Download 1 - Healthcare Improvement Scotland

1
DISCUSSION
1.1
Scope of the HTA
This HTA evaluates the issues of clinical effectiveness, cost effectiveness, patients’ needs
and preferences, and organisational issues that pertain to the introduction and
development of PET imaging facilities for the management of cancer in Scotland. As
outlined in section 1, this report has focused on full-ring PET scanners and on the use of
the radiopharmaceutical FDG. This is appropriate as gamma cameras and combined
PET/CT machines have a weaker evidence base than full-ring PET and most oncology
applications use FDG.
This HTA has taken data and evidence from a broad range of sources (including, but not
limited to, peer-reviewed literature, preprints and manufacturer submissions) and
critically appraised it to ensure that analyses of clinical and cost effectiveness are as
robust as possible.
1.1.1
Clinical effectiveness - NSCLC (section 4)
There is clear evidence from the systematic review and meta-analysis conducted by
HTBS that FDG-PET imaging is both more sensitive and more specific than CT scanning
in mediastinal staging for N2/N3 lymph nodes in patients with potentially operable
NSCLC. There is some evidence from less robust studies that FDG-PET more accurately
detects previously unsuspected metastatic disease. In terms of changes in patient
management, published studies indicate that after FDG-PET, between approximately
10% and 40% of patients had management altered. However, these results arise from case
series that may specifically select patients and so may be biased.
Three studies have reported the findings of surveys of the use of FDG-PET in NSCLC in
routine clinical settings. The most recent of these (Seltzer et al., 2002) illustrates the
problematic nature of these surveys and the danger of attempting to draw conclusions
from them. They sent survey questionnaires to 292 physicians, who referred 744
consecutive lung cancer patients for FDG-PET. Only 48% of the physicians responded to
the questionnaire and this covered just 37% of the lung cancer patients.
Two randomised controlled clinical trials (Boyer et al., 2001 and van Tinteren et al.,
2002) have been performed to assess the effect of FDG-PET scanning in NSCLC. In both
trials patients were randomised between conventional staging for mediastinal
involvement and conventional staging plus FDG-PET scanning. The primary outcome in
both cases was the number of ‘futile’ thoracotomies avoided. The trials produced
apparently conflicting results; van Tinteren et al. (2002) reported a 50% reduction in the
number of ‘futile’ operations, whereas Boyer et al. (2001) reported no difference between
the two groups. This discrepancy appears to be caused by a difference in approach to
patient management between the two groups of investigators. Specifically, Boyer et al.
(2001) report that, in their institution, patients with early N2 disease undergo surgery and
that a similar number of operations would have been avoided had the policy of avoiding
surgery for N2 patients, as in the Dutch study, been in place. Neither of these studies
reported quality of life measurements.
1.1.2
Economic evaluation NSCLC (Section 5)
Cost-utility analysis was used to compare seven diagnostic strategies for patients who
have undergone chest X-ray and biopsy and are thought to have potentially operable
NSCLC. Strategies 1 and 2 consider sending all patients to surgery or all to oncology and
were included for model testing purposes. Strategy 3 reflects current standard practice in
Scotland (without FDG-PET). Strategies 4 to 7 included FDG-PET in the diagnostic
pathway in a variety of ways, before or after mediastinoscopy. In line with other
economic models of NSCLC and anticipated use of PET in Scotland, it is assumed that
all patients have undergone a CT scan prior to implementing any of the strategies.
Of the plausible clinical strategies (strategies 3 to 7), 3 and 7 were shown to be cost
effective in the base case model for CT-negative patients, but strategy 7 was not cost
effective for CT-positive patients. In strategy 7 those who are FDG-PET negative are sent
to surgery, while FDG-PET positives are sent for a confirmatory mediastinoscopy and
then to surgery or non-surgical treatment and it is notable that the greater value is
achieved in this strategy for those patients who have better prognosis, i.e. the CTnegatives.
It also appears that the closer FDG-PET accuracy in detecting M1 disease approaches
that in detecting N2/3 disease the greater will be the cost effectiveness of moving to
strategy 7, particularly among CT-positive patients.
Strategy 1, all for surgery, also appeared to be promising in the model, but this strategy is
associated with a large number of futile operations and so would not be appropriate in
clinical practice. However, this highlights a weakness in the model, that it was not
possible to quantify the utilities associated with avoidance of futile surgery.
Another strategy of sending all patients for FDG-PET, prior to CT, is not cost effective
compared with strategy 7. This is not surprising as it is not possible to differentiate the
CT-negative and CT-positive patients in advance in this strategy and the value of PET in
CT-positive patients is less clear.
In CT-negative patients, the base-case analysis suggests that moving from strategy 3 to
strategy 7 is cost effective (ICER £10,475). However, in CT-positive patients, the case
for moving from strategy 3 to strategy 7 is weak (ICER £58,951) due to the poor
specificity of FDG-PET in these patients. Even for CT-negative patients, strategies 3 and
7 were not strongly differentiated by patient impact as measured by QALYs, and
different utility values could lead to different rankings between these two strategies. Thus
the value of using FDG-PET added to the current standard of diagnostic workup in terms
of QALYs is not clear.
Another way of evaluating the strategies is to consider the number of correct operations
undertaken and the number of futile operations avoided. Among CT-negative patients,
strategy 7 avoids an additional 6% of patients undergoing futile surgery compared with
strategy 3. This is due to the superior specificity of FDG-PET in CT-negative patients.
Among CT-positive patients only an additional 1% of patients avoid futile surgery with
strategy 7 compared with strategy 3.
It cannot be unambiguously stated which of strategies 3 and 7 is the more cost effective,
nor is it possible to estimate the probability of the individual strategies being cost
effective. The principal conclusion is that FDG-PET is most likely to be cost effective
when followed by a confirmatory mediastinoscopy in patients who are FDG-PET positive
in mediastinal lymph nodes.
It is also more likely to be cost effective in CT-negative than in CT-positive patients.
However, the information gaps render a definitive conclusion on the cost effectiveness of
using FDG-PET in NSCLC inappropriate at this time. Health services research in a
clinical setting is required to address the data gaps in diagnostic accuracy, particular for
distant metastases, in treatment life expectancies, and in determining patient utilities
associated with avoiding futile surgery.
1.1.3
Clinical effectiveness – Lymphoma (Section 6)
Although the studies of accuracy in restaging lymphoma after induction therapy are
generally retrospective and include heterogeneous patient groups (the majority of series
include both HD and NHL patients), a consistent picture emerges of FDG-PET being at
least as sensitive, and substantially more specific, than CT for the detection of viable
residual disease.
1.1.4
Economic evaluation – Hodgkin’s disease (Section 7)
The cost-effectiveness modelling was restricted to restaging HD. The model examined
the value of using FDG-PET as an adjunct to, or a replacement for, CT scanning for the
assignment of patients to consolidation therapy or surveillance after induction therapy.
The base-case analysis suggested that the use of FDG-PET after a positive CT scan
(strategy 4) and the use of FDG-PET to replace CT (strategy 5) were both cost effective
relative to the use of CT alone, provided the willingness to pay per life year exceeded
£1,000. Strategy 5, replacing CT by PET, was both clinically more effective and less
expensive than strategy 4.
Sensitivity analyses showed that both strategy 4 and strategy 5 remained cost effective
for at least 95% of simulations from the joint distribution of input values, provided that
the willingness to pay per life year exceeded £5,000. The probability of cost effectiveness
for strategy 5 at a specificity of 70% exceeded 95%, provided the willingness to pay
exceeded £5000.
Increasing the discount rate on benefits from 1.5% to 6% reduced the apparent superiority
of FDG-PET containing strategies relative to other approaches. However, there was little
impact on cost effectiveness for either strategy 4 or strategy 5, except that the probability
of cost effectiveness for strategy 4 in 20-year-old males reached 90% only if the value of
a life year exceeded £15,000.
Overall, the model predicts that 36% of patients restaged using CT alone will receive
unnecessary consolidation RT. This would be reduced to approximately 5% with either
FDG-PET strategy.
The robustness of the modelling results to uncertainties and altered assumptions,
alongside the low cost per life year gained and benefits in terms of avoidance of
unnecessary RT, indicate that FDG-PET provides substantial value in the restaging of
HD.
Although the role of FDG-PET scanning in NHL has not been modelled in this HTA, the
accuracy demonstrated in section 6 is likely to translate into significant patient benefits in
this indication. Since the main area of uncertainty in NHL is whether a combination of
CT and prognostic scores is sufficiently accurate in selecting patients for consolidation, it
will be appropriate to study the comparative accuracy of FDG-PET and conventional
methods in a prospective study.
1.1.5
Clinical effectiveness – Other clinical applications (sections 2.3 and 2.4)
1.1.5.1 Cancer
In the USA, Medicare currently reimburses FDG-PET imaging for specific management
decisions in NSCLC, SPN, lymphoma, colorectal cancer, head and neck cancers,
melanoma, oesophageal cancer and breast cancer and is considering extending its
reimbursement to include some central nervous system tumours.
A number of countries have undertaken HTAs of FDG-PET in cancer. Most have reached
similar conclusions that FDG-PET is more accurate than conventional technologies, but
that the evidence for translating this into patient benefit, even just change in patient
management, is weak and often relies on case series of selected patients. Consequently
definitive conclusions cannot be drawn about the clinical and cost effectiveness of PET in
these various indications at this time and further evaluation of the technology is
necessary.
In Australia, MSAC (2000 and 2001) concluded that there was insufficient evidence to
recommend unrestricted funding, but that FDG-PET is safe, and potentially clinically and
cost effective in a number of cancers (NSCLC, melanoma, recurrent colorectal cancer,
recurrent ovarian cancer, cervical cancer, oesophageal cancer, gastric cancer, lymphoma,
head and neck cancer, sarcoma). They recommended that interim funding be made
available for use of FDG-PET in these cancers, according to MSAC-approved
prospectively designed studies, with all data sent to a central coordinating body, to better
determine the clinical and cost effectiveness of FDG-PET.
The cancers highlighted by MSAC are wide ranging and some have a weaker evidence
base than others. Other HTAs would imply that the strongest evidence of clinical
effectiveness is available for NSCLC, SPN, recurrent head and neck cancer and
malignant melanoma (DACEHTA, 2001). DACEHTA concluded that the evidence for
the value of FDG-PET in recurrent colorectal cancer was sparse; it may be ‘important’
but was probably influenced by poor prognosis in this cancer. For breast cancer, it was
noted that there were a number of sources of error in the presented trials but that it looked
‘promising’. They note that clinical development is also being pursued in lymphoma,
oesophageal, brain and testicular cancer.
1.1.5.2 Cardiology, neurology and psychiatry
There is general agreement that, so far, the evidence of benefit in cardiology, psychiatry
and neurology is weaker. Furthermore, there are good alternative techniques to aid
clinical decision-making in cardiology. In dementia, the benefit achieved would probably
be small due to the modest benefit of currently available treatments. Consequently more
research is needed of the value of PET in these conditions before it is brought into routine
clinical use.
1.1.6
Safety (Section 4.6)
The literature shows no evidence of any important short-term adverse events related to
PET scanning. Therefore, it is reasonable to conclude that PET is essentially free from
short-term adverse effects.
There is a risk of second cancers posed by the radiation dose used in PET scanning, but
this is very small (a lifetime cancer risk of less than one in 3000 for a person of normal
life expectancy) and comparable with that associated with CT.
1.1.7
Patient issues (Section 8)
Patients need to be fully informed about the imaging process and any side effects.
Information given by consultants is valued but checks are needed to ensure that
information has been understood by the patient. Advice about current services,
counselling and any risks should be provided without people having to ask for it.
Information for carers is also needed.
There is evidence from lymphoma patients that some value the additional information
provided by an FDG-PET investigation and the reassurance that this provides. Patients
also value the timeous treatment they currently receive once the diagnosis has been made.
However, there is a perception that the system is ‘bottlenecked’ at the initial diagnosis
stage. Therefore it is important that the addition of a PET scan to the diagnostic work-up
does not lead to additional delays in the initiation of treatment.
PET imaging should be coordinated with other diagnostic procedures to minimise
travelling, disruption and anxiety. The facilities should be created to make the patient feel
comfortable and at ease with the process.
Following the introduction of clinical PET in Scotland, further research is required to
understand the needs and preferences of patients and carers.
1.1.8
Organisational issues and costings (Section 9)
PET facilities and cyclotrons should be organised to provide appropriate provision and
equitable access for all patients with cancers that may benefit from imaging. The layout
of the facility and production and transportation of radiopharmaceuticals must comply
with legal requirements. Specialist training and accreditation must be created for
radiopharmacists, radiochemists and cyclotron engineers and appropriate training must be
given to all those involved in the multidisciplinary cancer team.
Any PET facility would have to guarantee a reasonable service to patients from across
Scotland, without disadvantaging those in the more rural and remote areas, such as the
rural Southwest and the Highlands and Islands. The risk that the provision of PET
scanning might further slow down the progress from initial diagnosis to definitive
treatment, by introducing a further rate-limiting step in the patient’s journey, should be
recognised and addressed.
A PET facility incorporating a cyclotron to produce its own radiopharmaceuticals and
integrated with other nuclear medicine facilities has the lowest running costs and cost per
scan (£677). However, the capital outlay for such a facility is substantial (approximately
£4.25 million) and there would be a time delay to build the new facility. Capital outlay
may be reduced (£1.83 million) if the radiopharmaceuticals are available from an
alternative source and a cost per scan of £777 to £900 is estimated, depending on distance
from source and provider (NHS or commercial). Both these facilities have a total annual
running cost of just over £1 million.
It will take approximately two years to build a PET facility and a further year until it is
operating at full capacity. Interim solutions should therefore be considered, particularly
for the restaging of patients with HD. One possible interim option is the use of the John
Mallard Scottish PET Centre in Aberdeen, which is currently used as a research facility
but could potentially provide a service element for 2 or 2.5 days a week, with an
estimated throughput of 300 to 400 patients per annum. The use of other UK facilities for
HD staging could also be considered.
An alternative mode of delivery would be the use of a mobile facility. This would be
more expensive on a cost per scan basis (approximately £1,130) and for annual running
costs (approximately £1.5 million), but would be quicker to establish and would involve
very little capital outlay. However, there is little experience of such mobile PET facilities
in the UK and FDG would need to be sourced.
1.2
Assumptions, limitations and uncertainties
It may be argued that PET is being judged more stringently than previous diagnostic
tests. However, given the substantial capital and running costs associated with a PET
facility and the competing demands for limited health care resources, it is entirely
appropriate to subject it to evaluations that will determine its value in routine clinical
practice.
In summarising the Medicare reimbursement process for diagnostic tests, Newman
(2001) identified that reimbursement depends not only on the sensitivity and specificity
of the test, but also evidence of change in patient management or outcomes. The value of
a test must be considered in terms of its impact on clinical treatment.
This highlights the difficulty in assessing a diagnostic procedure. With the exception of
two trials in lung cancer (van Tinteren et al., 2002 and Boyer et al., 2001), and a small
number of economic modelling studies, the research literature has focused on the issue of
superior diagnostic accuracy, with little attention paid to ‘higher level’ outcomes
(Fryback & Thornbury, 1991) such as the outcome of the patient’s disease. The evidence
available of superior diagnostic performance, although important, does not directly
answer the key questions about final patient outcomes and quality of life. The analyses
attempted in this review are therefore necessarily based on modelling, and on
assumptions that are sometimes difficult to verify.
A common criticism of models is that the wide freedom of action given to the analyst
may cause bias (Buxton et al., 1997; Kassirer & Angell, 1994). Certainly, any largescale analysis of a problem risks bias, and in this respect an ambitious model is more at
risk than the dataset from a single randomised, controlled, trial. However, models usually
address larger problems than trials, considering how evidence can be translated into
clinical practice given a much longer time horizon than it would be practicable to study in
a trial.
1.2.1
Assumptions
Models require specification of the patient pathway and prediction of response along that
pathway until the death of the patient. Such modelling inevitably depends on a number of
assumptions. These have been obtained by discussion with experts and literature-based
estimates.
1.2.2
Limitations
This HTA has focused on the use of FDG-PET within oncology, and specifically in the
areas of preoperative mediastinal staging of NSCLC and restaging of HD. As explained
in section 1, this has been necessary to allow detailed economic modelling. However, the
conclusions stated here should be considered alongside the other HTA work presented in
section 2, which presents evidence on clinical effectiveness in other areas of oncology,
and for cardiology and neurology, and the need for structured clinical research (see
section 10.4).
As this HTA has focused on the ‘patient and societal’ outcomes of the technology
(Fryback & Thornbury, 1991) it has not looked at the more speculative ‘researchorientated’ uses of FDG-PET, such as monitoring response to therapy and following the
distribution of appropriately labelled cytostatic drugs (e.g. Strauss, 1997; Jerusalem et al.,
2000; Smith et al., 1998). Arguably, in doing so, it may understate the future value of
PET scanning to Scotland’s health.
Knowledge about the patient experience and patients’ needs and preferences in relation to
PET imaging is weak. Lack of published research in this area, the absence of patient
experience of PET in clinical practice in Scotland and difficulties in recruiting
participants for patient issues focus groups have resulted in a limited understanding of
these issues. This information needs to be gathered from a diverse group of patients.
As the utility value of different health states for patients or members of the public is not
known, the economic model could not be informed by this information. Additionally, it
would seem reasonable that PET may provide knowledge that has a role in reassuring
patients and reducing anxiety and that, as individuals, patients will value treatment
differently. This has been considered in the assessment, but could not be quantified.
Furthermore, appropriately using this qualitative information in an economic model poses
a considerable challenge.
It has not been possible to determine whether undertaking a PET investigation would
increase the time to diagnosis and subsequent treatment. Clearly this should be avoided
and so careful consideration should be given to the scheduling of PET scans. The
existence of such delays should be monitored as part of continuing health services
research in the use of PET in NHSScotland, by comparing times to diagnosis and
treatment for cancers in which PET scanning is, and is not, offered as part of the
management pathway. Similar research should be directed at ensuring that geographical
and socioeconomic equity of access to PET facilities is maximised.
1.2.3
Uncertainties
In NSCLC, univariate and bivariate sensitivity analyses have been used to draw out the
uncertainties in the model. These have been sufficient to identify the instability in the
model and the need to determine key pieces of information more clearly, particularly
valuation of avoidance of futile surgery.
For HD, uncertainties have been formally modelled in a multivariate manner using
Bayesian techniques and these have shown that the model is robust to all areas of
uncertainty.
1.3
Future developments
The information on imaging time used in this report has been obtained from St Thomas’
Hospital and is based on a PET scanner that is nine years old. There is anecdotal
information that recent advances in technology have resulted in reduced scanning times
and increased patient throughput, with a corresponding impact on the cost per
investigation. However, currently there are no published data to support this (see also the
discussion of PET/CT in section 2.5.5.2).
The current assessment is based on full-ring PET systems using BGO scintillation
crystals. New crystals are being developed that may improve the image quality of PET
scanners in the future. However, it is likely that these systems will be more expensive.
1.4
Research
Close cooperation is required among all those involved in cancer care to determine which
clinical areas might benefit most from PET imaging investigations. This applies both to
future scientific studies, to the evaluation of published data and to the planning of
diagnostic and treatment guidelines.
It is recommended that all patients undergoing a FDG-PET scan should have outcomes
recorded, either through participation in national or international clinical trials to confirm
and extend the current applications of FDG-PET, or through health services research
constructed to allow costs and patient outcomes to be recorded to inform economic
modelling. It will be particularly valuable to identify cancers with a good prognosis
where the accuracy of alternative diagnostic or response monitoring mechanisms is poor.
Appendix 27 recommends data that should be collected for the ongoing clinical and
economic evaluation of FDG-PET imaging in NHSScotland. Additionally, as indicated in
section 8, information about the patients’ experiences, preferences and needs in relation
to PET imaging needs to be recorded.
The collection of all data must, of course, comply with all regulations on confidentiality
and security of patient information and patient consent as presented in the report on
Protecting Patient Confidentiality (CSAGS, 2002).
It is clear that for most, if not all cancers, such trials cannot be confined to Scotland, but
must take place collaboratively across the UK, or possibly across Europe. However, it is
vitally important that Scottish patients are encouraged to enter clinical trials. A recent
review shows that only 2.4% of patients of all newly diagnosed lung cancer patients in
Scotland (small cell and non-small cell), were recruited into clinical trials in 1997-1998
(Scottish Executive Health Department, 2001c).
It is noted that the costings for the PET facility do not include research costs, so it will be
essential to obtain funding from elsewhere.
The National Cancer Research Institute (NCRI) is a UK body comprising the main cancer
research funders and is responsible for the strategic leadership of cancer research in the
UK. The National Cancer Research Network (NCRN) was established in April 2001 by
the Department of Health to improve the quality, speed and integration of cancer clinical
trials and thus to improve patient care. The NCRN is expected to double recruitment into
clinical trials in England within the next five years. It will do this through the creation of
cancer research networks, closely aligned to NHS cancer service networks, and in close
collaboration with NCRI on a range of issues that impact on the quality and management
of cancer research. The establishment of a Scottish Cancer Clinical Trials Network is
currently underway and it is proposed that this organisation will work in partnership with
NCRN (and therefore within NCRI). It is envisaged that the Scottish network will map
onto the three existing regional networks, which are established in the north, south, east
and west of Scotland. These networks provide an ideal framework on which to build
research governance requirements, including peer review and protocol development.
In the UK, the NHS HTA programme is also considering proposals for primary HTA
research in PET imaging. HTBS recommends that this be focused on the cancers
determined by DACEHTA to have promising evidence of clinical effectiveness (NSCLC,
SPN, recurrent head and neck cancer and malignant melanoma) and on lymphoma.
Three main areas of clinical and economic evaluation can be identified:
 translation of the superior accuracy of FDG-PET into clear patient benefits or cost
savings;
 translation of the ability of FDG-PET to image metabolism into clear patient benefits
or cost savings; and
 methods of using FDG-PET to facilitate other research in oncology.
These three areas are discussed in the following sections.
1.4.1
Exploiting the superior accuracy of FDG-PET scanning
Although there is considerable evidence that FDG-PET scanning is more accurate than
CT scanning in many forms of cancer, there are few published studies that establish the
impact of the superior diagnostic accuracy of FDG-PET on patient outcomes, such as
survival and quality of life in NSCLC. Trials of this kind will need to be designed and
justified by the detailed modelling of possible patient outcomes and associated costs and
benefits.
Studies using Markov models, as described for example, in Fenwick et al. (2000), can be
used to support the development of clinical studies. This type of approach, firmly based
on a combination of clinical knowledge and modelling, is likely to yield novel
approaches to the use of FDG-PET to improve patient survival and quality of life, and
will be vital if the promise of FDG-PET is to be realised.
Trials focusing on improving the delivery of effective treatment to patients rather than
diagnostic accuracy, are essential in proving and realising the value of PET scanning to
the NHS. In addition to trials focused on the ‘avoidance of futile therapy’ (e.g. van
Tinteren et al., 2002) FDG-PET may, more positively, help to improve survival by
improving the planning of radical RT.
1.4.2
Exploiting the imaging of function
In addition to better diagnostic accuracy, FDG-PET is able to give visual representations
of changes in the tumour that occur as a result of treatment. Consequently, FDG-PET
may be useful in identifying response early in a course of treatment (Smith et al., 2000),
for example in neoadjuvant therapy for breast cancer or in treatment of high-grade NHL.
This may enable an early change of treatment in non-responders, but this clearly needs to
be proven in a randomised trial.
1.4.3
Facilitating research
PET scanning may be of value in a number of ways in cancer research:
 in defining response to treatment in early phase studies (e.g. van Oosterom et al,
2001);
 ‘proof of principle’ studies to demonstrate that tumour response as determined by
pre- and post- treatment PET scans can serve as a surrogate outcome variable
(Prentice, 1989; Lin et al., 1997) for long-term survival in cancer trials;
 facilitating development through pharmacodynamic studies in clinical trials
(Aboagye et al., 2001); and
 improving selection of patients for clinical trials by better staging.
1.4.4
Approximate scan numbers in Scotland
Using a PET facility for a mix of routine clinical use for restaging HD and health services
research to inform economic models, the following calculations may provide a rough
guide to capacity requirements in Scotland. The recommendations for health services
research are based on DACEHTA’s clinical effectiveness conclusions (10.1.5.1)
(DACEHTA, 2001) and are estimates of the number of patients who might be eligible for
scanning if these recommendations were adopted in Scotland.
Estimates of incident cases are taken from the ISD website figures, which quotes for
1998 <http://www.show.scot.nhs.uk/isd/cancer/facts_figures/facts_figures.htm>.
When choosing cancers to be evaluated, it should be remembered that the maximum
capacity for a PET facility is estimated to be approximately six patients per day
(approximately 1500 patients per year). Combining the reasonably conservative estimates
presented here, approximately 1600 patients per annum would require scans.
1.4.4.1 Routine clinical use
Restaging HD: 130 incident cases, 75% receive chemotherapy, 90% response implies
approximately 90 patients.
1.4.4.2 Health services research
Restaging NHL: 1020 incident cases, approximately 50% receive chemotherapy, 90%
response rate implies 450 patients.
Staging NSCLC: In 1997, 880 patients underwent surgery for NSCLC, so it may be
estimated that 1000 FDG-PET scans may be required for those potentially eligible for
surgery in 2003. If FDG-PET scanning is restricted to CT-negative patients only, this
figure would be reduced to approximately 640 patients.
SPN: No Scottish incidence data, but comparison with imaging figures from US centers
suggests that up to 200 patients may require scans (MSAC recommends that PET
scanning be restricted to patients with low pre test probability of malignancy or who are
unsuitable for fine-needle aspiration biopsy). However, only between 80 and 120 of these
patients are likely to have potentially resectable CT-negative malignant disease, therefore
the additional number of scans required is unlikely to exceed 120 patients (and may well
be fewer).
Recurrent head and neck cancer: Scottish incidence of this cancer is approximately 1100
cases per annum, and estimates of five-year recurrence rate are as high as 50%
(Sidransky et al., 1998). In practice the number of patients requiring FDG-PET will be
lower than the 550 this suggests because some patients will be too sick to benefit from
further treatment and some will clearly have distant metastases. Hence in the summary
calculation a figure of 150 patients is assumed for recurrent head and neck cancer.
Malignant melanoma: The draft SIGN guideline on melanoma suggests that PET is only
likely to be of value in stage III or IV disease. There are roughly 600 incident cases per
year in Scotland. US data (Coleman, 2002) suggest that 12% of cases are stage III/IV,
data from New Zealand’s Ministry of Health (1999) suggest that ~ 20% are stage III/IV.
Consequently, the number of scans needed is unlikely to exceed 100.
1.5
Summary and conclusions
HTAs from around the world agree that there is insufficient evidence to fully recommend
FDG-PET imaging as a standard technique in cancer management at this time. However,
improvements in diagnostic accuracy compared with other imaging modalities and weak
evidence of change in patient management from case series, indicate that FDG-PET is
‘potentially’ clinically and cost effective. Cancers for which there is general agreement of
potential value are NSCLC, SPN, recurrent head and neck cancer and malignant
melanoma.
There are only two good quality clinical studies that evaluate how FDG-PET has
improved patient outcomes. Both of these are in NSCLC, but they give somewhat
conflicting results as to the value of FDG-PET in avoiding futile surgery and are
dependent on the decisions taken by surgeons after FDG-PET, with benefit only
demonstrable if an operation on N2 patients is considered futile.
The economic modelling work undertaken in this HTA is particularly valuable for
assessing the role of PET in restaging HD where potential benefit (avoiding long-term
morbidity associated with unnecessary RT) is large, but also occurs a long time after the
scan. Collection of such outcome data is difficult in a clinical trial and this is a good
example of where a detailed model quantifying all associated uncertainties is helpful.
This model showed that either FDG-PET strategy was more cost effective than the
current practice, with use of FDG-PET instead of CT being most cost effective. This
shows the value of modelling work that can link changes in accuracy, with patient
management and long-term outcomes using evidence from a variety of sources and
sophisticated analyses of uncertainty to provide reassurance about the robustness of the
model.
The economic evaluation for staging NSCLC contains inherent uncertainties in the input
assumptions and indicates that FDG-PET is cost effective in CT-negative patients; if
those who are negative are sent for surgery and those who are positive are sent for
mediastinoscopy. Other possible uses for FDG-PET scanning, such as to replace
mediastinoscopy completely, do not appear cost-effective in this setting. However, this
model is less robust than that for HD and further work is needed to ensure that the value
of avoiding futile surgery is captured in the model.
The economic models both indicate that the value of FDG-PET would appear to be
greatest where the accuracy of other imaging or diagnostic techniques is poor and where
knowledge from FDG-PET imaging can lead to substantially better prognosis for the
patient. It is this finding that should drive future work with FDG-PET into its potential
clinical role.
Overall following the synthesis of evidence on clinical and cost effectiveness,
organisational issues and patient needs and preferences, HTBS believes that FDG-PET
can be a valuable tool in cancer management.
Claxton et al. (2002) suggest four possible recommendations from an HTA - ‘implement,
implement with further research, do not implement but conduct further research, do not
implement’. In the vocabulary of this article the recommendation from HTBS for FDGPET scanning is in the second category, i.e. that FDG-PET imaging should be
implemented in Scotland and that further research should be undertaken to confirm and
extend its usefulness.
FDG-PET is recommended for routine clinical use in restaging HD, in properly organised
health services research for other high-grade lymphomas, and in patients with NSCLC
who are CT-negative. Its use in SPN, recurrent head and neck cancer and malignant
melanoma looks promising from the viewpoint of diagnostic accuracy and research into
the specific value of FDG-PET in terms of patient outcomes and economic value in these
cancers should be determined as an early priority.
1.6
Recommendations to NHSScotland
As a result of this HTA, HTBS has made recommendations to NHSScotland about the
clinical and cost effectiveness of PET imaging for cancer management, these are
presented in full in the Health Technology Assessment Advice on positron emission
tomography (PET) imaging in cancer management (HTBS, 2002a). Listed below is the
summary of recommendations.

It is recommended that a PET imaging facility including a cyclotron, dedicated to
clinical use and specific health services research applications, should be set up in
Scotland to allow Scottish patients and researchers to realise the potential benefits of
FDG-PET imaging in cancer management as rapidly as possible. It should be linked
to an existing cancer centre, with functional links to the existing PET facility in
Aberdeen.

It will take approximately two years to build such a facility, so interim solutions for
the provision of PET imaging should be considered, particularly for the re-staging of
patients with Hodgkin’s disease. Possible options are the use of the John Mallard
Scottish PET Centre in Aberdeen, other UK facilities, or the use of a mobile PET
facility in a fixed location in Scotland.

All patients who require re-staging of Hodgkin’s disease should be sent for a FDGPET scan. Extension to the restaging of all patients with lymphoma should be
investigated by further research.

Appropriate research should be undertaken to inform economic modelling in order to
produce a robust assessment of the value of FDG-PET imaging in the staging of
patients with NSCLC who are CT-negative in the regional lymph nodes.

For other cancers, FDG-PET is likely to add most value where existing
diagnostic/monitoring techniques have poor accuracy and information from PET
imaging can substantially improve prognosis. This should be evaluated through health
services research, taking account of the clinical effectiveness results from other
international HTAs. Research priorities should be agreed with multidisciplinary
expert groups, Regional Cancer Advisory Groups, the Scottish Cancer Group, the
NHS HTA programme and other international research organisations. All research
should be coordinated with the Scottish Cancer Clinical Trials Network.

All patients undergoing FDG-PET should have outcomes recorded, either through
participation in a national or international trial to confirm and extend the current
applications of FDG-PET imaging or through health services research designed to
allow costs and patient outcomes to be recorded for economic modelling.