PubMed Health. A service of the National Library of Medicine, National Institutes of Health.

Cooper KL, Meng Y, Harnan S, et al. Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) for the Assessment of Axillary Lymph Node Metastases in Early Breast Cancer: Systematic Review and Economic Evaluation. Southampton (UK): NIHR Journals Library; 2011 Jan. (Health Technology Assessment, No. 15.4.)

4Assessment of cost-effectiveness

This section of the assessment focuses on the health economics of enhanced imaging techniques in the assessment of axillary lymph node metastases in comparison with standard diagnostic techniques. It includes a brief review of existing economic evaluations of the relevant imaging techniques in the assessment of axillary lymph node metastases and a detailed explanation of the methodologies and results of the economic model.

Review of existing cost-effectiveness evidence presents the results of the review of economic literature. The modelling approach adopted for this study is discussed in Independent economic assessment – methods, with the results of the analysis being presented in Independent economic assessment – results.

Review of existing cost-effectiveness evidence

The primary objective of this review was to identify and evaluate studies exploring the cost-effectiveness of enhanced imaging techniques in the assessment of axillary lymph node metastases. The secondary objective was to evaluate methodologies used to inform our own economic evaluation.

The literature was searched using the strategy described in Chapter 3, Methods for reviewing effectiveness and Appendix 1. Published economic evaluations of PET or MRI in the assessment of axillary lymph node metastases in breast cancer were included in the review. The search identified 245 citations. Of these, 242 were excluded at the title/abstract stage and one was excluded at the full-text stage. In total, two studies were included in the review: one of PET119 and one of MRI.120

One published economic evaluation of PET in the assessment of axillary lymph node metastases in breast cancer was identified.119 The model studied breast cancer in general, rather than early-stage breast cancer in particular. A decision tree model was built which did not include the lifetime of the patient or breast cancer recurrence. Furthermore, patient utilities and QALYs were not used in the model. The second paper compared the cost-effectiveness of MR lymphangiography-based strategies with that of SLNB in the axillary staging of early breast cancer.120 However, the model did not consider the short- and long-term adverse events (e.g. lymphoedema) that are associated with SLNB. The diagnostic pathway modelled did not represent the typical pathway in the UK, where ultrasound and ultrasound-guided biopsy are also used. The disease pathway in the model did not include the locoregional relapse and subsequent remission states which are important health states for breast cancer patients. All costs of the study were based in the USA and are unlikely to represent the costs in the UK, given the significant difference in the organisation and funding of health services between the two countries. The literature review confirmed the need for new published economic evaluations in this area.

Independent economic assessment – methods

Objective

The aim of the model was to evaluate the effects on patient outcomes and cost-effectiveness of enhanced imaging techniques (MRI and PET) compared with standard techniques in the assessment of axillary lymph node metastases in women with early-stage breast cancer. Two axillary sampling techniques, 4-NS and SLNB, are used currently in the UK. It is beyond the remit of this assessment to compare 4-NS and SLNB. The enhanced imaging techniques (PET and MRI) are therefore compared with the two baseline sampling techniques separately.

Diagnostic methods

The diagnostic methods that were evaluated in the model (MRI, PET, 4-NS and SLNB) were discussed in detail in Chapter 1, Current methods for assessment of axillary metastases and Chapter 1, Description of technology under assessment.

Structure of the model

A probabilistic discrete-event simulation model has been developed in simul8 (SIMUL8®, Boston, MA, USA) to explore the costs and health outcomes associated with the assessment of axillary lymph node metastases and the treatment of women with early breast cancer.

Discrete-event simulation concerns the modelling of a system as it evolves over time by a representation in which the state variables change instantaneously at separate and countable points in time.121 In the context of health-care modelling, patients are individually represented in a discrete-event simulation model, and normally have associated attributes indicating their distinctive demographical information and diagnostic and/or disease history.

The model differs from classical Markov state transition models, in which the state transition probabilities of patients are evaluated during fixed time intervals and patients may remain in one state after each evaluation. In discrete-event simulation, the time spent in each health state is sampled from a distribution when an individual patient enters this state. If one state can transit to multiple states, then the timing to each subsequent state is sampled and compared, and the patient will transit to the state that has the shortest transition delay.

The discrete-event simulation model consists of two main parts: the diagnostic pathway, which represents current and alternative diagnostic strategies (including PET and MRI), and the treatment pathway, which represents the disease progression among various health states and the management of patients with early breast cancer after the diagnosis of axillary lymph node metastases. A hypothetical cohort of 5000 early breast cancer patients was modelled. Each individual patient follows a specific diagnostic path and will obtain one of the four diagnostic results: TN, FP, TP or FN. Short- and long-term adverse events associated with sampling diagnostic techniques (4-NS and SLNB) and the associated cost and utility implications are also determined for each patient. The diagnostic results will influence the time spent in each of the subsequent health states, which is sampled from exponential distributions based on yearly transition probabilities. The starting age of patients was 56 years, which is based on the clinical effectiveness review within this assessment. The model was run for the remaining lifetime of patients.

Resource use and utilities are mainly taken from published literature. Input parameters are assigned probability distributions to reflect their imprecision and Monte Carlo techniques are performed to reflect this uncertainty in the results. Results are presented in terms of net health benefit and cost per incremental QALY gained.

Diagnostic pathway

The status of axillary lymph node metastases was assessed for all early breast cancer patients. Current methods of assessment consist of clinical examination followed by ultrasound.17 If the result of ultrasound is positive, an ultrasound-guided fine-needle or core-needle biopsy will be conducted. If axillary metastases are identified via the biopsy (TP or FP), then the patients will be managed as node-positive patients (i.e. patients who have axillary lymph node metastases) and ALND will be performed, normally at the same time as the main breast cancer surgery is carried out.

For those women whose axillary metastases have not been identified by ultrasound or biopsy (i.e. either ultrasound or biopsy result is negative), current management involves the surgical removal of only some of the axillary lymph nodes (axillary sampling via either 4-NS or SLNB) for histological examination. Axillary sampling is normally performed at the same time as the main breast cancer surgery. Depending on the results of axillary sampling, patients will be managed either as node-negative patients (i.e. patients who do not have axillary lymph node metastases), who will receive no further investigation at that time, or as node-positive patients, who will undergo ALND to remove all axillary lymph nodes. Figure 13 illustrates the current standard diagnostic pathway.

FIGURE 13. Standard and alternative imaging replacement diagnostic pathway in the School of Health and Related Research (ScHARR) model.

FIGURE 13

Standard and alternative imaging replacement diagnostic pathway in the School of Health and Related Research (ScHARR) model.

Apart from the two baseline 4-NS and SLNB strategies, six alternative strategies that involve either MRI or PET were evaluated. Two alternative strategies are to replace the axillary sampling methods with either MRI or PET (scenarios 1 and 2). Another four alternative strategies are to add MRI or PET before 4-NS (scenarios 3 and 4), and to add MRI or PET before SLNB (scenarios 5 and 6) in the diagnostic pathway. In theory, a biopsy (fine-needle or core-needle biopsy) could be undertaken in the event of a positive MRI or PET result in the alternative diagnostic pathways. However, MRI-guided or PET-guided biopsy is not currently available in most centres in the UK and no clinical studies were identified to provide data on this. Therefore, these techniques were not included in our assessment. The eight diagnostic strategies were as follows:

  • baseline 1: 4-NS
  • baseline 2: SLNB
  • scenario 1: replace sampling with MRI
  • scenario 2: replace sampling with PET
  • scenario 3: add MRI before 4-NS
  • scenario 4: add PET before 4-NS
  • scenario 5: add MRI before SLNB
  • scenario 6: add PET before SLNB.

The cost-effectiveness of the alternative MRI or PET replacement strategies was evaluated using the diagnostic pathway illustrated in Figure 13, in which MRI or PET replaces the current axillary sampling procedures. In order to evaluate the other four alternative strategies, the standard pathway was modified to create an alternative diagnostic pathway (Figure 14). In the alternative pathway, enhanced imaging techniques will be carried out for patients who have negative ultrasound or biopsy results. If the results of the imaging techniques are positive, no axillary sampling is performed and the patients are regarded as node positive and go on to receive ALND. If the results of imaging techniques are negative, further axillary sampling (4-NS or SLNB) is still performed as in the standard pathway.

FIGURE 14. Alternative imaging addition diagnostic pathway in the School of Health and Related Research (ScHARR) model.

FIGURE 14

Alternative imaging addition diagnostic pathway in the School of Health and Related Research (ScHARR) model.

Disease pathway

The diagnostic results will affect the choice of adjuvant therapies and the probability of locoregional relapse and developing metastatic diseases (e.g. patients with FN diagnoses, who have metastatic nodes which are not detected and removed, are more likely to suffer from relapse). Certain diagnostic techniques are associated with long-term adverse events, such as lymphoedema, which may have lifetime cost and utility implications. Therefore, the disease pathway of patients with early breast cancer is also modelled.

All patients with early breast cancer receive adjuvant therapy after the main breast cancer surgery. Node-positive patients normally receive chemotherapy followed by hormonal therapy (where appropriate) while node-negative patients normally receive only hormonal therapy (where appropriate).17 The aim of the adjuvant therapies is to reduce the risk of cancer recurrences. Following the adjuvant therapy, patients may enter into a disease-free survival state of post-adjuvant therapy and may potentially stay in this state for the rest of their lives (i.e. cured). Some patients may, however, experience locoregional relapse during or after the therapy. Patients who are in the post-adjuvant therapy state may experience locoregional or metastatic relapse. Patients experiencing locoregional relapse receive further treatment (e.g. surgical removal of lymph nodes, chemotherapy, radiotherapy, hormonal therapy). The patients may then enter a further remission period without evidence of cancer until death or further relapse to metastatic disease. Metastatic/distant relapse is not considered curable. Patients experiencing a metastatic relapse receive active palliative treatment to control symptoms and improve quality of life, a period of supportive care and ultimately a period of intensive end-of-life care for the last few days/weeks of life. Patients may also die owing to other causes in any health state.

In the UK, women with breast cancer receive follow-up examinations for a number of years following their treatment. The aim of this follow-up is to detect any recurrences earlier and therefore the frequency and effectiveness of follow-up may affect the overall effectiveness of the diagnostic strategies assessed in this study. In theory, axillary metastases in patients misdiagnosed as FN may be identified by either follow-up or self-presentation. However, in practice it is difficult for a clinician to determine whether axillary metastases identified by follow-up or self-presentation are actually due to previous misdiagnosis or due to recurrence. Because the issue of follow-up is outside the scope of the assessment and not enough published evidence is available on the effectiveness of follow-up (especially for patients with FN results), the model did not explicitly represent follow-up.

Health states

There are 10 health states within the disease pathway part of the model:

The disease pathway is shown in Figure 15. Each individual patient starts from one of the four adjuvant therapy states, depending on the previous diagnostic result.

FIGURE 15. Treatment pathways in the School of Health and Related Research (ScHARR) model.

FIGURE 15

Treatment pathways in the School of Health and Related Research (ScHARR) model.

Model state transitions

The following health-state transitions are possible in the model:

  1. adjuvant therapy – patients can move to:
    1. locoregional relapse
    2. death from other causes
  2. post-adjuvant therapy – patients can move to:
    1. locoregional relapse
    2. metastatic relapse
    3. death from other causes
  3. locoregional relapse – patients can move to:
    1. remission
    2. metastatic relapse
    3. death from other causes
  4. remission – patients can move to:
    1. metastatic relapse
    2. death from other causes
  5. metastatic relapse – patients can move to:
    1. death from breast cancer
    2. death from other causes
  6. death from breast cancer – absorbing state
  7. death from other causes – absorbing state.

Model assumptions

The model employs a number of simplifying assumptions, which are detailed below.

  • The sensitivity and specificity of biopsy, axillary sampling (4-NS and SLNB), and imaging techniques (MRI and PET) are independent of preceding diagnostic results.
  • The sensitivity and specificity of MRI is based on all identified studies, with no distinction made between different types of MRI (see Chapter 3, Quantity and quality of research available). This assumption is tested in the sensitivity analysis.
  • Seroma, surgical drain and infection are the short-term adverse events associated with diagnostic techniques (4-NS, SLNB and ALND) considered by the model.
  • Lymphoedema is the only long-term adverse event considered. Lymphoedema is classified as either mild/moderate or severe.
  • Studies have reported adverse events associated with SLNB, whereas no studies were identified which quantify the short-term adverse events associated with 4-NS or compare the probability of adverse events between SLNB and 4-NS. Therefore, the probability of adverse events is assumed to be equal for 4-NS and SLNB.
  • Short-term adverse events increase the costs, but do not affect quality of life.
  • Long-term adverse events (i.e. lymphoedema) affect both costs and quality of life for the rest of the patient's life.
  • During the adjuvant therapy period, node-positive patients receive chemotherapy plus hormonal therapy (where appropriate) and node-negative patients receive hormonal therapy (where appropriate).
  • Patients receive adjuvant therapy for a fixed 5-year period. Node-positive patients receive chemotherapy for half a year, followed by hormonal therapy for 4.5 years. Node-negative patients receive hormonal therapy for 5 years. This is the maximum time patients may stay in this state. Patients may, owing to model dynamics, spend < 5 years in the adjuvant therapy state if the sampled time to locoregional relapse or death from other causes is < 5 years.
  • Following locoregional relapse patients cannot experience further locoregional relapse; they can only experience metastatic relapse.
  • Death rates for non-breast cancer causes are based on UK mortality statistics and applied across all health states. These are not adjusted to exclude breast cancer mortality, and so may overestimate the risk of dying due to non-breast cancer causes.

Model inputs: accuracy and costs of diagnostic techniques

The model inputs of accuracy and costs of diagnostic methods were summarised in Table 18. The sensitivity and specificity of clinical examination and biopsy were based on previous published studies.41,42,47,94 The sensitivity and specificity of ultrasound for clinically negative patients were calculated based on either the size criterion (60.9% and 77.3%, respectively) or morphology criterion (43.9% and 92.4%, respectively) from a systematic review by Alvarez et al.47 We used the averages to represent overall sensitivity and specificity assuming both size and morphology are used to assess axillary lymph node metastases. The sensitivity and specificity of ultrasound for clinically-positive patients were estimated based on expert opinion, as no data were identified from published studies.

TABLE 18. Accuracy and costs of diagnostic methods.

TABLE 18

Accuracy and costs of diagnostic methods.

The sensitivity of 4-NS was based on two identified studies with data from 335 patients.122,123 The sensitivity of SLNB was based on a systematic review and meta-analysis of 69 studies undertaken by Kim et al.125 with data from over 8000 patients. All studies were included in the NICE guideline.17 The mean sensitivity of 4-NS is slightly higher than that of SLNB (94.5% vs 93%) according to literature reviewed within the NICE guideline. However, it is important to note that the sensitivity of SLNB is based on a significantly larger sample size and should be more robust. The specificities of 4-NS and SLNB are set at 100% as, by definition, there should be no FP cases when histological methods are used.

The costs of clinical examination, ultrasound, biopsy, MRI and ALND were obtained from NHS reference costs.55,56 Apart from scanning the axilla, MRI is currently also used in the pre-surgical evaluation of breast tumours for some patients. However, the procedure is performed in a small proportion of women with breast cancer (e.g. lobular cancers and patients having neoadjuvant chemotherapy) and it is likely that axillary and breast MRI scans would be undertaken separately, as pre-contrast scans would be required for both procedures. Therefore marginal cost savings of axillary MRI scans due to breast MRI scans are not considered and we assumed the full NHS reference costs for MRI in the model.

The costs of PET were calculated based on a published UK study.66 The costs of breast surgery were calculated based on NHS costs of total mastectomy surgery [Healthcare Resource Group (HRG) codes are JA07A, JA07B and JA07C] and intermediate breast surgery (HRG codes are JA09A and JA09B),56 assuming that two-thirds of patients receive intermediate breast surgery and one-third of patients receive mastectomy.

Sentinel lymph node biopsy and 4-NS are assumed to be carried out at the same time as the breast surgery. ALND is assumed to be carried out at the same time as the breast surgery, if no sampling is performed beforehand (e.g. patients are diagnosed as node positive by biopsy). No UK costs of SLNB, 4-NS and ALND (at the same time as breast surgery) were identified from published studies. One study from the USA was identified which reported the costs of breast surgery alone, SLNB together with breast surgery and ALND together with breast surgery.20 The relative ratios between breast surgery and SLNB together with breast surgery, and between breast surgery and ALND together with breast surgery, can be calculated. These ratios were used to adjust the UK costs of breast surgery to obtain the costs of SLNB and ALND together with breast surgery. The procedure of 4-NS together with breast surgery was assumed to increase the costs of breast surgery alone by 10%.

Model inputs: probability and costs of short-term adverse events

The model inputs of probability and costs of short-term adverse events were summarised in Table 19. The probabilities of developing short-term adverse events due to SLNB and ALND were estimated based on published studies. No studies were identified that quantify the short-term adverse events associated with 4-NS. Based on expert opinion, it is assumed that 4-NS is associated with the same probabilities of developing short-term adverse events as SLNB. Sensitivity analysis was carried out to test the assumption that patients are more likely to develop adverse events for 4-NS than SLNB. The costs of short-term adverse events were based on a study in the US, as no UK costs were identified.

TABLE 19. Probabilities and costs of short-term adverse events.

TABLE 19

Probabilities and costs of short-term adverse events.

Model inputs: costs and utilities of health states

The model inputs of costs and utilities of health states are summarised in Table 20. Patients with node-negative results (TN and FN) are assumed to receive hormonal therapy for 5 years (where appropriate). For patients with FP results, the TN nodal status will be picked up by the following ALND. Therefore, patients with FP diagnoses also receive hormonal therapy. It is assumed that 81% of patients are oestrogen receptor positive, which means that they will respond to hormonal therapy.126 Among these patients, it is assumed that 90% receive aromatase inhibitors [anastrozole (Armidex®, AstraZeneca), exemestane (Aromasin®, Pfizer) or letrozole (Femara®, Novartis)] and 10% receive tamoxifen (Nolvadex, Istubal, Valodex). It is also assumed that each patient has one clinic visit and one mammogram per year in the adjuvant therapy state. The annual cost of aromatase inhibitors, tamoxifen and mammography is estimated to be £1002 based on a published study.129

TABLE 20. Costs and utilities of each health state.

TABLE 20

Costs and utilities of each health state.

Patients with TP results are assumed to receive chemotherapy for 6 months (£8788) followed by hormonal therapy for 4.5 (£1002 per year). It is assumed docetaxel (Taxotere®, Sanofi-aventis)-based chemotherapy is used.17 The costs of chemotherapy were calculated based on a published study.129

Annual costs for the post-adjuvant therapy state are assumed to be £0. Annual costs for the locoregional and metastatic relapse states and the death state were calculated based on a published study and are £4737, £10,196 and £3321, respectively.129 For patients in the remission state after locoregional relapse, the annual costs for the first 5 years were assumed to be the same as for patients in the adjuvant therapy state receiving hormonal therapy (£1002). The costs are assumed to be £0 after 5 years in the remission state.

The source of utility data used in the model is from Tengs and Wallace,130 which is a systematic review of health-related quality of life estimates from publicly available source documents. Given that the health-related quality of life in the general population decreases with age, it is important to take this into account in the model. General population utility estimates from Ara and Brazier131 were applied using a regression analysis of utility versus age. The age-related utility is calculated by the following formula (Equation 1):

Utility = A × (Age) + B × (Age × Age) + C
[Equation 1]

where A = −0.0001728, B = −0.000034 and C = 0.9584588.

The utilities for all health states are multiplied by this age-related utility value for each year of the model.

Model inputs: transition probabilities between health states

Transition probabilities between health states are summarised in Table 21. When a patient starts adjuvant therapy, the expected life expectancy of the patient is determined by the life table.132 The patient will die from other causes once the expected life expectancy is met. The transition probabilities from the adjuvant therapy state to the locoregional recurrence state depend on the diagnostic results for lymph node metastases (i.e. TN, FP, TP and FN). Node-negative patients, including TN and FP, will have lower transition probabilities and node-positive patients, including TP and FN, will have higher transition probabilities. In particular, patients with FN results will have the highest transition probability because they have been denied ALND and chemotherapy, needed to reduce the risk of recurrence. The annual transition probabilities for locoregional recurrence were based on a study by Orr et al.,133 which provided the estimates of annual transition probabilities of recurrence in patients with negative results (0.03), TP results (0.09) and FN results (0.14). The study assumed that patients with TP results receive chemotherapy and patients with FN results do not receive chemotherapy (and only receive hormonal therapy). The same assumption is used in this assessment.

TABLE 21. Transition probabilities between health states.

TABLE 21

Transition probabilities between health states.

When a patient enters the adjuvant therapy state, the model uses exponential distributions to sample the time to locoregional relapse according to the above annual transition probabilities. The sampled time to locoregional relapse will then be compared with the time to death (according to the life table) and the 5-year maximum period for adjuvant therapy. Depending on which event happens first (locoregional relapse, death due to other causes or finishing the adjuvant therapy), the patient will transit to the corresponding state after the time delay. The methodology used to determine which state the patient transits to is the same for other health states.

When patients enter the post-adjuvant therapy state, they may experience locoregional or metastatic relapse, or they may die from other causes. The annual transition probabilities of locoregional relapse and the time to death from other causes are assumed to be the same as under the adjuvant therapy state. The transition probabilities to metastatic relapse are 0.0023 for node-negative patients (TN and FP), 0.0052 for TP patients, and 0.0094 for FN patients.120

If patients enter the locoregional relapse state, they may enter a subsequent remission state, may have metastatic relapse, or may die from other causes. It is assumed that patients can stay in the locoregional relapse state for a maximum of 1 year. The annual probability of developing metastatic cancer in the first year of locoregional relapse is 0.18,134 which is much higher compared with disease-free survival states (i.e. adjuvant therapy and post-therapy states). Orr et al.133 suggested that the annual probability of death for patients with locoregional relapse is 0.30. This includes death due to both breast cancer and other causes. The model does not distinguish between death from breast cancer and death from other causes once a patient enters the locoregional relapse state. The maximum lifetime of a patient is still bounded by the life expectancy of the patient (i.e. death due to other causes).

If patients enter the remission state, they may still experience metastatic relapse before death. The average annual probability of developing metastatic cancer from the remission state is 0.13134 and the probability of death (for all reasons) is assumed to be the same as in the locoregional relapse state, which is 0.30.

Metastatic cancer is assumed not to be curable and the annual probability of death from metastatic relapse is 0.37.129

Model inputs: probability, costs and utilities of long-term adverse events

The model inputs of probability and costs of long-term adverse events (i.e. lymphoedema) are summarised in Table 22. The probabilities of developing lymphoedema due to SLNB and ALND were estimated based on published studies.4850,53 The probability of having lymphoedema due to 4-NS was assumed to be the same as SLNB, as no data were identified for 4-NS.

TABLE 22. Probabilities and costs of long-term adverse events.

TABLE 22

Probabilities and costs of long-term adverse events.

Lymphoedema was classified as either mild/moderate or severe. A literature search was undertaken, but no studies reporting utility for patients with lymphoedema were identified. The proportion of patients within each category and the utility decrements of each category were therefore estimated from a published study reporting quality of life using the FACT-B + 4 (Functional Assessment of Cancer Therapy for Breast Cancer, adding a four-item arm subscale) quality-of-life instrument.135 The study reported the data regarding the quality of life of breast cancer patients who suffer from different degrees of lymphoedema, using the FACT-B + 4 quality-of-life instrument. The utility decrements were estimated based on these quality-of-life data, therefore the decrements do not represent the true utility decrements due to lymphoedema. Sensitivity analyses were carried out to explore the impact on the cost-effectiveness results caused by changing the estimated utility decrements. The annual additional costs due to lymphoedema were based on expert opinions from the Sheffield Lymphoedema Service.

The utility decrement represents the reduced quality of life for patients with lymphoedema.

Discounting

The economic analysis assumes that both costs and QALYs are discounted at 3.5% per annum, in line with current recommendations from Her Majesty's Treasury.136

Univariate sensitivity analysis

In order to explore the impact on the cost-effectiveness results of changes to individual parameters and assumptions, a number of sensitivity analyses were performed.

Sensitivity and specificity of magnetic resonance imaging and positron emission tomography

The analysis is limited by the small number and size of MRI studies, and the wide variations between and within studies in terms of the MRI method used. A sensitivity analysis was carried out to decrease the mean sensitivity of MRI to the lower CI (from 90% to 78%) and maintain the mean specificity of MRI. Another sensitivity analysis was carried out to decrease the mean specificity of MRI to the lower CI (from 90% to 75%) and maintain the mean sensitivity of MRI.

In order to test the sensitivity of model results to increased MRI accuracy, a sensitivity analysis was carried out to increase both the sensitivity and specificity of MRI to the levels for USPIO-enhanced MRI. USPIO-enhanced MRI is a subtype of MRI that appears to have higher sensitivity and specificity (98% and 96%, respectively). In this sensitivity analysis the cost of MRI was assumed to increase by £100 to take account of the additional cost of the contrast agent used in USPIO-enhanced MRI.

Regarding PET, a sensitivity analysis was carried out to increase the sensitivity of PET to the higher CI (from 63% to 74%) and maintain the mean specificity.

Utility decrements and additional costs for lymphoedema

The main advantage of imaging techniques is to reduce short- and long-term adverse events including lymphoedema. Therefore, the utility decrements and additional costs for lymphoedema will impact on the cost-effectiveness of imaging techniques compared with sampling methods. Data on the long-term costs and utility impact of lymphoedema are, however, limited. Two sensitivity analyses were carried out to increase/decrease the utility decrements for lymphoedema by 50%. Another two sensitivity analyses were performed to increase/decrease the additional costs due to lymphoedema by 20%.

Probabilities of relapse for false-negative patients

Two sensitivity analyses were carried out to increase/decrease the probabilities of locoregional relapse for patients with FN diagnoses by 20%. Due to lower sensitivity, imaging techniques, especially PET, produce more FN cases than 4-NS and SLNB. The probabilities of relapse for patients with FN diagnoses were changed so that the impact on model results can be assessed.

Costs of sampling methods

High-quality UK cost data for 4-NS and SLNB procedures have not been identified. The costs used in the model were derived from non-UK studies. Sensitivity analyses were carried out to increase/decrease the costs of 4-NS and SLNB by 20%.

Probabilistic sensitivity analysis

Probabilistic sensitivity analysis (PSA) was undertaken to demonstrate the impact of uncertainty in the key model parameters and to generate information on the likelihood that each of the diagnostic strategies is optimal.

The sensitivity and specificity of a diagnostic test are generally correlated. To maintain this correlation, the sensitivities of each diagnostic method are sampled from a beta distribution, while the specificities of the test are derived based on the sampled sensitivity. The sensitivity and specificity are linked by the prevalence and the overall accuracy of the test, which are assumed to be constants. Therefore, when the sensitivity is sampled, the specificity can be calculated deterministically.

Equation 2 is the formula for calculating the test accuracy. After rearranging Equation 2, the model applies Equation 3 to derive test specificity from sensitivity. The overall accuracy of each diagnostic method is presented in Table 23, where the prevalence of early breast cancer among breast cancer patients is assumed to be fixed at 41.2%. The beta distributions representing the sensitivity of each diagnostic method are based on trial data from previous literature and the systematic review within this assessment (MRI and PET).

TABLE 23. Overall accuracies of each diagnostic method.

TABLE 23

Overall accuracies of each diagnostic method.

Accuracy = Sensitivity × Prevalence + Specificity × (1 − Prevalence)
[Equation 2]
Specificity = (Accuracy − Sensitivity × Prevalence)/(1 − Prevalence)
[Equation 3]

Health utilities and the probabilities of developing short- and long-term adverse events were modelled using beta distributions. Costs were sampled from normal distributions where standard errors can be calculated. Transition probabilities among health states and other costs were sampled from uniform distributions bounded by a 10% increase or decrease in the mean value.

The PSA was carried out by allowing the key model input parameters to vary according to the uncertainty specified in their probability distributions, with 500 sets of random numbers used to generate 500 parameter configurations, which produce 500 sets of model outputs. All model results were based on the PSA model outputs.

To demonstrate that 500 replications is enough to obtain accurate model outputs, the cumulative mean total costs and total QALYs of the baseline 4-NS diagnostic strategy based on 2000 replications were calculated. A significance level of 5% was used to construct the CI around the cumulative means. The analysis suggests that the CI was sufficiently narrow and the cumulative mean stabilises after 500 replications are performed.

Independent economic assessment – results

This section details the results of the health economic model. The cost-effectiveness results of imaging techniques are presented as marginal estimates when compared against the standard sampling methods of 4-NS and SLNB. All results are presented in terms of net benefits and incremental cost per QALY gained.

Base-case estimates of cost-effectiveness

The base-case estimates given below are the mean estimates from the 500 runs of the PSA. For each strategy, results are presented in terms of the diagnostic results, the total number of diagnostic and surgical procedures performed, the total costs and QALYs, the net benefit and incremental cost-effectiveness.

Diagnostic results

The proportions of patients whose lymph node diagnostic results are TN, FP, TP and FN are presented in Table 24 and Figure 16.

TABLE 24. Diagnostic results of each strategy.

TABLE 24

Diagnostic results of each strategy.

FIGURE 16. Proportion of people with FP and FN diagnostic results under each strategy.

FIGURE 16

Proportion of people with FP and FN diagnostic results under each strategy.

Key findings from the diagnostic results

Replacing sampling
  1. The number of FP cases increases significantly when sampling is replaced with imaging techniques (from 0.2% to 6.3% and 3.6% for MRI and PET, respectively). The main reason is that imaging techniques have lower specificity (89.7% and 94.2% for MRI and PET, respectively).
    Patients with FP diagnoses will receive ALND, as a stand-alone procedure (if detected by 4-NS or SLNB where the breast surgery is performed at the same time) or at the same time as the breast surgery (if detected by imaging techniques), which they actually do not need. The surgery is associated with short- and long-term adverse events which will both increase costs and affect quality of life of the patients. Since ALND is carried out for patients with FP diagnoses, the negative nodal status will be confirmed and the patients will be managed as node-negative patients afterwards.
  2. The number of FN cases increases slightly when the sampling methods are replaced with MRI. FN cases increase significantly when the sampling methods are replaced with PET (from around 1% to 7.2%) due to the low sensitivity of PET (63.4%).
    For patients with FN diagnoses, as no ALND will be performed, the true nodal status will remain unknown. The FN patients will miss the ALND which they actually need, resulting in a higher risk of locoregional and distant relapse which have significant costs and quality of life implications.
  3. As MRI has a lower specificity and a higher sensitivity than PET, the strategy that involves MRI will have more FP cases and fewer FN cases than strategies involving PET. However, the evidence on the accuracy of MRI is less robust, given that there are fewer studies on MRI than PET. The systematic review in the assessment also demonstrated that the sensitivity and specificity of both PET and MRI vary significantly between studies.
  4. The two strategies of replacing axillary sampling with imaging techniques produce higher levels of FP cases and (particularly for PET) FN cases. These strategies may be considered unacceptable on clinical grounds, even if they are found to be more cost-effective.
Adding imaging techniques before sampling
  1. When the imaging techniques are placed before the sampling methods (scenarios 3–6), the number of FP cases is increased from baseline to the same extent as in the corresponding replacement strategies (as expected according to the diagnostic pathway).
  2. The benefit of putting imaging techniques before sampling methods is that they will identify a proportion of TP patients (depending on the sensitivity of the tests) who will undergo the ALND straight away (at the same time as the main breast surgery), rather than undergoing both sampling (at the same time as the breast surgery) and a separate ALND procedure. This will reduce costs and possibly morbidity associated with having two sequential operations.
  3. As expected, the number of FN cases is reduced when imaging techniques are placed before sampling due to the use of two sequential diagnostic tests. When MRI is placed before the sampling methods, the proportion of FN cases drops to about 0.1%.
  4. Strategies that place imaging techniques before sampling methods produce fewer FN cases. However, they also produce significantly more FP cases, especially in the case of PET. This may be considered unacceptable on clinical grounds.

Resource use for diagnosis and surgical procedures

Table 25 presents the number of main diagnostic tests and surgical procedures carried out under each diagnostic strategy based on 5000 patients. Breast surgery is performed as a stand-alone procedure only if the negative nodal status is obtained by an imaging technique and no sampling methods are used (in scenario 1 or 2).

TABLE 25. Number of diagnostic tests and surgical procedures carried out for each diagnostic strategy (based on 5000 patients).

TABLE 25

Number of diagnostic tests and surgical procedures carried out for each diagnostic strategy (based on 5000 patients).

The key findings from the resource use results

Replacing sampling

When sampling methods are replaced with imaging techniques, all ALND procedures will be performed at the same time as the breast surgery as node-positive patients are diagnosed by either biopsy or non-invasive imaging techniques. It is also possible that breast surgery is performed as a stand-alone procedure if negative nodal status is obtained by the imaging techniques.

The same numbers of imaging techniques are carried out in scenarios 1 and 2, in which sampling methods are replaced with MRI and PET. There are more ALND procedures in scenario 1 than in scenario 2 (2283 vs 1877) as MRI is associated with more TP and FP cases than PET (see Table 24) due to its higher sensitivity and lower specificity. For the same reason, there are fewer stand-alone breast surgeries in scenario 1 than in scenario 2 (2717 vs 3123).

Adding imaging techniques before sampling

When imaging techniques are introduced before the sampling methods, ALND will be performed as a stand-alone procedure if positive nodal status is obtained from sampling procedures. ALND will be carried out at the same time as the breast surgery if positive nodal status is obtained from either imaging techniques or biopsy. As in the two baseline scenarios, it is not possible to have a stand-alone breast surgery when the imaging techniques are placed before the sampling methods.

As the imaging techniques are performed before the sampling methods, the numbers of imaging techniques performed are the same as the replacement scenarios. Compared with the two baseline scenarios, the numbers of sampling procedures carried out are reduced (from 3913 to 2716 if MRI is placed before sampling and to 3123 if PET is placed before sampling). The reduction is more evident when MRI is placed before sampling than PET, as MRI is associated with more positive cases (both true and false), which do not require further sampling methods.

Adverse events

The numbers of short- and long-term adverse events associated with each diagnostic strategy are presented in Table 26 and Figure 17. The numbers of short- and long-term adverse events are proportional to the number of sampling and ALND procedures undertaken (see Table 25). The model assumes that the probabilities of short-term adverse events are the same for both 4-NS and SLNB, while ALND is associated with much higher probabilities of developing adverse events.

TABLE 26. Adverse event cases associated with each diagnostic strategy.

TABLE 26

Adverse event cases associated with each diagnostic strategy.

FIGURE 17. Adverse event cases associated with each diagnostic strategy.

FIGURE 17

Adverse event cases associated with each diagnostic strategy.

The key findings from the adverse event results

Replacing sampling

The two replacement strategies (scenarios 1 and 2) have both fewer short- and long-term adverse events than the two baseline strategies, despite more ALND procedures being undertaken. This is due to the number of sampling procedures avoided (see Table 25). The PET replacement strategy has fewer adverse events than the MRI replacement strategy as fewer ALND procedures are performed.

Adding imaging techniques before sampling

In general, there are more short- and long-term adverse events when imaging techniques are placed before sampling methods (scenarios 3–6). Under these scenarios, some sampling procedures are avoided (if positive nodal status is obtained from imaging techniques). However, more patients will undergo ALND (either stand-alone or with breast surgery) in these scenarios as the number of patients with both TP and FP diagnoses will increase (see Table 24). The model suggests that the adverse events associated with increased ALND procedures outnumber the adverse events associated with avoided sampling procedures (ALND is associated with significantly higher probability of developing adverse events than sampling methods).

Survival results

The 5-year survival rates for patients with different diagnostic results are presented in Figure 18. Patients with axillary lymph node metastases (both TP and FN) have lower survival rates than patients with negative nodal status. In particular, patients with FN results are associated with the lowest survival rate, because they do not receive ALND or chemotherapy that may reduce the chance of recurrence.

FIGURE 18. The 5-year survival rates for patients with different diagnostic results.

FIGURE 18

The 5-year survival rates for patients with different diagnostic results.

The 5-year survival rates of all patients with early breast cancer and the absolute number of deaths per 10,000 patients presenting with early breast cancer are presented in Table 27 for each tested diagnostic strategy. The overall survival rate of each strategy is dependent on the proportion of patients with each diagnostic result (see Table 24) and the individual survival rate for patients with different diagnostic results (see Figure 18). As patients with FN results have the lowest survival rate, diagnostic strategies that are associated with more FN results have lower overall survival rate (e.g. PET replacement strategy). The absolute differences in overall survival rates among tested diagnostic strategies are relatively small (range from 87.52% to 88.1%). This is because the absolute numbers of patients with FN results only account for a small proportion of patients (range from 0.1% to 7.2% as shown in Table 24). The absolute difference in the number of deaths during the first 5 years per 10,000 early-stage breast cancer patients is also presented in Table 27. This shows the change in absolute mortality for each tested diagnostic strategy, using the 4-NS baseline as the reference strategy.

TABLE 27. The 5-year survival rates and the absolute number of deaths in England for patients with early breast cancer (comparing different diagnostic strategies).

TABLE 27

The 5-year survival rates and the absolute number of deaths in England for patients with early breast cancer (comparing different diagnostic strategies).

Cost-effectiveness results (net benefit analysis)

Positron emission tomography and MRI are assumed to be associated with no short- and long-term adverse events. However, due to the lower accuracy of the imaging techniques, more FP and FN cases will be produced, which will lead to increased costs, worse quality of life due to adverse events, and in some cases higher probability of recurrence and subsequent death from breast cancer. Economic modelling provides a systematic way to understand and quantify the complex trade-offs between the advantages and disadvantages of the imaging techniques, so that the overall cost-effectiveness of alternative strategies can be determined.

Net benefit is the increase in effectiveness (Δ E), multiplied by the amount the decision-maker is willing to pay per unit of increased effectiveness (RT), less the increase in cost (Δ C). The formula for calculating net benefit is:

Net benefit = RTΔE − ΔC > 0
[Equation 4]

A strategy is most cost-effective if it has the highest positive net benefit. Thresholds of willingness to pay per QALY of £10,000, £20,000 and £30,000 were used to calculate the net benefit of each strategy.

Two baseline strategies (4-NS and SLNB) are considered. Both 4-NS and SLNB are currently used in the UK. It is not within the scope of this assessment to compare these sampling methods. Tables 28 and 29 summarise the net benefits of each strategy using either 4-NS or SLNB as the baseline strategy. Note that scenarios 1 and 2 appeared in both tables because they are comparable to both 4-NS and SLNB strategies. The total costs and QALYs of each diagnostic strategy are plotted in Figures 19 and 20.

TABLE 28. Total costs and QALYs and the net benefit of each diagnostic strategy using 4-NS as baseline.

TABLE 28

Total costs and QALYs and the net benefit of each diagnostic strategy using 4-NS as baseline.

TABLE 29. Total costs and QALYs and the net benefit of each diagnostic strategy using SLNB as baseline.

TABLE 29

Total costs and QALYs and the net benefit of each diagnostic strategy using SLNB as baseline.

FIGURE 19. Total costs and QALYs of diagnostic strategies using 4-node sampling as baseline.

FIGURE 19

Total costs and QALYs of diagnostic strategies using 4-node sampling as baseline.

FIGURE 20. Total costs and QALYs of diagnostic strategies using sentinel lymph node biopsy as baseline.

FIGURE 20

Total costs and QALYs of diagnostic strategies using sentinel lymph node biopsy as baseline.

The horizontal axis of Figures 19 and 20 represents the total QALYs accrued by each diagnostic strategy and the vertical axis represents the total costs associated with each strategy. The lines in the figures denote the cost-effective frontiers if PET and MRI replacement strategies are excluded based on clinical grounds.

The total and breakdown costs (costs associated with diagnostic tests or short-term adverse events and costs associated with health states or long-term adverse events) of each strategy are illustrated in Figure 21.

FIGURE 21. Costs associated with each diagnostic strategy.

FIGURE 21

Costs associated with each diagnostic strategy.

Key findings from the net benefit results

Replacing sampling
  1. When 4-NS is used as the baseline (see Table 28 and Figure 19), the most cost-effective strategy is to replace sampling with MRI (scenario 1), which has the highest net benefits under all willingness-to-pay thresholds tested. The next most cost-effective strategy is to replace sampling with PET (scenario 2). The baseline 4-NS strategy is dominated by both scenario 1 and scenario 2, as they have lower total costs and higher total QALYs.
  2. When SLNB is used as the baseline (see Table 29 and Figure 20), the most cost-effective strategy is still to replace sampling with MRI (scenario 1), which has the highest net benefits under all willingness-to-pay thresholds tested. The next most cost-effective strategy is also to replace sampling with PET (scenario 2). The baseline SLNB strategy is dominated by both scenarios 1 and 2, as they have lower total costs and higher total QALYs.
  3. MRI has reasonably good sensitivity and specificity and lower cost than PET, 4-NS and SLNB. Compared with the baseline 4-NS and SLNB strategies, the disadvantages of the MRI replacement strategy are that it is associated with more FP cases (increased from 0.2% to 6.3%) resulting in many node-negative patients undergoing unnecessary ALND, and more FN cases (increased from around 1.0% to 1.9%) who are left at higher risk of cancer recurrence. The advantage of the MRI replacement strategy, compared with the two baseline strategies, is that many node-positive patients will be correctly diagnosed by MRI and undergo ALND (at the same time as the breast surgery) rather than undergoing two surgical procedures (4-NS or SLNB followed by ALND). For TN patients, the advantage of the MRI replacement strategy is that these patients will be correctly diagnosed without the need for a sampling procedure. The sampling procedures are associated with increased costs and risk of short- and long-term adverse events. The model suggests that the advantages of the MRI replacement strategy outweigh the disadvantages in relation to benefits as expressed by QALYs.
  4. The advantages and disadvantages of MRI compared with sampling methods also applies to PET. Compared with the baseline strategies, the model also suggests that the advantages of PET outweigh the disadvantages for both costs and QALYs. Compared with the MRI replacement strategy, the PET replacement strategy has similar total costs but significantly lower total QALYs. This is because PET is associated with more FN cases due to lower sensitivity and patients with FN diagnoses are more likely to experience locoregional and metastatic relapse.
Adding magnetic resonance imaging or positron emission tomography before sampling

The MRI and PET replacement strategies may be deemed unacceptable on clinical grounds due to higher numbers of patients with FN and FP diagnoses. When the replacement strategies are excluded, the baseline 4-NS and SLNB strategies were only compared with the strategies of adding MRI or PET before sampling methods.

  1. The most cost-effective strategy is to retain the baseline 4-NS strategy (when 4-NS is used as the baseline) or to place MRI before SLNB (when SLNB is used as the baseline).
  2. The advantages of the strategies of adding MRI or PET before sampling methods are that there are fewer FN cases (reduced from around 1.0% to 0.1% for MRI) due to the use of two sequential tests, and fewer sampling procedures performed (because sampling methods are avoided if MRI or PET results are positive). The disadvantages of these strategies are that there are more FP cases because the specificities of MRI and PET are lower than those of SLNB and 4-NS (FPs increase from 0.2% to 6.3% for MRI prior to SLNB, which is the same as for the MRI replacement strategy). Overall, the cost-effectiveness results suggest that there are both higher costs and higher QALYs associated with strategies of adding MRI or PET before sampling methods compared with the baseline 4-NS and SLNB strategies.
  3. In terms of cost-effectiveness, the model results suggest that adding MRI prior to SLNB is cost-effective, whereas adding MRI prior to 4-NS is not. This is because the addition of MRI means that fewer sampling procedures are required, and the cost saving associated with this is greater for SLNB than for 4-NS because SLNB is more costly than 4-NS.
  4. The absolute differences in QALYs among the baseline 4-NS and SLNB strategies and the strategies of adding MRI or PET before sampling are very small. When the MRI and PET replacement strategies are excluded, the total QALYs range from 8.122 to 8.126 when 4-NS is used as the baseline and from 8.119 to 8.125 when SLNB is used as the baseline. This implies that there is no significant absolute improvement in QALYs when MRI or PET are added before 4-NS or SLNB. For example, although the model results suggest the strategy of adding MRI before SLNB is cost-effective, the change from the baseline SLNB strategy to the alternative strategy of MRI before SLNB only increases the QALYs by 0.005. The main reason that the alternative strategy is cost-effective is that there is an even smaller increase in total costs (relative to the QALY increase).

Cost-effectiveness results (incremental analysis)

The incremental cost-effectiveness analyses were performed assuming that MRI and PET replacement strategies are deemed unacceptable on clinical grounds. Tables 30 and 31 show the incremental cost-effectiveness analyses where 4-NS and SLNB are used as the baseline strategy.

TABLE 30. Incremental cost-effectiveness analysis of diagnostic strategies using 4-NS as baseline (excluding MRI and PET replacement strategies).

TABLE 30

Incremental cost-effectiveness analysis of diagnostic strategies using 4-NS as baseline (excluding MRI and PET replacement strategies).

TABLE 31. Incremental cost-effectiveness analysis of diagnostic strategies using SLNB as baseline (excluding MRI and PET replacement strategies).

TABLE 31

Incremental cost-effectiveness analysis of diagnostic strategies using SLNB as baseline (excluding MRI and PET replacement strategies).

The cost-effectiveness plane for the MRI before 4-NS strategy versus the baseline 4-NS strategy is presented in Figure 22. The cost-effectiveness plane for the MRI before SLNB strategy versus the baseline SLNB strategy is presented in Figure 23.

FIGURE 22. Cost-effectiveness plane for MRI before 4-node sampling (4-NS) strategy versus baseline 4-NS strategy.

FIGURE 22

Cost-effectiveness plane for MRI before 4-node sampling (4-NS) strategy versus baseline 4-NS strategy.

FIGURE 23. Cost-effectiveness plane for MRI before SLNB strategy versus baseline SLNB strategy.

FIGURE 23

Cost-effectiveness plane for MRI before SLNB strategy versus baseline SLNB strategy.

Both Figures 22 and 23 demonstrate that MRI before sampling strategy may lead to either an increase or decrease in QALYs compared with the baseline strategy. The advantage of this strategy in terms of QALYs is therefore uncertain. Figure 22 shows that the MRI before 4-NS typically generates higher total costs than the 4-NS strategy. Figure 23 shows that MRI before SLNB strategy may lead to either an increase or a decrease in total costs compared with the SLNB strategy. The benefits offered by these strategies are not clear-cut.

Univariate sensitivity analysis

Sensitivity and specificity of magnetic resonance imaging

When the sensitivity of MRI is reduced from 90% to 78% (the lower CI) while maintaining the mean specificity of 90%, the strategy of MRI replacement is still the most cost-effective strategy when either 4-NS or SLNB is used as baseline. If the MRI and PET replacement strategies are rejected on clinical grounds, then the conclusions differ from the baseline results. When SLNB is used as the baseline, the most cost-effective strategy is to retain the baseline SLNB strategy when a willingness-to-pay threshold of £20,000 per QALY is used. This differs from the baseline results, where the most cost-effective strategy is the addition of MRI before SLNB.

When the specificity of MRI is reduced from 90% to 75% (the lower CI), while maintaining the mean sensitivity of 90%, the PET replacement strategy becomes the most cost-effective strategy when a willingness-to-pay threshold of £20,000 per QALY is used. This conclusion differs from the baseline results where the MRI replacement strategy is most cost-effective. If the MRI and PET replacement strategies are rejected on clinical grounds, then the strategy of adding MRI before SLNB is dominated by the baseline SLNB strategy. This means it is cost-effective to retain the baseline SLNB strategy.

When the sensitivity and specificity of MRI are increased to the levels of USPIO-enhanced MRI (from 90% to 98% and from 90% to 96%, respectively), the MRI replacement strategy remains the most cost-effective strategy. If the MRI and PET replacement strategies are rejected based on clinical grounds, then the most cost-effective strategy is to add MRI before 4-NS (when 4-NS is used as baseline) and to add MRI before SLNB (when SLNB is used as baseline).

The sensitivity analyses demonstrate that the sensitivity and specificity of MRI have a significant impact on the cost-effectiveness results.

Sensitivity of positron emission tomography

When the sensitivity of PET is increased from 63% to 74% (the upper CI), while maintaining the mean specificity of 94%, the baseline cost-effectiveness results do not change. The total QALYs of the three strategies that involve PET, including the PET replacement strategy and strategies to add PET before 4-NS and SLNB, were all increased. However, the increase is not significant enough to alter the conclusions relating to cost-effectiveness. The sensitivity analysis demonstrates that the sensitivity of PET does not appear to have a significant impact on cost-effectiveness results.

Utility decrement for lymphoedema

When the assumed utility decrement for lymphoedema is reduced by 50% (i.e. from 9.9% to 5.0% for mild/moderate lymphoedema and from 12.3% to 6.2% for severe lymphoedema), the MRI replacement strategy is still the most cost-effective strategy. However, the total QALYs for the PET replacement strategy, which is the second most effective strategy, becomes the smallest among all diagnostic strategies modelled. The PET replacement strategy is associated with the fewest cases of lymphoedema (see Table 26) and is therefore most affected. The cost-effectiveness results remain unchanged if the MRI and PET replacement strategies are rejected on clinical grounds.

When the assumed utility decrement for lymphoedema is increased by 50% (i.e. from 9.9% to 14.9% for mild/moderate lymphoedema and from 12.3% to 18.5% for severe lymphoedema), the baseline cost-effectiveness results do not change. Although the total QALYs for all strategies are reduced due to a higher utility decrement for lymphoedema, the sensitivity analysis shows that the decrease is smallest for the PET replacement strategy, as this strategy has the smallest number of lymphoedema cases. However, the MRI replacement strategy is still the most cost-effective.

The sensitivity analyses demonstrate that the PET replacement strategy is most affected by the change of utility decrements for lymphoedema. However, the overall cost-effectiveness results do not appear to be significantly affected by this parameter.

Additional costs of lymphoedema

When the annual additional cost of lymphoedema is decreased by 20% (i.e. from £66.50 to £53.20 for mild/moderate lymphoedema and from £1180 to £944 for severe lymphoedema) or increased by 20% (i.e. from £66.50 to £79.80 for mild/moderate lymphoedema and from £1180 to £1416 for severe lymphoedema), the baseline cost-effectiveness results do not change. The sensitivity analysis demonstrates that the additional cost of lymphoedema does not appear to have a significant impact on cost-effectiveness results.

Probability of relapse for false-negative patients

When the probability of relapse for patients with FN diagnoses is reduced by 20% (i.e. from 0.140 to 0.112 for locoregional relapse and from 0.0094 to 0.0075 for metastatic relapse), the MRI and PET replacement strategies remain the most and second most effective strategies. However, if the MRI or PET replacement strategies are rejected on clinical grounds, then the most cost-effective strategy is either the baseline 4-NS strategy or the SLNB strategy (depending on which baseline is used) which dominate the strategies of adding MRI before 4-NS and SLNB, respectively.

When the probability of relapse for patients with FN diagnoses is increased by 20% (i.e. from 0.14 to 0.17 for locoregional relapse and from 0.0094 to 0.0113 for metastatic relapse), baseline cost-effectiveness results do not change. The total QALYs for all strategies are reduced due to the increased probability of relapse. The sensitivity analysis shows that the decrease in QALYs is most significant for the PET replacement strategy. The total QALYs for this strategy, which dominates the baseline 4-NS and SLNB strategies in the baseline results, becomes the lowest among all strategies. The PET replacement strategy is affected the most because it is associated with the largest number of patients with FN diagnoses.

The sensitivity analysis shows that cost-effectiveness results are affected by the change in probability of relapse for FN patients. Among all strategies, the PET replacement strategy is most affected.

Cost of 4-node sampling

When the cost of 4-NS is decreased by 20% (i.e. from £2099 to £1679) or increased by 20% (i.e. from £2099 to £2518), the baseline cost-effectiveness results do not change. The sensitivity analyses demonstrate that the cost of 4-NS does not appear to have a significant impact on cost-effectiveness results.

Cost of sentinel lymph node biopsy

When the cost of SLNB is decreased by 20% (i.e. from £2728 to £2182), the MRI replacement strategy remains the most cost-effective strategy. However, if the MRI and PET replacement strategies are rejected on clinical grounds and SLNB is used as the baseline, then the most cost-effective strategy is to retain the baseline SLNB strategy when a willingness-to-pay threshold of £20,000 is used. This differs from the baseline results where the most cost-effective strategy is the addition of MRI before SLNB. When the cost of SLNB is increased by 20% (i.e. from £2728 to £3274), the baseline cost-effectiveness results do not change.

The sensitivity analyses demonstrate that the cost of SLNB influences the cost-effectiveness results, when the cost of SLNB is decreased.

Discussion of cost-effectiveness and modelling results

Diagnostic results

The baseline (4-NS and SLNB) strategies produce the smallest number of FP cases among all strategies. The number of FN cases produced by the two baseline strategies is also very small (1.1% for 4-NS and 1.3% for SLNB). In the MRI replacement strategy, the number of FP cases is increased significantly from 0.2% to 6.3% and the number of FN cases is increased to a lesser extent, from around 1.0% to 1.9%. In the PET replacement strategy the numbers of both FP and FN cases are increased significantly, from 0.2% to 3.6% for FP cases and from around 1.0% to 7.2% for FN cases. Overall, the PET replacement strategy produces the largest number of FP/FN cases among all the diagnostic strategies tested.

If MRI or PET is placed before sampling methods, the number of FN cases is reduced from around 1.0% to 0.1% if MRI is placed before sampling and to around 0.5% if PET is placed before sampling. The number of FP cases remains the same as for the MRI and PET replacement strategies.

The baseline strategies produce the lowest number of FP cases. The strategies of adding MRI before 4-NS and SLNB produce the lowest number of FN cases. Overall, the baseline strategies produce the smallest number of combined FP and FN cases. The MRI and PET replacement strategies may be considered unacceptable on clinical grounds, as they both generate more FP and FN cases than current standard practice. The strategies of adding MRI or PET before sampling also produces more FP cases, although the number of FN cases is reduced.

Number of procedures

Under the baseline sampling strategies a proportion of patients will need two separate surgical procedures: a sampling procedure (4-NS or SLNB) and subsequent ALND. In the replacement strategies, no sampling procedures are needed and the ALND procedures are carried out for TP and FP cases. Compared with the baseline strategies, the total number of ALND procedures carried out is increased for the MRI replacement strategy (due to more FP cases) and decreased for the PET replacement strategy (due to less TP cases).

If MRI or PET is placed before the sampling methods, the numbers of sampling procedures carried out are reduced compared with the baseline 4-NS and SLNB strategies because both TP and FP cases detected by MRI or PET will receive ALND surgery without sampling procedures. The reduction is more evident when MRI rather than PET is placed before sampling, as MRI is associated with more positive cases (both true and false). However, due to the increase in FP cases, the strategies of adding MRI or PET before sampling are associated with more ALND procedures than the baseline 4-NS and SLNB strategies.

Adverse events

The number of short- and long-term adverse events is proportional to the number of 4-NS, SLNB and ALND surgical procedures carried out. Adverse events are more frequent for ALND than 4-NS and SLNB. Among all diagnostic strategies modelled, the PET replacement strategy is associated with the lowest number of adverse events, followed by the MRI replacement strategy. The PET replacement strategy is associated with the smallest number of ALND procedures. The strategies of adding MRI or PET before sampling produce more adverse events than the baseline 4-NS and SLNB strategies, because more ALND procedures are carried out.

Survival rates

Patients with axillary lymph node metastases have lower survival rates (both TP and FN) than patients with negative nodal status (both TN and FP). Patients with FN results have the lowest survival rates because they do not receive ALND or chemotherapy that may reduce the risk of recurrence.

Compared with the two baseline strategies, the overall survival rates of early-stage breast cancer patients are lower for the MRI or PET replacement strategies and higher for the strategies where MRI or PET is placed before 4-NS and SLNB. The absolute differences in overall survival rate among tested diagnostic strategies are relatively small, as the absolute number of patients with FN results only account for a small proportion of all patients.

Cost-effectiveness analyses – baseline results

The PET and MRI strategies are compared with two baseline techniques – SLNB and 4-NS – which are both used currently in the UK. It is beyond the remit of this assessment to compare 4-NS and SLNB.

The MRI replacement strategy is the most cost-effective strategy and dominates the two baseline strategies. The higher QALYs of the MRI replacement strategy are driven by fewer cases of lymphoedema, which has a lifelong impact on quality of life. The PET replacement strategy is the next most cost-effective strategy and also dominates the two baseline strategies. Compared with the MRI replacement strategy, the PET replacement strategy has significantly lower QALYs, which is driven by more FN cases who are more likely to experience locoregional and metastatic relapse.

The cost-effectiveness results demonstrate that, on the population level, it is beneficial to replace invasive sampling methods with the non-invasive imaging techniques of MRI or PET. If the MRI or PET replacement strategies are used, a small proportion of patients will be wrongly diagnosed as FP or FN, which will impact on life-years gained and quality of life for these patients. However, the majority of patients will be correctly diagnosed by MRI or PET, without the need for sampling procedures. This will improve their quality of life owing to avoidance of short- and long-term adverse events such as lymphoedema. The model results suggest that the health benefits gained by the majority of patients outweigh the negative impact on reduced survival and lower quality of life of a small proportion of patients. The imaging replacement strategies, especially for MRI, also cost less than the baseline 4-NS and SLNB strategies. Overall, the analysis predicts that it is cost-effective to replace 4-NS or SLNB with MRI or PET.

Despite the cost-effectiveness results, the MRI and PET replacement strategies may be considered unacceptable on clinical grounds, due to higher numbers of FP and FN cases. If this is the case, then the most cost-effective strategy is the 4-NS strategy (if 4-NS is used as the baseline) or the addition of MRI before SLNB (if SLNB is used as the baseline). However, these results are less robust than the results for the replacement strategies. The differences in costs and QALYs between strategies are small and therefore the results are sensitive to changes in the input parameters. More robust evidence is needed on the costs of 4-NS and SLNB and the costs of MRI and PET. In addition more robust evidence on the sensitivity and specificity of 4-NS is also needed.

The strategies of placing MRI or PET before sampling may also be rejected on the clinical grounds that they are associated with more FP cases. In order to have a similar level of FP cases to the sampling methods, the specificity of MRI and PET needs to be improved to be close to 100% which, by definition, is the specificity of 4-NS and SLNB. For the MRI or PET replacement strategies, in order to have similar levels of FP and FN cases to the sampling methods, both. the sensitivity and specificity have to be improved to the levels of 4-NS and SLNB. The most promising technique is the USPIO-enhanced MRI, which has a mean sensitivity of 98% and specificity of 96%. These figures are, however, based on a limited number of small studies. Further studies are needed to confirm the robustness of these figures.

In general, based on the estimates of sensitivity and specificity of MRI and PET in this assessment, the analysis predicts that it is cost-effective to replace 4-NS or SLNB with MRI or PET which will accrue more QALYs and cost less at the population level. Within the two replacement strategies, it is more cost-effective to replace sampling with MRI than PET.

Cost-effectiveness analyses – sensitivity analysis results

The sensitivity and specificity of MRI have a significant impact on the cost-effectiveness results, and change the results in terms of the most cost-effective strategy. Further evidence on the sensitivity and specificity of MRI is therefore needed.

The utility decrement for lymphoedema has a significant impact on the cost-effectiveness of the PET replacement strategy, as the strategy is associated with the smallest number of lymphoedema cases. If the assumed utility decrement for lymphoedema is reduced, the PET replacement strategy no longer dominates the baseline 4-NS and SLNB strategies. Further studies on the costs and quality of life of lymphoedema are needed.

The probabilities of relapse for FN patients also have a significant impact on the cost-effectiveness results, particularly for the PET replacement strategy. The PET replacement strategy no longer dominates the baseline 4-NS and SLNB strategies when the probabilities of relapse for FN patients are increased.

The change in cost of SLNB has an impact on the cost-effectiveness of the strategy of adding MRI before SLNB. When the cost of SLNB is decreased, the strategy of adding MRI before SLNB becomes less cost-effective than the baseline SLNB strategy.

Sensitivity analyses also suggest that cost-effectiveness results appear to be robust when the model inputs of sensitivity of PET, the additional costs of lymphoedema and the costs of 4-NS are changed.

In general, the MRI replacement strategy remains the most cost-effective strategy and dominates the baseline 4-NS and SLNB strategies in most of the sensitivity analyses undertaken. The PET replacement strategy is not as robust as the MRI replacement strategy, as its cost-effectiveness is significantly affected by the utility decrement for lymphoedema and the probability of relapse for FN patients. When the imaging replacement strategies are excluded, the cost-effectiveness of adding MRI before 4-NS or SLNB is affected by the change of model inputs of MRI sensitivity and specificity, the probabilities of relapse for FN patients and the cost of SLNB.

Limitations of the analysis

The main limitations of the cost-effectiveness analyses include:

  • Evidence on the sensitivity and specificity of 4-NS is limited and is less robust than evidence on SLNB. The adverse event rates of 4-NS are assumed to be the same as rates for SLNB, but this may underestimate the adverse event rates of 4-NS.
  • The sensitivity and specificity of MRI and PET vary significantly across different studies. The evidence for MRI is less robust than the evidence for PET, given that it based on a limited number of small studies.
  • The sensitivity and specificity of MRI and PET are assumed to be independent of previous tests.
  • The quality of evidence on the cost of lymphoedema and the impact of lymphoedema on quality of life is poor.
  • The quality of evidence on the costs of short-term adverse events is poor.
  • More robust costing information for the baseline sampling procedures and for MRI and PET are also needed for the UK setting.
© 2011, Crown Copyright.

Included under terms of UK Non-commercial Government License.

Cover of Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) for the Assessment of Axillary Lymph Node Metastases in Early Breast Cancer: Systematic Review and Economic Evaluation
Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) for the Assessment of Axillary Lymph Node Metastases in Early Breast Cancer: Systematic Review and Economic Evaluation.
Health Technology Assessment, No. 15.4.
Cooper KL, Meng Y, Harnan S, et al.
Southampton (UK): NIHR Journals Library; 2011 Jan.

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