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PHARMAC and Herceptin for early-stage breast cancer in New
Zealand: Herceptin or deception?
Martin Rosevear
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Abstract
Pressure to fund Herceptin (trastuzumab) for use in
early-stage breast cancer is a welcome development for those patients who may
benefit. However such a decision would have major implications since the health
gains made by trastuzumab come at a very high cost (when compared to health
gains achieved by other drugs currently funded on PHARMAC’s schedule). The
budget for trastuzumab (estimated to be NZ$30m/annum but this is currently being
negotiated) will be funded from district health board (DHB) budgets, which will
impact other patients unless DHB budgets are appropriately increased. In
comparative terms, this proposed expenditure is almost the same as what is
currently being spent on all other oncology agents together, and is similar to
the total cost of hospital services in New Zealand regions such as Wairarapa and
Marlborough.
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Drug
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Herceptin® (trastuzumab) (Roche)
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Indication
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Reduces disease progression in breast cancer with an
over-expressed HER2 gene, representing approximately 15–20% of women with
breast cancer.1
Patients with HER2-positive breast cancer are a relatively
vulnerable group. Patients with metastatic cancer and expressing HER2 have a 50%
shorter survival time relative to other patients with breast cancer, and
approximately 70% of breast cancers will eventually develop into the metastatic
form.5
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Recommended
dose & duration
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Trastuzumab for the indication of early HER2-positive breast
cancer is provisionally licensed for use subsequent to surgery and adjuvant
chemotherapy. Following adjuvant chemotherapy (or in combination with
chemotherapy with adjusted dose), an initial dose of 8mg/kg followed by 6mg/kg
body weight every 3 weeks for 1 year.1
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Clinical
efficacy
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Trastuzumab as an adjuvant treatment in early breast cancer
when used sequentially to standard chemotherapy has been shown in the interim
results of one published open label clinical trial to improve the disease free
survival after 2 years from 77.4% to 85.8%.1
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Background
Trastuzumab is a recombinant monoclonal antibody against
HER2 and has been available for advanced (metastatic) stage cancer since 2001.
In March 2006, New Zealand became the
first country to give trastuzumab provisional approval for the aggressive HER2
form of early breast cancer.2
Media and public interest in the trastuzumab debate has been
strong, both in New Zealand and internationally. A recent high court decision in
the UK found the local NHS trust acted ‘irrationally and unlawfully’
when it refused to pay for Ann Marie Rogers’s treatment. The three Court
of Appeal judges said there was no "rational basis" for "preferring one patient
to another." They ruled that the focus should be on what a doctor felt was right
for their patient. The ruling does not mean primary care trusts will be forced
to provide the drug but it does set the precedent that giving the drug to some
women but not others is unlawful.3
New Zealand Government policy
Government policy seeks to make cost-effective drugs and
other treatments available to patients on a fully subsidised basis where health
benefits have been proven in high quality evidence based trials. We understand
that the district health boards (DHBs) will fund Herceptin. Therefore the DHBs
must balance their existing budgets to fund this service (presumably by
achieving additional efficiencies or reducing services), or DHB budgets must be
increased.
Current situation
On 23 March 2006, Medsafe announced provisional approval for
trastuzumab for the treatment of women with early breast cancer who test
positive for the HER2 gene once they have had surgery and completed adjuvant
chemotherapy. The provisional approval limited treatment to those women who have
a normal heart function before treatment starts and requires women using
trastuzumab to have their heart function checked by echocardiogram every three
months during treatment.13
PHARMAC is currently developing its policy on trastuzumab
and negotiating the terms of support. Based on costs of NZ$70,000/patient, this
could see a NZ$30m/annum bill2 covering 430
patients. This should be compared to
PHARMAC’s total budget in 2003 for community pharmaceuticals of $568m,11
and $47m spending by PHARMAC or DHB hospitals on all cancer agents under the
‘cancer basket’.14 In addition, it is noted that it costs
approximately $30m/annum to provide hospital services to communities of 30,000+
people such as Wairarapa and Marlborough.
The decision to enter into negotiation over the subsidy of
trastuzumab appears to be driven by public pressure rather than strong
scientific evidence. The decision may also have implications for other users of
PHARMAC’s drug schedule, who may not be as well-resourced to wage a media
campaign to support their needs, as the supporters of trastuzumab are.
Economic analysis
There is one published economic analysis of trastuzumab in
early breast cancer,12 but its results are difficult to interpret in the New
Zealand setting; and other analyses relate to advanced disease. In 2001, the
UK’s National Institute for Clinical Excellence (NICE) provided estimates
of the cost of trastuzumab for advanced breast cancer ranging from
£38k/QALY to
£19k/QALY
depending on treatment.5 A US investigation into metastatic cancer
estimated US$125k/QALY.6
Currently PHARMAC’s budget enables it to fund drugs
nominally up to NZ$20k/QALY, although some such as antipsychotic drugs are
purchased in quantity at NZ$43k/QALY2 and small quantities are purchased at
higher rates. However we understand that while PHARMAC uses cost/QALY results as
part of its funding consideration, it has no cost/QALY threshold which
automatically ensures funding.
The recent results reported from trials (Piccart-Gebhart et
al (HERA trial)1 and Romond et al)7 involving early breast cancer indicate
possibly stronger health gains.
However PHARMAC’s PTAC Advisory Committee has
indicated the following concerns with these results:8
- The
HERA results were interim, and both the benefit and safety data for early breast
cancer are premature;
- Both
papers have omitted to publish all results;
- The
Romond paper omitted to publish the treatment arm that was directly relevant to
this indication. Therefore they considered efficacy results of the paper were
found to be of limited value; and
- The
risk of cardiotoxicity had to be especially managed and
in the case of early disease,
the addition of trastuzumab could put at risk
patients who would otherwise have survived.
However in an effort to provide some estimate of
trastuzumab’s impact on early-stage breast cancer, we have used data from
the Romond paper to provide a hypothetical estimate of cost/QALY results.
Survival results at four years have been combined with the effects of aging as
observed in the life expectancy for women in the general population10 to
extrapolate a very simplistic picture by the authors of this paper:
Indications are:
- 50
years is the average age at diagnosis for HER2-positive breast cancer patients
who have an average life expectancy of perhaps 8 years, versus 35 years
calculated life expectancy for women of the same age in the general population.
- The
trastuzumab arm shows a hypothetical benefit of approximately 1.6 years, versus
patients receiving standard treatment only. This benefit is the area between the
two treatment curves in the graph above.
But this
simplistic analysis raises a number of questions:
- How
long does the therapeutic value of trastuzumab last? Does the differential
reported in the trials persist, or are their latent toxic effects yet to be
observed which could reduce or totally remove any persistent benefits for
trastuzumab? For instance it is known that trastuzumab is cardiotoxic, with
approximately 20% discontinuing trastuzumab treatment due to cardiac problems in
the Romond trials, and a further 14% discontinuing for other reasons (noting
that Romond results were for a different regimen). Will the death rate from
heart failure or other toxic side-effects remove short-term benefits in the
longer term?
- Will
additional courses of trastuzumab be required to increase persistence?
Therefore when estimating a $/QALY for early
breast cancer, uncertainty exists in the following issues:
- Increase
in life expectancy due to trastuzumab in the long-term, and associated savings
due to delays in recurrence or terminal cares;
- The
quality of life (relative to a normal population) that is provided during those
extended years following treatment. Adjustments between 30% to 50% to convert
extended life in metastatic cancer to the normal population have been
used;5
- The
duration of treatment required to obtain long-term benefits; and
- NZ$/patient
cost of a course of trastuzumab.
Given the
uncertainties above, it can be estimated that the cost per QALY could lie
somewhere between:
NZ$88k and NZ$100k+
...where the lower bound has been estimated using the
analysis above (without adjusting for other costs/savings nor quality of life)
and the upper bound has been estimated using the published results for
metastatic cancer. Note that this estimate has not allowed discounting of future
costs and benefits (standard for such analyses), which would likely mean an
increase in the cost/QALY.
Comment
Evidence suggests trastuzumab can bring benefit to
early-stage breast cancer in the short-term. However, these benefits come at a
high cost, which appear to be above the margin at which PHARMAC has historically
subsidised drugs. As such, funding of trastuzumab could come at a high cost to
other users of publicly funded pharmaceuticals and other health services.
Disclosures:
None.
Author information:
Martin Rosevear, Director, Outcome Management Services (a consultancy
specialising in health and public sector economics), Wellington
Correspondence:
Martin Rosevear; Outcome Management Services, 42 Seaview Rd, Paremata,
Wellington. Email; martin.rosevear@omsl.co.nz
- Piccart-Gebhart
MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy
in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–72. Available
online. URL: http://content.nejm.org/cgi/content/full/353/16/1659
Accessed June 2006.
- Hayman
K. Warning over Herceptin hype. Christchurch: The Press; 2006. Available online.
URL: http://www.stuff.co.nz/stuff/0,2106,3621782a7144,00.html
Accessed June 2006.
- Martin
N. Woman wins fight for breast cancer drug. London: Daily Telegraph (UK); 2006.
Available online http://www.telegraph.co.uk/news/main.jhtml?xml=/news/2006/04/13/nhercep13.xml
Accessed June 2006.
- Metcalfe
S, Dougherty S, Brougham M, Moodie P. PHARMAC measures savings elsewhere to the
health sector . N Z Med J. 2003:116(1170). URL: . http://www.nzma.org.nz/journal/116-1170/362/
- National
Health Service. TA34 Breast cancer – trastuzumab: Guidance. London:
National Institute for Clinical Excellence (NICE); 2002. Available online. URL:
http://www.nice.org.uk/page.aspx?o=29280
Accessed June 2006.
- Elkin
EB, Weinstein MC, Winer EP, et al. HER-2 Testing and Trastuzumab Therapy for
Metastatic Breast Cancer: A Cost-Effectiveness Analysis. Journal of Clinical
Oncology. 2004;22:854–63. Available online. URL: http://www.jco.org/cgi/content/full/22/5/854
Accessed June 2006.
- Romond
EH, Perez EA, Bryant J, et al. Trastuzumab plus Adjuvant Chemotherapy for
Operable HER2-Positive Breast Cancer. N Engl J Med. 2005;353:1673–84.
Available online. URL: http://content.nejm.org/cgi/content/full/353/16/1673
Accessed June 2006.
- PTAC
meeting minutes for February 2006. Wellington: PHARMAC; 2006. Available online.
URL: http://www.pharmac.govt.nz/pdf/ptacmins.pdf
Accessed June 2006.
- Survival
results of Romond paper can be found at: http://content.nejm.org/cgi/content/full/353/16/1673
- Statistics
New Zealand. Total Female Population Life Table 2000-2002. Available online.
URL: http://www.stats.govt.nz/NR/rdonlyres/8EA99547-7E92-4FDB-9BCB-4F2807914AC2/0/App1Tables.xls
[Click on Table A1.2 tab at the foot of the spreadsheet.] Accessed June
2006.
- PHARMAC
Annual Plan 2004/2005. Wellington: PHARMAC; 2004. Available online. URL: http://www.pharmac.govt.nz/pdf/AP2005.pdf
Accessed June 2006.
- Neyt
M, Albrecht J, Cocquyt V. An economic evaluation of Herceptin in adjuvant
setting: the Breast Cancer International Research Group 006 trial. Ann Oncol.
2006;17:381–90.
- Media
release. Herceptin (trastuzumab) provisionally approved. Wellington: Ministry of
Health; 2006. Available online. URL: http://www.moh.govt.nz/moh.nsf/by+unid/6C8344DC08AE29C9CC257139007FA389?Open
Accessed June 2006.
- Media
release. Cancer drug funding a challenge – PHARMAC. Wellington: PHARMAC.
Available online. URL:http://www.pharmac.govt.nz/pdf/071205a.pdf
Accessed June 2006.
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