It all started typically enough a couple of weeks ago, with a request to review and comment on a study presented at the recent cancer meetings involving a new radiation therapy technique for the treatment of early stage breast cancer.
My comments-which were broadcast on a widely watched network evening news program-were reasonably straightforward: the study was interesting, but the treatment wasn't ready for widespread use until more information and longer follow-up was available.
Shortly afterwards, I got a phone call from someone representing the company concerned about my statements and offering further information about the study. Now, I find myself trying to figure out how to sort through the research results and match what I have learned to what I think is the premature promotion of a potentially valuable new technique in the treatment of breast cancer for some women.
The interest in this new treatment is easy to understand. Women with early stage breast cancer can be successfully treated by removing the cancer from the breast (what we call a "lumpectomy"), then treating the remaining breast tissue with radiation therapy to the entire breast over a period of several weeks.
Usually the radiation goes well, but the women need to return daily for treatment over several weeks. This is a problem for many women-especially those who live in rural parts of the country where they have to travel long distances to the treatment center or for disadvantaged, older or disabled women who have difficulty getting around or have problems getting a ride to the radiation center.
With the new treatment, dubbed "TARGIT", the doctors can give a single dose of radiation to the breast at the same time they do the lumpectomy. For many women, no further radiation treatment is needed.
The question when using this type of approach-which is called "partial breast radiation"-is whether or not it will effectively prevent recurrence of the breast cancer next to where the lump was removed and in the other parts of the breast where areas of breast cancer may be lurking but not otherwise detectable.
The study itself was reasonably straightforward, as indicated in a paper published in the medical journal The Lancet simultaneously with the presentation of the study at the cancer meeting.
There were two approaches the researchers used to enter women into the study. In one approach, a woman was diagnosed with breast cancer and randomly assigned to undergo a lumpectomy and either receive the single TARGIT treatment at the time of surgery, or receive traditional, several weeks of whole breast radiation postoperatively.
After her surgery, if she was in the TARGIT treated group and her pathology showed some signs of more aggressive breast cancer, she would also receive the traditional radiation therapy over several weeks in addition to having already been treated with TARGIT. Basically, women with poor prognostic findings on their pathology ended up getting both forms of radiation.
There was another group of women who underwent their lumpectomy without TARGIT. Then, after their pathology was reviewed and no signs of aggressive breast cancer were found, they were randomly assigned to receive TARGIT or traditional radiation therapy. If they were assigned to the TARGIT group, they had to go back to the operating room to have their wound reopened and the treatment administered. None of the TARGIT treated women in this arm of the study received additional whole breast radiation, since their pathology specimens had been reviewed before they were randomly assigned to a treatment group.
Now for some numbers:
2232 women participated in the trial, evenly divided at the "top line" into TARGIT or traditional treatment groups (1113 and 1119 respectively). 996 of the women assigned to TARGIT received the treatment they were randomized to, while 1025 of the women in the whole breast radiation group received their allocated treatment.
In the TARGIT group of 996 women, 854 received only TARGIT and 142 had to have additional radiation. That means, according to the authors, about 14% of the women entered into the study who thought they were only going to get limited radiation in fact got both types of radiation consisting of TARGIT and several weeks of whole breast radiation. The authors noted that that was close to the expected number anticipated before the study to require both treatments which was 15%.
In terms of what types of patients were treated, the authors reported that most of the women were less than 70, and 86% of the cancers were less than 2 cm in size. Most of the cancers did not appear aggressive under the microscope, and 83% of the patients had tumor confined to the breast with no lymph node involvement. Almost all were hormone sensitive.
As far as local recurrences in the breast-which is the primary outcome of the study-they were surprisingly low in both groups, close to 1% for each treatment approach. The expectation at the start of the study was that 6% of the women would have their breast cancer come back in the affected breast. The authors note that over the 10 years since the study started, however, rates of local breast cancer recurrence in women treated with lumpectomy and standard radiation therapy have declined significantly.
Sounds good, so far.
The authors make the case that they can "draw cautious yet reasonable conclusions about efficacy" of the TARGIT treatment based on their results so far. They also point out that when they started the study, they expected that the size of the breast cancers treated in this program would be up to 3.5 cm in diameter. However, each center that participated in the study set up their own criteria for selecting women to be entered into this trial. The result was that many of the cancers were much smaller, and most were less than 2 cm in size. In fact, a good number were less than 1cm in diameter.
The authors commented in their research paper:
"Allowing clinicians to be liberal in their intended inclusion criteria increased appeal and encouraged wider participation, yet led to a fairly homogeneous low risk patient sample, which showed an unsurprising conservatism among participating clinicians in this pragmatic trial."
The authors go on to make another very important and appropriately cautionary comment as they concluded their remarks in the published report:
"The implications of our results for the day-to-day clinical practice will be affected by emerging data from these trials, as well as the individual circumstances of the patient. Furthermore, we need longer term follow-up of our own trial to monitor the clinical appearance of new primary tumours outside the index quadrant or delayed recurrences inside the index quadrant. If the results of these trials reflect our results then the range of techniques available will mean that clinicians and patients will have a choice and could make individualised decisions based on the evidence available for each technique, patient preference, local resources, and professional expertise. 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 4 years), the results are valid only for patients with the clinicopathological features similar to those in this trial." (emphases mine)
The authors conclude their report with the following statement:
"Our 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. Together with the developments in adjuvant systemic therapy, these advances could substantially reduce the effect of a breast cancer diagnosis and treatment on a woman's life."
All of this is true, and well-stated. A new approach that may be useful, yet there still remains additional work to be done. I have no problem with those comments and assessments.
But some questions remain about the study itself, and some troubling questions about whether or not TARGIT is being actively promoted in the medical community and to the lay public.
I don't want to go into great detail here-it would probably bore you even more than I have already with this level of information-but there are questions whether the study really represents what the researchers intended.
Left to your own devices, you would be reasonable in thinking that this is a treatment technique that could be applied to all women who undergo a lumpectomy and radiation.
Unfortunately, in my opinion, that is not the case.
For whatever reason, as noted by the authors, they intended more women with larger breast cancers to be treated in this trial. The women who were entered into the study did not represent the typical spectrum of primary breast cancer in this country. Many of the participants had small cancers, most were not aggressive under the microscope, few had lymph node involvement, and most were hormone sensitive.
All of these factors suggest that this was a very favorable group of women with breast cancer. As such, the results of this study cannot be applied to the larger universe of women with breast cancer, and the authors note their disappointment that centers were very conservative in entering women into the trial.
Then there is the question of how many women treated in typical fashion in this country would end up getting both TARGIT and traditional whole breast radiation. The study says 14%. I believe this significantly understates the number at risk, depending on how this treatment is used in everyday medical practice.
If anything, the way patients were entered into the trial reduced the number of women who would have had to receive additional radiation. The deck was (perhaps unintentionally) "stacked" to decrease that number. Let me try to explain in simple terms what I mean.
As I mentioned previously, there two ways women received their TARGIT treatment. One group-which I will call the "conventional" approach--had their TARGIT therapy at the same time they had their surgery, then a determination was made after the surgery whether or not they needed whole breast radiation.
The other group didn't receive their TARGIT treatment until after their primary surgery was done and the pathology reviewed. This latter group only received either TARGIT treatment or standard breast radiation. There was no need for any of those women to receive both treatments, the way the trial was constructed. For the women in this group, they had to go back into the operating room at least a couple of days after their surgery to have their wound reopened and the TARGIT therapy applied.
Of 996 women who were randomized to receive TARGIT therapy, about 360 came from the group that knew ahead of time they would only receive the TARGIT therapy. The other approximately 636 women were in the "conventional" group that received TARGIT and may have needed additional whole breast radiation in addition to TARGIT therapy. Of those approximately 636 women, 142 went on to get whole breast radiation.
What that means is that of the women who were treated the way we would likely use TARGIT therapy in this country, about 22%--not 14%--went on to additional radiation. Given the fact that these women likely had smaller breast cancers than might otherwise be the case, I would suspect that in "real life," an even greater percentage of women treated in this fashion would end up still requiring conventional radiation therapy after their TARGIT treatment given the fact there would be a greater likelihood that their tumors would be more aggressive under the microscope or have other findings that would suggest more aggressive behavior of their cancers. Those women would still have to receive the very treatment this approach is trying to avoid, namely multiple weeks of whole breast radiation.
What bothers me is that I haven't heard anyone emphasizing these points in the various reports on this study. What I have seen is a press release from the company that makes the machine extolling its value in the treatment of breast cancer.
In contrast to what the researchers had hoped-namely that women with breast cancers up to 3.5 cm in diameter would be in the study-they ended up with a majority of women with small breast cancers. This might well make the results of the study better than they would otherwise have been. At the least, it means that the results of this study should only be applied to women with similar breast cancers, not to all women who might otherwise be candidates for lumpectomy and radiation.
Here is what one of the lead investigators said in the press release issued by the company that makes the machine:
"Now that the TARGIT-A trial has demonstrated that single-dose intraoperative radiation treatment using INTRABEAM is equivalent in efficacy and safety to traditional radiotherapy in the longest-running clinical trial of its kind, TARGIT treatment has the potential to become the new standard of care in breast cancer."
Another highly regarded breast cancer specialist was quoted in the same release:
"This is a critical breakthrough for women and a major advance in our ability to tailor treatments for women, depending on the biology of their tumors..."
The CEO of the company said:
"INTRABEAM has the potential to become the new global standard treatment for breast cancer. We will continue to invest in this field, to enable as many patients as possible to receive INTRABEAM treatment."
Nowhere is there a statement of caution, similar to what the researchers said in their report. Nowhere is there any comment about the fact that the women in this study had small cancers with more favorable prognoses. Nowhere is there any caution that these results may not be broadly applicable to the universe of women undergoing lumpectomy and radiation. And nowhere is there a statement that a reasonable percentage of women who receive the TARGIT therapy may still need to get the entire breast radiated.
I guess I get a bit frustrated when I have to reconcile the claims with the data. I am not saying that this is not a reasonable treatment for some women. It may well turn out that with further time and study that this may become a standard of care.
But I continue to be troubled by stories that end up in the press or on television touting a particular treatment and give hope to many patients, families and their physicians that somehow this is a "done deal."
It isn't a done deal in my opinion, and I certainly hope that the record is being presented more honestly to the profession than it has been in the press releases. As I said in my comments on the newscast, this isn't ready for prime time-until some very important questions are addressed.
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