Results of Clinical Trials with the Intrabeam System

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Based on the hypothesis that index quadrant irradiation is sufficient, in July 1998 we introduced the technique of TARGIT (Vaidya 2002; Vaidya et al. 2001, 2002b, 2004b) radiotherapy delivered as a single dose using low-energy x-rays targeted to the peritu-moral tissues from within the breast using the Intrabeam device. In patients with small well-differentiated breast cancers, which are now the majority, this could be the sole radiotherapy treatment. In those with a high risk of local recurrence elsewhere in the breast (e.g. lobular carcinoma and those with an extensive intraductal component, EIC), it would avoid any geographical miss, and in combination with EBRT, may even reduce local recurrence.

In the pilot studies in the United Kingdom, the United States, Australia, Germany, and Italy testing the feasibility and safety of the technique, 301 patients (302 Cancers) underwent TARGIT as a boost dose (Vaidya et al. 2005a) and also received whole-breast EBRT. The median follow-up at the time of writing was 27 months, but the first patient was treated in July 1998 and the longest follow-up was 80 months). Amongst these patients, four have had local recurrence. These included one with diffuse recurrence at 10 months, one with a focus of DCIS in the scar at 32 months and two with a new primary outside the index quadrant at 40 and 77 months. It appears that given as a boost, TARGIT yields very low recurrence rates (actuarial rate = 2.6% at 5 years).

In addition, during this pilot phase, 22 patients (Vaidya et al. 2005b) received TARGIT as the sole modality of radiotherapy. For these patients, the median follow-up at the time of writing was 26 months for these patients and one patient had a local recurrence after 5 years.

Apart from two patients treated early in these studies, wound healing has been excellent. The cosmetic outcome was assessed formally in available patients treated in the United Kingdom at a median follow-up of 42 months by a surgeon and a nurse not involved in the trial (Vaidya et al. 2003). On a scale of 1-5 (with 5 being the best), the mean scores for appearance, texture and comfort of the breast given by these observers were 3.5, 2.7 and 3.7. The corresponding scores given by the patient herself were 4, 3.1 and 3.5.

The multicenter randomized trial TARGIT (Vaidya 2002; Vaidya et al. 1999, 2002d, 2004b) using the Intrabeam system is now recruiting patients in the United Kingdom, Germany, Italy, the United States, and Australia. This is a randomized trial in which patients are enrolled prior to tumor excision to receive either IORT or conventional whole-breast radiotherapy. However, each center may decide that patients randomized to IORT who are found to have certain pathological findings (e.g. lobular carcinoma or an EIC) may subsequently receive whole-breast irradiation in addition. This facility allows pragmatic management of patients with an equipoise that can be decided by every individual center. Furthermore, the trial allows the radiotherapy to be delivered at a second procedure, after the final histopathology is available and eligibility criteria are met satisfactorily. Initially, at University College London we were exclusively delivering IORT at the time of the primary operation. The Australian group found that it is if it is given at a second procedure, it is easier to manage clinically and logistically. At Dundee, we are using both approaches which allow us to recruit patients from another hospital that is part of the same National Health Service trust, but is situated some distance away in Perth.

The first patient was randomized in the TARGIT trial in March 2000. At the time of writing, 8 centers are recruiting in this trial and in the last year the accrual had picked up significantly—over 425 patients had been randomized. The final goal is just over 2232. The outcome measures are local recurrence, cosmetic outcome, patient satisfaction and cost analysis., and it is expected that the first results of this trial will be available in 2007.

It is well recognized as in every adjuvant situation that postoperative whole-breast radiotherapy is an over-treatment 60-70% of times since only 30-40% of patients will ever get a local recurrence after surgery alone. Our approach using IORT intends to refine the treatment of breast cancer patients by introducing a risk-adapted strategy: the elderly patient with a TlGla tumor should perhaps be treated with a different kind of therapy such as TARGIT only, as compared to the young patient with a T2G3 tumor who would have a more accurate boost with TARGIT in addition to whole-breast radiotherapy. The TARGIT trial is testing exactly such a strategy. Hence, the TARGIT trial should not be mistaken for a trial solely designed to compare IORT with postoperative radiotherapy, when actually, it is testing two different treatment approaches—the conventional blanket approach versus the new approach of tailored treatment.

The Milan trial (ELIOT) using the Novac7 has also been recruiting since November 2000 at a fast rate and their preliminary results are encouraging. In their pilot studies (Veronesi et al. 2005), 590 patients affected by unifocal breast carcinoma up to a diameter of 2.5 cm received wide resection of the breast followed by IORT with electrons (ELIOT). Most patients received 21 Gy intraoperatively, biologically equivalent to 58-60 Gy in standard fractionation. After a median follow-up of 20 months, 19 patients (3.2%) had developed breast fibrosis and 3 patients (0.5%) local recurrences, 3 patients ipsilateral carcinomas in other quadrants, and another 5 patients contralateral breast carcinoma. One patient (0.2%) died of distant metastases.

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