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‘Soft’ chemotherapy delays breast cancer progression for elderly
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Adding metronomic oral cyclophosphamide, or “soft” chemotherapy, to trastuzumab plus pertuzumab increased median PFS among elderly patients with HER-2-positive metastatic breast cancer with an acceptable safety profile, according to study data published in The Lancet Oncology.
“We know that the chemotherapy agent docetaxel combined with trastuzumab [Herceptin, Genentech] and pertuzumab [Perjeta, Genentech] is effective in younger patients with HER-2-positive metastatic breast cancer, but docetaxel is ‘classical’ chemotherapy that can be significantly toxic and, thus, affect quality of life, especially [for] older women,” Hans Wildiers, MD, PhD, medical oncologist at University Hospital Leuven in Belgium, said in a press release. “Of course, quality of life is important for all patients, but it has special significance [among] the elderly, particularly when used for palliation. We, therefore, decided to study whether combining trastuzumab and pertuzumab with the ‘softer’ chemotherapy metronomic oral cyclophosphamide would be active and have less toxicity than when used with docetaxel, or whether we could even omit chemotherapy and only administer trastuzumab and pertuzumab in this age group.”
The researchers performed a multicenter, open-label, randomized phase 2 trial of 80 patients with HER-2-positive metastatic breast cancer. All patients were aged 70 years or older, or 60 years older with confirmed functional restrictions.
Wildiers and colleagues used an online randomization system to assign patients to receive either 50 mg per day of metronomic oral cyclophosphamide plus trastuzumab and pertuzumab (n = 41) or trastuzumab and pertuzumab alone (n = 39). Patients received a loading dose of 840 mg of pertuzumab followed by 420 mg every 3 weeks, and a loading dose of 8 mg/kg of trastuzumab followed by 6 mg/kg every 3 weeks.
PFS at 6 months served as the main endpoint.
The median age was 76.7 years. Seventy percent of patients had a potential frailty profile based on the geriatric screening G8 score. Those who experienced disease progression after treatment in either group were eligible for treatment with trastuzumab emtasine (Kladcyla, Genentech).
Estimated 6-month PFS was 46.2% (95% CI, 30.2-60.7) in the trastuzumab and pertuzumab group compared with 73.4% (95% CI, 56.6-84.6) in the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group (HR = 0.65; 95% CI, 0.37-1.12).
At a median follow-up of 20.7 months (interquartile range, 12.5-30.4), patients assigned metronomic oral cyclophosphamide demonstrated a significantly longer PFS of 12.7 months (95% CI, 6.7-24.8) compared with 5.6 months (95% CI, 3.6-16.8).
The most common grade 3 to grade 4 adverse events included hypertension (15% in the trastuzumab and pertuzumab group vs. 12% in the metronomic oral cyclophosphamide group), followed by diarrhea (10% vs. 12%), dyspnea (5% vs. 10%), fatigue (8% vs. 5%) and pain (5% vs. 5%). Four patients (10%) assigned to the metronomic oral cyclophosphamide group experienced thromboembolic events.
“These results were encouraging, [because] we found that with gentle therapy, we could delay tumor growth in a significant proportion of frail patients for long periods,” Wildiers said in the release. “Our study also indicates that trastuzumab plus pertuzumab and metronomic oral cyclophosphamide and trastuzumab-DM1 allow us to delay, or even avoid entirely, more toxic chemotherapy like docetaxel in these patients. In this age group, maintenance of quality of life and the avoidance of toxic side effects may be just as important as survival.”
Wildiers and colleagues are “to be congratulated on their demonstration of a framework for clinical trials in older, more frail patients with HER-2-positive metastatic breast cancer,” Charles E. Geyer, Jr., MD, associate director for clinical research at Massey Cancer Center at Virginia Commonwealth University, wrote in an accompanying editorial
“Clinical trials are a global perquisite for establishing new treatment standards, but eligibility criteria generally restrict participation to fit populations with minimal comorbidities,” Geyer wrote. “These criteria contribute to underrepresentation of older populations with functional limitations in most clinical trials. ... Treatment with dual antibodies plus oral cyclophosphamide should be evaluated further.” – by Andy Polhamus
Disclosures: Wildiers reports grants from Roche, as well as personal fees to his institution from Amgen, Celldex, Novartis, Pfizer, Puma and Roche. Please see the full study for all other authors’ relevant financial disclosures. Geyer reports personal fees from Heron Therapeutics and Myriad, as well as advisory and travel fees from AstraZeneca, Genentech and Macrogenics.
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