TARGIT (TARGeted Intra-operative radioTherapy) is a technique of giving radiotherapy to the tissues surrounding a cancer after its surgical removal. The technique was designed in 1998 at the University College London. Ongoing randomized controlled trials are testing whether TARGIT is either equivalent or superior to conventional course of external beam postoperative radiotherapy for breast cancer.
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TARGIT is a method where the radiation is applied during an operation and targeted to the peri-tumoural tisues. TARGIT technique was designed at University College London[1] by Jayant S Vaidya (who coined the TARGIT acronym) and Michael Baum along with Jeffrey S Tobias in 1998. The term was first used when the technique was described[2], and the protocol for a randomised trial was published by the Lancet[3]. One can say that TARGIT is a special method of intraoperative radiotherapy (IORT).
When breast cancer is surgically excised, it can come back (local recurrence) in the remaining breast or on the chest wall in a small proportion of women. Adjuvant radiotherapy is necessary if breast cancer is treated by removing only the cancerous lump with a rim of surrounding normal tissue, as it reduces the chance of local recurrence significantly. When cancer does come back, it most commonly occurs in the tissues surrounding the original cancer (the tumour bed), even though there are multicentric cancers in remote areas of the breast. This suggests that it is most important to treat the tumour bed[4]. The rationale for TARGIT is to deliver a high dose of radiation precisely to the tumour bed. Conventional radiation techniques such as external beam radiotherapy (EBRT) following surgical removal of the tumor have been time tested and proven to be effective. EBRT is usually given as a course of whole breast radiotherapy and an additional tumour bed boost. However, it has a few drawbacks; for example, the tumour bed where the boost dose should be applied can be missed ("geographical miss") due to the difficulties in localization of the complex wound cavity even when modern radiotherapy planning is used. Additionally, the usual delay ("temporal miss") between the surgical removal of the tumour and EBRT may allow a repopulation of the tumour cells. These potentially harmful effects can be avoided by delivering the radiation more precisely to the targeted tissues leading to immediate sterilization of residual tumour cells. Furthermore, TARGIT inhibits the stimulating effects of wound fluid on cancer cells, suggesting for the first time, a beneficial effect of intraoperative radiotherapy on tumour microenvironment[5][6].
The machine used for TARGIT is Intrabeam (Carl Zeiss, Germany). It is a miniature and mobile X-ray source which emits low energy X-ray radiation (max. 50 kV) in isotropic distribution. Due to the higher ionization density caused by soft X-ray radiation in the tissue, the relative biological effectiveness (RBE) of low-energy X-rays on tumour cells is higher when compared to high-energy X-rays or gamma rays which are delivered by linear accelerators. The radiation which is produced by mobile radiation systems has a limited range. For this reason, conventional walls are regarded sufficient to stop the radiation scatter produced in the operating room and no extra measures for radiation protection are necessary. This makes TARGIT accessible in most operating rooms. The surgical technique[7] is relatively simple but needs to be meticulously followed[8].
The largest experience with TARGIT and the best evidence for its potentials exists in breast cancer where a substantial number of patients have already been treated.[9].
The TARGIT-A Trial was an international multicenter prospective randomised phase 3 clinical trial designed to test whether a single dose of targeted intraoperative radiotherapy could replace the usual 3-6 week course of postoperative radiotherapy. The trial original accrual goal of 2232 is completed and the results were announced at the American Society of Clinical Oncology meeting in Chicago (ASCO, June 4-8, 2010) and simultaneously published online on 5 June 2010 in the Lancet - Online First[10]. The local tumour control using single-dose targeted intraoperative radiotherapy was found to be equivalent to several weeks' of whole breast external beam radiotherapy. The difference in local recurrece rate between the two treatments at 4 years was 0.25% (95% CI -1.0% to +1.5%) which means that TARGIT could be at most 1.5% worse or 1% better than whole breast radiotherapy. TARGIT also caused less radiotherapy related toxicity than whole breast radiotherapy. A brief explanation of the results is at [1] and in a short interview on eCancerTV
In an invited lecture at the Churchill Hospital in Oxford, quoted in the Sydney Morning Herald, Professor John Boyages, author of Breast Cancer:Taking Control l expressed concern about the early release of the TARGIT trial. He noted that the average follow-up for all patients in the trial was only 2 years and that this was far too short to determine its routine efficacy [2]. However, this criticism had already been addressed by the authors within the original paper PDF
At the St Gallen Breast Cancer Conference (16-19 March 2011) the consensus amongst over 4000 breast cancer experts was that TARGIT alone could be used as the only radiation treatment in selected cases after breast conserving surgery.
TARGIT as a tumour bed boost:' In conventional EBRT, the boost is delivered at the end of a complete course of EBRT. Clinical evidence suggests that boost radiation improves treatment outcome for breast cancer.[11]. With TARGIT the boost can be delivered intraoperatively without any delay and more precisely as compared to conventional EBRT. A multicenter clinical trial has demonstrated that the boost administered with IORT resulted in a lower than expected rate of local recurrence (1.73%) as compared to an EORTC study which used external boost radiation.[12].[13][14]. As a tumour bed boost, TARGIT has been found to have a better than expected effectiveness[9][13][14]These results have prompted the inclusion of TARGIT boost as an option to EBRT boost in national clinical guidelines of many countries including Germany. Whether TARGIT is superior to an EBRT boost is being tested in a randomised trial (TARGIT-B).
The normal tissue tolerance does not allow a second full-dose course of EBRT, even after several years. So, TARGIT is an option for patients with recurring cancer that already had traditional radiation therapy and are not suitable for a second radiation treatment.
IORT was found to be useful and feasible in the multidisciplinary management of many solid tumours but further studies are needed to determine the benefit more precisely. Single-institution experiences have suggested a role of IORT e.g. in brain tumours and cerebral metastases, locally advanced and recurrent rectal cancer, skin cancer, retroperitoneal sarcoma, pancreatic cancer and selected gynaecologic and genitourinary malignancies.[15].
' Other study groups using similar protocols and concepts have also demonstrated the effectiveness and safety of IORT in breast cancer patients.[16],[17]
TARGIT has had a long clinical experience since 1998 and is found to be safe and well tolerated.
Pilot studies: In a study which examined acute side effects after boost radiation in patients with breast cancer, treatment was well tolerated with no grade 3/4 acute toxicity. Rare adverse effects following TARGIT included wound healing problems (2 %), erythema grade I-II (3 %), palpable seroma (6 %) and mastitis (2-4 %).[18][19]
Large prospective randomised study In the randomised TARGIT-A trial, the overall complications was equivalent between TARGIT and whole breast radiotherapy. There were more seroma needing aspiration in the TARGIT group. This was more than compensated for by the more troublesome radiotherapy related side effects that were less common with TARGIT than with whole breast radiotherapy.
In 1998, the International Society of IORT (ISIORT) was formed to foster the scientific and clinical development of IORT. The ISIORT has more than 1000 members worldwide and meets every two years[20].
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