Editor’s Note
	When to pull the trigger

At a Breast Cancer Update working group meeting a couple of years ago, a community-based oncologist presented the case of a woman in her thirties with newly diagnosed ER-positive, HER2 tic breast cancer. The patient, a nurse and a young mother of two small children, was like many or most people in this situation: desperate to do something aggressive against the tumor.

The physician, who understandably empathized with the patient’s plight, initiated therapy with goserelin, anastrozole, trastuzumab, capecitabine and docetaxel. We know from our Patterns of Care studies over the years that few oncologists would recommend this type of untested “shotgun” approach even though an extensive clinical research base demonstrates the value of each of these therapies individually.

I asked the two breast cancer clinical investigators on the faculty for this working group event to respond to the doc’s unusual treatment plan. Both gulped and tactfully indicated that they probably would not have taken the same approach and would more likely have chosen either conventional endocrine therapy (tamoxifen) or trastuzumab alone or with a taxane. However, the researchers and the other community docs in attendance commented that they understood the thinking behind the treatment decision made in this case.

So do I, and the topic of what constitutes evidence-based oncologic treatment is a constant theme in our CME programs. Clearly, we cannot require Phase III randomized trial evidence for every or even most decisions in cancer medicine, and we must be able to integrate input from a variety of resources and feel comfortable that the recommendations we make for patients are ethical.

The recent history of research and practice on adjuvant trastuzumab is perhaps the most dramatic example of the issue of when to “pull the trigger” on a highly promising yet unproven therapy that is part of major ongoing Phase III randomized trials. The adjuvant trastuzumab trials were initiated in 2000, following Dennis Slamon’s pivotal randomized trial demonstrating a survival advantage when this monoclonal antibody was added to chemotherapy in the metastatic setting.

In dozens of interviews for our CME programs during the years following that historic study, I heard several very consistent messages from almost every breast cancer clinical investigator.

1. Although we had been disappointed in the past by therapies that seemed promising but failed to demonstrate value in randomized trials (eg, high-dose chemotherapy with stem-cell transplant), virtually all researchers expected adjuvant trastuzumab to work. This sentiment increased markedly after the ASCO 2004 meeting, when Aman Buzdar presented results of a trial of trastuzumab combined with neoadjuvant chemotherapy that demonstrated a 65 percent complete pathologic response rate, albeit in a very small number of patients.
   
   
2. Since Charles Geyer’s presentation of the cardiac safety findings from NSABP-B-31 at the 2003 San Antonio Breast Cancer Symposium, we have had a generally accurate estimate of the downside of adjuvant trastuzumab integrated into an anthracycline-based chemotherapy regimen.
   
   Specifically, a three to four percent incidence of clinical congestive heart failure is associated with this sequence. We have also known for some time that trastuzumab is generally very well tolerated and does not seem to add to the other specific and nonspecific downsides of chemotherapy.
   
   
3. Until the recent release of the initial results of the major adjuvant trastuzumab trials, virtually all researchers strongly cautioned against using adjuvant trastuzumab outside a protocol setting, and our Patterns of Care surveys have consistently demonstrated that docs in practice supported this message. Even for women with multiple node-positive, HER2-positive tumors, trastuzumab was usually not raised as an adjuvant option.

One very notable exception was Dennis Slamon, who in an interview for the Breast Cancer Update audio series in 2002 told me about a number of patients who were not eligible for or did not wish to participate in his BCIRG 006 trial, whom he treated off protocol with trastuzumab. One of these patients was a marathon runner with node-negative, HER2-positive disease, who received TCH to protect her heart while still attacking the tumor.

Of course, things changed on April 25, 2005, when the NCI issued a press release announcing that the combined analysis of NSABP-B-31 and NCCTG-N9831 demonstrated a dramatic reduction in relapse rate and mortality when trastuzumab was added to chemotherapy. These data, along with the HERA trial data presented at ASCO in May, instantly changed breast cancer management as we knew it. Our most recent national Patterns of Care survey currently demonstrates that adjuvant trastuzumab is now the standard of care for most women with node-positive and higher-risk, node-negative, HER2-positive tumors.

OK, now I have to be the bad guy and, like some Monday-morning quarterback complaining that the Dolphins should have made a greater effort to push the ground game, ask the painful question: In the 18 months between Chuck Geyer’s San Antonio presentation and the NCI press release in April 2005, should we have been more liberal about presenting the option of adjuvant trastuzumab to some patients?

I don’t know the answer to that question, but I will mention another relevant anecdote: In 2003, our CME group conducted three breast cancer patient perspectives “town hall” meetings in New York, Miami and Houston. In total, we hosted about 1,200 breast cancer patients and their loved ones, all of whom listened to nationally recognized clinical investigators discuss a variety of clinical situations and then responded to a number of multiple choice questions, using electronic keypad polling, on how they viewed the risks and benefits of various interventions.

One of the most interesting scenarios we presented was that of a younger patient with a HER2-positive tumor and multiple positive lymph nodes. At each of the three meetings, a substantial number of patients in the audience indicated that if they were in that situation, they would want to receive adjuvant trastuzumab off protocol. What makes this finding even more intriguing is that this preference emerged in spite of the strong urging of the faculty at each meeting to utilize adjuvant trastuzumab only as part of a clinical trial.

The obvious difference between the perceptions of the investigators and the patients on this issue was particularly dramatic in Houston in November 2003, where local MD Anderson legend Gabriel Hortobagyi, along with panelists Peter Ravdin, Eva Singletary and Debu Tripathy, carefully explained the potential cardiac risks of trastuzumab and why they believed that adjuvant trastuzumab should not be utilized off study. Nonetheless, 44 percent of the patients indicated a preference for trastuzumab.

These meetings left me with an uncomfortable feeling about whether or not we were fulfilling our ethical obligation to patients. Then, in April we learned that, as predicted by the experts, the adjuvant trastuzumab trials demonstrated a major treatment benefit. While the early reported advantages are of greater magnitude than expected, there were essentially no surprises with these new data sets.

The point of this mental exercise is not to be critical. We are blessed with oncology leaders who — like their brethren and sistren in community practice — do the best they can and make recommendations to patients with the most sincere intent. However, the trastuzumab experience forces us to at least take a step back and rethink how we present treatment options to patients.

In this regard, Herbert Hurwitz — in a recent interview for our colorectal cancer series — made an interesting comment on the topic of when it’s acceptable to discuss and utilize an unproven therapy. Herb was the principal investigator of the breakthrough IFL-bevacizumab trial in metastatic colon cancer that was presented at ASCO 2003 and led to the first FDA approval of this anti-VEGF agent.

As a result of these encouraging results in the metastatic setting, bevacizumab is following its older sister, trastuzumab, into the adjuvant setting and is currently being evaluated in large, randomized, adjuvant colorectal cancer trials in the United States and elsewhere, including NSABP-C-08, which randomly assigns patients with Stage II and III disease to FOLFOX alone or with bevacizumab.

My question to Herb was, “In view of the trastuzumab experience, should clinicians consider raising the issue of bevacizumab as a point of discussion in select patients with colorectal cancer in the adjuvant setting?” I have discussed this issue with many other colorectal cancer investigators as part of our audio programs, and like the breast cancer specialists commenting earlier this year on nonprotocol trastuzumab, virtually all have said that they would not support the consideration of bevacizumab off protocol for such patients. Herb had a somewhat more open approach:

“For me, the issue of whether or not to treat a patient off protocol with an experimental approach depends on the nature of the protocol. I usually do not treat a patient off protocol with therapies being tested in Phase I or Phase II studies, with all the literature biases and other biases in that setting. However, when a regimen has been credentialed enough to be part of a Phase III regimen, I’m more than willing to talk in detail with a patient about considering that directly — including how much we don’t know, the inconveniences and the fiscal and biological toxicities that accrue by taking the treatment. I think the less we know about the effects of a therapy, the more we need to spend time being sure the patient is fully informed of what the pros and cons of that management strategy would entail.”

Herb’s point about the unknown is key, and clinical investigators including Herb express far less certainty that bevacizumab will be effective and safe adjuvant therapy than was expressed in 2004 about trastuzumab.

With these difficult-to-answer issues as a background, the enclosed audio program features a panel of community-based medical oncologists presenting cases from their practices to clinical investigators Drs Aman Buzdar, Kevin Fox, Gershon Locker and Eric Winer. The issue of when to pull the trigger surfaces here numerous times in discussions about challenges such as the use of adjuvant aromatase inhibitors combined with ovarian suppression in premenopausal patients and the management of patients with visceral metastatic crisis. Herb Hurwitz provides a construct for us to begin to evaluate these dilemmas, and his advice to involve the patient is perhaps the key to clinical decision-making in these situations.

— Neil Love, MD
NLove@ResearchToPractice.net
December 12, 2005