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Trastuzumab in the adjuvant setting: Is concurrent treatment better than sequential?

Trastuzumab in the adjuvant setting: Is concurrent treatment better than sequential?

ABSTRACT: The question remains open, since the final analysis of the only head to head concurrent vs sequential trial has not yet been reported.

STOCKHOLM—Published data overwhelmingly support the use of trastuzumab (Herceptin) concurrently with chemotherapy, according to John Crown, MD, a consultant oncologist at St. Vincent’s Hospital in Dublin, Ireland. On the other hand, there is no evidence that sequential delivery is less effective than concurrent therapy, and it is definitely less toxic, commented Ian E. Smith, MD, head of the Breast Unit at Royal Marsden Hospital in London.

At ESMO 2008, Drs. Crown and Smith debated whether a concurrent or sequential regimen is the optimal delivery strategy for trastuzumab in HER2- positive breast cancer patients.

Evidence for concurrent therapy
The evidence for concurrent therapy comes from three major trials: NSABPB31 and the Intergroup NCCTG N9831 (joint analysis), the BCIRG 006 trial, and the FinHer trial, Dr. Crown said.

The joint analysis of the two U.S.-based trials, which evaluated doxorubicin/ cyclophosphamide followed by paclitaxel (AC→T) with or without trastuzumab, showed a staggering improvement in disease-free survival (DFS) at four years, with a highly significant hazard ratio (HR) of 0.48 with the addition of trastuzumab.

Similarly, in BCIRG 006, recurrences were significantly reduced with concurrent therapy. BCIRG 006 evaluated AC→T (docetaxel), AC→TH (trastuzumab), and a nonanthracycline regimen of docetaxel (Taxotere), carboplatin, and trastuzumab (TCH), based on laboratory findings of synergy among these agents.

AC→TH and TCH were both significantly better than the nontrastuzumab AC→T arm, reducing recurrences by 39% and 33%, and risk of death by 41% and 34%, respectively. TCH was associated with significantly less cardiotoxicity and may, therefore, be preferable, Dr. Crown said.

Finally, FinHer compared docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide (FEC) with vinorelbine followed by FEC, with or without a short course of trastuzumab (nine weekly cycles).

“Longer follow-up should tell us whether a briefer, less expensive trastuzumab regimen can be substituted for longer schedules,” Dr. Crown said.

The HERA study was positive for sequential trastuzumab, with HRs of 0.64 for DFS and 0.66 for OS, but HERA has problems, according to Dr. Crown.

HERA randomized patients to trastuzumab or observation after treatment with any chemotherapy regimen, which for 68% of patients lacked a taxane and for 6% lacked an anthracycline. Many, therefore, received obsolete chemotherapy that failed to take advantage of the possible synergy between taxanes and trastuzumab, he said.

The only truly negative trastuzumab study to date was the PACS-04 trial, which compared a regimen with docetaxel (E75, D75) to one without (FE100C), followed by one year of trastuzumab or observation. Th e outcome was sobering: Four-year DFS was similar between the arms (73%). “While I favor concurrent therapy, I would have predicted that sequential trastuzumab would be better than no trastuzumab,” he said.

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