Monday June 7 2010
Standard therapy applies radiation to the whole breast
A new approach to radiotherapy presents a “dramatic advance” in the treatment of breast cancer, reports The Independent. It says that research into single doses of targeted radiation has increased our understanding of the cancer, potentially shortening treatment times and saving the NHS millions of pounds.
This study was a large, well conducted, international trial comparing different forms of radiotherapy in a select group of over 2,000 women with early breast cancer. The research tested the use of a single dose of radiotherapy directed at the tumour site during breast-conserving surgery, comparing it to the current approach of giving several weeks of post-operative, whole-breast radiotherapy. The study found that cancer recurrence rates were similarly low among both treatment groups, but that many unpleasant side effects were less common with the new treatment. The researchers estimate that it could lead to substantial savings for the NHS because it reduces the workload of radiotherapy departments.
Further follow-up of the women will establish its safety and effectiveness in the long term. On the basis of published results from this study, further practical research into the potential cost-effectiveness of this approach can be expected.
Where did the story come from?
The study was carried out by researchers from University College London and international research institutions across the world. The research was funded by University College London Hospitals (UCLH), UCLH Charities, the UK’s National Institute for Health Research Health Technology Programme, National Health and Medical Research Council, and the German Federal Ministry of Education and Research. The study was published in the peer-reviewed medical journal The Lancet.
National newspapers have reported the findings of this large, well conducted randomised controlled trial in a fair and balanced way.
What kind of research was this?
This was a large, international, multi-centre randomised controlled trial (RCT) that investigated the effectiveness of a new approach to radiotherapy for treating women with breast cancer. This approach, called targeted intraoperative radiotherapy (TARGIT), differs from conventional treatment as it uses a special probe to release targeted radiation at the site of a tumour rather than applying radiation to the whole breast.
The women included in the study had invasive ductal carcinoma, the most common form of breast cancer, which begins in the milk ducts and spreads into the surrounding tissue. It was set up as a non-inferiority trial, which means that the aim was to see if the new treatment could be declared as ‘no worse than’ (non-inferior to) existing standard care. This is different in design from the usual RCTs, which set out to establish whether a new treatment is better than an existing one.
The researchers note that, although whole breasts removed through a mastectomy show a large proportion of pre-cancerous cells outside the original site of the tumour, observation suggests that the large majority of recurrent cancers occur in the same quadrant of breast in which the primary tumour had existed. This led the researchers to question if an alternative policy of localised control of breast cancer may be appropriate in selected patients, specifically whether using TARGIT (plus additional whole-breast radiotherapy in the approximately 15% of patients that still had poor features on final pathology) was comparable with the current policy of post-operative, whole-breast radiotherapy. They also made estimations of how the use of their therapy programme would affect the workings of the NHS.
What did the research involve?
The study enrolled women aged over 44 years from a number of treatment centres across nine countries. All women had unifocal (one tumour on one side) invasive ductal breast carcinoma and were scheduled to undergo breast-conserving surgery, which is the removal of the affected breast tissues with preservation of the unaffected portion of the breast.
Over the past 50 years, the most common approach to treating early invasive cancer has been to perform breast-conserving surgery followed by post-operative external beam radiotherapy to the whole breast. The radiotherapy schedule usually consists of several sessions over a period of three to seven weeks, and the researchers report that, due to breast cancer being common, the number of women experiencing adverse events from radiotherapy is high. The new approach being investigated delivers radiotherapy to the immediate vicinity of the primary tumour at the time of surgery, potentially exposing women to only a single dose of radiation.
The researchers randomly assigned 2,232 women to follow either a standard treatment programme of whole-breast radiotherapy after their surgery or the TARGIT programme of intraoperative radiotherapy following the excision of their tumour. Some women received the radiotherapy at the time of the first surgery, while others received it later when they were operated on again to clear some involved margins (regions of tissue around the original tumour that showed evidence of cancer). If post-operative investigations revealed more advanced disease in those who received TARGIT at the time of their first surgery, or if more surgery was needed to clear the original tumour margins, the women were offered whole-breast radiotherapy. The study was not blinded, i.e. all investigators and patients knew which treatment they would be receiving.
The main outcome of interest in this study was local recurrence of cancer in the breast. The women were assessed at their entry into the trial and were followed up at three and six months after their procedure, and then every six months thereafter up to five years. After five years of follow-up, they were followed up annually for up to ten years. The researchers also collected information on toxicity and adverse effects of radiotherapy. Of the 1,113 women randomised into the TARGIT group 89% received the treatment they were initially assigned. In total 92% of the 1,119 women randomised to whole-breast radiotherapy received their treatment. Although not all women went on to receive the treatment they were randomised to (for example, some had a mastectomy, some had surgery only) the researchers analysed the women in the groups to which they were originally assigned. This is known as intention to treat analysis and is the most robust way to analyse data in a randomised controlled trial. The data were analysed using survival analysis, which is an appropriate way to analyse these data.
What were the basic results?
The majority of women in the trial had small, grade 1 or 2 tumours (grade 3 denotes faster growing cancer cells) and no spread of cancer to the lymph nodes. Some 66% of women were also receiving hormonal treatment and 12% were receiving chemotherapy.
The study found that there was no significant difference in the number of local recurrences between the two groups of women. After four years, six women who received TARGIT had a local recurrence, compared with five in the whole-breast radiotherapy group (0.95% recurrence in the TARGIT group compared with 1.2% in the comparison group at four years). These results show that TARGIT was not inferior to the usual treatment regimen.
In terms of adverse events, more women who received TARGIT experienced wound seroma (collections of plasma in the wound site) and required fluid to be drained. However, the researchers state that this problem “was more than compensated for by significantly lower radiotherapy-related complications” (for example, pain in the irradiated region).
How did the researchers interpret the results?
The study found that, for selected women with early breast cancer, a single dose of radiotherapy given at the same time as breast-conserving surgery (using TARGIT) should be considered as an alternative to external beam radiotherapy delivered over several weeks. They say that their “results bring us closer to a scenario in which a patient with early breast cancer might complete all her local treatment, surgical excision, sentinel lymph node biopsy and radiotherapy at one or two visits, without having to stay overnight in a hospital bed”.
This large randomised controlled trial provides good evidence of the effectiveness of this treatment regimen for a selected group of women with invasive breast cancer. The women were 45 years or over, had a small tumour size (generally smaller than 3.5cm) and generally low grade cancer (mainly grade 1 or 2). There are other trials ongoing that the researchers say will inform the implications of their results for day-to-day clinical practice.
The researchers say that “We wish to urge caution while applying these results to clinical practice; although targeted intraoperative radiotherapy provides effective local control in the period of peak hazard (first four years), the results are valid only for patients with the clinicopathological features similar to those in this trial.” On this basis, TARGIT treatment should not be assumed to be suitable for women in other circumstances, such as younger women or those with more aggressive cancers.
The researchers highlight a potentially important benefit of this approach to treatment: that of reduced workload in the radiotherapy centre and savings to the NHS. They say that studies from other countries suggest that the treatment of breast cancer patients currently accounts for about a third of the work in radiotherapy departments (in some parts of the world) and this high workload may be responsible for some of the delays in treatment. They also estimate that the NHS could save £15million per year with the use of TARGIT. The details behind this estimate have not been described in this publication.
Overall, this is high quality research that is well reported. The researchers highlight one potential weakness in the design of their non-inferiority study that lies within their original calculation of the number of people they would need to recruit to the trial to ensure there was no difference between the treatments. This estimate was based on a five-year local recurrence rate of 6% (the best estimate at the time the trial started in 1999). When the trial eventually ran, the control group had actually had a much lower recurrence rate of 0.95% at three years. This is equivalent to a five-year local recurrence rate close to 1.5% (i.e. lower than they anticipated in their original calculations) and suggests that treatment for this type of breast cancer has improved substantially over the years.
This discrepancy between the estimated and observed recurrence rates meant that the researchers had to repeat the power calculation for the trial. However, they say that even after taking this into account they believe that the trial was large enough and continued for long enough for them to be confident that there is no important clinical difference between the treatment outcomes rates.
A comment piece by Drs David Azria and Celine Bourgier that accompanies this article in The Lancet says that the findings contradict the previous hypothesis that intraoperative radiotherapy irradiates an insufficient amount of breast tissue. The commentators also conclude that while long-term results are awaited, they are already convinced that in elderly patients, “accelerated partial-breast irradiation is the new standard and intraoperative radiotherapy is an excellent approach”.
Further follow-up of the women is planned and it will establish longer-term safety and efficacy outcomes. It is possible that these results will inform routine treatment regimens for a select group of women with early breast cancer. On the basis of published results from this study, further research will need to be conducted into the potential cost-effectiveness of this approach to treatment before the real potential savings to the NHS can be established.