The results of the only clinical trial so far to look at the relative impact of administering Roche’s Herceptin (trastuzumab) at the same time as, or following, chemotherapy are a rallying call for doctors to use the breast cancer drug concurrently, says the lead researcher for the US study.

The N9831 trial, presented at the 32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium in the US, found that breast cancer patients using Herceptin and chemotherapy at the same time had a relative 25% reduction in the risk of recurrence of cancer or death, compared with women who were given Herceptin after chemotherapy.

Overall, the addition of one year of Herceptin to chemotherapy, whether sequentially or concurrently, was associated with a 33% reduction in the risk of cancer returning compared with chemotherapy alone.

This was the outcome highlighted by Roche, along with the finding that at least 80% of patients receiving one year of Herceptin were still alive and disease-free at five years of follow-up. It was not the angle, though, taken by lead investigator Dr Edith Perez, chair of the North Central Cancer Treatment Group (NCCTG) Breast Committee and a breast cancer researcher at the Mayo Clinic in Jacksonville, US.

In the US, Dr Perez noted, Herceptin is approved for use on either a sequential or a concurrent treatment schedule with adjuvant (i.e., post-surgery) chemotherapy. In much of the rest of the world, she added, Herceptin is given sequentially.

“The results of this trial have been eagerly awaited in the US and in many nations as this is the only trial developed to define the optimal way to incorporate Herceptin in the context of adjuvant chemotherapy,” Dr Perez commented. “The goal was to decrease the risk of cancer recurrence, and we have shown that concurrent use is the best way to achieve that.”

This could mean, the researcher suggested, that “up to 10,000 women around the world each year may have a better outcome if Herceptin is used along with chemotherapy. Given that, I believe this study will lead to a global re-evaluation of how Herceptin is used.”

Roche’s comment on the relative benefits of concurrent versus sequential administration were considerably more subdued. “While the study clearly showed the long-term benefits with either regimen, there was a trend for the concurrent regimen being more beneficial to patients,” it acknowledged.

Point of contention

The optimal duration and timing of Herceptin treatment have been a point of contention for some time now, and inevitably cost-effectiveness has entered the debate. Previous clinical trial results have indicated that the sequential approach may not be as effective as concurrent treatment.

Where the cost issue really comes into focus, though, is with suggestions (notably from the small FinHer trial) that a short duration of treatment with concurrent Herceptin could be even more effective – and possibly also less cardiotoxic – than concurrent therapy with the 52-week Herceptin regimen recommended as gold standard by Roche.

This was what underpinned the controversial decision by the New Zealand funding agency, PHARMAC, to cover a nine-week concurrent regimen of Herceptin and chemotherapy for women with HER2-positive early breast cancer in May 2007.

The stance was subsequently overruled, though, by the incoming New Zealand government in December 2008. The victorious National party had made a pre-election promise to fund the full 52-week course.

The primary endpoint of N9831, a Phase III, randomised, multicentre, open-label trial of one year’s adjuvant trastuzumab, was to demonstrate superiority in disease-free survival of the Herceptin treatment arms versus chemotherapy alone.

A total of 2,448 patients were randomised to chemotherapy alone (Arm A, doxorubicin and cyclophosphamide, then paclitaxel), chemotherapy with sequential Herceptin (Arm B) or chemotherapy with concurrent Herceptin (Arm C).

When the outcomes of Arm A were compared with Arm B, five-year disease-free survival increased from 72% in Arm A to 80% in the group taking chemotherapy followed by Herceptin, the researchers reported. In a further comparison, five-year disease-free survival in the concurrent Herceptin group was 84% versus 80% in Arm B.

The annual CTRC-AACR symposium is organised by the Cancer Therapy & Research Center (CTRC) at UT Health Science Center, San Antonio and the American Association for Cancer Research (AACR).