On March 1, 2001, a clinical trials panel discussion was held at the Miami Breast Cancer Conference. The purpose of this first-ever event was to explore the relevance of current phase 3 randomized trials to non-protocol-related treatment decisions in breast cancer. An internationally respected group of six clinical investigators* reacted to interactive keypad questions presented to the audience of approximately 1,000 physicians. The following edited transcript of the discussion is supplemented by commentary by Dr Monica Morrow and Dr Nancy Davidson, Miami faculty members who did not participate in this panel but were interviewed shortly after the meeting. To view this, click on the word Commentary. This presentation is also supplemented by a number of links to useful references, figures, soundbites and Web sites.

*Panel Members:
Michael Baum, ChM, FRCS
Joseph Costantino, PhD
J Michael Dixon, MD
Richard Margolese, CM, MD, FRCS
Hyman Muss, MD
Victor Vogel, MD

Guest Commentators:
Nancy Davidson, MD
Monica Morrow, MD

Moderator:
Neil Love, MD

Dr Love: Our goal today is to create a dialogue between the audience and this distinguished group of researchers, and we'll start out with an interactive question to assess the current level of participation of our audience in breast cancer clinical research.

Participation in Clinical Trials - Select Publications

About how many breast cancer patients (or high-risk women) have you entered on clinical trials in the last year?

Commentary by Monica Morrow, MD

Dr Love: Sir Richard Peto has demonstrated a recent dramatic reduction in breast cancer mortality both in the United Kingdom and United States. This reduction is multifactorial in origin, and likely to be related to the widespread use of mammographic screening and adjuvant systemic therapy with both cytotoxics and tamoxifen. The scientific background of this encouraging trend is the emergence of randomized clinical trials, and one major goal of our panel today is to encourage physicians to enter patients in studies.

Clinicians who don't participate in trials often are uninformed about the questions being addressed until results are presented at meetings or results of research findings are published in journal articles. A central hypothesis of our trial panel today is that ongoing clinical trials are very relevant to practicing clinicians, including those who do not participate.

Another goal of this panel is to provide feedback to researchers on how clinicians view the randomizations in trials currently being offered to patients. To do this, we're going to talk about three cases and nine current and proposed clinical trials.

One important factor in the integration of clinical trials into practice is the emotional energy present in the patient, family and healthcare team. To provide some orientation for us, we're going to hear from several breast cancer survivors about how they felt in the first few weeks after diagnosis:

Comments from Breast Cancer Patients

Dr Love: It is always difficult when a patient turns to you and says, "Well, suppose it were you," or "Suppose it were someone in your family, your mother, what would you do?" We find those questions a challenge to deal with, but that's what our patients want to know. This is the feeling and the idea that we want to bring into today's discussions of randomized clinical trials.

We are going to focus on the current and proposed NSABP trials and your management of three patient cases as they relate to entry into clinical trials.

The first case is that of a 67-year-old woman with a suspicious lesion on her mammogram in the upper outer quadrant. Core biopsy shows infiltrating adenocarcinoma. Her physical exam is negative, including the axilla, and she wishes to have breast conservation.

The first interactive question we want to address for this case (and I'd like the panel to vote as well) is, "How should the axilla be approached?"

In general, what would be your suggested non-protocol approach to the axilla in this case?

Commentary by Monica Morrow. MD

Dr. Love: So, the audience is leaning heavily toward sentinel node biopsy — even in a non-protocol setting. Mike Dixon, in general, how would you approach a patient like this in terms of the axilla off protocol?

Professor Dixon: In the U.K., this question is fairly straightforward because sentinel node biopsy is not yet accepted as a standard form of therapy. If we're doing clinical trials, we have to be careful to wait for the results of those trials before we introduce something new into clinical practice. In the U.K., we have an ongoing clinical trial looking at this issue, and the current view is that outside of these clinical trials, patients should receive the standard accepted treatment — some form of axillary dissection.

Research Leader Commentary

Dr Love: That's a perfect lead-in to our next interactive question and a discussion of the clinical trials related to sentinel node biopsy. Dr. Dixon referred to clinical trials. There are several studies right now for which a patient in this situation would be eligible, and we'd like to see how the audience would feel about entering this patient on these studies. Let us put aside practical issues such as time and money and focus on how you feel about the issue of randomization.

One study for which the patient would be eligible is NSABP trial B-32. The principal investigator is David Krag at the University of Vermont. This is going to be a large study — the projected accrual is 4,000 patients within four years. The participation criteria are invasive breast carcinoma with clinically negative lymph nodes — like this patient. The technique used is technetium and blue dye. One arm will be randomized to receive sentinel node biopsy followed by axillary dissection. The other arm will have a sentinel node biopsy and, if negative, there will be no further surgery. If the sentinel node is positive, the patient receives an axillary dissection. Essentially, the focus of this randomization is to look at the sentinel node-negative patient and determine whether this is adequate as a procedure. The sentinel node-negative patient is randomized to either no further surgery or axillary dissection. So, in order to enter into a trial like this, the patient would have to agree to be randomized between receiving an axillary dissection or not.

NSABP B-32 Trial: Phase III Randomized Study of Sentinal Node Dissection with or without Conventional Axillary Dissection in Women with Clinically Node-Negative Breast Cancer Protocol  Eligibility  Invasive cancer with clinically negative nodes ARM 1 Sentinel Node Resection with Axillary Dissection ARM 2  Sentinel Node Resection +Sentinel Node   Axillary Dissection  - Sentinel Node   No Axillary Dissection

Research Leader Commentary

The next interactive question is:

How would you feel about offering this patient participation in the NSABP B-32 sentinel node trial?

Commentary by Monica Morrow, MD

Dr Love: So, almost all of the audience would offer this trial. Richard Margolese is one of our panelists and a member of the NSABP. Richard, what are your thoughts on the responses here?

Dr Margolese: Sentinel node techniques accurately find lymph nodes 92 to 97 percent of the time, but what does this mean in treating a patient? Are there therapeutic implications of leaving the axilla untreated? The impact of this can only be measured in a randomized trial. NSABP B-04 — done a generation ago — suggests that nothing happens if you don't treat the axilla and that's probably true. But, radiation therapists today critique that study as under-powered, and there has been much discussion about radiation of the axilla and/or surgical treatment of the axilla. Whether we do a mastectomy or lumpectomy, we have not left axillary disease untreated.

The B-32 study will help determine the implications of interpreting a negative sentinel node biopsy as negative and not treating the axilla. The purpose of this trial panel is not to tell the audience that this or that is a good technique, but to help us all understand how to get new information through the clinical trial mechanism, so that we can all believe in it.

Dr Love: In this situation, a practitioner participating in a trial like this one would have to be able to say to a patient, "We're going to flip a coin about axillary dissection," which is a pretty significant procedure.

Dr Muss: I want to point out that we've changed many of our cancer treatments based on just a few percent difference in survival. We don't know whether sentinel node biopsy is as effective as an axillary dissection. Dr. Peto's data says that local control probably impacts survival in a small percent of patients. B-32 is powered to look at this two to three percent, and we are committed to this in Vermont. Before we take a 200- or 500-patient trial that looks pretty good and etch it in stone — the way we often do in medicine — we should do this trial. I also want to point out that it is not different in concept from the B-06 trial — comparing lumpectomy and mastectomy. Many institutions that are committed to this study — including ours — don't offer sentinel node biopsy outside the trial. This trial is a major economic and clinical trial commitment.

So, I caution that although we do have some large trials with data that look very good, we could be underwriting a procedure that may turn out to be a little less efficient in the long run. And that's why this clinical trial is so important.

Dr Love: Let's see if we can create even more controversy here, by reviewing the American College of Surgeons' sentinel node trial. The principal investigator, also a speaker at this meeting last year, is Dr Armando Giuliano. This is another huge trial, with a projected accrual of approximately 7,600 early-stage patients (Stage I or IIA) amenable to lumpectomy.

Research Leader Commentary

Grube et al. A Decade of Sentinel Lymph Node Mapping in Breast Cancer: A Hypothesis - Driven Journey Toward a New Paradigm. Poster, Miami Breast Cancer Conference 2001.


The ACOS has actually separated this into two trials. For Z-10, patients have breast conservation with sentinel node biopsy and immunohistochemistry of the sentinel node along with bone marrow aspirations. If the sentinel node is positive, participants then move into the second part of the trial — or second study actually, Z-11 — where the randomization occurs between axillary dissection versus no further surgery. So, in contrast to NSABP B-32, this trial randomizes women who are sentinel lymph node-positive between receiving axillary dissection or no axillary dissection.

Obviously, here we're getting into the issue of the therapeutic value of axillary dissection. Let's see what the audience thinks about the Z-10 and Z-11 trials.

How would you feel about offering this patient participation in the American College of Surgeons (ACOS) trial, and specifically the randomization for a positive sentinel node?

Commentary by Monica Morrow, MD

Dr Love: The audience seems to be leaning more towards not offering this trial. Dr Baum, what are your thoughts about entering a patient like this in the ACOS trials and the issue of the therapeutic value of axillary dissection in a woman whose sentinel node is positive?

Professor Baum: I am fairly relaxed about not treating the axilla. I was involved a study many years ago that randomized nearly 3,000 patients to no treatment for the axilla versus treatment. We're out to 25 years now, and surprisingly there was no difference in survival. However, there was a penalty to pay — uncontrolled axillary disease at the time of death. It worked out that you had to treat about 1,000 axillae to prevent 70 cases of uncontrolled disease at the time of death. So, I think there is a quality of life issue in controlling the axilla. You have a choice between surgery and radiotherapy after a positive sentinel node. I am lukewarm about this trial because I would rather rely on the surgeon than the radiotherapist to control the axilla.

Professor Dixon: We considered participating in the ACOS studies, and the general view in our unit was that this looks like an interesting study, and we're looking forward to seeing the results, but we're not sure about whether we'd put anybody in it. It's one of those studies where you think, "What a great idea, but it'd be kind of nice if I watched it from the sidelines, rather than get involved." It's kind of worrying, isn't it? We've done a big, long-term follow-up study comparing node sampling, and node-negative patients did not receive treatment to the axilla. There are differences of some concern, but the ACOS trials are interesting, and I'll look forward to seeing the results

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