CHICAGO – Negative results of two adjuvant therapy studies reported at an oral session at the ASCO Annual Meeting here suggest that a plateau has been reached with cytotoxic agents for early stage breast cancer and that research should be redirected to studying novel agents and refining technologies for selecting which patients can derive benefit from chemotherapy in this setting.
Both trials found that adding another cytotoxic agent to a standard regimen failed to improve outcomes.
In the NCI-sponsored CALGB/CTSU 49907 trial, capecitabine was associated with a lower survival rate and more serious adverse events compared with standard cytotoxic chemotherapy for early stage breast cancer.
This study, presented by the lead investigator, Hyman B. Muss, MD, Professor of Medicine at the University of Vermont, focused exclusively on women age 65 and older. The results were disappointing, because capecitabine, an oral drug, is easier to administer than infusional cytotoxic chemotherapy and is a good choice for patients with poor access to cancer clinics where intravenous chemotherapy is delivered. Another potential advantage of capecitabine in elderly patients is its purported “gentler” side effect profile.
Dr. Muss was also awarded this year's ASCO B.J. Kennedy Award for Scientific Excellence in Geriatric Oncology, titling his award lecture, “Older Women with Breast Cancer; the Silent Majority.”
The average age at diagnosis of breast cancer in the patients in the study was 64, and two-thirds of women with breast cancer are older than age 65, yet this is one of the few trials to evaluate chemotherapy specifically in older women. “We thought it was important to study older patients, because few of them enter clinical trials,” Dr. Muss said. “Adjuvant chemotherapy improves the chances of cure, and we wanted to see if an oral chemotherapy agent would be as effective as intravenous chemotherapy in this older group of patients.”
In addition to NCI funding, the study received some support from Roche, the manufacturer of capecitabine.
In an unplanned subset analysis, the major benefit of standard therapy (CMF or AC) was observed in hormone receptor-negative patients, who made up about 30% of the study population. Women with hormone receptor-negative tumors on standard chemotherapy were about two times more likely to have relapse-free survival and about two times more likely to live compared with those treated with capecitabine.
“This interaction of treatment and hormone receptor status is from an unplanned subset analysis and is hypothesis-generating,” Dr. Muss said.
The study included 633 women age 65 and older with early breast cancer. Tumors were at least 1 cm. Patients had Stage T 1–4 disease, with up to three positive nodes and no metastatic disease. Patients with any hormone receptor status or HER-2 status were included.
Patients were randomized to receive either six cycles of standard doses of CMF or four cycles of standard doses of AC based on physician and patient decision or six cycles of capecitabine (14 days every three weeks for 6 cycles). Hormone receptor-positive patients (about 70% of all patients) were recommended for endocrine therapy after completion of chemotherapy.
At baseline, both groups of patients were well balanced for demographic factors; about 35% were between 65 and 69; 60% were age 70 to 79; and 5% were age 80 or older. Ninety-seven percent of patients had a Performance Status of 0–1; 80% were Caucasian; 11% were blacks.
Fewer patients in the CMF arm got the planned treatment: about 60% of CMF versus 80% of capecitabine. Hematologic adverse events were seen in about 50% of patients in the standard chemotherapy arm versus 3% of those treated with capecitabine.
Adverse events were reported in 69% of the CMF-treated group, 59% of the AC-treated group, and 34% of the capecitabine arm.
At a median follow-up of 24 months, the relapse-free survival rate (alive with no breast cancer) was 89% for standard chemotherapy and 80% for capecitabine.
Deaths occurred in 7% of patients treated with standard chemotherapy and 12% of those in the capecitabine arm. The number of breast cancer-related deaths were eight and 18, respectively, and two treatment-related deaths were reported in the capecitabine-treated group. “Patients in the capecitabine arm were 1.85 times more likely to die,” Dr. Muss said.
Unique Pill Cap
A unique feature of this trial was the incorporation of an adherence measure using a pill bottle with a cap that contained a computer chip that recorded each time the bottle was opened. Dr. Muss said that although this doesn't tell you how many pills the patients actually took, it does give a reasonable estimate of compliance. About 85% of patients on capecitabine took 80% or more of the prescribed doses.
“This study was a brave attempt to grasp the benefit of adjuvant chemotherapy for older women,” said the study's Discussant, John Crown, MD, of St. Vincent's Hospital in Ireland. “There is a dearth of data to inform the controversy of whether adjuvant chemotherapy is effective in older patients.”
Studies to date have been equivocal, Dr Crown said. A 1995 report found no benefit for adjuvant chemotherapy in women 70 and older, while a 2000 overview showed a trend toward benefit in this older age group. Dr. Muss' study was stratified for age groups, but the results in patients over age 70 have not yet been analyzed.
“Although the conclusion of the study was that CMF/AC is superior to capecitabine for relapse-free survival and overall survival, another conclusion could be that the data make it likely that adjuvant chemotherapy is beneficial in older patients. Although the results of the study are probably valid, it is possible that changing the dose and schedule of capecitabine could achieve better results,” Dr. Crown said.
In a separate interview, Ramona Swaby, MD, a medical oncologist specializing in breast cancer at Fox Chase Cancer Center, said she applauded Dr. Muss for his effort in targeting this special population. “Older women are not the bread and butter of clinical trials. The entire oncology community supports trials in special populations.”
Dr. Swaby also said that older patients should be treated according to biological age, not numerical age. If patients are in good general health, the probability is that they can derive benefit from the same treatments as younger patients.
Dr. Crown also pointed out that elderly people are younger-appearing and -acting than in years past, and that the biggest determinant of survival is health comorbidities.
“In older patients, we should base decisions on available data and clinical status,” he said. “Elderly patients should be enrolled in clinical trials.”
Gemcitabine Added to Standard Chemotherapy
An interim analysis of the tAnGo trial, presented at the same session, showed that adding gemcitabine to standard chemotherapy conferred no additional benefit over chemotherapy alone in patients with early-stage breast cancer treated with sequential paclitaxel-containing, epirubicin/cyclophosphamide chemotherapy.
Overall survival was identical between the two groups. The trial failed to confirm the hypothesis that adding another cytotoxic chemotherapy agent to sequential adjuvant chemotherapy would improve outcome.
“Adding gemcitabine at this dose and schedule conferred no additional benefit in disease free survival or overall survival,” stated the lead author, Christopher J. Poole, MD, of the University of Birmingham in the UK.
Patients enrolled in the trial had resectable breast cancer with clear margins. Any axillary lymph node status and hormone receptor status were allowed.
The large study included 3,152 patients recruited at 127 centers. More than 50% were younger than 50 at randomization, and 45% were premenopausal; 51% were estrogen receptor-positive (ER+), 36% had four or more positive lymph nodes, and 41% had one to four positive lymph nodes.
The groups were well balanced for tumor size, hormone receptor status, tumor grade, and other disease characteristics. Both regimens were tolerable, and toxicities were similar between the two arms.
‘The Last Tango’
This could be “the last tango” for large adjuvant trials in early breast cancer, Dr. Crown said during his discussion of this trial. “I was surprised that no advantage was seen for the addition of gemcitabine. Most likely the results of the trial are correct at this dose and schedule.”
Dr. Crown said that although there had been some negative studies of anthracyclines and taxanes, overall the data suggested incremental benefits for these agents as adjuvant therapy. However, he does not believe that the same large trial programs undertaken for anthracyclines and taxanes should be repeated for gemcitabine.
Dr. Swaby agreed with Dr. Crown: “The days of looking at standard cytotoxic chemotherapy agents in clinical trials are over. Now we are focusing on molecularly targeted agents. For example, several trials have shown the added benefit of combining bevacizumab with chemotherapy, and this is being evaluated in the adjuvant setting in currently accruing adjuvant clinical trials.
“Additionally, a recent trial by [Stephen] Jones et al showed docetaxel-cyclophosphamide to be a reasonable non-anthracycline approach, especially for older patients.”
Commenting on both Dr. Muss's and Dr. Poole's trials, Dr. Crown said: “The adjuvant movement is like the Titanic—lumbering and slow to change direction. It will have to adapt more quickly to changed circumstances like the molecular revolution.
“These trials close the chapter on adjuvant therapy with chemotherapy. We have more important things to address. We need to move away from large, multi-thousand patient adjuvant chemotherapy trials that look at nuanced differences between cytotoxic regimens and focus our efforts on new molecular agents.”