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PHARMAC funding of 9-week concurrent trastuzumab
(Herceptin) for HER2-positive early breast cancer
Scott Metcalfe, Jackie Evans, Ginny Priest
From 1 July 2007, trastuzumab (Herceptin®) will be
funded in New Zealand for the treatment of HER2-positive early breast cancer.
Funding will be available for patients receiving trastuzumab when administered
for 9 weeks concurrently with taxane chemotherapy. Docetaxel will also be funded
for early breast cancer when given concurrently with trastuzumab.
Last year the Journal published a Special Series
article and related correspondence about the use of trastuzumab in HER2-positive
early breast cancer.1,2,3 Since then, in July
2006, district health boards (DHBs) and PHARMAC decided not to fund trastuzumab
as a 12-month sequential regimen at that time,* but committed to ongoing active
review of the evidence. After considering further evidence and following
consultation, PHARMAC and DHBs have decided to fund a 9-week concurrent
trastuzumab regimen.
We describe some of the background and reasoning behind
PHARMAC’s decisions.
HER2-positive breast cancer and trastuzumabHuman epidermal growth factor receptor 2 protein
(HER2/neu)-positive (IHC 3+ or FISH positive) breast cancers are
aggressive tumours accounting for ~15-20% of early breast cancers. Trastuzumab
(Herceptin) is a recombinant DNA-derived humanised monoclonal antibody that
selectively binds to the extracellular domain of the HER2 protein on the surface
of breast cancer cells. Appendix 1 further describes
Her2/neu overexpression/amplification in breast cancer and its
treatments, including trastuzumab.
HER2-positive breast cancer affects 340–400 new
patients in New Zealand each year. There are important regional variations in
the extent of testing for HER2-positivity, and Maori and Pasifika women tend to
present with later disease. Appendix 2 describes aspects
of the epidemiology of HER2-positive early breast cancer in New Zealand.
Trastuzumab is registered in New
Zealand4 for the treatment of patients with
metastatic HER2-positive breast cancer, and also has provisional approval for
the treatment of HER2-positive early breast cancer following surgery and
completion of adjuvant chemotherapy; this latter indication is based on the
results of, and the treatment regimen used in, the HERA phase III clinical
trial.5
Trastuzumab has been funded by DHBs for HER2-positive
metastatic breast cancer since 2002, and is available through DHB
hospitals.† The funding of trastuzumab and taxanes (paclitaxel and
docetaxel) for metastatic breast cancer resulted from PHARMAC taking over
management of the ‘Cancer Basket’ of oncology medicines; these
medicines were determined by the Ministry of Health and DHBs and did not undergo
formal clinical or economic assessment by PHARMAC.
Trastuzumab for HER2-positive early breast cancer—treatment regimens and available trial dataTo date, adjuvant treatment of HER2-positive early breast
cancer with trastuzumab has been investigated in two broad treatment
regimens:
There
have been five open-label randomised controlled trials (RCTs) reporting outcomes
for adjuvant trastuzumab against standard treatment in HER2-positive early
breast cancer to
date6—HERA7
(12-month sequential), NSABP
B318,9 (12-month
concurrent post-anthracycline), NCCTG N983110,11
(12-month sequential, or 12-month concurrent post-anthracycline), BCIRG
00611 (12-month
concurrent), and FinHer12 (9-week concurrent
pre-anthracycline).‡ Specific regimes studied in the trials are briefly as
follows (detailed in Appendix 3):
The design and some results
from these trials are summarised on the bpacnz
website (http://www.bpac.org.nz/magazine/2007/april/herceptin.asp),
Adjuvant! online (http://www.adjuvantonline.com/breasthelp0306/Trastuzumab.html)
and in the tables in Appendix 3, with the following table and figures
summarising the primary efficacy results in terms of disease-free survival
(DFS):
Table 1. Hazard ratios and absolute
improvements in DFS by trial and regimen type and across studies (PHARMAC
analysis)
 Notes:
Figure 1. Hazard ratios for
disease recurrence by trial and regimen type and across studies (PHARMAC
analysis)
 Figure 2. DFS in adjuvant trastuzumab trials in
HER2-positive early breast cancer for untreated and treated groups, including
minimum confident improvements (PHARMAC analysis)
 Altogether, the results to date from the RCTs indicate that
adjuvant trastuzumab confers a benefit in DFS and overall survival compared to
standard chemotherapy, reducing both disease recurrence and overall deaths by
5.6% and 2.5% respectively at 2.2 years median follow-up (mf/u) compared with
standard chemotherapy alone— a relative reduction of
~1/3rd compared with standard chemotherapy
alone. All RCTs showed statistically significant DFS gains (except N9831
sequential arm, Arm B), with significant overall survival gains demonstrated in
the joint B31/N9831 analysis (published as the Romond
paper10), BCIRG 006 and HERA trials. Further
details of the study results are provided in Appendix
4.
However, there are disparities in trastuzumab treatment
efficacy between the studies, i.e. differences in the HRs for DFS and overall
survival between studies and regimens, and differences in the ranges of the
confidence limits for those HRs:
Grouping together the results across the trials
with similar treatment regimens, overall (pooled) results for DFS vary
between:
In addition, the
trials have a number of methodological issues that may affect their validity.
Results from all five trials reported to date have been preliminary
(interim)—all continue to follow-up patients, and none have met their
preset target event accruals for final analysis. It is difficult to assess the
quality of two RCTs (B31 and N9831) because reporting has been limited to either
a published joint analysis for B31 and the N9831 control and concurrent arms
(Arms A and C) (Romond 200510)—with
little disaggregation into the separate
studies11 or description of key validity
aspects of the separate studies—or a conference slideshow presentation for
N9831.12 Results for BCIRG 006 also have been
limited to conference slideshow
presentations.13 All trials are open-label in
design (unblinded), and allocation concealment methodology is not reported
adequately (except for FinHer)—where inadequate or unclear allocation
concealment has been associated with 30-40% larger estimates of treatment
effects13 Finally there is variable reporting
of compliance, contamination and co-intervention between the studies. Further
details on the quality of the trials are available in
GATE14 appraisals undertaken by EPIQ at http://www.health.auckland.ac.nz/population-health/epidemiology-biostats/epiq/critical_appraisal_library/Herceptin15**
Importantly, the result for the N9831 sequential arm (Arm
B)—no statistically significant benefit of 12 months sequential
trastuzumab over standard chemotherapy, HR 0.87 (95% CI 0.67-1.13)—raises
questions about the efficacy of 12-month sequential trastuzumab and its place as
the perceived ‘standard of care’. Trials examining trastuzumab as
concurrent therapy (i.e. trastuzumab in combination with a taxane for 9–10
weeks or 12 months) consistently report better results in terms of DFS than
sequential trastuzumab. The results of the FinHer trial to date appear to be
comparable to those of the longer treatment regimens, although statistically
significant overall survival gains have not been demonstrated to date (see Appendix 4).
Overall, the information available to date from all the
clinical trials examining the use of trastuzumab for HER2-positive early breast
cancer indicates that the optimal treatment schedule and duration of treatment
for trastuzumab has not yet been determined. Appendix 4 describes this in depth.
PTAC has reiterated that there is still uncertainty about the best way to
administer trastuzumab in terms of optimal treatment duration, dose and schedule
(sequential to, or concurrent with, chemotherapy, before or after
anthracyclines); minimising cardiovascular toxicity; and long-term clinical
outcomes (fully minuted in Appendix 5).
PHARMAC and its decision-making processesThe Pharmaceutical Management Agency (PHARMAC) is the
government agency that, under the New Zealand Public Health and Disability Act
2000, is responsible for securing the best health outcomes reasonably achievable
from medicines within the funding provided (the allocated pharmaceutical
budget). PHARMAC applies nine decision criteria when making pharmaceutical
funding decisions (http://www.pharmac.govt.nz/who_are_pharmac.asp),
has a fixed budget, and integrates clinical and economic assessment to help
determine the next best use of this funding.
PHARMAC’s role is to allocate taxpayer funds
efficiently and ensure medicines are assessed comparably to result in fair
funding decisions. Cost-effectiveness and budgetary impact (determining the
relative value for money of a proposal in order to achieve best health gains
from the budget available) are two of PHARMAC’s nine decision criteria (http://www.pharmac.govt.nz/who_are_pharmac.asp).
The way that PHARMAC has considered funding of the 9-week option for trastuzumab
is no different to any other targeting means that PHARMAC uses to get the best
health gains for a given medicine and ensure that other patient groups are not
denied other treatments.
PHARMAC relies on objective advice from its clinical
advisory body, the Pharmacology and Therapeutics Advisory Committee (PTAC) (http://www.pharmac.govt.nz/ptac.asp),
on pharmaceutical agents and their benefits (section 50(1)(a) New Zealand Public
Health and Disability Act 2000). Full minutes of relevant discussion about
trastuzumab at the February, May, August and November 2006 and February 2007
meetings of PTAC are attached as Appendix 5.
PHARMAC has an established consultation process for proposed
changes to the Pharmaceutical Schedule. PHARMAC consults (and is required to
consult) with sections of the public that, in PHARMAC’s view, may be
affected by decisions on those matters (including relevant clinical and patient
groups)16,17 to ensure it has all necessary
information before making a decision. PHARMAC consulted with interested parties
on whether or not to fund the 9-week concurrent trastuzumab regimen (http://www.pharmac.govt.nz/pdf/200307)
over a 3 week period during March/April 2007.
Nine-week trastuzumab regimen concurrent with docetaxel will be funded from 1 July 2007Following consultation, PHARMAC recently announced funding
for trastuzumab for HER2-positive early breast cancer when administered for 9
weeks concurrently with taxane chemotherapy. Because in the
FinHer14 regimen docetaxel was the taxane of
choice, PHARMAC has also approved funding for docetaxel for early breast cancer
when given concurrently with trastuzumab; paclitaxel is already funded for node
positive early breast cancer.
The 9-week concurrent regimen is considered by PHARMAC to be
clinically effective and cost effective in terms of improving DFS, and
affordable for DHBs in terms of drug and resource costs. PTAC considered that
the information on short term trastuzumab treatment from the FinHer and ECOG
E219818 trials suggested that comparable health
gains, and possibly less cardiac toxicity, could be achieved with a shorter
trastuzumab treatment regimen compared with 12 month treatment regimens. The
Committee also considered that the FinHer results cast doubt over the optimal
duration/timing for administration of trastuzumab; and that numbers of patients
treated were not insignificant and the data were valuable. Having taken into
account the views of its Cancer Treatments subcommittee (CaTSoP),††
PTAC recommended the 9-week regimen be funded with a high priority (fully
minuted in Appendix 5).
The shorter duration concurrent regimen for adjuvant
trastuzumab in the FinHer study14 was based on
the concept of trastuzumab acting synergistically when given concurrently with
taxane chemotherapy,19 as suggested by data
from the use of this combination in the metastatic disease
setting.20 Subsequently, this hypothesis has
also been supported by the trial N9831 comparison of sequential vs. concurrent
administration of trastuzumab.12 In theory,
this short duration regimen may also be safer for patients in terms of
cardiotoxicity risks, since trastuzumab is administered at a low overall dose
and prior to cardiotoxic anthracycline
chemotherapy‡‡—administration of trastuzumab in combination
with taxane chemotherapy following completion of anthracycline chemotherapy is
associated with higher risks of cardiac toxicity than other treatment regimens.
The efficacy results (DFS in the HER2-positive groups
treated with trastuzumab compared with no trastuzumab) of the FinHer trial
demonstrate that administration of 9 weeks of trastuzumab concurrent with
chemotherapy is effective in the treatment of HER2-positive early breast cancer
(HR 0.42 (95% CI 0.21-0.83), absolute benefit 13.5% at 3 years mf/up), and PTAC
considered these health gains comparable to the HERA trial results.
The evidence to support the 9-week concurrent regimen is
sufficient in itself to justify funding. In short, advantages with the regimen
are:
Patients may also benefit from the convenience of
the shorter timeframe and fewer infusions.
Some parties have questioned the reliability and validity of
the 9-week concurrent trastuzumab regimen—because of the small sample
size; use of vinorelbine (not docetaxel) in half of the patients; statistically
non-significant results for overall survival at this time (HR 0.41(0.16-1.08));
and the evidence for short duration treatment being limited to this one study.
These issues are canvassed in Appendix 4, but it is
noted here that:
PTAC’s view was that the number of
patients treated in the FinHer study was not insignificant and that the data
from this trial were valuable (fully minuted in Appendix 5).
Practical aspects of the 9-week concurrent trastuzumab regimenDetails of how the subsidy rules will be amended in the
Pharmaceutical Schedule can be found on the PHARMAC website at http://www.pharmac.govt.nz/pdf/030307b.pdf
The funded 9-week concurrent treatment regimen is not
covered by the current New Zealand Datasheet for trastuzumab. Trastuzumab has
provisional consent in New Zealand for HER2-positive early breast cancer when
administered as sequential treatment (i.e. ‘... following surgery and
completion of adjuvant chemotherapy’), based on the 12 month data from the
HERA trial.7 Therefore, prescribers of the
funded regimen must be aware of, and comply with, the provisions of section 25
of the Medicines Act 1981.22,23
§§§
Of note, the Australian indication for trastuzumab is for
‘in association with chemotherapy’ and allows for 12 months
sequential, 12 months concurrent or 9 weeks concurrent treatment regimens to be
used.24 The Australian Product Information
dosing section states that the optimal dosage regimen and treatment duration
have not been defined, and that favourable risk/benefit ratios have been
demonstrated with the regimens of the HERA trial, B31/N9831 trials and the
FinHer trial.
Twelve-month sequential treatment is not presently a funding optionThe 12-month sequential regimen (as per
HERA7 and the current NZ
datasheet6) has not been approved for funding
by PHARMAC and DHBs for reasons relating to the uncertainty surrounding long
term clinical benefits and risks21,25,26 the
high budgetary impact, effects on DHB services provision, and its associated
relatively high cost per quality adjusted life year (QALY)**** (i.e. the
proposal was relatively poor value for money compared with other pharmaceutical
funding options). In August 2006 PTAC recommended that 12-month sequential
treatment with trastuzumab be declined, for similar reasons (fully minuted in
Appendix 5).
In short, the 12-month sequential regimen does not provide
the level of, and certainty about, health benefits that PHARMAC would expect to
get from spending $25 million per annum compared with other investment
options.8,21 ††††
To date no new information has emerged to suggest that
funding the 12-month sequential regimen is a viable option for PHARMAC or DHBs.
In fact the already significant questions over the extent that sequential
treatment prevents recurrence have only increased:
In addition, other questions over the
long-term impact of demonstrable cardiac toxicity still remain (also Appendix
4). The impact of possible long-term cardiac effects should not be disregarded
when it is likely that 70% or more of women with HER2-positive early breast
cancer will still be alive at 10 years with standard adjuvant chemotherapy
regimens without trastuzumab (see Appendix 1).
It has been suggested that the apparent waning of efficacy
in HERA is due to cross-over contamination, where patients in the placebo-arm
were offered trastuzumab treatment, in a non-randomised fashion, once the
12-month DFS results emerged. However, in the 23-months’ median follow-up
publication, Smith et al.9 reported that
results from a censored analysis (where cross-over patient data were removed)
(DFS HR 0.63) were much the same as those from the intention-to-treat analysis
(ITTA; DFS HR 0.64). Therefore, this waning in efficacy cannot be explained
simply by cross-over contamination alone. Importantly, this cross-over has
limited the ability of this study to examine longer-term outcomes for 12
months’ sequential trastuzumab compared to standard chemotherapy, because
the standard chemotherapy arm has largely been lost, possibly to a point where
longer-term comparison questions from this study can never be resolved.
Hence, the now apparent lack of significant benefit in the
unpublished results from part of trial
N983110,12 and the reduced effect after 23
months’ median follow-up from HERA7,9
means that PHARMAC's original estimate of the cost-effectiveness of the 12 month
sequential regimen may have been overly optimistic (base case NZ$70-80,000 per
QALY).21 A formal update of the PHARMAC cost
utility analysis of the 12-month sequential
regimen21—including the recently
published overall survival data from the HERA 23 month median follow
up9—would be unlikely to show trastuzumab
treatment to be any more cost-effective than suggested by the original analysis,
as the majority of changes would disfavour trastuzumab. Therefore, PHARMAC has
not formally updated the original analysis of the 12 month sequential
trastuzumab regimen. Further details are available on the PHARMAC website at http://www.pharmac.govt.nz/pdf/030307e.pdf
(an appendix to the PHARMAC technology assessment report for
trastuzumab21).
Further publications arising from these two studies,
including the third arm of HERA where patients were given 2 years of trastuzumab
and longer term follow-up outcomes, are awaited with
interest.28,29
Trastuzumab around the worldA number of other countries have approved funding for
trastuzumab, using a 12-month treatment regimen. In most of these countries,
assessment of funding a medicine is limited to the licensed indication which is
largely dictated by data provided by, and supported by, the supplier. The
licensed indications for trastuzumab treatment regimens vary throughout the
world. In the United States, where trastuzumab is marketed by Genentech,
trastuzumab is approved for use in combination with taxane chemotherapy
(concurrent treatment).30 In Europe, however,
it is registered for 12 months treatment after completion of all chemotherapy
(sequential treatment). Alternatively, in Australia there are a number of
options for using trastuzumab including long and short duration, and using it
concurrently with, or sequentially to, taxane
chemotherapy.24
Funding for cancer treatments in New Zealand takes place
within DHBs’ budgets, so choices have to be made about how to allocate
spending most efficiently.31 Most other
countries, including the United Kingdom and Australia, do not appear to have
such direct budgetary constraints and associated prioritisation processes. The
fact that other OECD countries fund 12 months Herceptin is not in itself a
reason for New Zealand to follow-suit; funding decisions need to be made within
countries’ own decision-making frameworks, priorities and healthcare
environments. Different countries have differing funding mechanisms and levels
of governance and process, from ‘no assessment required’ (with
associated opaque trade-offs) to more comprehensive decision-making and explicit
prioritisation systems. PHARMAC relies on its established process and Decision
Criteria when making funding decisions.
In the UK, the National Institute for Health and Clinical
Excellence (NICE) makes its recommendations independent of budgetary
considerations.32 However, debate in the UK is
now suggesting that funding of 12 months trastuzumab is forcing the National
Health Service to cut the funding from other health services, underlining the
need to make careful choices.33 Trastuzumab
underwent inaugural assessment under NICE’s single technology appraisal
process, where (contrary to standard appraisals) evidence is provided solely by
the supplier34 (where for instance the FinHer
data and the unpublished N9831 sequential data were not
provided26). One commentary has stated that
NICE might never have deemed the 12-month sequential (HERA) schedule to be cost
effective had FinHer been assessed as a
comparator.27
Similarly, it is not readily apparent from information to
date whether other countries have carefully weighed up the 9-week concurrent
versus 12-month trade-off. This is not to judge those decisions—each
country will decide what is right for them—but meaningful comparison of
New Zealand’s approach to other countries needs to know whether the
trade-off has been explicitly considered. At present, no such meaningful
comparison seems possible.
PTAC’s view on trastuzumab for early breast cancer has
differed from those of clinical committees in other countries. There has been a
strong emphasis by PTAC and PHARMAC on the uncertainty with the current clinical
evidence27 and corresponding impact on future
outcomes, given the cost. PTAC also took into account both the 12-month
regimen’s unfavourable cost effectiveness compared to other funded
medicines or medicines awaiting funding, and the practical implications for DHBs
of administering this medicine under a 12-month regimen. In several countries,
commitments were made to fund trastuzumab for HER2-positive early breast cancer
prior to its evaluation by the European Agency for the Evaluation of Medicinal
Products (EMEA) and assessment by the relevant technology appraisal
agencies.35
This is not the first time New Zealand has chosen a
different path to other countries. For instance PHARMAC declined to fund COX-2
inhibitors in 2004 because of concerns over both safety and cost—a stance
better understood with time.36
Conclusion and final commentsThis paper describes PHARMAC’s clinical and economic
considerations for trastuzumab for HER2-positive early breast cancer. Like all
funding decisions, a wide range of factors are relevant and important to inform
decision-making. While some may argue that clinical effectiveness alone
is what is important, the reality of funding decisions in a cost
constrained environment (where Health dollars are not infinite) is that clinical
effectiveness must be considered alongside other relevant decision factors. Such
factors include economic and practical considerations, and comparison with other
health opportunities—the very basis for PHARMAC’s nine Decision
Criteria. Hence clinical and funding imperatives are inextricable to
PHARMAC’s decision making.
A comparison of the 12-month sequential and the 9-week
concurrent trastuzumab regimens, in terms of both opportunity cost (costs of
trastuzumab and impacts on DHB services related to administration) and
cost-effectiveness, is included in Appendix 6.
With the funding of the 9-week concurrent regimen, DHBs and
PHARMAC have sought a practical and workable solution to enable subsidised
access to an effective trastuzumab treatment for HER2-positive early breast
cancer patients. DHBs support the funding of 9-week trastuzumab, and have stated
the $6 million per annum overall cost (which includes drug cost and
administration costs) of providing this regimen to be viable.
There is need for women with HER2-positive early breast
cancer to be able to fully and readily access this fully funded option for
trastuzumab. However, simply listing trastuzumab on the Pharmaceutical Schedule
in this setting will not necessarily reduce the regional variations in testing
for HER2-positivity that already occur, nor improve ethnic
disparities—where current health inequalities have
existed37 before and regardless of the
availability of trastuzumab (Appendix 2). Health need,
the availability of other treatments and the Government’s priorities for
health funding (which include cancer) are also included in PHARMAC’s
decision criteria; as with breast cancer, there are other areas of high need
that also need to be considered when assessing competing funding choices (see Appendix 1).
PTAC considers that more clinical research is needed to
determine if long duration concurrent treatment (12 months) is more efficacious
than short duration concurrent treatment (9 weeks), and has recommended that a
comparative study should be performed (Appendix 5). PHARMAC remains open to the
possibility of funding longer regimens of trastuzumab, if data indicate that
funding would not result in unacceptable opportunity costs. To this end, PHARMAC
has already committed funding for international efforts (the SOLD trial) to
resolve the question of optimal
duration,38§§§§ given the
lack of direct head-to-head comparative evidence for the superiority of either
9-week or 12-month regimens.
Competing interests: None.
Author information: Scott Metcalfe, Chief
Advisor Population Medicine; Jackie Evans, Therapeutic Group Manager; Ginny
Priest, Analyst/Health Economist, PHARMAC, Wellington
Correspondence: Dr Scott Metcalfe, PHARMAC,
PO Box 10254, Wellington. Email: scott.metcalfe@pharmac.govt.nz
Endnotes:
* In July 2006, PHARMAC decided not to fund the
12-month sequential regimen at that time. There is uncertainty about the
long-term treatment benefits in relation to the very high cost and impact on
hospital services. This uncertainty has implications for future treatments
measured against (or added to) standard-of-care regimens that include 12-months
of sequential trastuzumab in the clinical trial setting.
PHARMAC was asked by the supplier to make a decision on
funding 12-month trastuzumab predominantly on the basis of the results of the
HERA trial’s interim report of the effects of 1-year’s sequential
treatment after 12 months median follow-up (Piccart-Gebhart et al NEJM
20057). PTAC raised a concern over the
durability of response and the long-term balance of safety and efficacy. PHARMAC
had concerns over the uncertainty from a cost-effectiveness point of view for
such a relatively large investment in a pharmaceutical (around $25m per annum
out of a total cancer spend of about $50m per annum), in relation to
PHARMAC’s legal responsibility to ‘secure for eligible people in
need of pharmaceuticals, the best health outcomes that are reasonably achievable
from pharmaceutical treatment and from within the amount of funding
provided’ (s47 NZPHD Act 2000). According to PHARMAC’s analysis, in
order for 12-month trastuzumab to be considered cost-effective in comparison
with other pharmaceuticals being considered for funding, the response would have
to be durable and become progressively better over time. This finding was
consistent with the result of other international
analyses.26 8
† Currently docetaxel and paclitaxel are funded
and available through DHB hospitals for metastatic breast cancer (Stage IV), and
paclitaxel for node-positive early breast cancer.
‡ A sixth study, ECOG E2198 (Sledge et al. SABCS
200618), which compared 12 months with 10 weeks
trastuzumab given concurrently with paclitaxel, was presented as a poster at the
San Antonio Breast Cancer Symposium in 2006; however this study has not reported
outcomes against standard treatment.
§ Numbers of patients in the study arms reported
in the HERA trial differ between the first (12-month median follow-up) and
second (23-month median follow-up) interim publications of the trial
(Piccart-Gebhart et al. NEJM 2005, Smith et al. Lancet 2007)
** PHARMAC commissioned Dr. Susan Wells, Senior
Lecturer in Clinical Epidemiology at EPIQ (Effective Practice, Informatics &
Quality Improvement www.epiq.co.nz),
University of Auckland to further critically appraise the five relevant clinical
trials (HERA, B31, N9831, BCIRG006, and FinHer) using the full Graphic Appraisal
Tool for Epidemiology (GATE) framework (http://ebm.bmj.com/cgi/content/full/11/2/35),
in order to summarise and independently assess the strength and quality of all
the available relevant RCTs.
Dr Wells obtained both specialist clinical
epidemiological peer review and specialist oncologist content review of each of
the GATE appraisals. The analysis was restricted to critically appraising the
five individual RCTs as published or otherwise reported; it was not intended to
integrate the epidemiological evidence with patient preferences, policy issues
or clinical considerations, nor provide a meta-analysis or systematic review or
other formal policy advice.
†† The CaTSoP recommended that, in the
absence of availability of funding for 12-months treatment, 9-week treatment
would be reasonable and gave this recommendation a high priority. The
subcommittee did however wish to emphasise that this recommendation was strongly
based on financial considerations, since the subcommittee had more confidence in
the 12-month treatment results.
‡‡ “Hypothetically, all (or almost
all) breast cancer cells need to be eradicated for cure. Concomitant
administration of the most effective agents available is an obvious strategy to
achieve complete eradication of all subclinical cancer. Based on in vitro data,
the combination of trastuzumab and docetaxel may be one of the most synergistic
ones of all the trastuzumab combinations available to date. These in vitro
findings are supported by the clinical data suggesting high activity of the
docetaxel plus trastuzumab regimen in the adjuvant, preoperative systemic, and
metastatic setting. Long duration of adjuvant administration of single-agent
trastuzumab might also result in cancer cell eradication and gradual death of
dormant cancer cell populations, although the bulk of evidence suggests that
trastuzumab administered in combination with chemotherapy is more effective that
trastuzumab given as a single agent.” (Joensuu – SOLD
protocol)
§§ The efficacy results of the FinHer trial
suggest that concomitant administration of trastuzumab with docetaxel is
effective in the treatment of HER2-positive early breast cancer. In the FinHer
study trastuzumab was administered weekly concomitantly either with 3-weekly
docetaxel or weekly vinorelbine, followed by 3 cycles of FEC in each arm.
Docetaxel improved recurrence-free survival as compared to vinorelbine (hazard
ratio 0.58, 95% CI 0.40 to 0.85), and trastuzumab improved recurrence-free
survival as compared to the same chemotherapy administered without trastuzumab
(hazard ratio 0.42, 95% CI 0.21 to 0.83). During a median follow-up time of 3
years these treatments were not associated with detectable cardiac toxicity. The
data suggest that the combination of docetaxel plus 9-week concomitant
trastuzumab is effective and well tolerated in the treatment of HER2-positive
breast cancer.
*** More patients would be eligible for trastuzumab
under the FinHer regimen than the 12 month HERA sequential regimen or Romond
(B31, N9831 Arm C) concurrent regimen, because patients receive their
cardiotoxic chemotherapy (anthracycline) after trastuzumab in the 9-week
regimen, therefore, more patients would be expected to meet the cardiac
inclusion criteria required for trastuzumab treatment. Using the methods and
base assumptions used in the KCE 2006 report (pages 51, 72), applying excess
rates of LVEF decline (sourced from Romond 2005, etc.–see KCE
20068) to age-specific New Zealand HER2+ve
breast cancer registration data (Cancer Register breast cancer registrations
August 2001-December 2005, obtained from NZHIS) means potentially 18% more
patients would be able to receive trastuzumab treatment with the 9-week
concurrent regimen as per FinHer compared with 12-month sequential or concurrent
treatment regimens.
 ††† The low cardiotoxicity observed
in FinHer could also be explained by the relatively low cumulative total dose of
180 mg/m2 epirubicin while the maximum tolerated cumulative dose of epirubicin
is around 720mg/m2. In the B31/N9831 studies doxorubicin was administered at a
cumulative dose of 240 mg/m2 while its maximum tolerated cumulative dose is only
500 mg/m2. Epirubicin is generally presented as a less cardiotoxic agent
compared with doxorubicin. The KCE report8
states that in terms of cardiotoxicity that no conclusions however can be drawn
on the relative importance of the trastuzumab anthracycline treatment order, on
the duration of trastuzumab administration, nor on the type of anthracycline and
its dose. Multiple variables differ between the pre- and post-anthracycline
regimens studied.
‡‡‡ The minimum extent that disease
recurrence can confidently be expected to reduce in FinHer was 17% ((HR 0.42
(95% CI 0.21-0.83), hence minimum relative hazard reduction
(RHR) = 1-0.83 = 0.17). This compares with a 19% minimum extent that disease
recurrence can confidently be expected to reduce with 12-month sequential
treatment (combined HERA 23-month median follow-up and N9831 Arm B data overall
HR 0.70 (0.61-0.81), hence minimum RHR =1-0.81 = 0.19)
§§§ Section 25 of the Medicines Act 1981
allows the practitioner to "procure the sale or supply of any medicine" for a
particular patient in his or her care. "Any medicine" includes approved and
unapproved medicines. The Act puts no restriction on the use of a medicine, even
in a situation in which it is contraindicated. However, whether the practitioner
uses approved or unapproved medicines, they must provide care of an adequate
professional and ethical standard. Clinicians need to obtain informed consent
from their patients for such ‘off-indication’ use.
Section 25 prescribing is not unusual in oncology or
other areas of medicine, with rates stated to be up to 40% in adults and up to
90% in paediatric patients.23. Routine
off-label use can be justified if there is high-quality evidence supporting
efficacy or effectiveness.23 There are already
a number of unapproved indications present in the Pharmaceutical Schedule
listings for cancer treatments.
The evidence required to make a funding decision is not
necessarily the same as that required to instigate a Datasheet change. In the
context of a funding decision, PHARMAC considers that the level of evidence for
9-week concurrent trastuzumab, when combined with other decision criteria, does
justify giving clinicians and patients the choice to access a funded treatment
under Section 25. There would be no compulsion on oncologists or their patients
to exercise that choice. The evidence required for a change to the Datasheet may
need to be different, since the Datasheet dictates the supplier and Medsafe
liabilities with respect to a product.
With any product there is a continuum of data, ranging
from weak data in some settings, to statistically strong and repeatable data in
other settings. Decisions regarding different applications of this continuum of
data are based on different ‘hurdles’ for levels of evidence. For
example Section 29 and Section 25 of the Medicines Act 1981 specifically aim to
permit clinicians to use their discretion where they consider that the available
evidence justifies prescribing a drug for a particular patient outside the
Medsafe approved indication. In some cases it appears that evidence will simply
not have been made available to the regulator to enable Datasheet changes.
**** A QALY (quality-adjusted life year) is a standard
economic measure that considers how treatment affects patient quality of life
and quantity of life; QALYs combine the effects of changes in the length and
quality of life that result from treatment. The difference in net costs and
QALYs between treatments informs the relative cost-effectiveness of an
intervention, with a lower cost per QALY being more cost-effective. For further
details, see PHARMAC’s Prescription for Pharmacoeconomic Analysis at http://www.pharmac.govt.nz/pharmo_economic.asp
†††† PHARMAC’s indicative
cost-utility analysis for 12-month trastuzumab suggested relatively poor quality
adjusted survival benefits and nominal savings to DHBs, at $70-80,000/QALY base
case. This analysis showed a large range of plausible outcomes, largely due to
the uncertainty surrounding duration of benefit and untreated disease
progression. However, none of the plausible outcomes gave sufficient confidence
that 12 months of trastuzumab treatment would be a cost-effective use of health
funds compared with other investments.
‡‡‡‡ PHARMAC
analysis of the two HERA publications (Piccart-Gebhart 2005, Smith 2007).
The 23-month median HERA f/u (Smith 2007) comprises
cumulative hazards over the entire 23 months, with 218+321=539 first disease
recurrence events—in turn comprising events and hazards reported as
accruing by the first 12 months median f/u (Piccart-Gebhart) (127+220=347
events) and then the complement of events for the remaining time period
(539-347=192), i.e. events occurring in the time since the first analysis.
Analysis therefore involves subtracting events recorded as accruing in the first
time period (12 months median follow-up) from the cumulative events recorded as
accruing over the whole time period analysed to date (23 month median
follow-up). This derives numbers of events occurring in the time since the first
analysis, in order to calculate period-specific rates and relative risks. In
turn this allows testing for statistical interaction (comparing the two time
periods) using standard binomial methods (Matthews & Altman BMJ 1996 http://www.bmj.com/cgi/content/full/313/7061/862,
Altman & Bland BMJ 2003 http://www.bmj.com/cgi/content/full/326/7382/219).
See Appendix 4 for further details.
§§§§ The Synergy
or Long Duration (SOLD) study will assess the incremental efficacy and risks of
adding an extended period of sequential trastuzumab to a short course of
concurrent therapy (prior to anthracyclines) in HER2-positive early breast
cancer. The trial, planned to enrol 3,000 patients internationally and follow
them for at least 5 years, will compare 9 weeks’ trastuzumab, concurrent
with chemotherapy (the FinHer regimen), compared with an additional 42 weeks of
trastuzumab.
References:
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