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Recommendations for use of Trastuzumab (Herceptin®)

Statements of evidence

STATEMENTS LEVEL OF EVIDENCE17* TRIAL AND REFERENCE
In women with HER2-positive early breast cancer following surgery:  
Combination with chemotherapy
The addition of adjuvant trastuzumab to adjuvant chemotherapy improves disease-free and overall survival compared to adjuvant chemotherapy alone in women with node-positive or node-negative primary tumours larger than 1 cm II BCIRG 006;4
HERA;7
NCCTG-N9831;6
NSABP-B316
No trials have examined the benefit of adjuvant trastuzumab in women with node-negative primary tumours 1 cm or smaller    
Single-agent trastuzumab
There are no data regarding use of single-agent adjuvant trastuzumab without prior chemotherapy    
Combination with systemic therapies other than chemotherapy
There are no data from randomised trials about the use of adjuvant trastuzumab with non-chemotherapy systemic therapies in the absence of prior treatment with chemotherapy drugs.    
A non-randomised subgroup analysis of one randomised trial has shown no increased toxicity with adjuvant trastuzumab in patients receiving concurrent adjuvant radiotherapy after 1.5 years of follow-up III NCCTG-N983118
Optimal dose, schedule and duration of administration
Overall survival benefit has been demonstrated in studies that used trastuzumab for 1 year II HERA;7,8
NCCTG-N9831;6
NSABP-B316
An ongoing randomised trial is comparing adjuvant trastuzumab use for 1 year versus 2 years    

Relapse-free survival benefit has been shown in one small phase III study using trastuzumab for 9 weeks concurrently with vinorelbine or docetaxel
II FinHer5
Weekly (loading dose of 4 mg/kg then 2 mg/kg) and 3-weekly (loading dose of 8 mg/kg then 6 mg/kg) dosing is effective; no direct comparison of weekly and 3-weekly schedules is available II FinHer;5HERA;7NCCTG-N9831;6NSABP-B316
Randomised trials have used adjuvant trastuzumab concurrently and sequentially with chemotherapy II FinHer;5
HERA;7
NCCTG-N9831;
6 NSABP-B316
A randomised comparison of adjuvant trastuzumab sequential to, or concurrent with adjuvant chemotherapy is ongoing   NCCTG-N983119
In women with HER2-positive locally advanced or inflammatory breast cancer:
A phase II study suggests that use of trastuzumab with preoperative chemotherapy in locally advanced or inflammatory breast cancer is safe and feasible III Hurley20
In women with HER2-positive breast cancer undergoing preoperative chemotherapy:    
The use of trastuzumab following neoadjuvant chemotherapy and surgery shows improved progression-free survival in women with breast cancers that are 2–5 cm in size II HERA7
There is evidence from a small randomised phase III trial that adding concurrent trastuzumab to preoperative chemotherapy increases the proportion of women obtaining pathologic complete response (pCR) II Buzdar9
In women with HER2-positive metastatic breast cancer:
Combination with systemic therapies
Trastuzumab in combination with chemotherapy leads to superior response and improved progression-free survival and overall survival compared with chemotherapy alone II M77001;11
Slamon12
Trastuzumab combined with a taxane (either docetaxel or paclitaxel) shows superior efficacy compared to taxane monotherapy II M77001;11
Slamon12
There is conflicting evidence about the addition of carboplatin to the combination of trastuzumab with a taxane (docetaxel or paclitaxel) II BCIRG 007;13
Robert21
Trastuzumab with anastrozole in women with HER2-positive hormone dependent metastatic breast cancer leads to improved progression-free survival compared with anastrozole alone II TAnDEM22
Phase II trials have shown evidence of safety and efficacy of trastuzumab with other single-agent systemic chemotherapies (gemcitabine, vinorelbine) III Burstein;23,24
Jahanzeb;25
O’Shaughnessy;26
Papaldo27
Phase II trials are examining the safety and efficacy of trastuzumab with other targeted therapies (gefitinib, pertuzumab)   Moulder & Arteaga;28
Walshe29
Single-agent trastuzumab    
The role of first-line and subsequent line single-agent trastuzumab compared to standard systemic therapy has not been evaluated in randomised trials    
Data from phase II trials support the efficacy of single-agent, first-line and subsequent line trastuzumab therapy III Baselga30,31
Continued use of trastuzumab post-progression  
No randomised trials have addressed the continued use of trastuzumab alone or in combination with chemotherapy after progression of metastatic disease    
Optimal dose, schedule and duration of administration
There is no evidence that a higher weekly dose (loading dose of 8 mg/kg then 4 mg/kg) is superior to a lower weekly dose (loading dose of 4 mg/kg then 2 mg/kg) of trastuzumab II Vogel14,15
Phase III trials in metastatic disease using weekly dosing schedules have continued to disease progression in the absence of unacceptable toxicity II M77001;11 Slamon12
There is phase II and pharmacokinetic evidence that 3-weekly dosing (loading dose of 8 mg/kg then 6 mg/kg) gives therapeutic serum trastuzumab concentrations similar to weekly dosing once steady levels are reached and is effective and safe; however there is no direct comparison of weekly and 3-weekly dosing III Baselga31
Adverse events:
Trastuzumab with chemotherapy is associated with an increased incidence of cardiac dysfunction compared with chemotherapy alone. Long-term toxicity is unknown^ II FinHer;5 NCCTG-N9831;6NSABP-B316
Trastuzumab with chemotherapy containing an anthracycline is associated with clinically relevant cardiac dysfunction in a significant proportion of patients II M77001;11 Slamon12

* More detailed information regarding trial results and levels of evidence are provided in the document Trastuzumab for HER2-positive breast cancer: a systematic review which can be accessed via the NBCC** website www.nbcc.org.au ^ For more information about adverse events associated with adjuvant trastuzumab see page 14 of this guideline.

** In February 2008, National Breast Cancer Centre (NBCC), incorporating the Ovarian Cancer Program, changed its name to National Breast and Ovarian Cancer Centre (NBOCC). In July 2011, NBOCC amalgamated with Cancer Australia to form a single national agency, Cancer Australia, to provide leadership in cancer control and improve outcomes for Australians affected by cancer.

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