Concepts and techniques of intraoperative radiotherapy (IORT) for breast cancer
- First Online:
- Cite this article as:
- Reitsamer, R., Sedlmayer, F., Kopp, M. et al. Breast Cancer (2008) 15: 40. doi:10.1007/s12282-007-0001-4
- 204 Downloads
The standard treatment for early breast cancer comprises wide local excision, sentinel lymph node biopsy or axillary lymph node dissection, adjuvant medical treatment and radiotherapy to the whole breast. Many studies suggest that local control plays a crucial role in overall survival. The local recurrence rate is estimated to be 1% per year and varies between 4 and 7% after 5 years and up to 10 to 20% in the long-term follow up. On the basis of low local recurrence rates the concept of whole breast irradiation comes up for discussion, and partial breast irradiation (PBI) is increasingly under consideration. Intraoperative radiotherapy (IORT) is referred to as the delivery of a single high dose of irradiation directly to the tumor bed (confined target) during surgery. PBI (limited field radiation therapy, accelerated partial breast irradiation APBI) is the irradiation exclusively confined to a breast volume, the tumor surrounding tissue (tumor bed) either during surgery or after surgery without whole breast irradiation. Various methods and techniques for IORT or PBI are under investigation. The advantage of a very short radiation time or the integration of the complete radiation treatment into the surgical procedure convinces at a first glance. The promising short-term results of those studies must not fail to mention that local recurrence rates could probably increase and furthermore give rise to distant metastases and a reduction in overall survival. The combination of IORT in boost modality and whole breast irradiation has the ability to reduce local recurrence rates. The EBCTCG overview approves that differences in local treatment that substantially affect local recurrence rates would avoid about one breast cancer death over the next 15 years for every four local recurrences avoided, and should reduce 15-year overall mortality.
KeywordsIntraoperative radiotherapy Breast cancer Breast conserving surgery Boost radiation
The standard treatment for early breast cancer comprises wide local excision (WLE), sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND) and whole breast radiotherapy (WBRT) plus adjuvant medical treatment if indicated. Many studies and the EBCTCG overview data suggest that local control plays a crucial role in overall survival [1, 2]. The EBCTCG overview suggested that differences in local treatment that substantially affect local recurrence rates would avoid about one breast cancer death over the next 15 years for every four local recurrences avoided, and should reduce 15-year overall mortality . The local recurrence rate is estimated to be 1% per year and varies according to the literature between 4 and 7% after 5 years and goes up to 10 to 20% in the long-term follow up [1, 3, 4, 5, 6, 7]. The majority of patients, who develop local recurrences do so within 2 to 5 years [1, 8]. Patients with local recurrences have an increased risk of distant metastases, and local recurrence seems to be an independent predictor of distant metastasis [8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26, 27]. Patients who develop local recurrences in the short term have a worse prognosis than patients who develop local recurrences in the long term [1, 8]. Based on these data and for psychological reasons of the patients, the reduction of local recurrence rates should be one of the treatment goals. Many factors contribute to the reduction of local recurrence rates, such as modern surgical techniques, the extensive pathologic evaluation of specimen and margins, the increasing use of adjuvant systemic therapies and the extensive use of radiation therapy.
Standard radiation therapy comprises 50 to 55 Gy in daily fractionations for 5 to 6 weeks. The additional application of an external boost radiation of 10 to 16 Gy to the tumor bed can reduce the local failure rate by 40% [18, 19, 20, 21]. With this therapy an excellent local tumor control can be achieved. On the basis of low local recurrence rates the concept of whole breast irradiation comes up for discussion, and partial breast irradiation (PBI) is increasingly under consideration. Various methods for PBI are under investigation, but long-term results are not available. PBI may be delivered during surgery as a single fractional dose or after surgery in various fractionations. Intraoperative radiotherapy is delivered as a single fractional dose during surgery as PBI and can be applied as an anticipated boost irradiation during surgery with additional whole breast radiotherapy (WBRT) after surgery.
Intraoperative radiotherapy (IORT): The term IORT is referred to as the delivery of a single fractional dose of irradiation directly to the tumor bed (confined target) during surgery.
Partial breast irradiation (PBI) or limited field radiation therapy, accelerated partial breast irradiation (APBI): Irradiation exclusively confined to a breast volume, the tumor surrounding tissue (tumor bed) either during surgery or after surgery.
Boost irradiation: Dose escalation to a confined breast volume (tumor bed).
Radiation time and dose for various radiotherapy methods
20 Gy at 1 mm, 5 Gy at 10 mm
Bid × 5 days
34 Gy at 10 mm
Bid × 4–5 days
ELIOT (Electrons intraoperative therapy)
The Italian approach delivers electrons directly to the tumor bed in the operating room immediately after excision of the tumor [22, 23, 24, 25, 26, 27]. A single dose of 21 Gy with energies up to 9 MeV, biologically equivalent to 58–60 Gy in standard fractionation, is applied from a mobile linear accelerator to the tumor bed, while shielding the thoracic wall with a lead plate. This approach allows the utilization as an IORT method and a PBI method. The advantages of this system are the precise application of one single high dose of irradiation directly to the tumor bed with complete skin sparing, and the great advantage of shortening the radiotherapy time from 6 weeks to one single fraction during surgery. Some questions are unclear, such as the effect of high single doses on late morbidity and cosmesis. The question of an increase in local recurrences in the non-irradiated breast has to be answered in the future. The prospective randomized ELIOT trial comparing the delivery of 21 Gy intraoperatively versus irradiation of 50 Gy to the whole breast and additional 10 Gy boost irradiation started in 2000 is still ongoing. First results after a median follow-up of 20 months in 574 patients, revealed 3 patients with local recurrences and further 3 patients with ipsilateral recurrences in other quadrants .
The Salzburg concept of IORT
The Salzburg concept combines IORT with postoperative WBRT [28, 29, 30, 31]. After wide local excision of the tumor, electrons are delivered directly to the tumor bed during surgery in boost modality. Electrons are provided by a linear accelerator in a dedicated unit with a dose of 9 Gy (10 Gy maximum target dose) and energies up to 8 MeV, biologically equivalent to 17 Gy with respect to the acute reactions on the tumor and normal tissue (α/β = 10) and biologically equivalent to 26 Gy with respect to the late reactions on the normal tissue (α/β = 3), according to the linear quadratic model. The Salzburg concept is not intended as PBI; radiation is delivered as an anticipated boost during surgery, postoperative whole breast irradiation for all patients is part of this concept. The advantage of this method is the complete skin sparing, the precise application of the boost directly to the tumor bed with a homogeneous tissue irradiation and with reduction of postoperative radiation time for 7 to 10 days (time of postoperative boost radiotherapy). As all patients receive postoperative radiotherapy to the whole breast, a reduction in local recurrence rates can be awaited, presumably due to the precise application of the IORT boost . The exact knowledge of the tumor bed is essential to apply the boost precisely to the target volume. The single high-dose radiation is delivered to a surgically defined target volume, while uninvolved or dose-limiting tissues are displaced, with the goal of enhanced locoregional tumor control. The surgeon and the radiotherapist precisely define the target volume by direct visualization and intraoperative ultrasound, and the high precision boost can be delivered and anticipated into the surgical procedure. In Salzburg so far 1,000 patients were treated with IORT in boost modality after breast conserving surgery and postoperative WBRT. Five-year actuarial rates for local recurrences, distant metastases and disease-free survival are available for the first 190 patients and have been published . After a median follow-up of 51 months, no local recurrence could be observed in patients with IORT boost and postoperative WBI.
Targit (Targeted intraoperative radiotherapy)
Targit has another approach. The authors use a miniature electron-beam-driven X-ray source called Intrabeam®, which emits low energetic so-called soft X-rays with 50 kV from the point source [32, 33]. Spherical applicators with various sizes are used to keep the irradiated tissue at a distance from the X-ray source. This device is inserted intraoperatively into the tumor cavity after excision of the tumor and emits X-rays from within the breast. After irradiation the applicator is removed and the wound is closed. This method is used as a PBI method without postoperative irradiation to the whole breast, although a combination with whole breast irradiation is possible. The ongoing Targit Trial was started in 2000 and compares this method as partial breast irradiation with conventional whole breast irradiation. The dose delivered to the tumor bed is inhomogeneous with a high dose of 20 Gy at the surface of the applicator, 10 Gy at 5 mm distance from the applicator surface and a low dose of 5 Gy at 10 mm distance from the applicator surface. This approach is very challenging and a prospective randomized multi-center trial is recruiting patients in the UK, Germany, Italy, Australia and USA.
There is a lot of data from brachytherapy to the breast as boost irradiation and as partial breast irradiation using LDR or HDR brachytherapy [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. Brachytherapy does not rank among intraoperative radiation methods, although the applicator needles are placed intraoperatively or later in a separate surgical procedure. The application of the needles requires high personal and cost effort and is uncomfortable for the patients. The irradiation time of 4 days means that the patient has to stay in the radiation room for this period, which is unacceptable for many patients. These are probably the reasons, that LDR brachytherapy has had no breakthrough and is not used anymore, although results were very promising. HDR brachytherapy can be delivered in two fractions per day for 4–5 days in an outpatient procedure. In three studies using interstitial brachytherapy as partial breast irradiation the 5-year local recurrence rates were less than 2%. The ongoing GEC-ESTRO APBI Trial compares interstitial brachytherapy alone versus external beam radiation therapy after breast conserving surgery for low risk invasive carcinoma and low risk ductal carcinoma in situ of the female breast. Accelerated partial breast irradiation consists of either HDR 30.3–32 Gy × 7–8 fx/4 days or PDR 0.60–0.80 Gy/h to 50 Gy (1 pulse/h, 24 h/day); patients in the whole breast irradiation arm will receive 50.4 Gy to the entire breast in 1.8 Gy fractions and 10 Gy Boost in 2 Gy fractions.
MammoSite® technique should be the further development of HDR brachytherapy [45, 46, 47, 48, 49, 50, 51, 52]. The device consists of an inflatable balloon with a double lumen catheter, which is placed inside the lumpectomy site. The balloon is inserted into the tumor cavity either immediately after excision of the tumor or in a second procedure postoperative ultrasound-guided percutaneously. An Ir-192 source can be placed into the center of the balloon. The radioactive source (seed) is inserted into the balloon through the catheter twice a day for 5 days. As there is only one radioactive source in the middle of the balloon, the tissue surrounding the balloon is irradiated very inhomogeneously with high doses on the surface of the balloon and a prescribed dose of 34 Gy (3.4 Gy/fraction b.i.d. for 5 days) in 10 mm distance of the balloon. The dose to the skin and to the thoracic wall depends on the distance balloon–skin and balloon–thoracic wall, respectively. The dose-limiting factor for MammoSite is the dose to the overlying skin and the dose to thoracic organs as heart and lung. Big breast volumes are needed to insert the balloon properly in a 3–4 cm cavity. The usage of multiple dwell positions within the catheter can optimise the isodose distribution but cannot optimise inhomogeneity. Mammosite is used as partial breast irradiation method. Irradiation time in total is 5 days. The NSABP B-39/RTOG 0413 trial comparing whole breast irradiation (45–50 Gy in 25 fractions) followed by optional boost (to >/=60 Gy) with three different partial breast irradiation techniques (multi-catheter brachytherapy 34 Gy in 3.4 Gy fractions or MammoSite balloon catheter 34 Gy in 3.4 Gy fractions or 3D conformal external beam radiation 38.5 Gy in 3.85 fractions) started to recruit in 2005 and will accrue 3,000 patients in 2.5 years. As this device is FDA approved since 2002, about 30,000 implants have been inserted in the USA, many of them outside any trial.
3D conformal partial breast irradiation
This is a new approach with partial external irradiation [53, 54]. High dose of external beam irradiation is applied to the tumor bed, which is clipped by the surgeon. Usually four radiation beams cover the PTV to a dose of 38 Gy in 10 fractions for 5 days. The high dose applied, includes the skin and the subcutaneous vessels and tissue. Hence bad cosmesis (teleangiectasies and fibrosis) can be awaited. This method is technically challenging, especially alignment is difficult due to the respiratory gate.
Assuming that local failure is responsible for a decrease in survival of patients with breast cancer, treated with breast conserving surgery and postoperative radiotherapy as proposed by some authors, the prevention of local recurrence has to be strived for. The EBCTCG overview reported that differences in local treatment that substantially affect local recurrence rates would avoid about one breast cancer death over the next 15 years for every four local recurrences avoided, and should reduce 15-year overall mortality. The Salzburg concept of IORT in boost modality combined with WBRT after surgery argues for the further reduction in local failure rates. The Salzburg data could demonstrate that immediate IORT boost combined with whole breast irradiation yield excellent local control, and a further reduction in local failure rates is possible compared to standard radiation schemes. At this moment the Salzburg model of IORT exclusively considers this fact; all the other models of (accelerated) partial breast irradiation run the risk of an increase in local failure rates associated with the risk of the decrease in overall survival rates. Various methods of partial breast irradiation have been reported. The huge advantage of a very short radiation period or an integration of the radiotherapy into the surgical procedure convinces at a first glance. The promising short-term results of those studies must not fail to mention that local recurrence rates will probably increase and furthermore give rise to distant metastases and a reduction in overall survival.
The risk of local recurrence in early breast cancer is highest during the first 5 years following diagnosis, irrespective of baseline prognostic factors. Thirty percent of local recurrences occur within 36 months after initial therapy. Several large series have reported that patients who develop local recurrences within 2 years have a significantly worse outcome than patients who develop local recurrences after more than 5 years. The longer the interval between the initial treatment and the occurrence of local recurrence, the better is the outcome [8, 10]. The development of distant metastases rises after the occurrence of local recurrence [16, 17], and the 5-year distant recurrence rates after local recurrence range between 25 and 40% [11, 12, 13]. Local recurrence is a prognostic and predictive factor for distant metastases and overall survival.
The advantages of IORT in boost modality are the precise boost application directly to the tumor bed without the risk of a topographic miss. The complete skin sparing avoids irradiation of the skin and therefore the generation of teleangiectasies. The target volume is smaller for the IORT boost than for the conventional postoperative boost techniques. Dose distribution is very homogeneous, and a dose of 9 Gy at the 90% reference isodose is biologically equivalent to 17 Gy for the tumor effect and to 26 Gy for the late effect on the normal tissue, so that tissue fibrosis should be minimal in the long-term follow-up. These factors result in good cosmesis. Furthermore, the postoperative WBRT can be reduced for 7 to 10 days. A point of criticism is the time gap between IORT boost and WBRT in patients who receive adjuvant chemotherapy. In those patients the time gap is up to 20 months. In a publication of Benchalal et al.  no increase in local recurrence rates was observed when radiotherapy was delayed to deliver adjuvant chemotherapy. In a recently published paper from the French group using IORT in boost modality plus postoperative WBRT very promising results based on local recurrences in the long-term follow-up were reported .
Many questions in partial breast irradiation are not yet answered, especially the optimal target volume, the correct prescription dose, dose distribution, required dose per fraction, long-term local control and late side effects or cosmetic results.
Long-term results for partial breast irradiation are available for interstitial brachytherapy. The results are excellent, but patient comfort is low (96 h in the radiation room with LDR technique) and the effort is high. HDR brachytherapy can be performed in an outpatient procedure, but the risk of skin retractions after iridium implants is high, especially after narrow distance of needles to the skin surface with poor cosmesis. Furthermore, there is a report by Perera et al.  wherein the 5-year actuarial rates of ipsilateral breast recurrence was 16.2% in patients who received HDR brachytherapy to the lumpectomy site as the sole radiation. This data should beware of the risks of partial breast irradiation if not appropriately performed.
MammoSite® technique was developed to improve the high technical effort of brachytherapy and to avoid the interlarding of the breast with multiple catheters. The insertion and the filling of the balloon catheter is a surgical procedure, and the question arises if the spreading of the wound bed by the balloon will worsen the cosmetic outcome in the long-term follow-up, although good cosmesis is reported in the short-term follow-up. Another problem is that only 20 to 25% of patients with breast conserving surgery are eligible for the MammoSite procedure [58, 59]. Thirty percent teleangiectasies are reported in the short-term follow-up if the balloon–skin distance is less than 7 mm. Skin spacing with a distance of at least 10 mm cannot be achieved in a majority of patients, especially with superficial situated tumors. Another problem is the dose inhomogeneity with only one seed in the middle of the balloon—dose distribution is not comparable to multi-catheter brachytherapy. Furthermore 34 Gy at 10 mm may be insufficient, especially in young patients.
Targit has all the advantages of IORT and PBI, but raises the question if 5 Gy at 10 mm from the surface of the applicator is sufficient for tumor control. The relative biological effect of low-energy X-rays is not yet completely understood and has to be established.
With ELIOT the question of increased late normal tissue toxicity arises as a consequence of the application of a high single dose of 21 Gy. Long-term results have to be awaited. Dose homogeneity and full coverage of the target volume are advantages as well as the single shot modality.
One very important question is, who needs radiotherapy anyway in early stage breast cancer? Are there groups of patients who need no radiotherapy? To date no group of patients can be identified in which radiotherapy after breast conserving surgery can be omitted. Even in selected patients with very good prognosis a substantial benefit of radiotherapy could be reported . In the very recent update of the EORTC study from Bartelink et al.  a benefit from boost irradiation in all patients irrespective of age could be observed. The phase III trials as mentioned above are accruing patients, and data are pending. Patients have to be followed up for a long time to estimate local disease-free survival, disease-free survival, overall survival and long-term side effects. Until these data will be available the combination of IORT in boost modality and WBRT seems to be a safe method with the advantages of the reduction in local failure rates and with a moderate reduction in postoperative radiation time.