1. 1. The Magnitude of benefit. By Osama Elzaafarany Assistant Lecturer of Clinical Oncology Medical Research Institute - Alex. University Adding Trastuzumab to adjuvant chemotherapy in Breast cancer patients
2. 2. Hey Doctor, Is it worthy to receive Herceptin?
3. 3. Trastuzumab: Humanized Monoclonal antibody, against human epidermal growth factor receptor 2 (HER2). Mediates antibody-dependent cellular cytotoxicity against cells that over-express HER2, and lacks effect on cells not over-expressing HER2. Half-life: 6 days.Dosing: 4 mg/kg IV over 90 minutes, THEN 2 mg/kg IV over 30 minutes qWeek during chemotherapy for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel/carboplatin). Weekly
4. 4. Evidence Based Medicine +ve trials -ve trial NSABP-B31 / NCCTG BCRIG 006 FNCLCC-PACS-04 Chemo alone VS Chemo + Herceptin
5. 5. NSABP-B31: (NEGM, 2005)
6. 6. +ve LNs High-risk ve LNs
7. 7. The B-31 and NCCTG trials have been jointly analyzed using: merged control arms (chemo alone) VS merged arms using concurrent Taxol + Herceptin. There were 4045 patients included in the joint analysis. Median follow-up of 3.9 years.
8. 8. Addition of adjuvant Trastuzumab to chemotherapy has both significant DFS and OS benefit compared with chemotherapy alone. 48% reduction in the risk of recurrence (P > 0.001). 39% reduction in risk of death ( P = 0.001).
9. 9. Kaplan-Meier estimates of (A) event-free survival and (B) overall survival. Disease events include local, regional, or distant recurrence; contralateral breast cancer; second primary cancers; or death as a result of any cause. Overall survival is measured from the time of study enrollment to last contact or death. AC,doxorubicin and cyclophosphamide; H, trastuzumab; T, paclitaxel.
10. 10. Absolute differences in DFS increased by number of LNs metas; it was most pronounced for patients with 10 +ve LNs, who had an unprecedented 27% absolute improvement.
11. 11. Cardiac safety: The rate of symptomatic heart failure was: 0.5% with chemotherapy alone. 2.0% with AC followed by paclitaxel and trastuzumab. 86% of patients in the Trastuzumab arms had either complete or partial resolution of the cardiac event in follow-up. Risk factors for cardiac events: Patients 60 years old (P=0.003). Patients with prior or current use of antihypertensive medication (P= 0.005). Patients with LVEF near the LLN at registration (P =0.033).
12. 12. TC + Herceptin AC-T + Herceptin AC-T 81 %84 %75 %5-ys DFS 91 %92 %87 %OS The addition of 1 year of adjuvant Trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer.
13. 13. The survival benefit and the risk of congestive heart failure (CHF) associated with adjuvant trastuzumab plus chemotherapy can be estimated as follows: Benefit VS Side effects For patients with high risk HER2-positive breast cancer, trastuzumab is associated with an absolute risk reduction (ARR) of death of 13.3 % (mortality rate=36.7 VS 50 % in controls). The number of patients needed to treat (NNT) to save one life is 8. For patients with low risk disease, the ARR is 3.3 % (10 VS 6.7 %, respectively). The NNT is 31. For patients at high risk for CHF prior to trastuzumab treatment, the absolute risk increase (ARI) of CHF associated with trastuzumab is 21 % (26 VS 5 % in controls). The number of patients needed to harm (NNH) is 5. For patients at low risk for CHF, the ARI is 2.1 % (2.6 VS 0.5 %, respectively). The NNH in this group is 48.
14. 14. The recent treatment guideline recommend adjuvant chemotherapy plus HER2-directed treatment for: All women with HER2-positive, node-positive breast cancer. Women with HER2-positive, node-negative tumors >1 cm in size. Improvement in disease-free survival (DFS, hazard ratio [HR] for recurrence 0.60, 95% CI 0.50-0.71), regardless of trastuzumab treatment duration or the administration schedule (ie, concurrent with chemotherapy or sequentially following chemotherapy). Improvement in overall survival (OS, HR for mortality 0.66, 95% CI 0.57-0.77) TAKE HOME MESSAGE