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									Tumori, 90: 13-16, 2004


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
  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

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. To investigate the issue               total dose of 21 Gy (prescribed at the 90% isodose) is
of whether in early stage breast cancer external radia-               compared with the standard external radiation regi-
tion therapy can be safely replaced by ELIOT, a ran-                  men, ie 50 Gy to the whole breast and 10 Gy as a
domized trial is now ongoing at the EIO: ELIOT at a                   boost to the tumor bed.

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