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This issue of Breast Cancer Update includes contributions from four practicing medical oncologists who are frequent participants in our Meet The Professors audio series, in which highly astute and learned community docs present real cases to clinical investigators. Over the years, our CME group has searched for oncologists with a flair for education to assist in creating programs that interest their colleagues, perhaps the most highly informed subspecialists in contemporary medicine.
The Breast Cancer Update audio series usually focuses on interviews with breast cancer clinical investigators, but for the enclosed issue, we decided to infiltrate the program with our guerrilla oncology fighters, beginning with a case presentation by Dr David Dresdner, a medical oncologist from St Petersburg, Florida, who is among the elite and ever-growing band of practicing oncologists helping us shape the MTP series.
Dr D presents a quite scary case of a 60-year-old woman with a history of
noninsulin-dependent diabetes who developed sudden and florid congestive
heart failure shortly after receiving anthracycline chemotherapy in the form of
dose-dense AC 
paclitaxel, followed by radiation therapy to the breast.
Dr D’s diagnosis, after comprehensive cardiologic and radiation oncology consultations, was anthracycline-related cardiomyopathy. The patient is currently doing well but continues to receive intensive pharmacologic cardiologic support.
I then queried clinical investigator Dr Julie Gralow about this case, and she concurred with Dr D’s findings but noted the unusually early onset of CHF after anthracycline-based therapy. Our discussion then shifted to Dr Gralow’s perspective on several related and intriguing presentations at the recent 2006 ASCO meeting in Atlanta on cardiac safety with adjuvant chemotherapy regimens containing anthracyclines.
MD Anderson’s Dr Sharon Giordano presented SEER and Medicare data from more than 30,000 women who had full Medicare coverage for a year before and after their diagnosis of early-stage breast cancer. Extensive information on the diagnoses and treatments of these women was available from the Medicare database. The key event evaluated in this analysis was the clinical diagnosis of CHF as per Medicare coding. Mean follow-up was a little bit more than five years.
The data are complex but strongly suggest that the high baseline risk of CHF
for older people is substantially increased with exposure to an anthracycline
— with even greater risk in patients with comorbid conditions, including
diabetes and hypertension
(Figure 1). Given that these
data were retrospective, it
is difficult to estimate an
absolute figure for the risk of
clinical events in this patient
population. However, selection
bias in this analysis may
mean that the adverse impact
of anthracyclines could have
been significantly underestimated.
Dr Lois Shepherd from the NCI Canada then discussed more data on our latest onco-acronym, “CRCD” (chemotherapy-related cardiac dysfunction). The patients in this prospective trial data set comparing CEF to CMF were considerably younger than those in the SEER-Medicare analysis, and the overall clinical risk of CHF was much closer to the one percent figure that is commonly described by oncologists to patients, although asymptomatic drops in ejection fractions were much more common in patients receiving “E” (see Figure 1.1). Another paper, by Dr Michele Halyard from an NCCTG adjuvant study, confirmed the apparent cardiac safety of using trastuzumab concurrently with radiation therapy to the breast and chest wall.
ASCO breast cancer program co-chair Cliff Hudis invited his colleague from Memorial Sloan-Kettering, cardiologist Dr Richard Steingart, to discuss these provocative papers. Dr Steingart had some unexpected and highly relevant thoughts, including the observation that “garden variety” CHF is usually a function of diastolic afterload related to hypertension, and therefore the ejection fraction is as likely to be normal as it is to be decreased. The bottom line is that there is much more to heart failure than measuring ejection fractions, and I, for one, walked out of this session deeply concerned that our previous sense of reassurance about the modest frequency of this toxicity may be seriously in error.
Dr Steingart’s comments, and the heightened awareness of the threat of treatment-related cardiac toxicity, highlight the potential clinical importance of several nonanthracycline-based chemotherapy regimens, including three discussed by Dr Gralow that might be particularly appropriate for older patients with cardiovascular risk factors:
1. A taxane alone
CALGB-40101 is currently comparing four or six cycles of dose-dense paclitaxel to the same schedules of dose-dense AC. Of great interest is the lack of a nondose-dense control arm. In fact, all four arms seem somewhat experimental. The cardiologists are rooting for the taxanes to be equally or more effective at reducing recurrence, but no data are yet available.2. Capecitabine
CALGB-49907 under the direction of Dr Hyman Muss is restricted to patients over age 65. This landmark study randomizes between dealer’s choice AC/CMF or capecitabine. Save your myocardium and hair, and lose the IV. Again, no data are available.3. TC (docetaxel/cyclophosphamide)
As discussed at length in the last issue of this series by principal investigator Dr Stephen Jones, a US Oncology trial he presented at the last San Antonio meeting demonstrated that TC resulted not only in a third fewer relapses than AC but also less toxicity. This is all the more interesting in that Steve, Sid Salmon and a few other colleagues essentially invented AC, and it took three decades of clinical research to find something that might be better.
During my discussion with Dr Dresdner, he mentioned that he has used adjuvant TC about a half dozen times in his practice, mostly for patients with prior cardiac events. After the sobering experience he had with his dose-dense patient, regimens like TC might be much more appealing for the large group of patients with diabetes, hypertension and other coexisting conditions.
Medical oncologists now wear many hats as they attempt to manage the side effects associated with new therapies. Aside from moonlighting as dermatologists charged with controlling rash induced by EGFR inhibitors and other cutaneously deforming agents, oncologists have been forced by these important ASCO data on anthracyclines, and the recent explosion of pressing cardiologic concerns in trials of adjuvant trastuzumab as discussed on this program by Dr Edith Perez, to add cardiology to their long list of clinical skills.
That’s why it is so helpful to have our CME pulse on docs in practice. For example, in a premeeting telephone conference for our most recent MTP extravaganza, Dr Dresdner told me not only about his fascinating pulmonary edema nightmare but also of a 68-year-old man with breast cancer, with very symptomatic widespread bone metastases and a clear-cut response to fulvestrant. During the MTP recording session, Dr Gralow mentioned a similar case in her practice, and right then and there we had ourselves the beginning of a potentially important case series. (Send in your successes and failures with endocrine therapy of men with breast cancer, and put your rare male patients with mets on SWOG study S0511 evaluating the combination of goserelin and anastrozole.)
The other three community docs featured on this program are Dr Bill Harwin, my former U of Miami colleague who now leads a group of 40-plus medical oncologists in Southwest Florida, Dr Atif Hussein, director of the cancer program at Hollywood Memorial Hospital, and Dr Dennis Lowenthal, one of the many non-Floridians who jet down to South Florida to stump the professors. Dr Lowenthal is from “Joyzee.”
Recently, Bill and Atif bravely volunteered for a superintense “mini-MTP” (three or four community docs and three faculty members) on renal cell cancer, a disease that used to be simple in that we didn’t have a whole lot to offer and now suddenly seems complicated and highly interesting with maybe a unique susceptibility to anti-angiogenic therapy, whatever that is.
At the end of this session with a brilliant trio of renal investigators (Drs Ronald Bukowski, Nicholas Vogelzang and Janice Dutcher), Bill, Atif, Charles Henderson of Atlanta, Bill’s colleague in progress Lowell Hart, and I were slack-jawed at how much great new stuff we had heard that afternoon.
The enthusiastic response our CME group has received to case-based sessions encouraged us to bring a bit of this into our Update series. For the last couple of years, we have used Breast Cancer Update’s third audio CD to do some “Phase I-II” educational experimentation, and on this program we have included the edited proceedings of an “eat and learn” luncheon that took place at the 2006 Miami Breast Cancer Conference.
For this unique event, we adapted the Meet The Professors format and invited Bill, Atif and Dennis to present vexing cases from their practices that fit within the meeting’s theme of Monoclonal Antibody Therapy for Breast Cancer, a title that would have seemed like science fiction 10 years ago. The discussion was recorded in front of about 800 starving surgeons and med oncs who swallowed lasagna and choice content in large and sometimes audible gulps and dish clacks on the audio track.
Our faculty members Drs Joyce O’Shaughnessy, George Sledge and Eric Winer discuss what we do and don’t know about monoclonal antibody therapy of breast cancer, not only that mysterious chameleon, bev, but also trastuzumab as adjuvant treatment of women with HER2-positive tumors.
Dr Lowenthal began the program by describing a 46-year-old woman with a triple-negative tumor that recurred in the chest wall and mediastinum less than three years after completing six cycles of adjuvant CAF.
Unable to obtain bevacizumab from the patient’s insurer, Dr Lowenthal started paclitaxel alone, but after less than two months, the disease was progressing rapidly. At the time of the luncheon, the patient had just begun docetaxel, capecitabine and bevacizumab — a creative and perhaps controversial decision — but, on the other hand, this patient’s situation was immediately life-threatening.
Dr Harwin then presented another vexing metastatic case that demonstrates the many and varied communication skills required in medical oncology community practice. The patient is a 51-year-old woman Bill treated with bevacizumab and paclitaxel about 10 days after Kathy Miller presented the E2100 data on this regimen at ASCO in May 2005. The patient had extensive bulky liver metastases but experienced a dramatic tumor response to treatment.
At that point, the big bad world of reimbursement reared its unattractive head. Specifically, after paying the first tab, the patient’s insurance company suddenly realized they were swallowing some serious charges and began questioning the use of bevacizumab.
Bill effectively described to these very interested bean counters the dramatic improvements in the patient’s well-being and the rapid reduction in size of multiple 6- to 7-cm hepatic lesions seen on CT scan, and the payer became silent. Of some amusement was that when the insurer asked to be sent the ASCO abstract discussing the E2100 trial, Bill had nothing to send because the presentation was a late, late, late breaker that was abstract-free.
To further challenge the faculty, the Miami luncheon then switched over to the very gratifying issue of adjuvant systemic therapy for patients with HER2-positive tumors. Dr Hussein presented a 44-year-old patient with a subcentimeter (0.8 centimeter) node-negative tumor that was ER-positive, PR-positive and HER2-positive.
Triple-positive, node-negative breast cancer is not uncommon and is perhaps the most controversial patient phenotype in the current management of early breast cancer. The cool thing about Atif ’s case is that the patient actually participated in BCIRG trial 006, which allowed for the inclusion of tiny node-negative tumors because Dennis Slamon believes in biology.
This woman was randomly assigned to receive the supposedly noncardiotoxic TCH (docetaxel/carboplatin/trastuzumab) regimen but had her trastuzumab held briefly for a minor drop in ejection fraction that then returned to normal and stayed there.
Bill presented a 33-year-old mom with another “triple-positive,” node-negative tumor. The tumor size (1.7 centimeters) made chemotherapy and trastuzumab a given, but what had the satiated Miami crowd talking among themselves as they limped back into the afternoon session was the potential for new endocrine treatment options for this patient subset.
And so it goes. Sincere thanks to Atif, Bill, David, Dennis and the many other highly informed and thoughtful people in practice who keep CME people like me honest and set a superior standard of patient care for fellows in training to emulate.
— Neil Love, MD
NLove@ResearchToPractice.net
August 18, 2006
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