Special Edition Breast Cancer Update: Cardiologic Issues in Breast Cancer Management 2008

JEAN-BERNARD DURAND, MD: Symptoms of heart failure and the side effects of cancer treatment can be similar. As a result, physicians may be missing signs of cardiotoxicity with only history and physical examination.

In 2004, an interesting study was published in the Journal of Clinical Oncology that examined patients who had a constellation of eight symptoms and their physicians’ ability to recognize these adverse events. It showed that 75 percent of the time, physicians did not pick up on what the patient was feeling. We might, therefore, have to rely on studies such as biomarkers, echocardiograms and MUGAs to better detect these symptoms.

The recommendations from a number of societies for patients receiving cardiotoxic drugs include an echocardiogram at baseline and when a change in symptoms occurs, such as lower extremity edema.

On physical exam, physicians should watch out for elevated neck veins, lower extremity edema, an S3 on exam or bilateral rales. The problem is that the sensitivity of these physical exam findings is low. The accuracy of diagnosing heart failure based on something as simple as bilateral lower extremity swelling is approximately 35 percent.

The best clinical predictor we have found has to do with weight gain. We teach patients about the “rule of twos,” which is if while on therapy they put on more than two pounds within two days, to contact us. We’re watching for an early sign of fluid retention, and we treat that aggressively. Ultimately, that keeps patients on track so that they do not have to discontinue their cancer therapy.

Special Edition Breast Cancer Update: Cardiologic Issues in Breast Cancer Management 2007

DENNIS J SLAMON, MD, PHD: In the adjuvant trastuzumab trials, we frequently saw patients with HER2-positive disease who were treated with AC but never received the taxane/trastuzumab therapy because they had declines in their LVEFs, yet those are not scored as toxicities.

It’s a greater negative when that happens than when other things happen because now you’re denying a potentially active drug to a woman who might benefit from it because you forced the agenda with the anthracycline. That happened between three and five percent of the time in all the studies that were examined, and it’s more frequent among older patients. The problem is that once physicians see the LVEF drop, they’re reluctant to take the risk.

I believe that oncologists are becoming increasingly aware that the cardiac toxicities might continue for longer than previously believed. The assumption had been that once we stopped trastuzumab, the cardiac problems reversed in a matter of a couple of weeks or months. However, the data — at least the BCIRG 006 data — show that they are longer lasting. We now know that a year and a half later, those subclinical LVEF declines seem to be maintained at some level.

We previously thought that the patients with clinical congestive heart failure improved with treatment. However, at least two thirds of them require continued treatment. That means that you can treat their congestive heart failure, but it doesn’t mean that you’ve made the heart better. I believe that these definitions must be more carefully stated when some of the data are presented.

Special Edition Breast Cancer Update: Cardiologic Issues in Breast Cancer Management 2008

HAROLD J BURSTEIN, MD, PHD: Monitoring ejection fractions in patients on adjuvant trastuzumab and deciding when to stop and start the agent is a difficult situation because we have a black-box warning about cardiotoxicity with the use of trastuzumab.

Clearly, these patients merit cardiac surveillance. It seems as if borderline ejection fraction at baseline, age and perhaps preexisting hypertension stand out as predictors of trastuzumab-related cardiomyopathy.

The patients still require surveillance, irrespective of those risk factors. My practicing algorithm is to check cardiac function at baseline, after the anthracycline-based chemotherapy, after three to four months of the taxane/trastuzumab combination and at some point again. It must be said that these safeguards were put in place when we did not know the clinical efficacy of trastuzumab.

The challenge arises in cases with high-risk breast tumors in which you are trying to bring important therapy to bear on the patient’s disease. When you are trying to combat these reductions in ejection fraction of unknown clinical significance, it’s tough to be a clinician because we have no hard and fast rules.

The rules in the trials were based on not knowing that trastuzumab would be a lifesaving drug for women.

Special Edition Breast Cancer Update: Cardiologic Issues in Breast Cancer Management 2008

DR DURAND: The use of trastuzumab has shifted to earlier and earlier and despite that, the safety data remain good. The data from the clinical trials show the incidence of heart failure is low — two to four percent — and we saw few deaths. The morbidity was higher than anticipated, but at the time these trials were conducted, we weren’t administering ACE inhibitors and beta blockers or trying to track these events as secondary endpoints. I believe that with medical intervention, the incidence of heart failure would probably be even lower.

In addition, we know that the reversibility of the trastuzumab-induced cardiac damage is excellent. At our institution, we have seen clinically that when we put these patients on beta-blockers and ACE inhibitors, they have an excellent ability to completely recover their normal heart function.

We presented a paper at the Heart Failure Society of America in 2002 on young women who were asymptomatic but developed small drops in heart function. Their heart function was in the range of 40 to 50 percent.

The patients wanted to remain on the trastuzumab because they knew it reduced their rate of disease progression by 50 percent, so we spoke with their oncologists and we put them on both an ACE inhibitor and a beta-blocker without stopping the trastuzumab. We never stopped the trastuzumab, their heart function went back to completely normal and our longest follow-up is now five years.

Breast Cancer Update Issue 6, 2008

DR PICCART-GEBHART: The issue of an anthracycline-versus a nonanthracycline-containing chemotherapy for a patient with HER2-positive, node-positive disease is a hot topic. In Europe, we are selecting the type of chemotherapy based on risk factors for cardiotoxicity, including age, obesity, poorly controlled hypertension and a left ventricular ejection fraction that is on the low end of the normal range prior to initiating therapy.

For patients who are at a higher risk for cardiotoxicity, it is reasonable to choose a nonanthracycline-based chemotherapy. I prefer TCH, the regimen that has been piloted in the BCIRG 006 study. It is important to be able to clearly explain to patients the side effects they can expect with this regimen.

For a 38-year-old woman who has five positive nodes but is in otherwise perfect health, we have two options. The five positive nodes are worrisome and indicate a higher risk for an early relapse. You do not want to give a six-month chemotherapy regimen and then start trastuzumab. It makes sense for such a woman to go with TCH or what we like to do in Europe, which is three cycles of FEC — this is anthracycline-based but only three cycles — and then move on to a taxane, which can be docetaxel or paclitaxel, administered concomitantly with trastuzumab.

Breast Cancer Update Issue 5, 2008

DR WOLMARK: The BETH study — the adjuvant trial being conducted by the NSABP and CIRG evaluating trastuzumab with or without bevacizumab — opened recently (Figure 26). I believe we need to know what the addition of bevacizumab to trastuzumab will yield in the adjuvant setting, based on some interesting preclinical work and early clinical findings. Cardiovascular concerns exist with both agents, so the NSABP and the CIRG are offering TCH as the template.

We made the decision not to use an anthracycline template to test the combination of trastuzumab and bevacizumab, with one of the rationales being the potential toxicity of using both agents on an anthracycline template.

However, some participating physicians, particularly those in Europe, will administer an anthracycline template along with bevacizumab and trastuzumab, so I believe we will receive an answer rapidly as to whether that regimen is tolerable.

Special Edition Breast Cancer Update: Cardiologic Issues in Breast Cancer Management 2008

DR DURAND: At our institution, with bevacizumab we have a recommendation that the patient’s blood pressure must be less than 140/90 for treatment, and that is incorporated into all our clinical trials. We have follow-up data that show our incidence of heart failure is actually quite low, less than two percent, if we control the patient’s blood pressure more aggressively. We are finding that we are able to keep women involved in these newer trials that include trastuzumab and bevacizumab on therapy much longer if we just do a better job of internal medicine.

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Renal Cell Cancer Update Think Tank Issue 1, 2008

WALTER STADLER, MD: I want to emphasize that we cannot minimize some of the cardiovascular toxicities of the multikinase inhibitors, sunitinib and sorafenib, in renal cell carcinoma. The rate of hypertension in the clinical trials is approximately 20 percent, and increases in blood pressure occur in probably two thirds to three fourths of patients. We’re talking about chronic treatment with these agents — perhaps years of treatment when we use these agents sequentially — and we’re talking about an elderly population, which may have multiple comorbidities, including cardiovascular disease.

We observe cardiovascular events, even with short follow-up, in the current Phase III trials — an increased risk of cardiovascular and cerebrovascular events. Attending to the cardiac toxicities from these agents will be an increasingly important issue in terms of patient care.

I tell patients that a risk of a cardiovascular or cerebrovascular event exists on the order of about three percent, in comparison to one percent in controls in the randomized trials.

Lung Cancer Update Issue 3, 2008

DR LYNCH: It appears that anticoagulation therapy can be part of the approach to lung cancer in patients who are receiving bevacizumab. It’s more difficult to come by data on patients who are receiving anticoagulants prior to therapy. I have been hesitant to use bevacizumab in that setting. I’m not simply concerned about the anticoagulants — I’m concerned about why they were receiving these agents.

Most of my patients who are anticoagulated have experienced an acute thrombotic event. I’ve been hesitant to use bevacizumab for the patient with a pulmonary embolism discovered at diagnosis, who has an acute need for heparin, whereas for the patient who has been receiving warfarin for a long time for atrial fibrillation, I suspect it’s fine to use bevacizumab. The concern is more for the patient who’s been acutely anticoagulated for a clotting event such as a deep vein thrombosis, pulmonary embolus or a myocardial infarction.

Colorectal Cancer Update for Nurses Issue 1, 2007

DR HALLER: The issue of wound healing in patients receiving bevacizumab is subjective. Surgeons evaluate wound healing every day, and I suspect if they knew their patient was on bevacizumab, they might say the healing was slower than usual. No huge difference exists in operative complications in patients receiving bevacizumab. The agent has a long half-life of more than 21 days, so even when the patients are six weeks out, they still have enough bevacizumab in their system to inhibit anything. The truth is that sometimes people need to go to surgery and don’t delay surgery just because they received a dose of bevacizumab two weeks ago.

A paper was published on patients who underwent liver resection after receiving six cycles of chemotherapy and bevacizumab, but the bevacizumab was held during the last cycle so that four weeks had elapsed between surgery and the last dose. The data revealed no obvious difference in regeneration of liver or bleeding, so while I believe that it’s an issue theoretically, and probably somewhat real, in practice it doesn’t seem to be a “deal breaker.” Nor is it a major issue for minor but necessary surgical procedures, such as insertion of a port or dental surgery.

Lung Cancer Update Issue 3, 2008

F ANTHONY GRECO, MD: Most of our protocols require a week between putting a port in and using bevacizumab. Personally, I have done it the same day for several patients, and so far I’ve not seen a problem. That’s not a huge incision and it doesn’t go through viscera.

I certainly wouldn’t use bevacizumab within a week after bowel resection. Sometimes patients who have received bevacizumab then have an emergency in which they need surgery and we don’t have a choice. Interestingly enough, most of those patients fare well, but I don’t tempt fate and undertake major surgery by design after proximate use of bevacizumab.

Lung Cancer Update Issue 2, 2008

JULIE R BRAHMER, MD: With regard to predictors of hemoptysis secondary to bevacizumab, there are many thoughts. Some believe the location of the tumor is important — central versus peripheral. Others believe a history of hemoptysis increases a patient’s risk. Still others feel it is related to the presence of tumor cavitation, which is borne out in a small analysis by Dr Sandler. Therefore, if tumor cavitation is present initially, I generally avoid using bevacizumab.

If the tumor develops cavitation while responding to bevacizumab, some recommend stopping bevacizumab. Some recommend using radiation therapy in that local area to try to decrease the risk of bleeding with bevacizumab. If cavitation did occur with therapy, particularly in a central lesion, I would seriously talk with the patient about the increased risk.

I don’t believe location is quite as important, because bevacizumab has been administered to patients with small cell lung cancer. Those tumors are all mainly central, and we’ve seen no increased risk of bleeding in that patient population.

Lung Cancer Update Issue 3, 2008

DR LYNCH: The eligibility criteria for the AVAiL trial and ECOG-E4599 did not restrict tumor location, and in subsequent reviews, central tumors didn’t appear to be a problem. So in my practice, having a tumor that’s central or abutting the pulmonary artery or aorta, in and of itself, doesn’t mean that patient can’t receive bevacizumab.

However, I believe we are learning that pretherapy cavitation may be significant. One of the big challenges now is how to manage tumor cavitation that develops in response to therapy. In a way, that’s what you’re hoping for because those cavitary responses are some of the best responses we see. However, they are associated with an increased rate of hemoptysis, which is of concern.

In my practice, when a patient’s tumor has an enormous cavitary response, I generally stop the chemotherapy and bevacizumab and observe that patient. That is completely unevidence based — I’m simply nervous in that setting. I believe we need to spend more time examining exactly how those patients fare.

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