SAN ANTONIO — What should clinicians do when a patient with HER2-negative breast cancer undergoes neoadjuvant chemotherapy but, disappointingly, residual disease is found at surgery?
A new study from Japan provides a surprising answer: treat patients with even more chemotherapy.
The study showed that adding capecitabine (Xeloda, Roche) to adjuvant therapy such as tamoxifen extended disease-free and overall survival for women with HER2-negative breast cancer that was not fully eradicated by neoadjuvant chemotherapy and surgery.
The CREATE-X (Capecitabine for Residual Cancer as Adjuvant Therapy) trial involved 900 Korean and Japanese women with HER2-negative breast cancer who did not have a pathologic complete response (pCR) or who had node-positive disease despite having undergone neoadjuvant chemotherapy with an anthracycline and/or taxane followed by surgery.
The women were randomly assigned to standard adjuvant therapy with or without eight cycles of concurrent capecitabine. The 5-year rate of disease-free survival — the primary end point — was better for the patients treated with oral capecitabine than for the control patients who were not (74.1% vs 67.7%; hazard ratio [HR], 0.70, P = .00524), investigator Masakazu Toi, MD, PhD, from Kyoto University Hospital in Japan, reported.
And overall 5-year survival was also better in the capecitabine group than in the control group (89.2% vs 83.9%; HR,0.60, P < .01).
"The balance of benefit and toxicity would favor the use of capecitabine in the postneoadjuvant chemotherapy situation, but prediction for the therapeutic benefit needs to be investigated further," Dr Toi said here at the San Antonio Breast Cancer Symposium (SABCS) 2015.
Capecitabine is not currently used in the adjuvant setting in this patient population in the United States, said Virginia Kaklamani, MD, from the University of Texas Health Science Center San Antonio, who is a codirector of the meeting.
"I was very impressed and surprised with the outcomes because I don't think the majority of us thought that giving more chemotherapy would be beneficial," Dr Kaklamani told Medscape Medical News.
She called the results "a major, major finding," and explained that the improved overall survival is even more impressive because of the related convenience; capecitabine is a pill that allows patients to make office visits every 4 to 6 weeks.
However, the findings are unlikely to significantly alter clinical practice in the United States, she said. "In our society, 'do no harm' really is taken very seriously, and in most cases, we want bigger studies and more studies to change the standard of care," she pointed out.
But she also said there is also another "big limitation" — insurance companies.
"Because [capecitabine] is an oral medication, in many cases it's hard to get reimbursed for it, even in metastatic breast cancer patients, because they have co-pays and a lot of issues about which pharmacies they can get it from. So in the adjuvant setting, it may be pretty hard to get it covered," Dr Kaklamani noted.
However, Lajos Pusztai, MD, DPhil, chief of breast medical oncology at the Yale Cancer Center in New Haven, Connecticut, told Medscape Medical News that he thinks capecitabine "will change practice," but in a qualified way.
This study will influence the management of some patients with extensive residual disease," he explained.
Study Stopped Early for Efficacy
In CREATE-X, patients were stratified by estrogen receptor (ER) status, age, neoadjuvant chemotherapy type, nodal status, receipt of 5-fluorouracil, and treatment institution.
After pathology results were obtained, patients were randomized to either standard therapy — hormonal therapy for hormone-receptor-positive patients or observation with no systemic therapy for receptor-negative patients — or to standard therapy plus capecitabine 2500 mg/m² per day for days 1 through 14 of each 21-day cycle for eight cycles.
The trial was stopped after 2 years of follow-up, when a planned interim analysis showed that it had met its primary efficacy end point, with a 2-year rate of disease-free survival of 82.8% in the capecitabine group and of 74.0% in the control group.
Safety data from the study, reported at the 2013 SABCS, showed that neutropenia and diarrhea of grade 3 or greater were significantly more frequent in patients treated with capecitabine. In addition, the incidence of adverse events of any grade were higher in the capecitabine group than in the control group for leucopenia, neutropenia, anemia, thrombocytopenia, elevated liver enzymes, total bilirubin, anorexia, diarrhea, stomatitis, and fatigue.
In all studies we have performed, from German studies to international studies, we have found no additional benefit of capecitabine, said Michael Untch, MD, from the Helios Hospital Berlin-Buch in Germany, after the presentation.
He asked whether CREATE-X patients had received the optimal dose and optimal number of cycles of neoadjuvant chemotherapy, "because this is crucial."
Dr Toi replied that the investigators discussed this and agreed from the outset to choose what was, at the time, the standard chemotherapy using anthracyclines and taxanes.
Perennial SABCS commentator Steven Vogl, MD, a breast cancer specialist in private practice in New York City, said that he views the study as having two different populations: ER-positive patients and triple-negative patients.
He said he believes that triple-negative patients have a lot more to gain from capecitabine. Because having a pCR is more momentous for triple-negative patients than for ER-positive patients. "If a triple-negative patient doesn't achieve a pCR, they do very badly; 60% of them have relapsed within 5 years," he said.
"I put it to you that really what this tells us is that if we have a triple-negative patient who doesn't achieve pCR after good neoadjuvant therapy, [capecitabine] is probably a reasonable option, even though it's quite toxic, and should be explored further" Dr Vogl explained. "I'm not sure if I would go home and treat my ER-positive patients who don't get a pCR with capecitabine, based on this study."
The patients in the study seemed to tolerate capecitabine well, at a dose that was 500 mg/m² higher than that used in the United States, said Hope Rugo, MD, from the University of California, San Francisco.
She noted that given the data that Japanese patients appear to have a higher tolerance for capecitabine, there might be a pharmacogenomic effect at work.
The study was supported by a grant from Specified Nonprofit Corporation–Advanced Clinical Research Organization and other donations to the Japan Breast Cancer Research Group. Dr Toi reports receiving a research grant from the Chugai Pharmaceutical Company. Dr Kaklamani, Dr Pusztai, Dr Vogl, and Dr Rugo have disclosed no relevant financial relationships.
38th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S1-07. Presented December 8, 2015.