Abstract
“…we could possibly complete all the treatment at the time of surgery by irradiating the tumor bed after the removal of the primary disease.”
The development of the classical radical mastectomy in the latter part of the 19th Century is credited to William S Halsted, of the Johns Hopkins Hospital, Baltimore (MD, USA) [1]. In 1922, Geoffrey Keynes, a surgeon at St Bartholomew's Hospital London (UK) began experimenting with the use of radium enclosed in hollow platinum needles in the treatment of advanced breast cancer. Following on from his experience with advanced disease, he took a courageous leap of faith and started treating women with early-stage breast cancer with local excision (lumpectomy) and radium needles inserted into the unaffected quadrants of the breast and the axillary plus supraclavicular lymphatic fields [2].
Over the last 30 years, the major change in surgical treatment of early breast cancer has been the shift towards breast conservation surgery (BCS). BCS was introduced to reduce the physical and psychological consequences of removing the whole breast. Trials performed in the 1970s demonstrated equivalent survival when comparing BCS plus radiotherapy with mastectomy [3].
“Over the last 30 years, the major change in surgical treatment of early breast cancer has been the shift towards breast conservation surgery.”
The meta-analysis conducted by the Early Breast Cancer Trialist's Collaborative Group comparing BCS with BCS plus radiotherapy demonstrated that the addition of radiotherapy reduced the risk of local recurrence by 75% and resulted in a disease-free survival advantage, with a decrease in the 15-year risk of dying of breast cancer from 31 to 26% in node negative patients, and from 55 to 48% in node positive patients [4].
Postoperative radiotherapy is therefore regarded as an integral component of BCS and cannot be safely omitted. There is evidence to suggest that this approach decreases the risk of local recurrence and, more importantly, improves survival [5].
How does radiotherapy work?
The aim of radiation is to kill tumor cells selectively without damaging normal cells. It works by generating free radicals, which cause single- or double-stranded breaks in cellular DNA. This affects tumor cells more than normal cells because tumor cells are less able to repair DNA damage than normal cells, and are more frequently in the radiosensitive part of the cell cycle.
If external beam radiotherapy works, why change?
We cannot underestimate the achievements of the last 100 years in shifting the paradigm of breast cancer treatment from the mutilation of the classical radical mastectomy to the modern default treatment of breast conserving treatment, sentinel node biopsy and whole breast irradiation (WBI). However, many problems related to WBI cannot be ignored, which limits the availability and convenience of the treatment:
WBI takes between 3 and 7 weeks to deliver, which is a great inconvenience for working women or the elderly who find the daily journeys exhausting;
In the UK, the treatment of breast cancer accounts for approximately a third of all the workload of radiotherapy departments;
Women in the developing world or those in wealthy countries who live in rural areas more than 100 miles from a center are denied the chance of BCS or are at great hazard of local recurrence if the treatment is omitted [6,7];
Geographic misses are commonplace in postoperative attempts to target the tumor bed [8];
Cosmesis is often impaired by the short- or long-term radiotoxicity, especially in women with collagen disease or those who have been treated by mantle radiotherapy for lymphoma in the past;
Delays in the start of chemotherapy or delays in the start of radiotherapy in order to accommodate chemotherapy might compromise either modality [9].
The paradox of local recurrence
After BCS, the results of most observational studies and clinical trials have demonstrated that 90% of recurrent disease in the breast is within the index quadrant in the presence or absence of WBI [10–12]. Furthermore, following the adoption of adjuvant endocrine therapy, the chance of a local recurrence outside the index quadrant is no more than the risk of a new contralateral tumor [13]. If that is the case, why do we not demand prophylactic treatment of the contralateral breast at the same time? This counterintuitive observation has both biological and clinical consequences. Biologically, this tells us that not all that looks like cancer under the microscope will behave like cancer if left to nature. The evidence to support the notion of latency amongst microscopic foci of breast cancer has been well documented in much of the contemporary scientific literature on the natural history of breast cancer [14,15]. The clinical consequences of this observation suggest that perhaps we do not have to treat the whole breast but only the immediate area around the tumor bed after removal of the primary disease or the index quadrant. If that is the case, then we could possibly complete all the treatment at the time of surgery by irradiating the tumor bed after the removal of the primary disease. This can be achieved by accelerated partial breast irradiation (APBI) over a period of 1 week, or by intra-operative radiotherapy (IORT) during surgery as a single fraction, which is the main focus of this article.
Accelerated partial breast irradiation
A number of different techniques of APBI are available that aim to decrease the volume of treatment and increase the daily fraction size of radiation that can be completed within 1 week (instead of 3–7 weeks). These include linac-based intensity-modulated radiotherapy, multicatheter interstitial brachytherapy, balloon-based APBI using the MammoSite™ brachytherapy applicator (Hologic, Inc., MA, USA) and a newly developed, modified form of balloon-based brachytherapy called Xoft Axxent Electronic Brachytherapy™ (Xoft, Inc., CA, USA)
At present, there is a lack of level 1 evidence in support of the efficacy of this approach; however, despite this, the technique of MammoSite brachytherapy is widely used in the USA [16,17]. There are a number of ongoing prospective, randomized, Phase III trials of APBI. However, they are not comparable since they vary in inclusion criteria, total dose, fractionation, volume and timing related to chemotherapy and hormone treatment. The National Surgical Adjuvant Breast and Bowel Project B and the Radiation Therapy Oncology Group have noted this shortcoming and are conducting an intergroup study, randomizing patients with early-stage breast cancer to WBI versus APBI. At present, APBI should be considered as under investigation only.
Intraoperative radiotherapy
The technique of IORT, which was pioneered by our group [18], allows the patient to receive all required radiation in a single fraction before they awake from surgery. The potential advantage of this approach includes delivering the radiation before tumor cells have a chance to proliferate, performing the radiation treatment under direct visualization at the time of surgery and decreasing costs to the healthcare providers.
“At present, accelerated partial breast irradiation should be considered as under investigation only.”
This is achieved by using the INTRABEAM™ (Carl Zeiss Surgical, Oberkochen, Germany) machine, which is a mobile, miniature x-ray generator powered by a 12-volt supply. Accelerated electrons strike a gold target at the tip of a 10 cm long drift tube with a diameter of 3 mm, resulting in the emission of low-energy x-rays (50 kV) in an isotropic dose distribution around the tip. The irradiated tissue is kept at a distance from the source by spherical applicators to ensure a more uniform dose distribution. The tip of the electron drift tube sits precisely at the epicenter of a spherical plastic applicator, the size of which is chosen to fit the cavity after the tumor is excised. Using this method, the walls of the tumor cavity are irradiated to a biologically effective dose (20 Gy to the tissue in contact with the applicator) that rapidly attenuates over a distance of a few centimeters. As a result, the vital organs are spared and the device can be used in any operating theater without the need of lead shielding [18].
The other IORT approach is electron intraoperative therapy, pioneered at the European Institute of Oncology in Milan, Italy. In this technique, a portable linear accelerator is used to deliver a single dose of 21 Gy radiations during the surgery [19]. With this approach it is necessary to perform the procedure in a specially shielded operating theater for radiation safety considerations.
Evidence
We have established the safety and tolerability of the technique in Phase II studies [20,21]. In 2008, we conducted a pilot study (targeted intraoperative radiotherapy [TARGIT]) on 299 patients (with 300 cancers) who underwent BCS for their breast cancer management. They all received a single dose of 20 Gy radiotherapy during surgery. This was instead of 1 week of radiation to the tumor bed (boost radiation); however, patients received standard external beam radiotherapy (EBRT) to the whole breast. A total of 32% of the patients were younger than 51 years; 57% of cancers were between 1 and 2 cm (21% >2 cm); 29% had a grade 3 tumor; and 27% were node positive. The treatment was well tolerated by all patients, and with median follow-up of 60.5 months (range: 10–120 months), eight patients had developed ipsilateral recurrence: the 5-year Kaplan Meier estimate for ipsilateral recurrence is 1.74% (standard error: 0.77).
“…the time has come to question the radical approach of radiotherapy in early breast cancer.”
Subsequently, a pilot study in August 2008, conducted by our colleagues in Milan on 101 patients, also confirmed low recurrence rate after a median follow-up of 36 months (five patients [0.5%] developed a local recurrence and three (0.3%) developed ipsilateral breast cancer) [19–22].
In March 2000, we launched an international, randomized trial comparing TARGIT versus EBRT as a non-inferiority study with the primary outcome of local recurrence, currently involving 31 centers across the world [23]. The recruitment goal of 2232 (powered to test noninferiority; hazard ratio: <1.25) is expected to be completed in the second quarter of 2010. The results of this study will provide level 1 evidence for this approach in the management of breast cancer patients. A subprotocol analysis of cosmesis indicates a superior cosmetic outcome in the first year for the patients receiving IORT, and equivalent cosmetic outcome has been achieved for the second and third year of follow-up between the two groups [24].
During this period, we offered IORT within three major centers in the UK, Germany and Australia, to a highly selected group of 80 patients with exceptional circumstances who were not suitable for randomization into a TARGIT trial and who also could not receive standard EBRT. This included patients who had received previous radiation (e.g., patients with recurrent cancer in the same breast or those who have been treated with mantle radiotherapy for Hodgkin's disease) or because of comorbidities, such as severe respiratory or cardiac problems, collagen or autoimmune disorders, or painful arthritis (which might prevent adequate abduction of the shoulder). After a median follow-up of 38 months, only two local recurrences were observed, an actuarial annual local recurrence rate of 0.75% (95% CI: 0.09-2.70%), suggesting that this approach may be considered in special circumstances in which EBRT is not feasible [25,26].
Concluding remarks
Over the years, we have moved from radical surgery for breast cancer treatment to BCS, and more recently from radical axillary surgery for staging of patients to a minimally invasive approach of sentinel node biopsy. Surely the time has come to question the radical approach of radiotherapy in early breast cancer. The implications of this leap into the dark are profound. If it proves beneficial, then many women will be spared up to 7 weeks of treatment and traveling back and forth to the radiotherapy center. Furthermore, tens of thousands of women in the developing world who live hundreds of miles from a radiotherapy unit, or in countries that cannot afford the multimillion pound investment, will be able to enjoy the advantages of breast conservation by bringing the radiotherapy units to the patient. In countries such as the UK, the waiting list for postoperative radiotherapy would vanish at a stroke, and we estimate the NHS would be saved £15,000,000 per year. We will have to watch this space; however, in our view, the future is bright.
Footnotes
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.