Herceptin - Trastuzumab in combinatie met anthracycline/docetaxel en of docetaxel - carboplatin geeft significant betere resultaten in ziektevrije periode bij borstkankerpatiënten met Her2-Neu positieve expressie, aldus fase III studie

12 december 2005: Bron: Clinical Care options en the 28th Annual San Antonio Breast Cancer Symposium

Herceptin - Trastuzumab samen met de chemo combinatie anthracycline/docetaxel en/of docetaxel/carboplatin geeft een hoog significante verbetering in de ziektevrije tijd van borstkankerpatiënten met Her2-Neu overexpressie. De bijwerkingen waren in alle drie de groepen nagenoeg gelijk. Wel was er verschil in hartklachten tussen de drie groepen maar deze lijken te voorkomen door een goede analyse vooraf en een goede begeleiding tijdens de kuur. In onderstaand artikel wordt dit uitgelegd maar we missen de kennis om dit ook in goed Nederlands te vertalen. Dus laten het zo in het Engels staan. Deze studie is de eerste die bewijst dat Herceptin in combinatie met een niet zo geheten taxane chemo (taxol bv.) een significante verbetering in resultaten geeft. Deze studie werd deze week gepresenteerd op het 28e jaarlijkse San Antonio Breast Cancer Symposium. Onderstaand artikel spreekt verder voor zich nemen we aan.

Interim data from BCIRG 006 show significant improvements in disease-free survival with anthracycline/docetaxel/trastuzumab and docetaxel/carboplatin/trastuzumab By Claire Sowerbutt December 09, 2005 Efficacy data from the first interim analysis of the 3-arm phase III BCIRG 006 trial, which compared anthracycline/docetaxel (AC-T) with anthracycline/docetaxel and 1 year of trastuzumab (AC-TH) with docetaxel/carboplatin and 1 year of trastuzumab (TCH), demonstrated that AC-TH and TCH were associated with significantly greater disease-free survival (DFS) in patients with HER2-positive breast cancer. The reported hazard ratios were 0.49 for AC-TH (P =.00000048) and 0.61 for TCH (P = .00015). There was no statistically significant difference in DFS between AC-TH and TCH. This study is the first to evaluate trastuzumab in combination with a nontaxane–containing chemotherapy regimen in the adjuvant setting.

The trial randomized 3222 women, approximately 30% with node-negative disease. At 23 months of follow-up, there had been 322 events and 84 deaths. While the data are not yet mature enough to assess overall survival, there is sufficient follow-up to assess cardiac toxicity and genetic influences on efficacy.

There was an approximate 2-fold increase in grade 3/4 congestive heart failure (defined as decline in cardiac left ventricular function ), arrhythmias, and myocardial infarction among patients treated with AC-TH, according to Dennis Slamon, MD, PhD, of the UCLA Jonsson Comprehensive Cancer Center, Los Angeles, California. “The interaction between and anthracycline seems to come to the fore here,” he said. The results showed a 0.95% incidence of cardiotoxicity in the AC-T arm compared with a 2.34% incidence in the AC-TH arm (P = .016 vs AC-TH). In the TCH arm, the incidence of cardiotoxicity was 1.33% (P = .1 vs AC-TH). “With respect to ischemia and myocardial infarction, the events were balanced. The incidence of clinically meaningful arrhythmias was not significantly different among the 3 treatment arms, although 5 events remain to be adjudicated,” Dr. Slamon said.

Importantly, 9% of patients in the AC-T arm, 17.3% in the AC-TH arm, and 8% in the TCH group experienced a > 10% decrease in LVEF. These differences were highly statistically significant (P = .002 for AC-T vs AC-TH; P < .0001 for TCH vs AC-TH). “The mantra we’ve all been told is that this is not a problem because patients get better. They recover quickly when they go off therapy,” Dr. Slamon said. “Certainly, their CHF gets better when they go on therapy, but that does not mean their heart disease is better,” he said.

Consequently, an analysis was done to evaluate the subclinical loss associated with declines in LVEF. The results for approximately 1000 patients per treatment arm showed a decrease in the mean for all patients. “With AC-T, we see a drop, and with AC-TH we see a significant drop, which does not return to baseline. This all revolves around an axis of approximately 4 points, which is taking all-comers” Dr. Slamon said. “So, 17% of patients have lost 10% of their heart function and about 3% had CHF. This phenomenon is real, and it is not short-term, despite what we’ve been told previously,” he explained. LVEF declines are more sustained with AC-T and AC-TH (> 550 days at last follow-up) than was previously thought.

Additionally, results from mapping of the HER2 amplicon (N = 2120) show that coamplification of the topoisomerase II alpha gene occurred in approximately 35% of HER2-positive patients and may confer a therapeutic benefit with respect to anthracycline-based/trastuzumab combination regimens. “Moreover, HER2-positive tumors that are not coamplified for topoisomerase II alpha—approximately 65%—do not appear to derive this same benefit and may be ideal candidates for nonanthracycline-containing, trastuzumab-based adjuvant regimens, thereby avoiding any potential cardiac toxicity,” Dr. Slamon said.

The overall incidence of grade 3/4 hematologic adverse events was similar among the 3 treatment arms, with more neutropenia and leukopenia in the anthracycline-containing arms and more anemia and thrombocytopenia in the TCH arm. “This is likely due to the effect of carboplatin on platelets,” Dr. Slamon said. Similarly, grade 3/4 nonhematologic toxicities were well balanced among the 3 treatment arms.

The BCIRG 006 slides are available to download here courtesy of Dennis Slamon, MD, PhD. For more information on BCIRG studies click here

Reference
Slamon D, Eiermann W, Robert N, et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC→T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Program and abstracts of the 28th Annual San Antonio Breast Cancer Symposium; December 8-11, 2005; San Antonio, Texas. Abstract 1

Her2-neu expressie, borstkanker, herceptin, trasatuzumab