|Julia Draznin Maltzman, MD|
|The Abramson Cancer Center of the University of Pennsylvania|
= Julia Draznin Matlzman, MD, Senior Editor
OncoLink had the distinct pleasure of interviewing Dr. Lawrence Solin about his research and interests in early breast cancer irradiation. He is articulate, eloquent, and well informed while being gregarious and engaging. It is easy to see why he was chosen to receive the Potamkin Foundation Award for outstanding research in the field by the Pennsylvania Breast Cancer Coalition. I asked him questions about various techniques of breast irradiation, DCIS, and about his predictions for the future direction of breast radiation oncology.
Congratulations on your award from the PA breast cancer coalition. The Potamkin Foundation Award is presented to individuals who perform outstanding work in breast cancer research. I know you have done a lot of work in early stage breast ca/DCIS as well as characterizing some of the late effects of radiation therapy. Can you tell me some more about your interests?
LJS: My interests have evolved over time. First we began by examining ways to conserve the breast and increase survival. Now there is very good long-term data that show that breast conservation is possible (lumpectomy with radiotherapy being in most cases as good as a mastectomy) and many women are surviving this disease. As you cure more people you start to think of ways of minimizing the complications of treatment. The goals now have changed. We want to maximize cure, maximize quality of life, and minimize late effects. Now we have better surgery, better radiology, better pathology, better chemotherapy, and better radiation therapy, and we need to maximize cure without the expense of side effects. That has been a paradigm shift.
Another paradigm shift that has taken place is that now radiation oncologists have to think about general health maintenance issues. We have to talk to our patients about getting screened for other malignancies, keeping their blood pressure low, monitoring their blood sugars, etc. In fact, just yesterday, I was counseling a patient on weight maintenance. Now that the public is surviving from their cancers, they are dying of other diseases. We have to start talking to patients about these issues now because ten years from now when they come down with their second cancer, it is too late.
One of my largest interests is in DCIS (ductal carcinoma in situ). We have an ongoing collaborative group study that has evaluated over 1,000 patients with real statistical power to look at a multitude of aspects. This collaboration is with radiation oncologists in the US, Canada, and Europe. Over 1,000 people is a large number. We have enough statistical power to look at primary events other than breast cancer. We can evaluate treatments for local recurrence. We can even estimate the rate of unusual events. We just updated our fifteen-year outcomes data for DCIS. This is a huge database with an enormous breadth of information. This is very exciting.
Coronary artery disease, secondary cancers, fibrosis, and maybe necrosis, are these some of the concerning aspects of late effects of radiation therapy?
LJS: We currently have an interest in studying heart disease after radiation treatment. We are studying complications that have not been well described before. We are finishing up a few studies trying to characterize this heart disease and then try to find ways of preventing it. There are some very interesting findings. Definitely heart disease is a potential complication of radiation therapy.
A few months ago the New England Journal of Medicine published two trials evaluating the added benefits of radiation therapy post lumpectomy in early stage breast cancer. These trials, I understand, were motivated by the fact that many women, in fact, would not experience a recurrence with lumpectomy and tamoxifen alone. And, we can now further reduce the risk of recurrence by some of the new hormone drugs available such as Arimidex and Letrozole. Thus women can avoid the side effects of radiation therapy. Can you comment about these trials?
LJS: Yes, these are two randomized, controlled, trials that looked at potentially low risk patients to ask the question of whether there is a subgroup of patients in whom the risk of recurrence is low enough that radiation therapy can be omitted. Both trials were underpowered to look at survival. The Canadian study said that radiation therapy substantially reduces local recurrence even for low risk patients and should be used. The CALGB study suggested that for older women over age 70, with small tumors (T1) radiation might be omitted. It was not powered to look at survival as an end point and had only five-year follow up. We know that the benefits of radiation therapy are increased at five to ten years after treatment. Furthermore, selecting appropriate patients for radiation treatment is nothing new. Radiation oncologists have always been selecting patients suitable for radiation. There are very healthy and motivated 70 year olds who would stand to benefit from radiation, just as there are 85 year olds with many co-morbid conditions who may not benefit from radiation therapy. So, we have already been doing what the study suggested namely offering therapy to people who would benefit, and discussing the pros and cons with the individuals who may not benefit as much and could potentially be harmed.
I should also mention that there exists very good long-term data (NSABP B21) that supports the use of radiation therapy with tamoxifen in small tumors in early stage breast cancer. These data are very strong.
Is there data trying to identify, genetically, for example, which women would benefit from radiation therapy and which can omit it?
LJS: No, not yet. We do know that there are some markers that can show some level of risk but none that can define the appropriate patients for the omission of radiation. It would be interesting to go back to the older trials (for example, NSABP-06 and NSABP- 21) and use the genetic markers to look at local failure. Maybe we can use the GHI panel (Genomic Health Inc, announced last year in San Antonio that their unique breast cancer assay can accurately and precisely quantify the likelihood of recurrence) for example.
Have the newer techniques such as accelerated partial breast irradiation or hypofractionated whole breast irradiation for early stage breast cancer, and changed any of these late effects? How?
LJS: No. We don't know yet. There has not yet been a large randomized, controlled, phase III clinical trial. We will soon open a phase III APBI (Accelerated Partial Breast Irradiation) study here in the US. The goal of APBI is to improve the quality of life without changes in local control rates and cosmesis. We already have very low rates of failure, low rates of cosmetic disfigurement, and low rate of toxicity with standard radiation therapy. If you want to change the paradigm, you have to do it very carefully and only in the context of a controlled clinical trial. This is what happened when everyone was excited about offering breast cancer patients stem cell transplants. It was a great idea intellectually, and medically it made sense. But in the end it did not help, and in fact, people died. Stem cell transplant carries with it a low but very real mortality potential. At Penn, we do not do APBI outside the context of a clinical trial. Furthermore, there are very little long-term data on it.
Partial breast irradiation, as I understand it, was born from the observation that most in breast recurrences occur in the surgical bed. So the thought was to irradiate it rather than the entire breast. Is this correct? It sounds good.
LJS: There are many good Phase I and II data, but now we need a phase III trial to gain a clear understanding of the risks and benefits of these techniques. The history of oncology is filled with ideas that proved to be appropriate after proper testing and those that did not.
There are philosophical reasons why it may not look so good after all. First off large daily fractions have been associated with increased risk of late toxicities. So we need to be concerned about potential toxicities that we currently don't see everyday. We need to be aware of not only local control of breast cancer but also cosmesis. Furthermore, there is some evidence that small even microscopic foci of disease can be found in the remainder of the breast not just the surgical bed. Whole breast radiation serves to sterilize the breast and deceases recurrence. By irradiating only the surgical bed there is a chance of recurrence in another part of the same breast.
You have to do controlled clinical trials. You can't do something because you think it is intellectually correct.
To my knowledge there have been four different approaches to accelerated partial breast irradiation:
LJS: There is very little long term data on any of these. The longest outcomes data have been on brachytherapy. In general, however, patients don't like it, as plastic catheters need to be placed in the breast. The MammoSite was just approved in 2002 so there aren't even five-year data on this technique. The intraoperative technique is used mainly in Europe. It is attractive because the patient does not have to come back. But this is an expensive proposition. The machines we use are enormous and can't be easily wheeled into an operating room. Again, we need properly controlled randomized trials.
Reduction of treatment time has also been a focus. This improves access to care and maximized resources.
LJS: There are a number of studies that show that radiation therapy is limited by (1) distance if a patient lives far from the radiation center, and (2) age older people with other co-morbid conditions may not tolerate it as well. Access in major cities is not really a problem. If you live in Philadelphia, for example, most patients are not very far away from a radiation oncology center.
So partial breast irradiation and hypofractionated treatments have as the main goal reducing overall treatment time. IMRT (intensity modulated radiotherapy), however, is a technique developed to improve dose homogeneity, target coverage, and of course, decrease toxicity. Can you give us your thoughts about IMRT?
LJS: IMRT is more interesting. There are good direct and indirect evidence showing that toxicity can be ameliorated by improved dose distribution. IMRT reduces dose inhomogeneity and reduces toxicity. Unfortunately, there are still no randomized trials. A change in dose distribution while keeping the absolute dose stable has never been tested. Furthermore, IMRT is operator dependent and differs in different institutions. Everyone does it a bit differently. But it is important to understand that this is not a new concept. Radiation oncologists have been employing this concept for decades with wedge filters -- placing wedges at certain angles to maximize dose homogeneity and minimize toxicity. This is not a new concept, just a new name with a higher price.
But you just said that you don't use partial breast irradiation because of lack of phase III data. Why do you use IMRT if it too lacks conclusive phase III data?
LJS: From a practical point of view, testing IMRT is much more difficult if not impossible. As I said, there is too much variation from place to place. Also, the concept is one that radiation oncologists already employ. We routinely use wedge filters to see which homogeneity is better. Plus, it is not a comparison of whole versus partial breast irradiation. You are still irradiating the entire breast, and just optimizing the homogeneity.
What is the future for radiation oncology and early stage breast cancer?
LJS: A few things: (1) integrating genomics to identify those patients who can safely omit radiation. It would be great to identify those patients for whom a directed treatment program is possible. (2) Learn to better use nodal radiation therapy, which something that we have not yet talked about today. And, (3) optimize the integration of therapies such as chemotherapy, hormone therapy, radiotherapy, and surgery.
I have one last question, it's about DCIS...
LJS: Omission of radiation therapy for DCIS is a strong question. Radiation therapy is for local control and this is arguably the most important aspect for these patients as they don't tend to die from the disease. It becomes a question of minimal therapy. There are three trials looking at radiation therapy for DCIS and all are positive. However, there have not been any trials for omission of radiation therapy by contemporary evaluation. Today our criteria are much more selective.