If I, or anyone I loved, had breast cancer I’d want to make damned sure they got the best possible treatment. This is at the core of issues surrounding how the drug trastuzumab (trade name Herceptin) is to be used. This morning Radio New Zealand reported that the Breast Cancer Aotearoa Coalition has made a submission to the Northern B Ethics Committee to stop New Zealand women entering a trial comparing short duration (9 week) and long duration (12 month) Herceptin treatments.
I understand that the submission is based on the results of another study, the PHARE trial. I will shortly summarise this study. I will also summarise the SOLD trial which the BCAC want stopped (in NZ). Before I do so, a disclaimer. I have no a priori position on whether a short or long duration treatment should be funded, I am not involved or have been involved in any Herceptin studies and I have no links whatsoever to the manufacturers of Herceptin (Roche pharmaceuticals). I have spoken publically against the process that resulted in the funding of 12 months of treatment. This was in 2008 when the National political party (not in government at the time) had as an election promise that they would fund 12 months of Herceptin rather than 9 weeks as Pharmac had proposed. My argument then, as now, was that it was wrong for a political party to make such a call. The independent entity, Pharmac, has been given the responsibility to make such calls and is required to base them on the best available evidence. If the politicians believe that those calls are not being made correctly, then they need to improve the funding for Pharmac or its structure so that we can all be confident the best calls are made. They should not try and override their calls for political gain, which is exactly what happened in 2008.
What is Herceptin and who benefits?
- Herceptin (transtuzumab) is a drug marketed by Roche for the treatment of HER-2 positive breast cancer.
- HER-2 refers to Human Epidermal growth factor Receptor 2 which is a protein that promotes the growth of breast cancer cells.
- HER-2 is present in only about 1 in 5 breast cancers.
- Herceptin is, therefore, only an option for up to 1 in 5 people with breast cancer.
- Herceptin improves survival. From the Cochrane review* of the efficacy and safety of trastuzumab (I paraphrase): “If 1000 women were given standard therapy alone (with no trastuzumab) then about 900 would survive. If 1000 women were treated with standard chemotherapy and trastuzumab for one year, about 933 would survive (33 more women will have their lives prolonged), about 740 would be free of disease recurrence (95 more women will not experience the disease return).”
- Herceptin increases heart toxicity: “If 1000 women were given standard therapy alone (with no trastuzumab) then five would have experienced heart toxicities. If 1000 women were treated with standard chemotherapy and trastuzumab for one year 26 would have serious heart toxicity (21 more than the chemotherapy alone group) due to the drug.”
The SOLD (Synergism Or Long Duration) trial
In women diagnosed with early breast cancer with high risk of recurrence who are HER2-positive this compares a 9 week course of trastuzumab with a 51 week course.
The study began recruiting in 2008 and is expected to be completed by January 2015.
The primary outcome is a comparison of the Disease-Free-Survival (DFS) at the end of the study in the two groups. DFS for an individual is the length of time they survive without symptoms of cancer after the end of the treatment. Secondary outcomes look at overall survival and measures of heart function and adverse events.
This is a world wide trial run by the Finnish Cancer Research Group and New Zealand patients may be eligible to enter. I understand Pharmac is providing $3.2M to support this trial**.
The Northern B Health and Disabilities Ethics Committee approved the ethics application for this study. It consists of lay and professional members and judges if a study is meeting a number of specific criteria designed to ensure study participants rights and interests are safeguarded.
The PHARE (Protocol for Herceptin as Adjuvant therapy with Reduced Exposure) trial
This study aimed to compare two treatments: six months and 12 months of Herceptin. The primary outcome was again Disease-Free-Survival. The aim was to recruit 7000 people, only 3400 were recruited.
The trial was reported as a non-inferiority trial. That is it tested if the six months treatment was not worse than the 12 month treatment. It did not show that six months was equivalent to 12 months. It also failed to show it was inferior. The trial had enough participants that if the lower bound of the 95% confidence interval of the Hazard Ratio*** had been greater than 1.15 then they could have drawn a positive conclusion about the difference in the two studies. It was not, the 95C%CI was 1.09-1.66 (ie the lower bound, 1.06, was not greater than 1.15). This did not stop Roche and others reporting that the trial showed women receiving six months had a 28% higher risk of dying or having cancer return than those at 12 months (ie 1.28 being halfway between 1.09 and 1.66).
The results have only been presented in abstract form at a conference. They have not gone through the rigorous peer review process yet, as far as I can tell. I have not seen any information on the cardiac toxicity outcomes.
Summary of the evidence
The Ethics committee must decide if the PHARE trial and any other relevant information is sufficient that it would be unethical for patients to continue to be offered the opportunity to participate in a 9 week v 1 year SOLD trial. This is a fair question to ask. The difficulty they face is that the PHARE trial was not a 9 week vs 1 year trial, the results were inconclusive, the results have not as far as I can tell undergone peer review, and the published results appear not to say anything about differences in the rates of adverse events, especially cardiac ones.
*Cochrane reviews are independent and adhere to strict quality control. They are about as “good as it gets” for assessing treatments.
**Under the NZ Public Health and Disability Act s48(c) one of the functions of Pharmac is “to engage as it sees fit, but within its operational budget, in research to meet [its] objectives…”
*** The Hazard Ratio in this case is simply how many times more or less a patient on 6 months compared to 12 months treatment is likely to not survive or still have cancer at the end of the study period.