TARGIT-A trial of Intrabeam TARGIT IORT for breast cancer: details

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What was done in the TARGIT-A trial?
      • The TARGIT-A trial was a randomised trial testing an individualised approach of radiation after lumpectomy for breast cancer.
      • The comparison in the TARGIT-A trial was between standard radiation therapy that is given over several weeks after a lumpectomy vs. a risk-adapted approach using single dose of TARGeted Intraoperative radioTherapy (TARGIT) using Intrabeam given at the time of lumpectomy.
      • The risk-adapted protocol recommended that if the patients who had received TARGIT IORT with Intrabeam were found to have high risk factors postoperatively, they also received whole breast radiation – which occurred in 15-20% of cases as expected in the protocol; otherwise, about 80% of such patients completed their treatment (surgery and radiation) during their lumpectomy.
      • The pre-specified non-inferiority margin was an absolute difference in local recurrence of breast cancer between TARGIT and EBRT of 2.5% — in simple terms, if the absolute difference in local recurrence between the two treatments being compared was less than 2.5%, they would be considered non-inferior to each other in terms of local control of breast cancer. Patient preference studies have suggests majority of patients consider such a 2.5% margin as appropriate.
      • 3451 patients from 33 centres in 11 countries participated in the TARGIT-A trial (UK, USA, Germany, Italy, France Poland , Switzerland, Norway, Denmark, Canada and Australia) from 24 March 2000 to 25 June 2012. (map).

TARGIT-A Trial Design

In the randomised TARGIT-A trial, two policies of local radiation treatment are compared:

Eligible patients were recruited at either of the two stages of their treatment in the pragmatic Targit trial:

Before the primary surgery (Prepathology randomisation)

This is the original method of entry into the TARGIT-A trial for a breast cancer patient. Once the decision to do a wide local excision (lumpectomy) is taken, and informed consent obtained, the randomisation takes place before surgery and if randomised to TARGIT, it is delivered to the fresh tumour bed immediately after lumpectomy for breast cancer. If at the postoperative pathology review, it is felt that they have a particularly high risk of local recurrence especially in other quadrants ( EIC, invasive lobular carcinoma or positive excision margins) then external beam radiotherapy can be added- all as part of the experimental arm of the trial. Centres could pre-specify additional such factors such as extensive lymphovascular invasion, multiple positive nodes, etc.

After the primary surgery (Postpathology randomisation)

This mode of entry into the trial was added to enable patients in whom the excision of the cancer had already been performed. This was logistically easier in some centres and theoretically allowed better case selection – although it required a second procedure to be performed. Randomisation in the Targit-A trial is performed after the the primary cancer is removed and if allocated to receive TARGIT, single session intraoperative radiotherapy is given as a day-case operation .

What was found? Results of the TARGIT-A trial
      • When TARGIT is given with lumpectomy, the 5-year local recurrence of breast cancer is similar to EBRT
      • When TARGIT is given as a second procedure, the difference in local recurrence between TARGIT and EBRT was more than 2.5%
      • Breast cancer mortality with TARGIT were similar to EBRT
      • Mortality from other causes  was significantly lower with TARGIT due to fewer deaths from  cardiovascular causes and other cancers.
      • The results remain stable with longer follow up. The results were the same for the large number (1222) patients who were treated between 2000-2008 and had a median follow up of 5 years.

Is the follow up of the TARGIT-A trial long enough?
      • Although breast cancer can continue to recur beyond 5 years, the peak hazard is in the first 2-3 years. More importantly, the beneficial effect of radiotherapy on local recurrence is mostly in the first 2-3 years with no further benefit beyond the first 5 years after surgery.
Effect of radiothearpy is limited to the first 5 years
The benefit from radiotherapy – shown by the difference in recurrence (red arrows) shown by the separation of lines representing radiotherapy and no radiotherapy, does not increase after the first 5 years