Trastuzumab/paclitaxel

Ruiz M, Salvador J, Bayo J, Lomas M, Moreno A, Valero M, Bemab6 R, Vicente D, Jimenez J, Lopez-Ladr6n A. Phase-n study of weekly schedule of trastuzumab, paclitaxel, and carboplatin followed by a week off every 28 days for HER2-I-metastatic breast cancer. Cancer Chemother Pharmacol 2008 62(6) 1085-90. 

A higher than expected incidence of CHF is also observed in patients treated with DOX and other cytotoxics (e.g., the taxane paclitaxel) or new generation targeted agents (e.g., the humanized anti-ErbB-2/neu monoclonal antibody trastuzumab) [3]. The cardiotoxic synergism of DOX with taxanes or... 

Trastuzumab is licensed for the treatment of early breast cancer that overexpresses human epidermal growth factor receptor-2 (HER2). It may be administered as monotherapy or in combination with, for example, paclitaxel, docetaxel (taxanes) or anastrozole (aromatase inhibitors). Since trastuzumab can cause cardiotoxicity, concomitant use with anthracyclines such as... 

Trastuzumab (Herceptin) [Antineeplastic/Monoover express the HERlIneu. protein breast CA adjuvant, w/ doxorubicin, cyclophosphamide, and paclitaxel if pt HER2/neu(+) Action MoAb binds human EGF receptor 2 protein HER2) mediates cellular cytotox Dose Per protocol, typical 2 mg/kg/IV/wk Caution [B, ] CV dysfxn, alla-gy/inf Rxns Contra Live vaccines Disp Inj SE Anemia, cardiomyopathy, nephrotic synd, pneumonitis Interactions t Risk of cardiac dysfxn W/ anthracycline, cyclophosphamide, doxorubicin, epirubicin EMS Cardiomyopathy, ventricular dysfxn and pulm tox have been reported monitor for Sxs of reduced cardiac Fxn OD Sxs unknown... 

Herceptin with cisplatin, doxorubicin or epirubicin plus cyclophosphamide, or paclitaxel. A comparison of serum levels of trastuzumab given in combination with various chemotherapeutic agents did not suggest the possibility of any pharmacokinetic interactions except in combination with paclitaxel. Although not statistically signihcant, mean serum trough concentrations of trastuzumab were consistently elevated, about 1.5-fold, when Herceptin was administered in combination with paclitaxel. However, trastuzumab and paclitaxel were used concurrently in clinical trials with positive outcome results. The concurrent administration of anthracyclines, cyclophosphamide, and trastuzumab increased the incidence and severity of cardiac dysfunction during clinical trials. 

For treatment of patients with metastatic breast cancer whose tumors overexpress the F1ER2 protein and who have received one or more chemotherapy regimens tor their metastatic disease trastuzumab in combination with paclitaxel is indicated for treatment of patients with metastatic breast cancer whose tumors overexpress E1ER2 protein and who have not received... 

Trastuzumab is indicated as a single agent for the treatment of patients whose breast cancer has an overexpression of the HER-2 protein and has been previously treated by standard chemotherapeutic regimen. Trastuzumab is administered in combination with paclitaxel in patients who have not been previously treated with chemotherapy and their tumors overexpress HER-2. The initial dose for trastuzumab is 4 mg/kg given as a 90-min infusion, and the weekly maintenance dose is 2 mg/kg administered as a 30-min infusion. Its half-life is 1.7 and 12 days when a dose of 10 and 500 mg is administered, and the volume of distribution is 44 ml/kg, which is serum volume on average. 

Carcinoma of breast (1) Adjuvant chemotherapy or tamoxifen after primary breast surgery Cyclophosphamide, doxorubicin, vincristine, methotrexate, fluorouracil, paclitaxel, mitoxantrone, prednisone, megestrol, androgens,1 aminoglutethimide, trastuzumab... 

P. Ghahramani. 2003. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel./. Clin. Oncol. 21 3965-3971. 

HER2-overexpressing breast cancer xenografts in vivo (243). Furthermore, trastuzumab enhanced the antitumor efficacy of multiple chemotherapeutic agents, including cisplatin, paclitaxel, and doxorubicin, in animal models (244-246). 

Following the results of these two pivotal studies, trastuzumab was approved by the FDA in 1998, the first mAh approved for solid tumor treatment. Its indicated use is in patients with metastatic breast cancer whose tumors overexpress HER2, either as a single agent for patients previously treated with chemotherapy or in combination with paclitaxel as first-line therapy. Thorough baseline cardiac assessment and extreme caution in patient with preexisting cardiac dysfunction is recommended. 

First-line treatment of her metastatic breast cancer should therefore incorporate the monoclonal antibody trastuzumab (Herceptin). NICE (2002b) have issued a technology appraisal on the use of trastuzumab in metastatic breast cancer which states that trastuzumab be used in combination with paclitaxel for women with tumours with excessive human epidermal growth factor receptor 2 (HER2) at levels of 3+ who have not had chemotherapy for metastatic breast cancer and for whom anthracycline treatment is inappropriate. ... 

Many clinicians now prefer to use docetaxel (licensed to be used in combination with trastuzumab for metastatic breast cancer) instead of paclitaxel as it is more convenient to administer (1 hour infusion for docetaxel instead of 3 hours for paclitaxel) and clinicians generally have more experience of using this agent in breast cancer therapy. The pivotal trial of this combination shows superiority of docetaxel and trastuzumab over docetaxel alone in terms of overall survival, response rate and time to disease progression with little additional toxicity (Marty etal., 2005). 

Cardiotoxicity Heart failure has been observed in patients receiving trastuzumab therapy alone or in combination with paclitaxel or docetaxel,... 

Docetaxel Etoposide Eluorouracil Gemcitabine Methotrexate Mitomycin Mitoxantrone Paclitaxel Pemetrexed Topotecan Trastuzumab Bevacizumab Bleomycin Busulfan... 

PACLITAXEL TRASTUZUMAB t risk of cardiotoxicity Possibly additive cardiac toxic effect Closely monitor clinically and by ECGs for cardiotoxicity... 

TRASTUZUMAB CYCLOPHOSPHAMIDE, DAUNORUBICIN, IDARUBICIN, PACLITAXEL t risk of cardiac toxicity Possibly additive cardiac toxic effect Monitor cardiac function closely-clinically and electrocardiographically. Avoid co-administration of trastuzumab with idarubicin except in clinical trials... 

Cardiotoxicity is a major concern with trastuzumab, particularly as it is often used in patients who are receiving or who have previously received anthracychne antibiotics (2). It occurs in 5% of patients given trastuzumab alone, in 13% of patients given trastuzumab with paclitaxel, and in 27% of patients given trastuzumab in combination with anthracyclines and cyclophosphamide (3). 

Seidman AD, Former MN, Esteva FJ, Tan L, Kaptain S, Bach A, Panageas KS, Arroyo C, Valero V, Currie V, Gilewski T, Theodoulou M, Moynahan ME, Moasser M, Sklarin N, Dickler M, D Andrea G, Cristofanilli M, Rivera E, Hortobagyi GN, Norton L, Hudis CA. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 2001 19(10) 2587-95. 

Trastuzumab also may cause infusion-related or hypersensitivity reactions (particularly with the first infusion). However, a more concerning possible side effect is cardiac dysfunction (including CHF). Although patients may develop cardiac dysfunction with trastuzumab alone, the incidence is significantly increased in patients who receive trastuzumab in combination with paclitaxel or in those patients with previous use of anthracyclines. 

Robert N, Leyland-Jones B, Asmar L, et al. Phase 111 comparative study of trastuzumab and paclitaxel with and without caraboplatin in patients with HER2/neu positive advanced breast cancer (Meeting abstract). San Antonio Breast Cancer Symposium 2002 A35. 

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