liac) were similar. Mean differences in dose between the Novac7 and Liac were contained for the suprapubic (0.7 mGy versus 1.2 mGy) and intrauterine (1.4 mGy versus 1.9 mGy) regions (p = 0.09; p = 0.10; t test), and somewhat larger for the subdiaphragmatic region close to the applicator (2.3 mGy versus 5 mGy; p = 0.04, t test). The Liac has a metal scattering foil for beam broadening in the treatment head, probably resulting in greater X-ray leakage. DISCUSSION The frequency and magnitude of effects of radiation exposure differ according to gestational age. Radiation sensitivity is high during early organogenesis with risk of microcephaly, urinary system defects, eye abnormalities, and skeletal maldevelopment. The estimated threshold dose for such effects is around 100–200 mGy. From 8 to 25 weeks there is a risk of mental retardation with an estimated threshold dose of around 300 mGy. For the most sensitive period (2–8 weeks) some authors suggest a threshold of 50 mGy, since this dose level may cause malformations and carcinogenesis in mice.28 The relative risks of childhood cancer after prenatal X-ray exposure for diagnostic purposes are 1.3–1.6 for leukemias and 1.4–3.2 for solid cancers, and exposure during the first trimester has a higher risk of cancer than exposure in the third trimester.29 To estimate the risk of radiation-induced cancer in humans, a linear non-threshold dose response is widely used and considered prudent (ICRP 90).18 However, animal experiments, data from atomic bomb survivors, and epidemiological studies do not provide strong support of a non-threshold effect of prenatal exposure, and indicate that the cancer risk is increased after doses as low as 10 mGy. As a result, Doll et al., Muirhead et al., and the United Nations Scientific Committee on the Effects of Atomic Radiation adopted an excess absolute risk coefficient of 6% per Gy [95% confidence interval (CI) 1.0–12.6%] for cancer incidence under 15 years of age following low-dose irradiation in utero.20–22 This coefficient corresponds approximately to an excess relative risk coefficient of 0.038 per mGy (95% CI 0.007–0.079) calculated by Mole from data collected by the Oxford Survey of Childhood Cancer.23 Such risk increases are in any event small for additional doses below 10 mGy.
ELIOT in Pregnant Women with Early Breast Cancer
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TABLE 1 Peripheral doses (mGy) measured with shielded TLDs at subdiaphragmatic and pubic surfaces of patients, in relation to radiation energy, applicator diameter (cm), bevel angle, and irradiation instrument (Novac7 or Liac) Instrument
Beam energy (MeV)
Applicator size (cm) and bevel angle (degrees)
Dose to subdiaphragmatic region (mGy)
1
N7
5
4–0
1.2
1
1.9
Nipple areola 20.8
16/90
2
N7
7
4–0
1
1.1
0.9
Lower-inner
23.2
21/90
3
N7
9
4–0
1.3
0.6
0.7
Upper outer
30.1
21/90
4
LIAC
8
5–15
4.4
1.2
1.3
External equatorial
26.8
21/90
5
N7
9
4–22, 5/5–0
1.2
0.4
0.6
Upper outer/ equatorial inner left
19.5
21/90 ? 21/100
6
N7
9
5–0
5
0.8
3.1
Upper outer
20.9
12/90
7
LIAC
8
5–0
3.8
1
2.2
Upper outer
20.3
21/90
8
LIAC
8
5–15
5.8
1.6
3.2
Upper inner
23.4
12/90
9
LIAC
8
5–0
8.5
1.6
1.4
Upper inner
25.3
21/90
10
N7
5
4–0
2.2
0.6
1.3
Nipple
22.6
16/90
11
LIAC
6
4–0
3.2
0.8
2.5
Nipple
26.2
16/90
12
LIAC
8
5–0
8.3
2
1.6
Periareolar
25.6
21/90
13 14
N7 LIAC
9 6
5–0 4–0
4.1 1.9
0.3 0.7
1 2.4
Upper central 28.3 Upper central 25.4
21/90 12/90
15
LIAC
8
5–15
4
0.3
0.9
Upper outer
21/100
Fetal dose estimates during radiotherapy are widely reported in the literature.29 External irradiation as adjuvant treatment for breast cancer during pregnancy may result in fetal doses exceeding the 100–200 mGy noted above, which is the threshold for deterministic effects.30,31 The dose fractionation can also influence the extent and nature of harmful effects: animal studies indicate that increasing fractionation reduces the adverse effects for a given total dose.32,33 In clinical practice, the total fetal dose is given over a long treatment time with low fractional doses: for a typical adjuvant whole-breast regimen in breast cancer of 50 Gy in 25 fractions, fetal exposure is estimated at 4–6 mGy per fraction and is not associated with reports of fetal damage.12,13,16 We performed in vivo dosimetry using TLDs placed both on the patients’ surface and directly inside the uterus, as surrogates for estimating the peripheral dose to the fetus during ELIOT. Our findings support our preliminary measurements performed within and on the surface of an anthropomorphic phantom, which indicated that skin measurements are closely similar to or slightly higher than internal doses.34 Our data show that the dose to the uterus during fulldose ELIOT for breast cancer can be kept below 10 mGy, similar to levels considered safe by the ICRP and others.18,19 This low dose was obtained simply using a welltolerated abdominal shielding apron and is also attributable
Dose to pubic region (mGy)
Dose to uterus (mGy)
Breast quadrant irradiated
Prescribed dose Body (Gy) (% isodose mass index (kg/ level) m2)
Patient
36.6
to the characteristics of the mobile linear accelerators, which are designed to minimize radiation leakage. Our findings therefore suggest that ELIOT is safe as it is associated with an absolute risk to the fetus that is indistinguishable from the background congenital abnormality rate and the lifetime risk of cancer. The dose to the uterus is expected to vary with distance of the uterus from the collimator; however, we did not systematically measure the distance between collimator and suprapubic region. Uterine dose tended to decrease with increasing body mass index (BMI) (Spearman’s = –0.23, p = 0.41, Table 1) as expected. The usual approach to pregnant women undergoing conservative surgery for breast cancer is to delay radiotherapy until after the birth of the child. However, delay may not be the best practice for women in the first trimester, although there are conflicting data regarding risk of breast recurrence as a result of delayed RT. The review of Woo et al. noted that mastectomy is traditionally considered the best choice for patients who want to continue the pregnancy, since it eliminates the need for postoperative irradiation in early-stage breast cancer.35 Our findings that RT with ELIOT may be safely given to pregnant women without delay raise the important possibility of performing conservative surgery in such women who would otherwise receive mastectomy. The positive psychological implications of our findings are also worth emphasizing. The pregnant woman is under
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stress and will be under much greater stress as a result of her breast cancer diagnosis and the decision regarding whether or not to abort. If she decides to continue with the pregnancy, she will then be surprised to learn her treatment must be more aggressive and more mutilating than that given to a nonpregnant woman with similar disease characteristics. ELIOT offers the pregnant woman the choice of receiving breast-conserving surgery without exposing her baby to a significant radiation risk, and preserves her breast. It is also important to note that conservative treatment of the axilla may be possible if she has a clinically negative axilla. Using our standard technique of injecting 12 MBq of 99mTc radiotracer, lymphoscintigraphy and sentinel node biopsy can be performed safely during pregnancy, in view of the very low fetal doses associated with this procedure (of the order of 10–100 lGy), which do not present any additional risk to the fetus, even if performed at the same time as ELIOT.5 We conclude by suggesting a novel approach to the pregnant woman with breast cancer, although decisions must be taken on a case-by-case basis in full consultation with the patient. After 30 weeks, the fetus is considerably closer to the breast than at earlier stages, so ELIOT appears less prudent, and since parturition can be safely induced earlier than 40 weeks it may be best to postpone conventional RT until after an induced delivery. During the first and second trimesters, however, intraoperative radiotherapy with ELIOT can be considered as a part of a breastconserving approach. Considering the second trimester, our preliminary experience in young women suggests that an intraoperative boost dose of 12 Gy could be administered to the pregnant woman if the time between this and conventional whole-breast RT after parturition does not exceed 16 weeks, and is preferably less, as recommended by international guidelines.36,37 We acknowledge, however, that partial breast irradiation in young women has not been studied, although it may be acceptable in certain conditions (pregnancy, and when the tumor is small). Again the possibility of induced early delivery could be considered, depending on fetal weight and maturation. During the first trimester, when the fetus is in the lower part of pelvic region, full-dose ELIOT (21 Gy) can be considered. We note finally that the ability to offer intraoperative radiotherapy to pregnant as well as other women depends not only on advanced irradiation equipment but also on a multidisciplinary treatment team in which the surgeon, radiation oncologist, medical physicist, and nuclear medicine physician work closely together. ACKNOWLEDGEMENTS The authors thank Dr. G. Raimondi (Ospedale Maggiore Policlinico, Milan, Italy) for technical assistance with the TLD dosimetry, the Associazione Italiana per la Ricerca sul
V. Galimberti et al. Cancro (AIRC), and the American Cancer Foundation (AICF) for providing support, and Don Ward for help with English.
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