Clinical Question (in PICO format if possible)Requires analysis? aComment and explanation
1Topic 1. Imaging investigations for assessing disease extent and response to treatment (including PET)4. Medium priority for analysisThe number of patients who would be affected by this topic depends on what strategy is taken (e.g. imaging for all versus imaging for a specific subgroup of patients), it could potentially affect all patients covered by this guideline as well as some of those who fall outside its remit (i.e. patients shown not to have metastatic disease). In 2003 roughly 44,000 new cases of breast cancer were diagnosed (www​.cancerhelp.org.uk). NICE have estimated that between 16 and 20% of these cases present with advanced disease with distant metastases (NICE, 2003), but a figure of 5% might be more representative (GDG expert opinion). In addition it has been estimated that 50% of the newly diagnosed cases (22,000 patients) will go on to develop metastatic disease at some point in the future (NICE, 2003), although the GDG feel a more realistic current estimate would be between 20 and 30% (8,800 – 13,200 patients).

A variety of imaging modalities are considered in this question for the assessment of metastatic breast cancer which differ enormously in cost. Routine access to the newer, more expensive modalities such as positron emission tomography (PET) would have major resource implications for the NHS in terms of the capital and staffing investments required to provide national access, since the routine use of PET for this purpose was not accounted for in the 2005 DoH framework for the development of PET services in England. The DoH estimates that the cost of installing one PET-CT scanner, including the associated building costs and annual revenue costs, is between £3.5 and £4.6 million (DoH, 2005). This estimate is based on a throughput of 2000 – 2500 scans per annum, per individial scanner. Staffing and training costs will also be high, since it takes 2 years to train staff to allow the scanner to become fully operational (www​.cancerhelp.org.uk). The NHS reference cost is not available but the Department of Health estimates the cost per PET-CT scan to be between £750 and £1,000 (DoH, 2005).

In addition to the (potential) high cost implications, the decision facing clinicians of whether to use one of these imaging techniques and which technique to choose will have economic consequences in terms of the treatment offered (for example a patient found to have extensive liver involvement or multiple lung metastasis might be advised to undergo chemotherapy in the first instance before going on to hormonal therapy) or even the possibility of requiring further tests. Whilst imaging is a valuable tool for assessing disease extent and response to treatment, the evidence does not evaluate the impact of imaging on treatment decision (ie. whether imaging translates into better treatment decisions for the patients and ultimately into an increase in quality of life). No evidence was found in a preliminary search of the literature that treatment decisions changed according to imaging results. In addition the differential impact of the resulting treatment is unclear. In economic terms the value of the imaging technique can only be assessed by comparing the alternative courses of action resulting from imaging and not imaging. If the action (i.e. the treatment chosen by the clinician) resulting from no imaging information is likely to be the same as the action taken on the basis of imaging results, then this topic would not be considered relevant for economic analysis.

Since it is not clear from the evidence that imaging ultimately results in health benefits for patients and it is unlikely that any QoL evidence will be available to inform an economic evaluation on this topic, this topic is not considered as high a priority as other topics covered in the guideline.
2Topic 2. Pathological assessment and re-assessment of tumour samples5. Low priority for analysisThis question asks whether it is effective and cost-effective to re- assess the hormone receptor status (both HER2 status and endocrine status) of a recurrence in patients where the status of the primary tumour is known. Re-assessment of tumour samples is currently not routine practice so there would be a significant change in NHS practice if this were to be recommended.

The re-assessment would be required for all patients with distant recurrence (i.e. metastases) as well as local recurrence, so all the patients covered by this guideline will be affected. NICE estimated the number of patients with MBC to be 20,000 (NICE, 2002a).

Data show that a change in endocrine status between the first biopsy and the biopsy at recurrence occurs in approximately 10–25% of patients with metastatic disease. There is no reliable evidence of a change in HER2 receptor status on recurrence. The question is whether the value of revealing this information outweighs the cost of reassessing the receptor status of recurrences in all patients. Even in the 10–25% of patients for whom a change in tumour endocrine receptor status is discovered, it may not affect the treatment decision - for example the patient may be unfit for chemotherapy. Of course this decision (whether or not the patient is fit for chemotherapy) could be made before carrying out the test. If the information gained from the re- assessment does make a difference to the decision of which treatment to offer (endocrine or chemotherapy - topic 4), there is uncertainty regarding the differential impact these treatments may have on outcomes such as overall survival and quality of life.

The costs associated with the reassessment of a tumour sample (laboratory and staffing costs etc) would be small. In a submission to NICE, Roche estimated the test for HER2 status at £21 per person (acited in NICE, 2002a). But since the number of patients who would need the test is large, the overall cost of testing would not be insignificant (estimated to be almost £0.5m for testing HER2 status alone). There will also be economic consequences in terms of the treatment given on the basis of the information. However it is not clear in which direction the cost of providing more appropriate treatment may shift. There are potential cost- savings by avoiding inappropriate treatment altogether, but there may be a net increase in cost of treatment if the treatment given in its place is more expensive (although this may produce a greater health benefit for the patient). The cost of false positive and false negative results (in terms of health benefits forgone or cost of inappropriate treatment given on the basis of the test results) will also need to be included, which depend on the diagnostic accuracy of the test. This would need to be compared to the harm/health benefit forgone of giving inappropriate treatment if the test was not carried out. The GDG do not consider these to be considerable for most patients since if the initial treatment doesn’t work, a different treatment combination will be initiated after a few weeks. However in a small group of patients this might be an issue.

Although the numbers of patients affected in this topic is large, the health benefits do not appear to be significant. In addition it is not clear that the financial consequences will be as high as other topics. Compared to other topics in this guideline, this one is considered a low priority.
3Topic 3. Management of breast cancer patients in the community setting3. High priority for analysisRoughly half of patients receiving chemotherapy would be eligible for chemotherapy at home (www​.cancerimprovement.nhs.uk).

There is very little evidence of the clinical effectiveness of community vs. outpatient delivery of intravenous (i.v.) therapies in patients with advanced breast cancer. There is evidence for patients with other forms of cancer such as colorectal cancer which suggests that home delivery is safe and does not increase the use of other health services such as primary care or emergency departments (Lowenthal et al 1996, Borras et al, 2001). However it is not clear that these results are generalisable to different chemotherapy regimes, such as those used in the treatment of advanced breast cancer. In addition there is no health benefit associated with the setting in which chemotherapy is delivered, although there is some evidence that patients are less likely to voluntarily withdraw from chemotherapy when it is delivered at home (Borras et al, 2001). Evidence on patient preference is mixed (King et al, 2000; Rischin et al, 2000).

A recommendation to routinely offer suitable patients the option to undergo chemotherapy at home would have significant resource implications for the NHS. These include the cost associated with home visits by a specialist nurse, the time to administer the i.v. therapy (at home only one patient can be seen by a nurse at any one time, whereas in an outpatient or inpatient setting one nurse can administer i.v. therapy to up to four patients in one session), the cost of safe disposal of the home kit and the potential impact on the use of other health services (eg. emergency).

Although there is very little clinical evidence available, the GDG are keen to pursue this topic because they feel some patients would benefit from chemotherapy at home. Since the economics are central to this decision they have requested this topic be considered a high economic priority. The value of attempting any substantial economic modelling for this topic is questioned since it will be underpinned by weak clinical-effectiveness evidence. However, various scenario analyses could be presented to the GDG and a sensitivity analysis undertaken to provide a starting point for further discussion.

In the likely absence of clinical evidence comparing different settings for the administration of i.v. therapies, an estimate of resource use and costs will be an important input to the final decision. As such this topic is considered a high economic priority.
5Topic 5. The clinical effectiveness and cost effectiveness of vinorelbine for breast cancer (update of technology appraisal)3. High priority for analysisNICE investigated the clinical- and cost-effectiveness of vinorelbine in the treatment of advanced breast cancer in technology appraisal no.5 which was updated by TA54 in December 2002. The appraisal is being updated within this guideline.

Vinorelbine was investigated within its licensed indications, as first-line and second-line treatment, either as monotherapy or in combination, following failure of adjuvant or first-line anthracycline therapy. Aggressive treatment of early stage breast cancer has led to an increase in the number of patients presenting with advanced or metastatic disease that is resistant to, or has failed, taxane and anthracycline therapy (Jones et al, 2004), so the number of patients affected by this topic is increasing.

In the original appraisal NICE estimated the number of patients eligible for 2nd-line treatment with vinorelbine was roughly 5,000 (NICE, 2002b). It is not clear how many patients would be eligible for 1st-line treatment with vinorelbine.

Evidence at the time of TA54 was scarce. The evidence reviewed for the appraisal showed no clinical benefit of vinorelbine monotherapy over other therapies as first-line treatment. Vinorelbine monotherapy as second-line treatment was slightly less effective than taxane therapy but was much less toxic. For a sub-group of patients (eg. elderly) this was considered a useful treatment option and was backed up by economic evidence. None of the RCT data favoured vinorelbine combinations and the case- series data did not provide a robust alternative interpretation. The economics involved in the original appraisal comprised of two literature reviews (one investigated the use of vinorelbine as a single agent and the other investigated vinorelbine in combination with other agents), with no independent modelling. The reviews found no economic evaluations investigating vinorelbine as combination therapy, and identified four economic analyses for vinorelbine monotherapy (Brown et al, 2001; Silberman et al, 1999; Launois et al, 1996; Leung et al, 1999), though one of these was in abstract form and therefore provided little detail. Three of these were fairly well conducted cost-effectiveness or cost-utility analyses, one of which was carried out in a UK setting from an NHS perspective (the remaining three were undertaken in Canada, the US and France). However they gave conflicting results, “when comparing the cost-effectiveness of vinorelbine, paclitaxel and docetaxel, one economic evaluation reported that vinorelbine was more effective and less costly than taxane therapy, one found vinorelbine to be less effective and less expensive than either of the taxanes and a third evaluation found vinorelbine to be less effective and more expensive than taxane therapy” (Lewis et al, 2002). In addition none of the studies adequately addressed the uncertainty surrounding their results. A search of the NHS EED database was performed to find economics papers published since the last review was conducted. Two relevant papers were identified after a full search of the literature; the HTA report (published by the appraisal assessment team) and one Dutch cost-utility analysis (Li et al, 2001).

This topic has high potential financial implications for the NHS- like all cytotoxic drugs, vinorelbine is expensive so the acquisition costs could be considerable. NICE estimated the average cost of treating each patient with vinorelbine monotherapy to be roughly £1,300 – £1,800, based on 9 to 12 doses per patient (NICE, 2002b). As with other chemotherapy agents, there are economic consequences associated with giving vinorelbine as monotherapy. If the treatment does not work, the option of using vinorelbine in combination with another agent (which may bring greater health benefits but at an increased cost), is ruled out.

It would be useful to undertake some independent modelling using the data appraised from clinical trials in the original HTA report (that which was not used in the economic evaluations) and any literature published since. This should remove some of the uncertainty surrounding the conflicting results of the three economic evaluations above.
6Topic 6. The clinical effectiveness and cost effectiveness of capecitabine for breast cancer (update of technology appraisal)3. High priority for analysisNICE investigated the clinical- and cost-effectiveness of capecitabine in the treatment of advanced breast cancer in technology appraisal no.62, published May 2003. Capecitabine was investigated within its licensed indications; in combination with docetaxel for patients who have failed anthracycline containing regimens and as monotherapy for patients who have failed taxanes and anthracycline containing chemotherapy or for whom further anthracycline therapy is not indicated. NICE estimated that roughly 7,500 patients would be eligible for capecitabine therapy (NICE, 2003).

The Committee concluded that, for the majority of individuals, capecitabine combination therapy should be the preferred clinical option over single-agent docetaxel but that taxane monotherapy should be considered as an alternative (given the high side-effect profile of capecitabine combination therapy). The evidence also showed that there was a place for capecitabine monotherapy which seemed unlikely to be less effective, and no more costly, than vinorelbine monotherapy, and it has the advantage of oral administration which may be preferred by some patients.

The potential financial implications for the NHS are high- like other chemotherapy agents, capecitabine is expensive so the acquisition costs would be considerable. NICE have estimated the acquisition cost of treating an individual with capecitabine for one 3-week cycle is roughly £1400 for combination therapy and £300 for monotherapy (NICE, 2003). Patients would need more than one cycle of treatment.

Like other topics in this guideline, this topic is an update of technology appraisal no. 62, so it is important that the economics of this topic are re-examined along with the clinical evidence.

A review of papers published since the TA has been conducted (revealing two new North American analyses; Verma et al, 2005; Verma & Ilersich, 2003) and a copy of the economic model included in the original manufacturer's submission has been obtained.

It is possible to update this model to include this new evidence and undertake further sensitivity analyses to better understand the uncertainty surrounding this decision.
7Topic 7. The clinical and cost effectiveness of taxanes in the treatment of advanced breast cancer (update of technology appraisal)3. High priority for analysisSimilarly, this topic is an update of a technology appraisal (TA30) so it is important that the economic evidence be re-examined along with the clinical evidence. This appraisal recommended the use of either taxane as 2nd-line treatment for MBC, where anthracycline treatment has failed or is inappropriate. NICE estimated that 5,000 patients would be eligible for this treatment (NICE, 2001).

Additionally, since the appraisal was published, a generic taxane has entered the market (generic paclitaxel). As the generic drug is cheaper than the proprietary equivalents this may increase the cost-effectiveness of taxane therapy (provided the generic paclitaxel is as effective as the branded drug, Taxol). NICE have estimated that the total cost per patient per cycle of paclitaxel is approx. £1,250 and £1,150 per cycle of docetaxel therapy. Each patient typically receives six cycles, so the total cost of paclitaxel and docetaxel treatment per patient is roughly £7,500 and £6,900 respectively.

In the original appraisal no economic evaluations for the first line treatment of breast cancer with a taxane were identified. In a search of the NHS EED database, there were no economic evaluations published on this topic since the TA was published.

For second-line treatment, seven economic evaluations were reviewed for the original appraisal. One compared paclitaxel with mitomycin but was submitted in confidence to NICE and therefore was not published in the subsequent HTA report. The other six compared paclitaxel and docetaxel in cost-utility analyses where the range of incremental QALYs gained was £1990-£2431. In addition three analyses compared docetaxel and vinorelbine - one of which was carried out in the UK and yielded a cost-utility ratio for incremental QALYs gained was £14,050. The original guidance did not give any indication as to which taxane was preferred for second-line treatment of breast cancer, despite the evidence showing that docetaxel has a highly favourable cost- effectiveness ratio compared with paclitaxel.

A search of the NHS EED database revealed no new economic evaluations. Despite the seeming lack of newly published studies, some independent modelling could address the short-comings of the evidence appraised for the TA. It would also be possible to investigate which taxane is most cost effective.
8Topic 8. In patients with metastatic breast cancer, which hormone treatments are (a) active and (b) which is the most effective?4. Medium priority for analysisEconomic analysis is not relevant to part (a) of this question, since there is no comparison involved.

However, part (b) raises economic issues. Hormone therapy is suitable for a significant proportion of MBC patients (patients with positive HR status).

Although the use of hormone therapy is well established, the drugs identified in the PICO table are high-cost interventions.

A search of the NHS EED database has identified five recent economic evaluations of aromatase inhibitors published since 2001 (Okubo et al, 2005; Dranitsaris et al, 2003; Simons et al, 2003; Verma et al, 2003; Hillner et al, 2001). The results of these seem to suggest aromatase agents, letrozole in particular, are cost-effective or cost-saving when compared to tamoxifen (or megestrol). Three of these are cost-utility analyses, although only one study (a cost-effectiveness analysis) is from the UK. The results of the non-UK studies may not be generalisable to the NHS setting.

The GDG feel that this topic is not a pressing health economic priority and that the economic analyses proposed elsewhere in this plan have the potential to be more useful. However for the reasons listed above this topic is considered a medium priority for economic analysis. If there is time after the high priority topics have been addressed, a literature review will be conducted.
9Topic 9. What chemotherapy regimes are effective in patients with metastatic breast cancer who are HER2-?5. Low priority for analysisThe HER2 (human epidermal growth factor receptor 2) status of a tumour is an important predictor of a patient’s prognosis, with HER2+ cancer being more aggressive and thus associated with a overall worse prognosis for the patient. HER2 status also limits the treatment choices available to the physician as treatment with biological therapies are not suitable for HER2- patients.

As mentioned above (see Topic 1), approximately 44,000 patients are newly diagnosed with breast cancer every year (www​.cancerhelp.org.uk), with roughly half of them going on to develop metastatic disease at some stage (22,000 patients). Of the patients with MBC some 20–25% would over-express the HER-2 protein, which leaves 75–80% of patients with tumours that are HER-2 negative. This gives an approximate number of patients that will potentially be affected by this topic of around 13,200 –16,500 patients (cited in NHSC report on Bevacizumab, 2006).

The interventions considered in this topic are older, less expensive chemotherapy regimes. Thus the financial implications are not as great as topics 5, 6 and 7.

No economic evaluations were found to have reported this specific population. It is not clear how patients with HER2tumours differ in terms of response to chemotherapy than patients with tumours with HER2+ status, although patients with HER2− status do have a better overall prognosis.

Since this topic is not associated with high cost implications for the NHS, it is considered a low priority for economic analysis.
10Topic 10: Which is most effective at treating patients with metastatic breast cancer – combination chemotherapy or sequential single-agent chemotherapy1. Not relevantThis topic will affect all MBC patients receiving chemotherapy.

The clinical evidence will obviously vary according to which sequence and which combination are compared but, in general, evidence suggests that chemotherapy agents are more active when given in combination but are also associated with a higher side-effect profile. The resulting overall effect on QoL is therefore uncertain. There may also be issues regarding the opportunity cost (in terms of health benefits forgone) of combination therapy which limits the use of a chemotherapy agent and therefore “uses up” the limited number of treatment options more quickly than sequential therapy.

The cost of the chemotherapy drugs are likely to be similar regardless of whether they are administered sequentially or in combination, nevertherless this cost to the NHS will be substantial (see previous topics).

This topic could be incorporated into the analysis for topics 5, 6 & 7 but to make this feasible a limited number of specific interventions and comparators will have to be made explicit. If the combinations to be investigated are not made specific (they aren't in the PICO table as it currently stands) then this topic will not be relevant for economic analysis.
11Topic 15. The appropriate chemotherapy regimes for patients with metastatic breast cancer who are HER2+ and have had prior anthracyclines (either as adjuvant or for MBC or where anthracyclines are inappropriate)3. High priority for analysisALthough with topic 16, this topic will update technology appraisal 34 which offers guidance on the use of trastuzumab for the treatment of advanced breast cancer. Again, it is important that the economic evidence be re-examined along with the clinical evidence.

It has been estimated that 20–25% of patients presenting each year will go on to develop MBC with tumours that over-express HER2 at the 3+ level, roughly 4,200–5,250 new cases per year (NHSC, 2006). The patient population considered in this topic includes HER2+ patients in whom an anthracycline regime has failed/is inappropriate. It is not clear how many patients fall into this category, although it will necessarily be less than the 20–25% of MBC patients over-expressing HER2.

The interventions of interest in this topic are trastuzumab in combination with a variety of different chemotherapy agents, compared to trastuzumab monotherapy. Whilst hormone therapy is the standard first-line treatment for HER2+ patients, chemotherapy may be considered instead if the disease is very aggressive (indeed patients with HER2+ disease have a 50% worse prognosis than those with HER2breast cancer). Ultimately all patients will stop responding to hormonal treatment and will therefore become eligible for trastuzumab and chemotherapy (patients who are oestrogen receptor-positive must also have failed to respond to appropriate hormonal therapy to be considered for trastuzumab therapy under current NICE guidance).

There is evidence that in patients who have not received prior treatment for MBC “the addition of trastuzumab to chemotherapy result[s] in significantly less disease progression and treatment failure, longer progression-free survival and greater complete and overall tumour response when compared to chemotherapy alone” (Lewis et al, 2002). The only new clinical evidence specific to this group was from a few case series, which present data for a very low patient number and with a very high level of bias due to the lack of comparator, blinding or randomisation etc. There seems to be little evidence to differentiate between these chemotherapy drugs combined with trastuzumab in terms of tumour response or progression free survival. No assessment of the QoL impact of these treatments has been made. The ill-health associated with adverse events from trastuzumab + chemotherapy treatment should also be accounted for in any economic evaluation, since many of those reported were severe (grades 3 and 4).

The list price for trastuzumab is £407.40 per 150 mg vial (BNF 53, 2007). The average costs used reported in TA34 for a typical patient receiving one course of combination therapy (trastuzumab with paclitaxel) is £15,481 (Roche, 2000), whilst one course of trastuzumab monotherapy is much cheaper, roughly £5,300 per patient (NICE, 2002b). Apart from the additional cost of the chemotherapy agent, the difference between the two figures is due to the fact that combination treatment is given for 38 weeks, compared to a 12-week course of monotherapy. This is not reflective of the course length of trastuzumab monotherapy that is given to patients in practice, so the true cost will be much higher. Technology appraisal 34 (2002) recommended trastuzumab + paclitaxel as an option for people with tumours expressing HER2 at levels of 3+ who have not received chemotherapy for metastatic breast cancer and in whom anthracycline treatment is inappropriate. The financial implications for the NHS from this recommendation (which refers to a population that differs slightly from the target patient population for this topic) were estimated at the time to be around £8.5m per annum (NICE, 2002b). “This estimate was based on the following assumptions: HER2 status is assessed in 20,000 patients with metastatic disease at a cost of £21 per test; 450 patients receive combination therapy costing an additional £15,500 to provide trastuzumab and paclitaxel instead of paclitaxel alone; each person receives four cardiac tests at a cost of £580 for each set of four tests. (Overall calculation: [20,000 x £21] + [450 x £15,500] + [1,600 x £580])” (NICE, 2002b). Thus the cost implications for this topic are likely to be high.

Overall, since there is evidence (albeit not high quality) to show that there are potential health benefits to using trastuzumab in combination with chemotherapy agents and evidence of a likely high cost implications for the NHS, this topic is considered a high priority for economic analysis.
12Topic 16. The management of patients with metastatic HER2+ breast cancer who:
  1. have had no previous treatment with a biological therapy
  2. are no longer receiving treatment with a biological therapy and have disease progression
  3. are having ongoing treatment with a biological therapy and have disease progression
3. High priority for analysisThis topic affects all patients with metastatic HER2 positive breast cancer, 20–25% of patients covered by this guideline.

All the biological therapies covered by this topic are considered to be expensive.

Generally the biological therapies are considered to be less toxic but nevertheless important side effects are seen, for example cardiotoxicity with trastuzumab, risk of thrombosis with bevacizumab and gastrointestinal toxicity with lapatanib.

16a - This group of patients is the same as the population considered in topic 15 above, although some will not have been exposed to anthracyclines. This part of topic 16 could be incorporated into the analysis planned for topic 15 if sufficient data are available. Topic 16 compares a greater number of interventions, including treatment with biological therapies.

There is a lack of clinical evidence for the patient populations in part (b) and (c) of topic 16.

16 c - Whilst there are economic implications for this topic, the usefulness of independent analysis is questionned since the clinical evidence led the GDG towards a negative recommendation. This part of topic 16 is therefore considered a low priority.
14Topic 18. The management of metastatic bone disease (inc. bisphosphonates, samarium, radiotherapy, surgery and rehabilitation)4. Medium priority for analysisEvery year, an estimated 9,000 breast cancer patients develop bone metastases in the UK (Botteman et al, 2006). These metastases are associated with considerable skeletal morbidity including severe bone pain, pathological fractures and spinal cord compression. These complications are in turn associated with a significant burden in terms of quality of life, resource utilization and costs. Despite the numerous technological interventions identified as part of topic 18, economic evidence was found only for bisphosphonates. The economic implications for the other interventions in this topic are not considered as relevant.

The clinical evidence reviewed for this topic varied in quality but suggests that bisphosphonates reduce the incidence of skeletally related events, make no impact on overall survival but improve the quality of life. There were inconsistent results on pain palliation (NCC-C Topic 18 summary).

Bisphosphonates vary in acquisition costs (between £165 and £195 per patient per month) and since they can be taken for months, if not years, they can have a significant financial impact on the NHS (Botteman et al, 2006). There are also potentially high cost-savings associated with averting the complications of bone metastases, such as spinal cord compression.

The economic evidence has already been reviewed for this topic. Six papers were included all of which present cost-utility (cost per QALY) analyses for the use of bisphosphonates in the prevention of skeletal-related events. Four of the six economic analyses are from the UK (Botteman et al, 2006; De Cock et al, 2005; De Cock et al, 2005; Ross et al, 2004), one is Canadian (Dranitsaris & Hsu, 1999) and one is American (Hillner et al, 2000). The economic modelling from a UK NHS and personal social services perspective indicates that use of bisphosphonates in the management of bone metastases from breast cancer appears to be very cost-effective, ranging from being cost-saving to £6,136 per QALY. Results of modelling in the North American context indicate that bisphosphonates may not be cost-effective, with estimates up to $305,500 per QALY. Although in general bisphosphonates seem to be very cost-effective in the UK, the results from Ross et al (2004) are not robust. In their analysis the base case result is sensitive to bisphosphonate cost, event rate, and event costs and although no sensitivity analysis on the cost per QALY is made explicit, they do present one-way sensitivity analysis showing the worst case scenario ranges from cost-saving to a higher incremental cost per patient per skeletal related event averted, 53 times higher than the baseline result. If we apply this to the baseline cost effectiveness estimate of £1,380 per QALY, bisphosphonates could range from being cost saving up to 53x higher overall, that is £73,140 per QALY. The papers reviewed also show conflicting evidence over which of the bisphosphonates is most cost-effective.

Further modelling work would help clarify both the degree of uncertainty around the base case cost-effectiveness result, and how individual bisphosphonates compare with each other on economic grounds. However since bisphosphonates, as a class of drugs, seem to be very cost-effective this further independent analysis is not considered a high priority.

This topic may in part be covered by topic 2 of the Metastatic Spinal Cord Compression (MSCC) guideline, currently in development at the NCC-C, although this focuses on the use of bisphosphonates (amongst other interventions) in the prevention of SREs and ultimately in the prevention of MSCC.
15Topic 19. The management of metastatic brain and meningeal disease (surgery, stereotactic radiotherapy, external beam radiotherapy, intrathecal chemotherapy, rehabilitation)4. Medium priority for analysisThere are a number of possible interventions that are used in the management of metastatic brain disease, but there is scarce economic evidence comparing them.

Autopsy series reportedly show that as many as 25% of patients who die of cancer will have intracranial metastases. (Sperduto, 2003). Although far fewer patients would present with symptoms to even be considered for the interventions in this topic.

It is claimed that sterotactic radiotherapy is cost-effective compared to surgical resection, since it is a one-day non-invasive treatment usually performed as an outpatient, which carries with it the associated savings and the advantage that multiple metastases can be treated in a single session.

Only one review paper on this topic was identified from an NHS EED search, which contained references to two cost-effectiveness analyses. It was not clear whether these analyses considered the relevant patient population.

This topic is considered a medium prority since the numbers of patients affected is not as great as for other topics. If time permits, a literature review will be conducted for this topic.
Topic 21. The management of lymphoedema in:
  1. Patients who have completed their primary treatment and have no active disease
  2. Patients who have advanced breast cancer (inc. disease of the axilla)
5. Low priority for analysisLymphoedema is the abnormal build-up of fluid in the lymphatic system. It can develop immediately after cancer surgery or radiation therapy, or it can develop months or years later. It is not only a complication of the disease but it can also be caused by treatment itself. Lymphoedema affects a small but not insignificant proportion of breast cancer patients (estimates vary between 12 and 29% of all women with breast cancer). At present there is no proven pharmaceutical treatment. Management aims to reduce or delay the progression of swelling and prevent associated infection. The management strategies considered in this topic are wide ranging interventions used singularly or in two- phase combinations. Similarly the costs associated with these interventions will vary but are relatively modest.

The GDG have noted that providing a co-ordinated service (where there is currently low provision) for lymphoedema management of patients who have no active disease (part a of this topic) is likely to have high implications for resource use and costs to the NHS. This is particularly true if it is thought that specialist investigations to confirm a diagnosis of lymphoedema are considered worthwhile. Despite these concerns being valid, a ‘co-ordinated service’ is not strictly being investigated in this clinical question. There is greater service provision for lymphoedema management amongst patients who have advanced breast cancer (part b to this question), so the GDG feel there is not likely to be such a high budget impact on the NHS for recommendations in this group of patients.

No economic evaluations comparing the specific interventions listed in the PICO table were identified on the NHS EED database. One economic evaluation from Australia (Gordon et al, 2005) compared two rehabilitation programs with no rehabilitation, which showed that one of the programs considered may be more cost-effective than the ‘do nothing’ option, although this result was not robust to sensitivity analysis. In addition these results are unlikely to be generalisable to the UK since the management strategies here are very different to those investigated in the Australian study. There is also very little clinical evidence on the interventions in the PICO table. As such this topic is considered a low economic priority.
17Topic 22. The management of patients with uncontrolled local disease in the presence of metastases or following primary treatment5. Low priority for analysisNo estimate has been found in the literature as to how many patients will be affected by this topic.

There is data from phase III trials to show that it is possible to achieve local control of cutaneous metastases with the application of topical agents such as miltefosine. No papers investigating the effect of major or simple resection plus radiotherapy were found.

Topical agents are not expensive so this treatment will not result in significant resource implications for the NHS. The surgical techniques listed as interventions will be more expensive. Even so the financial implications of this topic will not be as great as other topics- as such it is considered a low priority for economic analysis.
18Topic 23. In patients who have to make decisions about the management of their disease, do decision support methods produce better QoL and improve outcomes5. Low priority for analysisSince metastatic breast cancer is an incurable disease, patients are faced with difficult decisions about their treatment. These decisions involve a weighing up of personal preferences about the potential benefits and harms of one option over another. Decision support methods are designed as interventions to help people make specific and deliberative choices among options, including the status quo, by providing information on the options and outcomes relevant to a person’s health status.

In a preliminary search of the literature on the NHS EED database, no economic evaluations were identified for patients with metastatic breast cancer.

Three papers which looked at cost and resource use were identified from the 2003 Cochrane review “Decision aids for people facing health treatment or screening decisions” by O’Connor et al. One of these, a partial economic evaluation (a cost study) was identified relating to the use of decision aids for menorrhagia treatment (Kennedy et al, 2002). The analysis showed that none of the interventions had a major impact on health status, which is reported to be consistent with previous studies on decision aids. The study also showed a reduced relative rate of surgery (patients faced a choice between radical surgery and more conservative options) which would be an important economic implication; however surgery is not an option facing patients with metastatic breast cancer. The Cochrane review also notes that the impact of the decision aid is likely to be less important than the effectiveness of the available treatments.

The costs included in the analysis by Kennedy et al (2002). include total fixed intervention costs for the development and production of the booklet and videotape (one of the decision aids) including expert input as well as the cost of treatment chosen following the use of the decision aid. Further clarification from the GDG is needed to ascertain exactly when the decision aid is likely to be used in the patient pathway to determine how high the treatment-related costs are likely to be in this case. There may also be cost savings attributable to decision aids, although if these savings fall on the individual patient they would not be considered relevant costs for an economic evaluation carried out from the perspective of the NHS.

To compare the multitude of different options presented in the PICO table for this question in an economic evaluation is not feasible. Since it is not anticipated that these interventions will confer any health benefit to the patient (of course not the only concern for patients and the GDG, but certainly a main focus of economic evaluation) and the likelihood that the interventions considered will not have significant resource implications for the NHS, this topic will not be considered a priority for economic analysis.
19Topic 24. What is the most appropriate provision of information for patients with metastatic breast cancer who are considering treatment options and making treatment choices1. Not relevantAlthough the provision of information will be of great concern to patients and the GDG, it is not considered a relevant economic issue. There may be economic implications to do with the cost of health professionals’ time taken to deliver the information but this does not represent a significant financial implication for the NHS.
20Topic 25. The role of cancer-related fatigue management in advanced breast cancer patients5. Low priority for analysisFatigue has been defined as “a subjective and multi-dimensional concept with several modes of expression: physical, cognitive and affective” (Servaes et al, 2002). Estimates of prevalence of fatigue among patients with cancer in the palliative setting range from 48– 75%. The variation in this estimate is at least partly attributable to the fact that fatigue can be assessed in a number of ways. The relationships between fatigue and disease and treatment-related characteristics are also hard to characterise since they are seldom investigated properly (Servaes et al, 2002). This has led to a clinical interpretation of results of studies investigating various interventions becoming problematic.

“Patients who feel fatigue often say that even a small effort, such as walking across the room, can seem like too much” which seriously affects quality of life (although this is not quantified) (Servaes et al 2002). In a preliminary search, although there was some evidence to suggest a psycho-social intervention decreased fatigue in patients with MBC, no data was found to show whether any of the interventions offer an improvement in quality of life. On the other hand fatigue can also make patients avoid or skip cancer treatments which, if significant, would be important to capture in any economic analysis.

The number of different types of interventions addressed in the PICO table means an economic evaluation of this question is not feasible. If the GDG were to decide on a few major interventions representing a real choice to clinicians then independent analysis may be useful. However at present this topic is considered a low priority.
21Topic 26. What are the effective interventions used to support patients with advanced breast cancer5. Low priority for analysisNo clincial evidence was found on this topic. However the GDG are considering recommending that an appropriate key worker should be assigned to each patient with advanced breast cancer. Currently this role is often undertaken by existing memebers of staff on a ‘goodwill’ basis and formalising this role may not be cheap. Although this topic has some related financial implications, they are not as relevant as those shown in other topics.
a

  1. Not relevant’: questions where economic analysis is not appropriate (e.g. about definitions, prognosis or information needs for patient);
  2. In literature’: questions where high-quality, recent and relevant economic evaluations are already available;
  3. High priority for analysis’: questions where an economic analysis is planned (important implications and analysis is thought to be feasible);
  4. Medium priority for analysis’ questions where an economic analysis may be done (less important implications or questions over feasibility);
  5. Low priority for analysis’: questions where economic analysis could be done, but the expected impact on outcomes and NHS resources is low.

From: Appendix D, Economic plan

Cover of Advanced Breast Cancer
Advanced Breast Cancer: Diagnosis and Treatment.
NICE Clinical Guidelines, No. 81.
National Collaborating Centre for Cancer (UK).
Copyright © 2009, National Collaborating Centre for Cancer.

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