Adjuvant TCH or AC-TH – pro

Recent evidence has put TCH on par with other standard adjuvant regimens. Previously two independent phase II studies have shown that this combination of carboplatin and docetaxel (Taxotere®; Aventis Pharmaceuticals, Inc.; Bridgewater, NJ) is active in the first-line treatment of metastatic breast cancer. Based on these promising results of combining trastuzumab with chemotherapy, nonanthracycline alternatives were investigated, with many of them incorporating platinum agents. The Breast Cancer International Research Group (BCIRG) conducted two pilot phase II trials of patients with advanced breast cancer overexpressing or with amplified HER2, in which trastuzumab was administered in combination with carboplatin/docetaxel or cisplatin/docetaxel.
The benefit of adding carboplatin to paclitaxel and trastuzumab in the first-line treatment of HER2-overexpressing metastatic breast cancer was further shown in results from an ongoing phase III study.

In the Herceptin Adjuvant (HERA) trial, the addition of one-year trastuzumab following (neo)adjuvant chemotherapy with AC was superior to observation after chemotherapy in terms of disease-free survival (DFS) (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.43 to 0.67), recurrence-free survival (HR 0.50, 95% CI 0.40 to 0.63), and distant-disease-free survival (HR 0.40, 95% CI 0.40 to 0.66).
In a combined analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial and the North Central Cancer Treatment Group (NCCTG) N9831 trial, the addition of one-year trastuzumab concurrent with adjuvant paclitaxel following adjuvant doxorubicin and cyclophosphamide was superior to no trastuzumab in terms of disease-free survival (HR 0.48, p-value 3×10-12), time-to-first-distant-recurrence (TTR) (HR 0.47, p-value 8×10-10), and overall survival (OS) (HR 0.67, p-value 0.015).

In terms of using TCH regimen rather than AC+ paclitaxel/Herceptin, the NCCN does lsit it as an option, although it lists AC+T/Herceptin as the preferred option. There is a trial supporting its use, BCIRG 006. As with the other trials comparing chemotherapy alone vs chemotherapy plus trastuzumab, the addition of trastuzumab to AC T chemotherapy reduced the risk of disease recurrence by nearly 50% (hazard ratio 0.46, P < .01). The TCH triplet arm, which included trastuzumab, also led to better outcomes than chemotherapy alone (hazard ratio 0.61, P < .01). The comparison of the 2 trastuzumab-containing arms was underpowered, owing to the few events in each arm. However, as of the available follow-up, there is the suggestion that the risk of recurrence was lower in the AC TH arm than in the TCH arm.

An October 6, 2012 study in The New England Journal of Medicine included 3,222 women in three groups. One received Adriamycin (doxorubicin) and Cytoxan (cyclophosphamide) followed by Taxotere (docetaxel) (AC-T). One received AC-T plus 52 weeks of Herceptin (AC-T plus H). The last received Taxotere, Paraplatin (carbobplatin) and 52 weeks of Herceptin (TCH).

In terms of effectiveness, the AC-T plus H and TCH groups had similar disease-free and overall survival rates, and both were superior to the group that did not receive Herceptin.

In terms of side-effects, the AC-T plus H group experienced “significantly higher” rates of congestive heart failure and cardiac dysfunction than the TCH group. There were seven cases of leukemia in the AC-T plus H group and one in the TCH group.

The authors concluded that the addition of one year of Herceptin significantly improved disease-free and overall survival. The risk-benefit ratio favored the TCH combination over AC-T plus H, “given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia.” Subsequent editorial, leters and discussions in trhow away journals presented arguments for and against this conculsion.

Hayes DF. Steady progress against HER2-positive breast cancer.N Engl J Med. 2011 Oct 6;365(14):1336-8.

Edith A. Perez Carboplatin in Combination Therapy for Metastatic Breast Cancer The Oncologist, Vol. 9, No. 5, 518-527, September 2004; Trudeau M, Madarnas Y, McCready D, Pritchard KI, Messersmith H, Breast Cancer Disease Site Group. The role of trastuzumab in adjuvant and neoadjuvant therapy in women with HER2/neu-overexpressing breast cancer: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2006 May 12. 28 p. (Evidence-based series; no. 1-24). [58 references]

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. Breast Cancer Res Treat. 2005;94(suppl 1):S5. Abstract 1.

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