Tumori, 90: 13-16, 2004 INTRAOPERATIVE RADIOTHERAPY DURING BREAST CONSERVING SURGERY IN PATIENTS PREVIOUSLY TREATED WITH RADIOTHERAPY FOR HODGKIN’S DISEASE Mattia Intra1, Maria Cristina Leonardi2, Giovanna Gatti1, Anna Rita Vento1, Mario Ciocca3, Paolo Veronesi1, Guillermo Bassani1, Gabriela Rosali Dos Santos1, Julia Rodriguez1, Alberto Luini1, Roberto Orecchia2, and Umberto Veronesi1 1 Department of Breast Surgery, 2Department of Radiotherapy, University of Milan; 3Medical Physics Unit, European Institute of Oncology, Milan, Italy Aims and background: Women who have received radiotherapy and full-dose intraoperative radiotherapy with electrons for Hodgkin’s disease have an increased risk of developing (ELIOT) were performed. breast cancer. Breast-conserving surgery followed by breast Results: A total dose of 17 Gy (prescribed at 100% isodose) in irradiation is generally considered to be contraindicated in one case and 21 Gy (at the 90% isodose) in two cases was de- such patients owing to the high cumulative radiation dose to livered directly to the mammary gland without acute compli- the breast. Mastectomy is therefore recommended as the pre- cations and with good cosmetic results. ferred treatment option in these women. Conclusions: In women previously irradiated for Hodgkin’s dis- Methods: We report 3 patients affected by breast cancer who ease, ELIOT could avoid repeat irradiation of the whole breast, had previously been treated with mantle radiation for thereby permitting conservative surgical treatment. Hodgkin’s disease and on whom breast-conserving surgery Key words: breast cancer, breast-conserving surgery, Hodgkin’s disease, intraoperative radiotherapy, IORT, lymphoma. Introduction the thoracic wall, lung and heart, without rejecting the possibility of conservative surgery for small breast car- Women who have received radiotherapy for Hod- cinomas, we evaluated the potential of performing full- gkin’s disease (HD) have an increased risk of develop- dose intraoperative radiotherapy with electrons ing breast cancer. This risk is well documented and is (ELIOT) in women who had previously received radio- attributed to the incidental inclusion of portions of the therapy for HD. breast in the portals used to irradiate the mediastinum ELIOT is a new radiotherapeutic technique which de- with or without infraclavicular-axillary regions1,2. The livers a single dose of radiation directly to the tumor increased incidence of breast cancer depends on the pa- bed during the conservative surgical treatment of the tient and on treatment factors including radiation dose, breast cancer. At the European Institute of Oncology of radiation treatment field and age at treatment3. The esti- Milan (EIO), our interest has been focused on the use of mated risk is also affected by the duration of follow-up ELIOT as a single, exclusive treatment in selected lim- after radiotherapy and the method used to calculate ited-stage unifocal infiltrating breast carcinomas con- risk4. For such patients, several reports5,6 have suggest- servatively treated11-13. ed mastectomy as the treatment of choice for breast cancer arising after previous radiotherapy for HD. This Materials and methods is based on concern about possible severe sequelae aris- ing after a high total cumulative dose to portions of the Between June 1999 and December 2002, 355 breast breast. cancer patients (mean age, 59 years; range, 33-80) af- There is a little reported experience using alternative fected by unifocal infiltrating carcinoma with a mam- therapies to mastectomy: wide local excision alone, lo- mographic or echographic diameter equal or inferior to cal excision and interstitial brachytherapy, and local ex- 2.5 cm and candidate for breast-conserving surgery re- cision followed by local field external beam radiothera- ceived ELIOT as the sole radiation treatment, including py7-10. 9 patients who received 17 Gy (1 patient received bilat- In order to avoid a dangerous high total cumulative eral ELIOT) and 6 who received 19 Gy as part of the dose of radiotherapy to the whole breast, soft tissues of initial dose-finding study11,12. The remaining 340 pa- Acknowledgments: The authors thank the AIRC (Italian Association for Cancer Research) and AICF (American Italian Cancer Foundation), which partially funded this research project. Correspondence to: Mattia Intra, MD, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. Tel +39-02-57489725; fax +39-02-57489780; e-mail email@example.com Received April 30, 2003; accepted June 5, 2003. 14 M INTRA, MC LEONARDI, G GATTI ET AL tients received 21 Gy: 307 patients, 21 Gy prescribed at experience developed through different phases. A 90% isodose; 33 patients at 100% isodose. Of 355 pa- dose-escalation and toxicity study, described else- tients, 3 patients had been previously treated for HD where, was designed to define the maximum tolerated and received mantle radiation as shown in Table 1. dose in a single fraction, to establish an equivalence The breast cancer presentation in these 3 patients is between the value of the single ELIOT dose reached described in Table 2. The interval from completion of and the conventional fractionated schedule of external radiotherapy for HD to diagnosis of breast cancer was radiation and, finally, to assess the acute and interme- 16, 14 and 8 years. All patients underwent breast-con- diate toxicity of ELIOT11,12. The radio-surgical tech- serving surgery and radioguided sentinel node biopsy nique was then standardized to optimize each step of with histological examination of the sentinel node by the procedure13 and to investigate the issue of whether the technique commonly utilized in our Institution and in breast cancers up to 2.5 cm in diameter an external elsewhere described14. In all cases the sentinel node was radiation therapy can be safely replaced by ELIOT. free of metastasis and complete axillary dissection was For this, a randomized trial is now ongoing at the EIO. not performed. ELIOT at a total dose of 21 Gy (prescribed at 90% iso- dose) is compared with the standard external radiation regimen, ie, 50 Gy to the whole breast and 10 Gy as a boost to the tumor bed. The recruitment phase is ex- Table 1 - Presentation of and therapy for HD pected to finish in 3 years. Patient Age Diagnosis Stage Therapy Based on the radiobiological models used to predict no. (yr) radiation effects (linear-quadratic surviving fraction or 1 29 HD, MC IIA MOPP x 6, Mantle 36 Gy multitarget surviving fraction)15, we can estimate that a 2 28 HD, NS IIB MOPP x 4, ABVD x 4, Mantle 20 Gy dose of 60 Gy delivered at 2 Gy daily, which is the radi- 3 42 HD* IIB ABVD x 3, Mantle 40 Gy ation dose required to control the microscopical residual HD, Hodgkin’s disease; MC, mixed cellularity; NS, nodular sclerosis; disease after breast resection, is equivalent to a single MOPP, nitrogen mustard, vincristine, procarbazine, prednisone; ABVD, fraction of 20-22 Gy, when using an α/β ratio at 10 Gy, adriamycin, bleomycin, vinblastine, dacarbazine; *no histologic subtype determined. typical for tumors and acute reacting tissues. Using the same equation but calculating the tolerance of late re- sponding tissues (α/β ratio at 3 Gy), this equivalent val- ue increases to at least 110 Gy. The Linac does not pro- duce photons, but only delivers electron beams at four different energy levels: 3, 5, 7 and 9 MeV as nominal Table 2 - Presentation of breast cancer energies, corresponding to 4.5, 5.2, 6.5 and 7.8 MeV ef- Patient Age Interval (yr) since ELIOT dose fective energies at the phantom surface, respectively. no. (yr) radiation for HD The depth of 80% isodose ranged from 13 mm (3 MeV, 1 35 16 21 Gy (90% isodose), 7 MeV not used in clinical practice) to 24 mm (9 MeV). 2 42 14 17 Gy (100% isodose), 7 MeV In 1 patient, a total dose of 17 Gy (prescribed at 3 50 8 21 Gy (90% isodose), 9 MeV 100% isodose) using electron beams (7 MeV energy) Mev, mega electron volts. was delivered. In 2 patients, 21 Gy (prescribed at 90% isodose, 7 and 9 MeV of energy) were administered. The electron beams were delivered directly to the mam- mary gland after tumor removal and breast mobiliza- In all 3 patients ELIOT was performed. The radio- tion. surgical technique did not differ from the “classic” al- ready described technique in patients not previously ir- Results radiated for HD (no-HD ELIOT)13. The biological characteristics of the tumors are Radiation therapy device shown in Table 3. Two patients received adjuvant The dedicated ELIOT machine (Novac7, Hitesys, chemotherapy with cyclophosphamide-methotrexate/5- Rome, Italy) is a miniaturized linear accelerator that can fluorouracil followed by tamoxifen (20 mg/day) for 5 be moved by a robotic arm and docked in the operating years associated in one case to LHRH analogue for 2 room; it fulfills the statutory requirements with respect years. One patient received only tamoxifen (20 mg/day) to radiological protection. Additional barriers (from 5 to for 5 years. 15 mm lead) are provided for positioning around the ELIOT was well tolerated in all women without any operating table. A lead shield (15-cm thick) is also unusual acute reactions. In the only patient with a long placed under the surgical bed in correspondence with follow-up, no late sequelae have been observed, and the electron field (beam stopper). all women had an excellent cosmetic result. The pa- ELIOT delivers a single full-dose of radiation di- tients are free of disease after 34, 19 and 10 months of rectly to the tumor bed after removal of the tumor. Our follow up. IORT DURING BC SURGERY AFTER RT FOR HD 15 Table 3 - Characteristics of the breast cancer Patient no. Tumor site T N G ER, PgR KI67 CerbB2 PVI % % 1 UO 1c 0 (sn) 2 15, 25 11 - No 2 LI 1c 0 (sn) 3 0, 0 70 - No 3 C 1c (is) 0 (sn) 1 90, 90 13 - No UO, upper outer; LI, lower inner; C, central; is, extended intraductal component associated; sn, sentinel node; PVI, perivascular invasion. Discussion diation of the portion of breast gland to undergo ELIOT was necessary. Protective devices are placed between Previous radiotherapy, such as mantle radiotherapy the gland and the pectoral muscle: a dedicated lead disk for HD, is considered a contraindication to conservative 5-mm thick and an aluminum disk 4-mm thick, avail- breast surgery and radiotherapy16. This is based on con- able in various diameters (4, 5, 6, 8 and 10 cm) are cern about possible severe sequelae arising after a high commonly used. The wall protection was guaranteed by total cumulative dose to portions of the breast. Repeat the absorption properties of the lead and aluminum and irradiation of the breast can lead to severe fibrosis and the 9 mm outdistance created by the disks. The separa- soft tissue necrosis. The re-irradiation of the thoracic tion of the skin from the collimator in correspondence wall, lung and heart can also lead to serious local and to the surgical breach is fundamental in order to com- general complications, as a result of exceeding normal pletely avoid irradiation of the skin: if the skin lays in tissue tolerance6. In contrast, other reports17,18 have sug- contiguity with the Perspex collimator, its margin could gested that previous radiation is not necessarily a con- receive around 5% of the total dose. We developed a traindication to breast preservation and that it is possi- dedicated device to spare the skin completely from the ble to consider lumpectomy and breast irradiation for radiation delivery by ELIOT. This device consists of a those women in whom breast cancer develops many metallic ring of variable diameter (to provide a closer fit years after radiotherapy for HD. At present, no consen- sus exists regarding the correct interval between the to the patient’s anatomy), connected to fine, non-trau- mantle radiotherapy and breast irradiation and, given matic metallic hooks: the skin margins are hitched to the discordant results and the small number of women the hooks and gently stretched out of the radiation field. treated with breast-conserving therapy, mastectomy ELIOT was well tolerated without any unusual acute continues to be recommended as the standard treatment reactions despite the previous breast irradiation. Due to for patients previously irradiated for HD. the careful sparing of the subcutaneous vessels during In order to avoid a high total cumulative dose to por- the mobilization of the residual breast around the tumor tions of the breast or soft tissues of the thoracic wall, bed, we did not observe any ischemic or necrotic prob- partial breast irradiation has been proposed. This allows lems of the skin flap. No increased postoperative com- treatment of the tumor bed where, within the first 5 plications (pain, seroma, hematoma, infection) were ob- years of follow-up after breast-conserving surgery, the served in these 3 patients compared to the group of no- most local failures occur19. Interstitial brachytherapy or HD ELIOT patients. The length of hospitalization was local field external beam radiotherapy permits the high- not therefore prolonged. The cosmetic outcome was al- er risk area to be irradiated, thereby minimizing the risk so very good in all patients: no skin erythema was ob- of complications with good oncological and cosmetic served as a result of the complete removal of the skin results7-10. from the radiation beam. In June 1999, at the EIO of Milan we focused our in- The follow-up is too short (34, 19 and 10 months) to terest on the use of ELIOT as a single, exclusive treat- evaluate late sequelae in these 3 re-irradiated patients. ment in selected limited-stage unifocal infiltrating However, in the only patient with 34 months of follow- breast carcinomas conservatively treated. In the 3 pa- up, no complications have been observed. tients previously irradiated for HD, the dose delivered and the energy of electron beams of ELIOT did not dif- Conclusions fer from those in the other 352 patients submitted to ELIOT: in 1 patient, a total dose of 17 Gy (prescribed at In patients previously treated for HD, ELIOT dra- 100% isodose) using electron beams at 7 MeV energy matically reduces radiation exposure of the normal tis- was delivered. In 2 patients, 21 Gy (prescribed at 90% sues and, in particular, of the previously irradiated isodose, 7 and 9 MeV of energy) were administrated. breast, avoiding the high total cumulative dose to the The different electron energies (7 or 9 MeV) are related gland and soft tissues of the thoracic wall. In these pa- to the different thickness of the breast glands. The 17 tients, ELIOT could permit conservative surgical treat- Gy patient was part of the initial dose-finding study. ment independently of the interval between mantle ra- To ensure a good coverage of the target by the radia- diotherapy and breast cancer treatment, without acute tion dose and the maximal protection of the normal tis- local complications. A longer follow-up is necessary to sues in the operative area, adequate preparation for irra- evaluate the incidence of radiation-induced sequelae 16 M INTRA, MC LEONARDI, G GATTI ET AL and the local recurrence rate. 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