title: 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.
abstract: BACKGROUND
  Breast cancer is the most common type of cancer in women. Evaluation of axillary lymph node metastases is important for breast cancer staging and treatment planning.
  
  
  OBJECTIVE
  To evaluate the diagnostic accuracy, cost-effectiveness and effect on patient outcomes of positron emission tomography (PET), with or without computed tomography (CT), and magnetic resonance imaging (MRI) in the evaluation of axillary lymph node metastases in patients with newly diagnosed early-stage breast cancer.
  
  
  METHODS
  A systematic review of literature and an economic evaluation were carried out. Key databases (including MEDLINE, EMBASE and nine others) plus research registers and conference proceedings were searched for relevant studies up to April 2009. A decision-analytical model was developed to determine cost-effectiveness in the UK.
  
  
  METHODS
  One reviewer assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers and screened them against inclusion criteria. Data from included studies were extracted by one reviewer using a standardised data extraction form and checked by a second reviewer. Discrepancies were resolved by discussion. Quality of included studies was assessed using the quality assessment of diagnostic accuracy studies (QUADAS) checklist, applied by one reviewer and checked by a second.
  
  
  RESULTS
  Forty-five citations relating to 35 studies were included in the clinical effectiveness review: 26 studies of PET and nine studies of MRI. Two studies were included in the cost-effectiveness review: one of PET and one of MRI. Of the seven studies evaluating PET/CT (n = 862), the mean sensitivity was 56% [95% confidence interval (CI) 44% to 67%] and mean specificity 96% (95% CI 90% to 99%). Of the 19 studies evaluating PET only (n = 1729), the mean sensitivity was 66% (95% CI 50% to 79%) and mean specificity 93% (95% CI 89% to 96%). PET performed less well for small metastases; the mean sensitivity was 11% (95% CI 5% to 22%) for micrometastases (≤ 2 mm; five studies; n = 63), and 57% (95% CI 47% to 66%) for macrometastases (> 2 mm; four studies; n = 111). The smallest metastatic nodes detected by PET measured 3 mm, while PET failed to detect some nodes measuring > 15 mm. Studies in which all patients were clinically node negative showed a trend towards lower sensitivity of PET compared with studies with a mixed population. Across five studies evaluating ultrasmall super-paramagnetic iron oxide (USPIO)-enhanced MRI (n = 93), the mean sensitivity was 98% (95% CI 61% to 100%) and mean specificity 96% (95% CI 72% to 100%). Across three studies of gadolinium-enhanced MRI (n = 187), the mean sensitivity was 88% (95% CI 78% to 94%) and mean specificity 73% (95% CI 63% to 81%). In the single study of in vivo proton magnetic resonance spectroscopy (n = 27), the sensitivity was 65% (95% CI 38% to 86%) and specificity 100% (95% CI 69% to 100%). USPIO-enhanced MRI showed a trend towards higher sensitivity and specificity than gadolinium-enhanced MRI. Results of the decision modelling suggest that the MRI replacement strategy is the most cost-effective strategy and dominates the baseline 4-node sampling (4-NS) and sentinel lymph node biopsy (SLNB) strategies in most 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 false-negative (FN) patients.
  
  
  CONCLUSIONS
  No included studies directly compared PET and MRI.
  
  
  CONCLUSIONS
  Studies demonstrated that PET and MRI have lower sensitivity and specificity than SLNB and 4-NS but are associated with fewer adverse events. Included studies indicated a significantly higher mean sensitivity for MRI than for PET, with USPIO-enhanced MRI providing the highest sensitivity. However, sensitivity and specificity of PET and MRI varied widely between studies, and MRI studies were relatively small and varied in their methods; therefore, results should be interpreted with caution. Decision modelling based on these results suggests that the most cost-effective strategy may be MRI rather than SLNB or 4-NS. This strategy reduces costs and increases quality-adjusted life-years (QALYs) because there are fewer adverse events for the majority of patients. However, this strategy leads to more FN cases at higher risk of cancer recurrence and more false- positive (FP) cases who would undergo unnecessary axillary lymph node dissection. Adding MRI prior to SLNB or 4-NS has little effect on QALYs, though this analysis is limited by lack of available data. Future research should include large, well-conducted studies of MRI, particularly using USPIO; data on the long-term impacts of lymphoedema on cost and patient utility; studies of the comparative effectiveness and cost-effectiveness of SLNB and 4-NS; and more robust UK cost data for 4-NS and SLNB as well as the cost of MRI and PET techniques.
  
  
  BACKGROUND
  This study was funded by the Health Technology Assessment programme of the National Institute of Health Research.
authors.affiliation: School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: K L
authors.initials: KL
authors.lastname: Cooper
authors.forename: Y
authors.initials: Y
authors.lastname: Meng
authors.forename: S
authors.initials: S
authors.lastname: Harnan
authors.forename: S E
authors.initials: SE
authors.lastname: Ward
authors.forename: P
authors.initials: P
authors.lastname: Fitzgerald
authors.forename: D
authors.initials: D
authors.lastname: Papaioannou
authors.forename: L
authors.initials: L
authors.lastname: Wyld
authors.forename: C
authors.initials: C
authors.lastname: Ingram
authors.forename: I D
authors.initials: ID
authors.lastname: Wilkinson
authors.forename: E
authors.initials: E
authors.lastname: Lorenz
mesh_terms: D001365:Axilla; D001943:Breast Neoplasms / Q000473:pathology*; D003365:Costs and Cost Analysis; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D008198:Lymph Nodes / Q000000981:diagnostic imaging / Q000473:pathology*; D008207:Lymphatic Metastasis / Q000175:diagnosis*; D008279:Magnetic Resonance Imaging / Q000191:economics*; D049268:Positron-Emission Tomography / Q000191:economics*; D006113:United Kingdom