Disease Site Group Consensus
Question #1: Compared with Chemotherapy Alone, Does Trastuzumab in Combination with Chemotherapy Improve Clinically Meaningful Outcomes?
Two randomized trials (one phase III, one phase II) detected improved outcomes when trastuzumab was administered in combination with chemotherapy compared to chemotherapy alone. Specifically, Slamon et al detected improved overall response and time to progression (TTP) with first-line weekly trastuzumab and six cycles of three-weekly anthracycline-cyclophosphamide (doxorubicin at 60mg/m2 or epirubicin at 75mg/m2, cyclophosphamide at 600mg/m2) in anthracycline-naïve patients or paclitaxel (175mg/m2) in anthracycline-exposed patients. Although survival was statistically significantly better in the experimental arm as a whole, the difference in the subgroups (paclitaxel and anthracycline-cyclophosphamide) was not statistically significant. Extra et al detected improved overall response, TTP, and overall survival with the addition of weekly trastuzumab to docetaxel 100mg/m2 given every three weeks. Based on that randomized evidence, the Breast Cancer Disease Site Group (DSG) members felt it reasonable to recommend first-line trastuzumab in combination with either six cycles of three weekly paclitaxel (175mg/m2) or six cycles of three-weekly docetaxel (100mg/m2). In combination with trastuzumab, there was no data to suggest that one taxane is superior to the other in the first-line setting.
Among the 13 non-randomized trastuzumab and taxane combination trials, trastuzumab was always administered weekly in all but two. Schedule, dose, and duration of paclitaxel or docetaxel treatment varied greatly. Only two trials excluded women with prior therapy for metastatic disease. Many of the women in the 11 trials that permitted previous therapy for metastatic disease had received anthracycline or taxane regimens. Overall response rates in women receiving either taxane ranged from 49% to 69% where that outcome was reported. TTP ranged from 8.5 months to 12.4 months. Based on non-randomized evidence, the members agreed that weekly trastuzumab in combination with a taxane could be offered in the second-line or greater setting for women who have received chemotherapy previously for metastatic breast cancer. In combination with trastuzumab, there was no data to suggest that one taxane is superior to the other in the second-line or greater setting. Due to the lack of consistent evidence for one regimen, the members agreed that the dose, schedule, and duration of taxane should be individualized according to patient preference, local and institutional standard patterns of practice, and best clinical judgement.
Several trials have evaluated the efficacy of trastuzumab in combination with weekly vinorelbine at does of 25mg/m2 or 30mg/m2 until disease progression or unacceptable toxicity. Overall response rates for vinorelbine plus trastuzumab ranged from 52% to 86%, and TTP ranged from four months to 17 months. Based on this non-randomized evidence, the Breast Cancer DSG members felt it reasonable to offer trastuzumab in combination with vinorelbine, particularly for those women whose disease has progressed after previous therapy with anthracyclines and/or taxanes, either in the adjuvant or metastatic setting.
The Breast Cancer DSG members agreed that the evidence for trastuzumab in combination with gemcitabine, platinum salts, or liposomal pegylated doxorubicin is insufficient to recommend their use outside clinical trials at this time.
Question #2: Compared with Placebo or Observation, Does Single-Agent Trastuzumab Therapy Improve Clinically Meaningful Outcomes?
Among five non-randomized single-agent trastuzumab trials and one single-agent randomized trial of two trastuzumab doses, rates of overall response in the two first-line trials ranged from 19% to 28% and 12% to 26% in the four second- or greater-line trials. TTP was 3.5 months or 3.8 months depending on trastuzumab dose in one first-line trial. TTP in three second- or greater-line trials ranged from three to four months. Based on this evidence, the Breast Cancer DSG agreed that trastuzumab is effective as a single-agent for women with untreated metastatic breast cancer. Therefore, the use of single-agent trastuzumab, which is relatively non-toxic, could be an appropriate choice prior to initiating any type of chemotherapy, for those women who would like to avoid the side effects of chemotherapy (nausea and vomiting, alopecia and myelosuppression) for as long as possible. As there were no randomized trials identified comparing single-agent trastuzumab to chemotherapy, there is no way to judge the effect on overall survival.
The Breast Cancer DSG also agreed that the evidence suggests that trastuzumab has a unique mechanism of action, producing responses in women whose cancer has progressed following treatment with anthracyclines or taxanes, the most active chemotherapy agents in metastatic breast cancer. Therefore, the members offered the opinion that trastuzumab could be an appropriate second- or greater-line single-agent therapy for women who wish to avoid the side effects of further chemotherapy.
Question #3: What is The Best Way to Identify Women Who Will Benefit from Trastuzumab Therapy?
In general, among trials where subgroup analysis of the level of human epidermal growth factor receptor 2 (HER2)/neu overexpression was available, the most benefit was seen with an immunohistochemical (IHC) score of 3+ or fluorescence in situ hybridization (FISH) positivity. In the experience of the Breast Cancer DSG members, tumour samples scoring 2+ (weak membrane staining) by IHC testing should undergo FISH analysis and receive trastuzumab therapy if the FISH test is positive. Therefore, the Breast Cancer DSG members felt it reasonable to include a qualifying statement that trastuzumab combination therapy is appropriate for women whose tumours show IHC 3+ staining (i.e., moderate to strong membrane staining in at least 10% of tumour cells) or show HER2/neu gene amplification by FISH analysis (defined as HER2/CEP ratio ≥ 2).
Question #4: Adverse Events Associated with Trastuzumab
The risk of cardiotoxicity from trastuzumab in combination with anthracyclines led the Breast Cancer DSG members to conclude that this combination could not be recommended. Furthermore, women with significant pre-existing cardiac dysfunction should not receive trastuzumab therapy. Women receiving trastuzumab should undergo a thorough baseline cardiac assessment and continued monitoring for signs and symptoms of congestive heart failure during treatment.
In addition to cardiac events, hypersensitivity reactions, infusion reactions, exacerbation of chemotherapy-induced neutropenia, and pulmonary events leading to death have been infrequently or rarely reported with trastuzumab. While these events were not addressed in this systematic review, the Breast Cancer DSG believed that women should be monitored for hypersensitivity, infusion reactions, and neutropenia and treated accordingly.
Question #5: Trastuzumab Dose, Duration, and Schedule
While the two randomized trials that showed a benefit with combination therapy administered trastuzumab weekly, four non-randomized trials administered a loading dose of 8mg/kg followed by a three-weekly 6mg/kg maintenance dose. Pharmacokinetic and safety data suggest that the increased dose and reduced frequency of trastuzumab administration are feasible. The members of the Breast Cancer DSG agreed that until randomized controlled data are available to confirm the efficacy of three-weekly trastuzumab, weekly therapy should be considered standard. The members felt that it might be reasonable to switch to three-weekly maintenance trastuzumab (6mg/kg) at a later time in women who are finding weekly treatments difficult. In the members' experience, the decision to switch from weekly to three-weekly therapy should be based on concurrent chemotherapy scheduling and patient preference.
The two randomized trials that showed a benefit with combination therapy administered a loading dose of 4mg/kg followed by 2mg/kg weekly doses. There is little evidence to suggest that higher doses offer any added benefit. Therefore the DSG members agreed that a loading dose of 4mg/kg followed by weekly doses of 2mg/kg should be recommended.
There is little data available regarding trastuzumab therapy duration. There are no prospective data to suggest that continuing trastuzumab therapy beyond progression offers any benefit; thus, the Breast Cancer DSG members recommend trastuzumab therapy only until disease progression.
