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Research Protocol – Dec. 17, 2013
Imaging Techniques for Treatment Evaluation for Metastatic Breast Cancer
Table of Contents
- Background and Objectives for the Technical Brief
- Guiding Questions
- Definition of Terms
- Summary of Protocol Amendments
- Key Informants
- Peer Reviewers
- EPC Team Disclosures
Background and Objectives for the Technical Brief
Metastatic Breast Cancer
In spite of significant gains in detection and treatment, breast cancer continues to have a broad impact in the United States, with an estimated 234,580 individuals with new diagnoses in 2013.1 About 33 percent of individuals with breast cancer diagnosed between 2001-2007 had regional metastases, with a 5-year relative survival rate of 84 percent. Approximately 5 percent were diagnosed with distant metastases, most commonly to the bones, lungs, liver, or brain, and had a 5-year relative survival rate of only 23 percent.1
Several imaging modalities, including ultrasound, magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), PET-CT, and bone scintigraphy, are used to evaluate the effects of treatment for metastatic breast cancer.2 However, as outlined in guidelines from the National Comprehensive Cancer Network (NCCN) and the National Institute for Health and Clinical Excellence (NICE), evidence regarding the accuracy and effectiveness of these modalities to evaluate treatment of metastatic breast cancer is lacking, even though the type and results of imaging may strongly affect patient outcomes.2,3 Inappropriate use could lead to overtreatment. For example, use of MRI during breast cancer diagnosis and treatment planning is associated with longer time intervals from diagnosis to treatment4,5 and with potentially avoidable mastectomies.6-8 Alternatively, inappropriate use of imaging may also lead to undertreatment if additional foci of disease are not identified and these lead to disease progression. Furthermore, imaging modalities vary substantially in cost, ranging in direct costs from about $115 for ultrasound to $1114 for PET-CT,9,10 increasing the need to determine whether more expensive tests result in improved patient outcomes.
Current Practices in Imaging Metastatic Breast Cancer
Healthcare providers generally rely on recommendations from professional societies such as NCCN, the American Society for Clinical Oncology (ASCO), and the European Society for Medical Oncology (ESMO), to guide the use of imaging techniques to assess treatment response in metastatic breast cancer. However, these recommendations are not based on robust data. Current practice recommendations for managing metastatic breast cancer include imaging of the chest, abdomen, and bone, in addition to obtaining medical histories, physical examinations, and relevant laboratory tests.11,12 The most commonly used imaging modalities are chest/abdomen/pelvis CT and bone scans. PET-CT12 and abdominal ultrasound are also widely used.11 For patients with bone-only metastases, bone scans are the most common imaging modality, with supplemental use of x-ray, CT, MRI and/or PET-CT to evaluate localized symptoms.12,13
Objective of Technical Brief
Although multiple imaging modalities to evaluate metastatic breast cancer are used clinically, their comparative effectiveness in terms of health outcomes, patient satisfaction, or cost, has not been determined. The purpose of this technical brief is to understand current utilization patterns of metastatic breast imaging modalities in the U.S., emerging technologies, research in progress, patient values, and study design issues, in order to summarize the current state of the science and inform a conceptual framework for future comparative effectiveness research in this area. We will also evaluate whether certain imaging technologies may be more suitable for some subpopulations and attempt to determine if the technologies are being used appropriately. Although we will ask Key Informants about the role of biomarkers in imaging for treatment evaluation of metastatic breast cancer, a thorough exploration of emerging biomarkers and other non-imaging tests is beyond the scope of this Technical Brief. We will combine information we obtain from published literature, grey literature, and key informants in order to provide context for appropriate comparative effectiveness studies on imaging for metastatic breast cancer in the near future.
The questions below will guide the data collection for this technical brief. Question 1 will lay the groundwork for the literature review by describing each of the imaging modalities currently in use for treatment evaluation for metastatic breast cancer. We will describe the accuracy, benefits and potential risks of each modality, including sensitivity and specificity, safety, costs, adverse effects, and other issues. Question 2 will provide the context for how each of the imaging modalities is currently used, including U.S. Food and Drug Administration (FDA) approval status, need for additional equipment (e.g., contrast agents), and, when possible, we will describe reimbursement policies and how commonly each modality is used for metastatic breast cancer treatment evaluation. Using published studies and grey literature, Question 3 will describe the state of the current research on the use and safety of each imaging modality. Finally, in Question 4, we will identify important issues pertaining to metastatic breast cancer imaging, particularly areas of uncertainty surrounding ethical, economic, and safety issues, as well as areas of research that we expect to be pursued in the near future.
1. Overview of Different Imaging Modalities Currently Used to Evaluate Treatment of Metastatic Breast Cancer
- What are the imaging modalities currently used for metastatic breast cancer treatment evaluation in the United States?
- What are the advantages (e.g., sensitivity and specificity) and disadvantages (e.g., safety issues, cost) of each modality?
2. Context in which Different Imaging Modalities are Currently Used to Evaluate Treatment of Metastatic Breast Cancer
- What is the FDA status of each modality?
- What other resources (e.g., contrast agents) are commonly used with each modality?
- How commonly is each modality used?
3. Current Evidence for Each Imaging Modality
What published and unpublished studies have reported on the use and safety of each modality? When describing each study, include:
- Patient population (inclusion/exclusion criteria, age, race, cancer characteristics)
- Study design/size
- Concurrent and prior imaging modalities used
- Length of followup
- Outcomes measured (survival, recurrence, others)
- Adverse events or harms reported
4. Important Issues and Future Directions of Metastatic Breast Cancer Imaging for Treatment Evaluation
- Given the current state of the science, what are the implications for future diffusion of the imaging modalities for metastatic breast cancer?
- What are the economic, ethical, and privacy considerations that impact the diffusion of each imaging modality?
- Who (e.g., primary oncologist, interpreting radiologist, or payers) should make final decisions about the types of imaging ordered for metastatic breast cancer treatment evaluation?
- What are important areas of uncertainty for metastatic breast imaging modalities?
- What research questions would have the greatest impact for women with metastatic breast cancer?
A. Discussions with Key Informants
We will work with the Key Informants to understand current utilization patterns, emerging technologies, research in progress, patient values, and study design issues, in order to help summarize the current state of the science and inform a conceptual framework for future comparative effectiveness research on imaging for metastatic breast cancer. For example, we will seek input from Key Informants to create a comprehensive list of imaging technologies, including technologies not commonly used but that are in development and may be used in the U.S. in the near future. We will use this list to guide assessments of utilization among U.S. patients with metastatic breast cancer. We will also seek input from Key Informants to determine whether some imaging technologies may be more appropriate for certain populations and subgroups, and will evaluate concordance with actual utilization. Input from Key Informants will also be sought to determine safety issues that may be associated with imaging technologies and methods for assessing outcomes of different imaging strategies, as well as contextual issues that may affect use, including policies related to coverage and reimbursement. We will seek input from Key Informants to identify values patients place on different outcomes and how they weigh various trade-offs (e.g., increased sensitivity but decreased specificity). We will also seek input from Key Informants to identify ongoing clinical trials and other research on imaging for metastatic breast cancer and will discuss possible ethical concerns associated with each technology. We plan to identify Key Informants who are clinical experts/practitioners in radiology and oncology, representatives of patient perspectives, as well as payers, scientists, and members of professional societies.
Table 1 represents sample questions to be asked to each of the categories of Key Informants.
|Key Informant Category||Potential Questions|
|Clinical Experts/Clinical Researchers
|Product Developers/Industry Representatives
B. Grey Literature Search
We will conduct a search of the grey literature, which will be identified using advice from our Key Informants as well as Internet searches (e.g., clinicaltrials.gov, NIH Reporter, Google Scholar, ProQuest Dissertations and Theses, and/or PQDT Open). We will search for professional society consensus statements, conference abstracts and proceedings, and other preliminary, unpublished study findings. Professional societies may include American Society for Clinical Oncology (ASCO), the American College of Radiology (ACR), the American Cancer Society (ACS), the National Comprehensive Cancer Network (NCCN), and others.
C. Published Literature Search
Inclusion and exclusion criteria for our search of published literature are shown in Table 2.
|Population||Age 19 and above
Diagnosed with metastatic (stage IV) breast cancer
|Age 18 and below
Diagnosed with stages I-III breast cancer
|Intervention||Imaging for treatment evaluation||Diagnostic imaging or imaging used to assess stage|
|Comparator||Comparison of multiple imaging modalities
Changes in treatment decisions
Changes in patient decisions
Quality of life
Cost and resource utilization
|Setting||All care settings||None|
|Study design||Systematic reviews
Randomized control trials
Non-randomized control trials
Cohort studies (prospective and retrospective)
Letters to the editor with no primary data
|Other||English language||Non-English language|
We will systematically search, review, and analyze the available information for each guiding question. To identify articles for this review, we will conduct focused searches of PubMed and the Cochrane Library. An experienced research librarian will use a pre-defined list of search terms and medical subject headings (MeSH). Table 3 lists search terms and limits. We will also review the reference lists of identified publications and add any previously unidentified papers.
|Search #||Query||Number of Items Found|
|1||exp Diagnostic Imaging||1737346|
|2||exp Breast Neoplasms/dh, dt, pc, rt, su, th [Diet Therapy, Drug Therapy, Prevention & Control, Radiotherapy, Surgery, Therapy]||101054|
|3||exp Neoplasm Metastasis||157923|
|5||3 or 4||256416|
|7||exp "Outcome and Process Assessment (Health Care)"||726373|
|10||exp survival analysis/||190795|
|11||6 or 7||1163519|
|12||1 and 2 and 5 and 11||632|
|13||exp *Breast Neoplasms/dh, dt, pc, rt, su, th||64661|
|14||1 and 5 and 11 and 13||252|
|15||exp "Outcome Assessment (Health Care)"||703145|
|16||1 and 5 and 13 and 15||127|
|17||((treat$ or therap$ or interven$ or regimen$ or pharmacother$ or chemother$ or radiother$ or surger$ or surgic$) adj7 (effectiv$ or work$ or reduc$ or shrink$ or shrank or shrunk)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]||560424|
|18||1 and 5 and 13 and 17||90|
|19||18 not 16||70|
|20||limit 19 to english language||35|
|21||((assess$ or determin$ or evaluat$ or discover$ or learn$ or discern$) adj7 (effectiv$ or success$ or reduc$ or remission$ or shrink$ or shrank or shrunk)).mp.||187310|
|22||1 and 5 and 13 and 21||8|
|23||limit 22 to english language||7|
|24||16 or 20 or 23||166|
We will update the literature review by repeating the initial search during the peer review process. Any literature suggested by the Peer Reviewers or public comment respondents will be investigated and, if appropriate, incorporated into the final review. We will also study the reference lists of any systematic reviews that do not meet the inclusion criteria but are pertinent to our topic to identify additional studies that should be considered for this literature search. These “hand-searched” studies will also be evaluated against the inclusion and exclusion criteria outlined in Table 2.
We will develop forms that will be used to screen titles, abstracts, and full reviews and to gather information about study characteristics and the PICOTS (population, intervention, comparator, outcomes, timing, and setting) of each study. All titles and abstracts identified through searches will be independently reviewed for eligibility against our inclusion/exclusion criteria by a trained member (LG) of the research team. Studies marked for possible inclusion by any reviewer will undergo a full-text review. For abstracts without adequate information to determine inclusion or exclusion, we will retrieve the full text and then make the determination. All results will be tracked in an EndNote® database (Thomson Reuters, New York, NY). Each full-text article will be independently reviewed by two trained members of the research team (LG, CL) for inclusion or exclusion on the basis of the eligibility criteria described earlier. If all reviewers agree that a study does not meet the eligibility criteria, the study will be excluded. If the reviewers disagree, conflicts will be resolved by discussion and consensus or by consulting another member of the review team. Results will be tracked in an EndNote® database. We will record the reason that each excluded full-text publication did not satisfy the eligibility criteria.
For studies meeting inclusion criteria, we will design data abstraction forms to gather pertinent information from each article, including characteristics of study populations, interventions, comparators, outcomes, study designs, settings, and methods. All data abstractions will be reviewed for completeness and accuracy by another member of the team.
D. Data Organization and Presentation
1. Data Organization
Fields we will use for data abstraction are listed in Table 4. Data from the published literature will be integrated with information from the gray literature and discussions with Key Informants.
|Data Element||Endnote Reference Number, Author, Year|
|Study characteristics||Study design
Sample size at recruitment and followup rates
|Population characteristics||Age (mean, range)
Other cancer characteristics
|Intervention characteristics||Type(s) of imaging described|
|Comparator||Type(s) of comparators, if any|
|Outcomes measured||Tumor response
Changes in treatment decisions
Changes in patient decisions
Quality of life
Cost and resource utilization
|Timing||Timing of outcome measurement(s)|
|Setting||Setting of imaging (clinic, hospital, other)
2. Data Presentation
We will present our findings in the order of the guiding questions. We will summarize findings from the grey literature and the Key Informant interviews qualitatively. For guiding questions that have empirical evidence, we will present our findings in tables that describe the state of the evidence in terms of study characteristics, intervention characteristics, comparators, and the types of outcomes.
We will also present some of our findings graphically using a bubble graph similar to that published by Trikalinos, et al.14 This will allow readers to visually understand the research to date on these breast imaging modalities.
- American Cancer Society. Cancer Facts & Figures 2013. Atlanta, GA: 2013. http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-036845.pdf. Accessed October 9, 2013.
- National Comprehensive Cancer Network Inc. Breast Cancer. NCCN; 3/11/2013 2013. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed October 9, 2013.
- National Institute for Health and Clinical Excellence (NICE). Advanced Breast Cancer: Diagnosis and Treatment National Collaborating Centre for Cancer National Institute for Health and Clinical Excellence. London: 2009. http://www.nice.org.uk/nicemedia/live/11778/43305/43305.pdf. Accessed October 9, 2013.
- Bleicher R, Ciocca R, Egleston B, et al. Association of routine pretreatment magnetic resonance imaging with time to surgery, mastectomy rate, and margin status. J Am Coll Surg. 2009 Aug;209(2):180-7. PMID: 19632594.
- Hulvat M, Sandalow N, Rademaker A, et al. Time from diagnosis to definitive operative treatment of operable breast cancer in the era of multimodal imaging. Surgery. 2010 Oct;148(4):746-50; discussion 50-1. PMID: 20708761.
- Pettit K, Swatske M, Gao F, et al. The impact of breast MRI on surgical decision-making: are patients at risk for mastectomy? J Surg Oncol. 2009 Dec;100(7):553-8. PMID: 19757442.
- Katipamula R, Degnim A, Hoskin T, et al. Trends in mastectomy rates at the Mayo Clinic Rochester: effect of surgical year and preoperative magnetic resonance imaging. J Clin Oncol. 2009 Sep;27(25):4082-8. PMID: 19636020.
- Houssami N, Ciatto S, Macaskill P, et al. Accuracy and surgical impact of magnetic resonance imaging in breast cancer staging: systematic review and meta-analysis in detection of multifocal and multicentric cancer. J Clin Oncol. 2008 Jul;26(19):3248-58. PMID: 18474876.
- Centers for Medicare and Medicaid Services (CMS). Physician Fee Schedule. 2009. http://chfs.ky.gov/nr/rdonlyres/4fd6f67c-6c97-4061-a9fd-2441467201f2/0/mdfee2009rev4909r2.pdf. Accessed October 9, 2013.
- Centers for Medicare and Medicaid Services (CMS). Medicare Program: Changes to the Hospital Outpatient Prospective Payment System and CY 2009 Payment Rates CMS. 2009. http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/HospitalOutpatientPPS/downloads/CMS-1404-FC.pdf. Accessed October 9, 2013.
- Cardoso F, Costa A, Norton L, et al. 1st International consensus guidelines for advanced breast cancer (ABC 1). Breast. 2012 Jun;21(3):242-52. PMID: 22425534.
- Lin NU, Thomssen C, Cardoso F, et al. International guidelines for management of metastatic breast cancer (MBC) from the European School of Oncology (ESO)-MBC Task Force: Surveillance, staging, and evaluation of patients with early-stage and metastatic breast cancer. Breast. 2013 Jun;22(3):203-10. PMID: 23601761.
- Costelloe CM, Rohren EM, Madewell JE, et al. Imaging bone metastases in breast cancer: techniques and recommendations for diagnosis. Lancet Oncol. 2009 Jun;10(6):606-14. PMID: 19482249.
- Trikalinos TA, Terasawa T, Ip S, et al. Particle beam radiation therapies for cancer: Agency for Healthcare Research and Quality; 2009.
Definition of Terms
Not applicable to this research.
Summary of Protocol Amendments
No amendments have been made to the current version of this protocol.
EPC Team Disclosures
EPC core team members must disclose any financial conflicts of interest greater than $1,000 and any other relevant business or professional conflicts of interest. Related financial conflicts of interest which cumulatively total greater than $1,000 will usually disqualify EPC core team investigators.