Submissions

PHARMAC Consultation on a proposal to widen access to trastuzumab (Herceptin) and docetaxel (Taxotere) for adjuvant treatment of HER2 positive early breast cancer

The Response from the Breast Cancer Aotearoa Coalition

1. The PHARMAC Proposal                                                                       

2. Background to this Submission                                                     

            2.1 The Breast Cancer Aotearoa Coalition (BCAC)                      

            2.2 The Mission of BCAC                                                          

            2.3 General Comments                                                            

3. The BCAC Submission to the PHARMAC Consultation          

4.  Issues for BCAC Relating to the Proposed SOLD Trial            

5. Conclusion  

1. The PHARMAC Proposal

The Breast Cancer Aotearoa Coalition responds in this submission to the following PHARMAC proposal.

On March 20, PHARMAC announced a proposal to widen the access to trastuzumab and docetaxel to include adjuvant use for HER2 positive early breast cancer. If the proposal is approved by the PHARMAC Board, PHARMAC would fund treatment with trastuzumab for HER2 positive early breast cancer patients when it is administered for 9 weeks concurrently with taxane chemotherapy (docetaxel).

2. Background to this Submission

2.1 The Breast Cancer Aotearoa Coalition (BCAC)

PHARMAC has sought feedback on the proposed changes and this response is made on behalf of the Breast Cancer Aotearoa Coalition (BCAC). The BCAC represents seventeen of New Zealand’s breast cancer organisations. BCAC provides a united consumer voice, working to improve the detection, treatment, care and understanding of breast cancer in New Zealand.

2.2 The Mission of BCAC

‘The Breast Cancer Aotearoa Coalition will research, educate, support, promote informed choice, represent to relevant authorities, effectively advocate for and network to optimise the detection, treatment and care of those affected by breast cancer in Aotearoa New Zealand.’

2.3 General Comments

Breast cancer is the most common cancer for New Zealand women. Each year, around 2500 women are diagnosed with breast cancer in New Zealand and over 600 women die from the disease. 20-30% of those women diagnosed every year have HER2 positive cancer. Trastuzumab is currently funded in New Zealand (via Special Authority) only for women with advanced (metastatic) disease. Docetaxel is currently funded only for the treatment of metastatic breast cancer.

3. The BCAC Submission to the PHARMAC Consultation.

The members of BCAC are extremely concerned by PHARMAC’s proposal to fund only 9 weeks of Herceptin treatment on the basis of weak evidence from a small sub-group analysis from a study designed to compare the efficacy of vinorelbine with docetaxel.  In contrast, there is a vast body of high quality data from large, multi-centre international trials designed to test the efficacy of 12 months of Herceptin treatment that demonstrates the strong benefits in disease free survival (DFS) and overall survival of this treatment.  We list our main concerns below:

• PHARMAC is proposing to fund only 9 weeks of Herceptin to a maximum cumulative dose of 20mg/kg on the basis of the results of the FINHER study (Joensuu et al. 2006)  in which only 54 patients received the regimen now proposed for funding, i.e. FEC chemotherapy and docetaxel concurrently with 9 weeks of Herceptin.  The FINHER study was designed specifically to compare the efficacy of docetaxel and vinorelbine for the adjuvant treatment of early breast cancer.  The sub-group of 232 women in this study who had HER2 positive breast cancer were randomised to receive either docetaxel or vinorelbine and further randomised to receive either concurrent treatment with Herceptin or no such treatment.  Analysis of results from the HER2 positive sub-group showed a statistically significant benefit of Herceptin only in DFS and not overall survival at 3 years, and the confidence intervals for DFS were wide, demonstrating the uncertainty of this result. Significance with DFS could only be achieved when the group of patients who received the proposed Herceptin/docetaxel regimen was combined with the group who received the Herceptin/vinorelbine regimen.  Results for DFS in FINHER at 1 and 2 years do not appear to show statistical significance whereas the results of the 12 month regimens used in HERA (Picart-Gebhart et al 2005; Smith et al. 2007), the combined US studies (Romond et al. 2005) and BCIRG 006 (Slamon et al. SABCS 2006) do.  A comparison of results of DFS from FINHER at 3 years with HERA at 1 and 2 years do not support equivalence.  This issue will not be resolved without conducting an adequately powered head to head trial.  In short, there is insufficient evidence for the efficacy of the FINHER Herceptin/docetaxel sub-group regimen to base the treatment of New Zealand women with early HER2 positive breast cancer on this.
• A trial to compare 12 months with 9 weeks treatment has been proposed by Finnish researcher H. Joensuu (see issues raised re clinical trial later in this document), but oncologists who attended the recent St Gallen meeting have reported that this trial is unlikely to occur due to lack of support from other countries.   New Zealand women may thus be subjected to a treatment regimen which will never be properly tested.  Even in the unlikely event that the trial were to proceed as planned, with rapid international recruitment of 3,000 patients, it would take at least 4 to 6 years for the data to be accumulated, analysed, interpreted and published, during which time New Zealand women would be subjected to what is likely to be an inferior regimen.  In patient terms, this means lives would be lost as early and curable cancers are allowed to progress to metastatic and incurable as a result of refusal to implement a 12 month regimen already proven to be effective.
• PHARMAC cites Sledge (2006) in support of the effectiveness of a short regimen.  This pilot study was presented as a poster at the December 2006 San Antonio Breast Cancer Symposium.  The trial examined the cardiac effects of paclitaxel plus Herceptin prior to AC chemotherapy in 234 HER2 positive patients treated either with Herceptin for 10 weeks or 12 months, and showed no difference (3 CHF events in one arm, 4 in the other). The study was not designed or statistically powered to test the efficacy of 10 weeks vs 12 months Herceptin duration and thus does not provide supporting evidence. 
• There is extremely solid evidence for the effectiveness of 12-months of Herceptin treatment in reducing mortality and increasing disease free survival.  The evidence supporting this is derived from the data generated in several large international clinical trials involving over 12,000 women (Picart-Gebhart et al 2005, Romond et al. 2005, Slamon et al. 2006, Smith et al. 2007), in which around 8,500 women received 12 months of Herceptin treatment. The strength of the benefits has provoked 23 OECD countries to fast-track approval and funding for 12 month Herceptin regimens and this treatment is now accepted as the international ’gold standard’ for care of women with HER2 positive early breast cancer.  New Zealand women have the right to be valued as much and treated with the same respect and care as those in Australia, the UK, Canada and the other countries funding 12 months of Herceptin treatment.
• PHARMAC’s own expert sub-committee of oncologists, i.e. CATSOP, has recommended funding for 12 months of Herceptin given the certainty around the data demonstrating the effectiveness of this treatment. CATSOP only considered a 9 weeks’ treatment option when told that PHARMAC refused to fund 12 months. Likewise, the NZ Association of Cancer Specialists supports 12 months’ treatment given the strength of the trial data.  BCAC believes that New Zealand oncologists, the specialists trained to understand and effectively treat breast cancer, and not PHARMAC employees, driven largely by cost imperatives, should be defining and prescribing the most appropriate treatments for New Zealand breast cancer patients.
• The proposal only allows for Herceptin to be administered concurrently with taxane chemotherapy.  This will unnecessarily exclude patients intolerant of taxanes as well as those who would be better suited to a sequential treatment regimen for other medical reasons.  Both concurrent and sequential 12 month Herceptin regimens should be available to New Zealand women and the decision as to which is best should rest with the expert oncologist in consultation with the individual patient.
• The proposal states that Herceptin treatment must be commenced within 12 weeks of surgery thereby unnecessarily excluding those women for whom more than 12 weeks has elapsed following surgery.  In contrast, randomisation in the HERA study, which has shown DFS and overall survival benefits in all sub-groups (Picart-Gebhart 2005; Smith 2007) occurred within 7 weeks of day 1 of the last chemotherapy cycle or 6 weeks from the end of radiotherapy or definitive surgery, whichever was last,
• The proposal requires a normal Left Ventricular Ejection Fraction (LVEF) and thus unnecessarily excludes patients with a somewhat reduced LVEF for whom the risk of HER2 positive breast cancer is greater than the risk of a cardiac event. 
• CATSOP has noted that the FINHER regimen proposed by PHARMAC uses a less than optimal dose of epirubicin, i.e. 60 mg/m2 rather than the more widely used dose of 75 mg/m2.  Despite CATSOP’s suggestion that this dose be increased in any short duration regimen this is not part of the PHARMAC proposal.
• The proposed adoption by PHARMAC of a 9 week regimen will deny NZ breast cancer patients access to other international clinical trials offering new therapies in conjunction with the 12 month standard of Herceptin treatment, as the cost of conducting such trials in New Zealand will be prohibitive compared to other countries. If those trials lead, as intended, to the implementation of the new therapies, New Zealanders will miss out on these as well because there will be no proven treatment regimen involving those therapies in combination with only 9 weeks of Herceptin and no availability of 12 months treatment.  This problem has already been encountered in Auckland where neoadjuvant study 0502 cannot be undertaken because the charges imposed by ADHB for Herceptin delivery exceed the study budget.   The ALTTO trial with 4 treatment arms comparing 12 months of Herceptin treatment with 12 months of Lapatinib, 12 months of both, and 3 months of Herceptin followed by 9 months of Lapatinib, planned to start in all 6 of New Zealand’s primary cancer treatment centres in June 2007, provides another example.  A further trial in which the effects of the anti-angiogenesis drug Avastin added to 12 months of Herceptin will be tested is yet another.
• One of our members has written: “A substandard or ill-tested treatment as an alternative to nothing is still a substandard or ill-tested treatment.The enforced alternative of "nothing" does not make it any better. In fact it may be worse, especiallyif it provides false hope andlittle improvement. PHARMAC’s decision, if unopposed, will lead to an era of experimentation to see if that is so. Oncologists will be exposed to the risk and consequences of having to adopt an off-label, unapproved and unproven treatment for their patients. My own experience of the medical practitioners who treated me was that they were people of integrity, compassion and skill. I do not want to see PHARMAC’s decision compromise their professionalism or ability to treat their patients.”

4. Issues for BCAC Relating to the Proposed SOLD Trial

• BCAC is concerned about the ethics of the proposed clinical trial being the only mechanism for patients to access 12 months of Herceptin treatment.  This would effectively coerce patients into participating in a trial where they would have a 50/50 chance of getting the gold standard treatment.  In other countries where this trial is being considered, patients have the option of standard treatment (12 months) off trial or participation in a trial.  In New Zealand they will not have this option under the current proposal.
• The trial protocol is based on the hypothesis that 9 weeks treatment (the experimental regimen) is not inferior to 12 months treatment (the standard regimen).  This design supports the notion that 12 months is standard treatment and 9 weeks is being tested against it (not the other way around). By funding the 9 week treatment programme and also financially supporting a 9 week trial, PHARMAC would be implementing the reverse of the hypothesis, namely, setting up a standard of 9 weeks of treatment and testing the 12 month treatment regime against that.  Clinical trials are commonly understood to provide the gold standard of treatment to all enrolled patients, and to then randomise some patients to a new and promising treatment that may improve outcome. 
• PHARMAC’s projected recruitment rates for patients in a clinical trial in NZ of 600 over 2 years appear unrealistic.  It is unlikely that this number of patients could be recruited within the time frame suggested.
• Even if the study had strong international support (which it does not) and patient recruitment was able to proceed in a timely fashion, the data from the trial would not be available for at least 4-6 years, during which time only the 9 week treatment will be government funded. New Zealanders will be unable to access the proven treatment of 12 months unless they are able to pay for it or they happen to be randomised in the trial to receive it. If 12 months is then proven to be more effective than 9 weeks, NZ women off trial will have been subjected to a substandard treatment instead of receiving the internationally accepted and adopted standard of care.  Such treatment is very likely to cost lives.
• If the proposed trial is not supported and undertaken in a number of countries around the world because a) insufficient patients choose to enrol b) oncologists do not support the trial design or prefer other trials on offer or c) the trial design is deemed unethical, then New Zealand women will have been subjected to an experimental regimen for which adequate data will never be collected.
• The commitment of funding (for administrative purposes) to an international trial – irrespective of whether any New Zealand patient is treated with Herceptin - is inconsistent with PHARMAC’s statutory role to fund medications for New Zealand patients.

5. Conclusion

Funding should urgently be established to provide Herceptin treatment of 12 months duration to New Zealand women with early HER2 positive breast cancer.  Herceptin should be made available for use both sequentially and concurrently with chemotherapy to allow appropriate prescribing depending on disease characteristics and patient need. 

Docetaxel should be funded for the treatment of New Zealand women with early breast cancer irrespective of whether their cancer is HER2 positive or not.  BCAC raised this matter with PHARMAC in our meetings with you on 24th June 2005 and 13th December 2005. We refer you also to our response to consultation on the PHARMAC proposal regarding funding of Pharmaceutical Cancer Treatments (PCTs) dated 10th March 2005, and to our response to PHARMAC’s consultation on funding paclitaxel dated 14th July 2006 regarding this matter.

Finally, if PHARMAC refuses to fund the proven 12 months Herceptin treatment and rationing is inevitable, thenthis should be doneon the basis of evidenceand honesty. There arebetter alternatives to introducing the 9 week FINHER sub-group regimen as the NZ "standard". 12 months of treatment should be clearly acknowledged as the standard of care (as it is in Australia, the UK, Canada and 23 OECD countries), with PHARMAC prepared to fund a portion of this. Women wouldthen be appropriately informed of the recommended, proven gold standard of treatment, and would not be misled into believing that 9 weeks is a treatment for which there is strong evidence or which will give them their best chance of survival. Those able to fund further treatment could then do so on the basis of a clear understanding of their options.

References
Joensuu et al. 2006 NEJM 354: 809-820
Picart-Gebhart et al. 2005 NEJM 353: 1659-1672
Romond et al. 2005 NEJM 353: 1673-1684
Slamon et al. SABCS 2006
Sledge et al. SABCS 2006
Smith et al. 2007 The Lancet 369: 29-36