By Douglas Steinberg, PhD

Doctors told Meleia Schwerdtfeger she had fibrocystic breasts, so the Waverly, Tennessee, resident ignored the occasional lumps that would appear and disappear in her chest. Two years ago, however, her husband noticed a particularly large, hard knot in her right breast, and Schwerdtfeger, then 44 years old, promptly called her gynecologist. Mammography, ultrasound, and a biopsy soon brought a terrible diagnosis: an invasive ductal carcinoma that had spread to some lymph nodes. Fortunately, further testing showed that she didn’t have distant metastasis. he tumor’s 5-centimeter span and its pattern of local spread—four out of 26 nearby nodes ultimately tested positive—meant that Schwerdtfeger had stage III breast cancer. After undergoing a grueling course of treatment, Schwerdtfeger remains free of disease almost two years after her diagnosis.

Maggie San Miguel of Austin, Texas, was diagnosed with stage III breast cancer in June 2002 with what her doctor told her was a tumor the size of a doorknob.

“After chemotherapy, I had a mastectomy followed by radiation,” she says. “But the strangest thing happened after my first chemo treatment—the tumor shrank from 10 centimeters to 5 centimeters.” Today, San Miguel is cancer-free and, along with enjoying yoga and biking, she is starting a local nonprofit organization called Bald Mama Society.

San Miguel and Schwerdtfeger happily exemplify a trend that physicians say has become particularly striking over the past 20 years: Multimodality treatment, combining chemotherapy, surgery, and radiation, is saving the lives of many patients with more advanced breast cancer.

Schwerdtfeger recalls an early conversation with her oncologist, Denise A. Yardley, MD, of the Sarah Cannon Cancer Center, Nashville. “I asked my family to leave, and I said, ‘I have one question: ‘Can you get this? I mean, am I looking at something impossible?’ And Dr. Yardley said, ‘It’s treatable.’ I said, ‘That’s all I want to know. Let’s start right now and just get on with it.’”
Her preoperative (neoadjuvant) chemotherapy, surgery, postoperative (adjuvant) chemotherapy, and finally radiation therapy all involved side effects, some serious. “I went through some really, really hard times,” Schwerdtfeger remembers. But she is counting on a substantial payoff for her ordeal—prevention or, at least, delayed recurrence of the disease. A token of her hope is the vacation home that she and her husband, who jointly run a mini-warehouse business, are now building. An even greater motivation for a bright future, she says, is her first grandson, born in June 2003.

One Stage, Many Diagnoses
Stage III encompasses a heterogeneous mix of breast tumors. The American Joint Committee on Cancer (AJCC), based in Chicago, periodically updates staging criteria to correspond to clinical and scientific advances. AJCC now divides stage III into substages A, B, and C based on tumor size and the number of lymph nodes involved (see box, page 12). Within each substage are further variations, so ask your physician to explain your stage. Certain large stage III tumors are often referred to as “locally advanced breast cancer.” Inflammatory breast cancer is also considered a stage III diagnosis.

The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program tracks breast cancer incidence. Its data suggest that stage III tumors are becoming less common, relative to earlier-stage disease. Oncologists say that a big spike in survival occurred when combination therapy—combining surgery, chemotherapy, and radiation—came into vogue about 20 years ago. Since then, there has been “an increasing realization that patients with locally advanced disease appear to do better if they are treated with all three modalities in some sequence,” says Antonio C. Wolff, MD, Johns Hopkins Kimmel Comprehensive Cancer Center, Baltimore.

Dr. Wolff cautions, however, that the best kind of clinical trial—large and with subjects randomly assigned to treatments—has yet to prove that three-modality therapy benefits stage III patients more than one- or two-modality therapy, so researchers are often forced to compare newer treatments with historical data. One difficulty with mounting such a study is that stage III patients are increasingly hard to find.

Chemotherapy Cocktails
Stage III patients routinely receive chemotherapy after surgery (adjuvant therapy) in an effort to destroy any micrometastases and invisible tumor remnants in the body.

The most commonly prescribed drugs include Cytoxan® (cyclophosphamide), methotrexate, 5-FU (fluorouracil), and the anthracyclines, Adriamycin® (doxorubicin) and Ellence® (epirubicin), given in combinations known as CMF, AC, FAC, or FEC.

In the past decade these drugs have received a boost from new drugs called taxanes, Taxol® (paclitaxel) and Taxotere® (docetaxel), which, when added in combination or sequenced with the older drugs, are seen as providing more efficacy. Another new drug Gemzar® (gemcitabine) is also being tested. All these compounds interfere in some way with DNA replication or cell division. Researchers determine the best combinations based on what has been shown to be effective against more advanced breast cancer.

“We start by looking at what is working with metastatic disease and extrapolate that the same therapy will be effective for patients with earlier-stage disease,” says William J. Gradishar, MD, Northwestern University’s Feinberg School of Medicine, Chicago. “The next step is to look at whether it would be useful in the neoadjuvant setting.”

Depending on the type of drug, dosage, and length of treatment, most chemotherapy drugs result in some temporary side effects, including fatigue, nausea, vomiting, hair loss, and mouth sores. Changes in the menstrual cycle may be temporary or permanent depending on the woman’s age. Other possible long-term effects, such as chemobrain or cognitive dysfunction (see CURE, Spring 2002), are being studied.

“There’s a variety of different recipes of chemotherapy drugs that are viewed as acceptable,” says Dr. Gradishar. “There isn’t one that’s the best for all situations.” But he cites a couple of considerations that might influence the choice of one chemotherapy cocktail over another: an oncologist’s “comfort level with certain regimens,” or the drugs’ toxicities.

Currently, varying combinations of these and other new drugs are being tested in clinical trials to determine best dosage, sequences, combinations, and delivery. A study presented in 2002 indicates that “dose-dense” treatment, which involves giving chemotherapy on a more condensed schedule, may increase both disease-free survival and overall survival. Studies to confirm these findings are still under way.

Treatment Options
Physicians increasingly are opting for neoadjuvant chemotherapy (before surgery) in patients with stage III disease.

“The first thing we try to decide is whether the patient is operable,” says Dr. Gradishar. “Aside from patients who have locally advanced breast cancer, which can be inflammatory cancer or unresectable based on attachment to underlying structures or ulcerating, there is another category of patients that are operable and may be able to have breast-conserving surgery if the tumor size is reduced. If we evaluate such a patient, neoadjuvant therapy will be utilized to reduce the size of the tumor.”

Besides shrinking the tumor so it can be removed and possibly offering the option of breast-conserving surgery (lumpectomy), neoadjuvant chemotherapy also shows physicians how the cancer will respond to a particular set of chemotherapeutic drugs. If the tumor does not respond as much as desired, other available chemotherapy drugs may be substituted after surgery. So far, however, there is no strong evidence that neoadjuvant chemotherapy will extend survival.

Ongoing clinical trials of multiple regimens of drugs continue to explore new drug combinations for both neoadjuvant and adjuvant chemotherapy in stage III breast cancer.

Schwerdtfeger had operable breast cancer, but chose chemotherapy both before and after her mastectomy. Her oncologist, Dr. Yardley, argues that doctors and patients should always consider neoadjuvant treatment.
“Someone with locally advanced breast cancer has significant disease, either by virtue of a big breast mass or lots of disease in lymph nodes—or both,” Dr. Yardley contends. “That is a big indicator that disease has gone somewhere else in the body—lung, liver, bone, brain. The whole rationale for neoadjuvant chemotherapy is to get a jump-start on giving a patient a treatment that goes everywhere.”

From the late 1980s through the ’90s, the Pittsburgh-based National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted a study of 1,523 patients with operable (not only stage III) breast cancer. Five-year survival rates were essentially the same whether chemotherapy was administered before or after surgery. Another NSABP study of 2,411 patients with operable breast cancer is now comparing two neoadjuvant regimens to chemotherapy that is given both before and after surgery. Preliminary data from this study suggest that a particular neoadjuvant regimen—four cycles of Adriamycin/Cytoxan followed by four cycles of Taxotere—leads to a higher rate of pathological complete response, a situation where there is no evidence of cancer in the specimen.

Meanwhile, another concern about neoadjuvant chemotherapy is raised. When it is used, doctors “don’t really know what there was beforehand because chemotherapy has the virtue, if it works properly, to destroy disease,” observes Abram Recht, MD, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston. “That makes it hard to actually figure out what patients’ risk of developing a recurrence is.”

In other words, he continues, “if you’re talking about individuals who have surgery first, then we have reasonable information suggesting how they’ll do. If you have individuals who have chemotherapy first, then it’s much more up in the air.”

Hormone Therapy
Another approach to treating breast cancer lies in the hormone estrogen, which can latch on to receptor molecules studding the surfaces of certain breast cancer cells. The estrogen-bound receptor ultimately stimulates the cells to multiply, leading to tumor growth. Hormone therapy blocks this process.
“Hormone therapy does not itself kill tumor cells like chemotherapy, which can kill cancer cells,” explains Charles L. Vogel, MD, Cancer Research Network, Plantation, Florida. “Instead, tumor growth is slowed and the body’s own mechanism—something called apoptosis, or programmed cell death—takes over and leads to destruction of the tumor.”

Hormone therapy can succeed only if a tumor displays estrogen receptors. Sometimes the level of such receptors is too low for detection. If a test for the presence of progesterone receptors then turns out to be positive, that means there are still enough estrogen receptors to justify hormone therapy, says Hyman B. Muss, MD, University of Vermont College of Medicine, Burlington.
By starving malignant cells of estrogen and halting their growth, hormone therapy can actually cause tumor regression. Hormone therapy drugs usually prescribed for stage III breast cancer are the estrogen blocker Nolvadex® (tamoxifen), approved by the FDA in 1977, and the newer aromatase inhibitors, which shut down the production of female hormones estrogen and progesterone in postmenopausal women.

Tamoxifen is a synthetic anti-estrogen that usurps the place of the real hormone without spurring tumor growth. Aromatase inhibitors prevent the body from converting testosterone (which women produce) into estrogen. Common aromatase inhibitors include Arimidex® (anastrozole), Femara® (letrozole), and Aromasin® (exemestane).

Studies suggest that aromatase inhibitors (see CURE, Spring 2003) are more effective than tamoxifen. Yet they can worsen osteoporosis and lead to a higher incidence of joint pain. Tamoxifen, for its part, slightly increases the risk of early-stage endometrial cancer and deep-vein thrombosis; hot flashes, cataracts, and mood swings are its other potential side effects.

For premenopausal patients, suppressing ovarian function (ovarian ablation) removes a major source of estrogen. Dr. Vogel says ablation is accomplished either by surgical removal of the ovaries; by radiation, which is seldom done today; or by pharmaceutically shutting off the ovaries (see CURE, Spring 2003) with injectable drugs like Lupron® (leuprolide) or Zoladex® (goserelin).
Europeans, he notes, tend to favor combining ovarian ablation with tamoxifen, while Americans are more skeptical about current data supporting such a treatment. Large-scale clinical trials are under way.

Another unsettled question concerns the duration of hormone therapy. Patients typically receive tamoxifen for five years after they have undergone surgery and chemotherapy. Controversy exists over evidence indicating that more than five years of tamoxifen treatment could actually stimulate tumor growth.
For frail, older patients, hormone therapy isn’t merely an adjunct to other treatments. “It might be a preferred treatment because someone picked out of a nursing home at 82 is generally not going to tolerate chemotherapy very well,” observes Dr. Muss. Administered by itself, he adds, “hormone therapy may do very well for long periods of time.”

Radiation Therapy
Before the advent of chemotherapy, doctors relied on radiation to shrink tumors preoperatively. But such treatment can nudge up the risks of certain postoperative complications. Wound healing, for example, can be impaired.
Far more common today is radiation therapy after breast-conserving surgery. The goal is to rid a broad swath of the chest, including the skin, of any malignant cells that surgery might have left behind—to inflict a postsurgical blow against tumor remnants, so to speak. Questions arise, however, over using radiation after mastectomy, which theoretically should leave little tissue in which local recurrence of a tumor could take root.

“I think everybody agrees that postmastectomy radiotherapy [PMRT] improves the overall outcome,” Dr. Recht says. But consensus breaks down, he adds, when doctors weigh the procedure’s costs and benefits for specific subgroups of patients. He recommends PMRT for stage III patients with four or more cancer-positive lymph nodes or with tumors larger than 5 centimeters.
Statistics from future studies should ultimately clarify which other patient subgroups could benefit from PMRT.

The Patient Perspective
Meanwhile, Kristina Chip, a nine-year survivor of stage III breast cancer, advises individuals with breast cancer not to obsess about numbers derived from clinical studies.

Chip, now 32 and a resident of East Lansing, Michigan, had a 9-centimeter tumor and underwent a mastectomy and chemotherapy.

“I had a quote of a 40% chance of survival for five years and 25% for 10 years,” she recalls. “Now did I live by those statistics? No. Did I let them influence the way I battled the disease? No.” Chip says she persisted by relying instead on the principle, “With a positive attitude and hope, you can conquer anything.”