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Gold LS, Lee CI, Devine B, et al. Imaging Techniques for Treatment Evaluation for Metastatic Breast Cancer [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2014 Oct. (Technical Briefs, No. 17.)
Imaging Techniques for Treatment Evaluation for Metastatic Breast Cancer [Internet].
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The availability of quantitative or qualitative data to address the guiding questions from our Key Informant interviews and the published and gray literature searches is presented in Table 2. Four imaging modalities are currently used in the United States for evaluating treatment response for metastatic breast cancer: bone scan, MRI, CT, and fluorodeoxyglucose (FDG)-PET/CT. We also identified four types of imaging not commonly used currently that might become important in the next 5–10 years: fluorothymidine (FLT)-PET/CT, F-fluoromisonidazole (F-FMISO)-PET/CT, fluoroestradiol (FES)-PET/CT, and PET/MRI.
Table 2
Availability of data in Key Informant interviews, published literature, and gray literature to address guiding questions.
In total, we interviewed nine Key Informants: five were clinicians (two of whom were medical oncologists who practiced at large academic institutions, two were radiologists at large academic institutions and one was a medical oncologist at a nonacademic research and treatment center), two were from product industry development companies, one was a patient advocate at a nonprofit advocacy organization, and one was an executive at a large cancer treatment center who provided both product purchaser and patient advocate perspectives. Three clinicians and one patient advocate were interviewed in the same phone call; all remaining calls were with only one Key Informant. Interviews lasted between 40–60 minutes and consisted of 8–13 questions. All interviews took place in October and November 2013. A summary of the interviews appears in Appendix B.
A summary of the findings from the published literature search is shown in Table 3 and the abstracted data are shown in Table 4. A full list of included and excluded studies is shown in Appendixes C and D. We abstracted data from a total of 17 publications.9-25 Where the two abstractors disagreed, a discussion was performed to come to conclusions. The study populations from eight publications were from the United States,9,14,19,20,22-25 eight were from Europe,10,12,13,15-18,21 and one was from Asia.11 All were cohort studies, of which seven were retrospective10,14,17,19,20,23,24 and ten were prospective.11-13,15,16,18,21,22,25 Twelve of seventeen studies10-18,20,22,25 presented comparators pertaining to the type of imaging used; seven of these10,13,15,16,18,20,22 compared metabolic response as measured by tracer uptake to response measured by anatomic imaging. Four studies12,14,17,22 compared metabolic response measured by tracer uptake to measures of tumor biomarkers. One study11 compared metabolic response as measured by two types of tracers (FDG- vs. F-FMISO-PET/CT). One study compared tumor response as assessed by bone scan compared with CT.25 Almost all of the studies (16 of 17)9-13,15-25 reported accuracy in detecting tumor response as an outcome. Seven9,10,14-16,21,25 reported overall survival and four14,17,23,25 reported progression-free survival. No studies reported recurrence-free survival, changes in treatment decisions, changes in patient decisions, quality of life, cost and resource utilization, or adverse events related to imaging. Only two studies2025 distinguished metastatic breast cancers that were initially diagnosed from those that were recurrences from nonmetastatic breast cancers. In total, the published literature reported on the imaging experiences of 557 women with metastatic breast cancer in the United States, Asia, and Europe. We estimate that approximately 792,000 women in the United States received imaging scans for the purpose of evaluating treatment of metastatic breast cancer (see Appendix F for details on this calculation) between 2003-2013, and thus the number of women enrolled in clinical studies to evaluate the benefits and harms of imaging for this purpose represented less than 0.1 percent of the women exposed to these procedures.
Table 3
Overview of published literature (n=17 studies), with number of metastatic breast cancer patients (n=557).
Table 4
Abstracted data from published literature.
Finally, a summary of the findings from the gray literature search are shown in Table 5. We identified three current or soon-to-be recruiting clinical trials pertaining to imaging for treatment evaluation for metastatic breast cancer.
Table 5
Overview of gray literature findings.
Summary of Imaging Trends for Treatment Evaluation of Metastatic Breast Cancer
We did not identify any studies that addressed imaging utilization trends for treatment evaluation of metastatic breast cancer. However, the Key Informants generally agreed that the trend of imaging for evaluation of treatment of metastatic breast cancer was toward stable or increased utilization; none speculated that imaging for this purpose would decrease in the near future. Additionally, the Key Informants identified several factors that may potentially influence utilization. For instance, all of the clinician, product purchaser, and patient advocate Key Informants reported that, in their experience, most payers readily reimburse for CT, PET-CT, bone scans, and other imaging modalities that are appropriate to the regions of the body where the metastases are located. However, the Key Informants indicated that some payers advocate for programs such as the use of Radiology Benefit Managers (entities used by private payers to require prior authorization) or peer-to-peer consultations (case discussions between ordering providers and radiologists), which may discourage physicians from ordering advanced imaging exams. Whether these mechanisms lead to more appropriate utilization is unclear. Several Key Informants also indicated that use of PET-CT can be influenced by the purchase of the expensive machinery and once the investment in the technology has been made, the scans will be used for many other indications besides treatment evaluation of metastatic breast cancer. One Key Informant indicated that insurance status might be more of a factor in community settings, with noninsured or underinsured patients being steered toward less expensive imaging. However, another Key Informant thought that physicians in academic centers might feel greater pressure to use more complicated and expensive technologies for fear of reprisals if they failed to order tests.
Summary of Shared Decisionmaking Regarding Imaging for Treatment Evaluation of Metastatic Breast Cancer
We did not find any published literature regarding patient involvement in decisionmaking regarding imaging for treatment evaluation of metastatic breast cancer. However, our Key Informants provided some information on this topic. They indicated that imaging is usually not the focus of patient education, both in terms of conversations that patients have with their care providers and the research that patients conduct on their own. Additionally, since physicians who interpret images usually interact with the ordering physicians rather than the patients themselves, patients are often under-informed about imaging and usually are not aware that they can engage in shared decisionmaking with their physicians regarding treatment evaluation by imaging.
Our Key Informants indicated that many patients are accustomed to receiving PET/CT and would not agree with receiving imaging followup only by CT after receipt of a previous PET/CT. Our Key Informants also reported that physicians might prefer to order tests based on their own experiences and biases, rather than spend time debating the merits of alternative imaging strategies with their patients.
Interestingly, the clinicians reported that they sometimes advocated for imaging less often to reduce the stress that patients feel while waiting for imaging results. Both Key Informant patient advocates reported that patients receive intangible value from receiving results of imaging scans that show their cancer is improving and are willing to experience the stress and anxiety of waiting for imaging results in order to potentially receive good news about their prognoses. Both patient advocates also reported that breast cancer patients are generally not concerned about the potential harm that could result from imaging, such as exposure to radiation from CT, PET, and PET/CT scans, because their therapies already involve such exposures.
Modalities Currently in Use
The imaging modalities currently in use and their key features, theoretical advantages, and theoretical disadvantaged are outlined in Table 6 and are described in more detail here.
Table 6
Imaging modalities and key characteristics.
Bone Scan (Scintigraphy)
Bone scans are used to identify areas of damage to the bones throughout the body. A small amount of a radionuclide tracer is injected intravenously and the patient is then scanned 2−3 hours later with a gamma camera that detects radiation emitted by the radioactive material. Areas of increased tracer uptake may indicate the presence of bone metastases. Although we could not find published data on how commonly bone scans are used to evaluate treatment of metastatic breast cancer, our Key Informants reported that bone scans are almost always used to evaluate treatment in patients who have been diagnosed with bony metastases. The Key Informants also reported that, because bone scans are less expensive than PET/CT, they may be ordered when PET/CT is not covered by the patient's insurance. Bone scans received FDA approval through the Medical Device Amendments of 1976, which allowed devices being clinically used to receive FDA approval without undergoing premarket approval or 510(k) clearance. The most commonly used radiotracer for bone scans is technetium-99m.26 Safety issues pertaining to bone scans include exposure to radiation from the injected radiotracer and, rarely, the potential for allergic reactions. The Key Informants indicated that most patients were not concerned with exposure to radiation from imaging because their treatments usually entailed much larger doses.
We found three published studies that described use of bone scans to evaluate treatment of metastatic breast cancer.10,20,25 Two compared PET tracer uptake (one evaluated FDG and the other evaluated FES) to bone scans and other types of anatomic imaging to determine tumor response. Although these studies were small (both had n=47), both studies found that the uptake of PET tracers were better predictors of response than bone scans (median response times were 6 and 87 months).10,20 The third study stratified patients as having progressive disease or nonprogressive disease according to CT and bone scans. These authors found that treatment response identified by CT at 6 months was associated with progression-free survival, but treatment response demonstrated on bone scans at 6 months was not, and neither type of imaging at 6 months was associated with overall survival.25
Although we did not find specific information about the future directions of bone scans, our Key Informants indicated that the technology was extremely useful and was not likely to be displaced by other technologies in instances of bone metastases. None of the Key Informants prioritized bone scans as a potential topic for future research studies.
Magnetic Resonance Imaging
MRI scanners utilize strong magnetic fields and radio waves to create images of the body part of interest. The magnetic field emitted by the scanner causes hydrogen atoms that are components of water molecules in the patient's body to line up in the direction of the magnetic field so almost all of them point either to the patient's head or to their feet. A few atoms out of every million, however, are unmatched and do not point toward the head or the feet. When the radio frequency pulse is emitted, the unmatched atoms spin the opposite way. At the same time, gradient magnets arranged inside the main magnet are turned on and off quickly, creating radiowave signals that are captured by receiver coils and are used to construct images composed of the body part being scanned. For breast MRI, gadolinium-based contrast agents are also used to assist with evaluation of breast tumors. These contrast agents alter the local magnetic field of the breast tissue and allow visualization of abnormalities in the tissue being scanned. MRI scanners, breast coils, and gadolinium-based contrast agents have all received FDA approval.27
One potential advantage of MRI in comparison with other types of imaging such as CT and PET/CT is that MRI does not involve exposure to radiation.28 Another potential advantage our Key Informants reported was that MRI was useful to evaluate treatment for patients with brain metastases who had received a baseline MRI. A potential disadvantage of MRI use is that the test may be difficult for claustrophobic patients to tolerate. Additionally, like bone scans, patients can experience allergic reactions to the contrast agents used for MRIs, but these are rare and most reactions are mild.29 We did not find any quantitative evidence describing how commonly MRI is used to evaluate treatment of metastatic breast cancer.
We identified four published studies9,15,16,20 that described use of MRI to evaluate treatment of metastatic breast cancer. Three of these compared treatment evaluation using tracer (FDG15,16 and FES20) uptake from PET/CT with imaging using MRI and CT and one did not compare MRI to another method of treatment evaluation.9 All three studies that compared conventional imaging and tracer uptake found correlations between tumor response using MRI and/or CT and PET radiotracer uptake.15,16,20 However, only one of these reported data on the correlation between anatomic tumor response determined by MRI or CT and overall survival and found no correlation (mean followup time 27 weeks).16
Computed Tomography
CT uses a series of x-ray images taken around a rotating arc to reconstruct and generate three-dimensional images of structures in the body. The data from CT scanners are transmitted to computers, which create three-dimensional cross-sectional pictures. While CT scans are valuable in identifying and anatomically localizing tumors, they have disadvantages such as exposure to ionizing radiation and the potential for adverse events from iodinated contrast agents, which range from mild (nausea, itching) to severe (cardiopulmonary arrest).30 Because CT systems were widely used prior to 1976, they received FDA approval through the Medical Device Amendments.27
Although we did not find published data on how commonly CT is used to monitor treatment of metastatic breast cancer, the clinical Key Informants reported that it is often used, especially in cases when staging PET/CT is not covered by insurance.
We identified seven published studies describing use of CT to evaluate treatment of metastatic breast cancer.10,13,15,16,18,20,25 Most of these (n=5)10,13,15,16,18 were conducted in Europe and all compared tracer uptake (FLT,13,18 FDG,10,15,16 and FES20) from PET/CT to anatomic imaging (including CT). Five of these studies found that uptake of the tracers was associated with changes in tumor volume measured by CT.13,15,16,18,20 As described in the MRI section, another study reported no significant correlation between treatment-related changes seen on conventional imaging using CT or MRI and survival (mean followup time 27 weeks).16 As described in the bone scan section, one study found that treatment-related changes seen on CT at 6 months were associated with progression-free survival, but changes seen on bone scans at 6 months were not, and neither was associated with overall survival.25
Positron Emission Tomography/Computed Tomography
A PET scan uses nuclear medicine imaging to produce three-dimensional color images of functional processes in the body. A patient is injected with a radioactive tracer and placed on a table that moves through a gamma ray detector array that contains a series of scintillation crystals. The crystals convert the gamma rays that are emitted from the patient into photons of light, which are amplified to electrical signals that are processed by a computer to generate images. The table is moved and the images are repeated so that a series of thin slice images of the body over the region of interest are assembled into a three-dimensional representation of the body. PET/CT scanners allow for a diagnostic CT scan to follow, providing anatomic correlation for the PET scan.
Several types of tracers have been developed for use with PET, including FDG, F-FMISO, FLT, and FES. FDG is the only tracer approved by the FDA for breast cancer imaging and is therefore the most widely used. Because tumors have increased glucose metabolism compared with noncancerous tissue, FDG has the ability to detect tumors on PET imaging. Specifically, tumor masses are relatively hypoxic compared with surrounding tissue, which activates the anaerobic glycolytic pathway. A consequence of enhanced glycolysis is the hyperactive trapping of FDG by tumor cells. Since 2006, all PET scanners purchased in the United States were combined PET/CT machines.31 Like bone scans and computed tomography, PET scanners received FDA approval through the 1976 Medical Devices Amendment and combination PET/CT devices received 510(k) clearance in 2000.27
Our Key Informants indicated that FDG-PET/CT is currently the most commonly used type of imaging for treatment evaluation of metastatic breast cancer. The main potential advantage of PET/CT is its ability to combine the functional information from FDG uptake with the higher resolution of CT for determining anatomic location and tumor morphology. Both the PET and CT scans are obtained during the same exam and images are post-processed into a fused series of images. However, the modality does have potential disadvantages, including the relatively high cost of the test and exposure of the patients to ionizing radiation.32 Largely because of these limitations, our Key Informants reported that they order PET/CT scans no more often than every 2-4 months during treatment for metastatic breast cancer, and only when patients are not obviously responding or worsening clinically.
Our Key Informants noted that PET/CT technology is relatively novel and few studies have prospectively evaluated long-term outcomes of its use in treatment evaluation for metastatic breast cancer. Additionally, the Key Informants felt PET/CT might be underused in community care settings, where access to a PET/CT machine might entail long travel times for patients or ordering physicians might not be accustomed to utilizing the technology.
Although the American College of Radiology provides accreditation of centers that use PET devices, they do not require standard procedures for preparing patients prior to their scan or require minimum interpretive volumes in order to remain accredited (as they do for breast MRI). Furthermore, interpretation of PET/CT scans is not monitored by any accrediting organization and no agencies exist to enforce the implementation of guidelines, resulting in inter-reader variability. The Key Informants also reported that PET/CTs for breast cancer are used relatively less frequently compared with PET/CTs for other solid organ malignancies, such that even at major cancer centers in large cities, only about 10 percent of the PET/CTs are related to breast cancer. Thus, the experience of PET/CT interpreting physicians for treatment evaluation of metastatic breast cancer may be somewhat limited due to relatively low volumes.
We identified a total of 15 studies describing use of PET to evaluate treatment for breast cancer.10-24 Ten of these described use of FDG,10,11,14-17,20,21,23,24 four described FLT,12,13,18,22 one described F-FMISO,11 and two described FES19,20 (two studies evaluated more than one kind of tracer). Four studies evaluating FDG-PET,10,15,16,20 two studies evaluating FLT-PET,13,18 and one study evaluating FES-PET20 compared tracer uptake values to anatomic imaging with MRI, bone scans, and/or CT, and these are described above.
Four studies compared tracer uptake (two looked at FDG14,17 and two examined FLT12,22) with tumor biomarkers as ways to evaluate response to therapy. One study of 102 metastatic breast cancer patients found circulating tumor cells (CTCs) were correlated with FDG uptake in 67 percent of patients and, in univariate analyses, both FDG uptake and CTCs were predictive of survival; however, in multivariate analysis, FDG uptake was no longer predictive of survival.14 The other study, conducted in Belgium (n=25), found only 28 percent concordance between FDG uptake and the tumor markers CA15-3 or carcinoembryonic antigen. This study did find a longer progression-free survival in patients who showed response on FDG-PET (11 months) compared with patients who were nonresponders (7 months).17 For the studies examining FLT, although sample sizes were small (n=14 and n=9), both found correlations between uptake of FLT and tumor markers (CA27.29 and CTCs).12,22 Additionally, one of the studies reported strong correlations between a baseline FLT-PET scan and a repeat scan 2−10 (median 4.5) days later (r=0.99 for standardized uptake value at 90 minutes between the scans at the two time points).18 This was the only study that we identified that presented results on the reproducibility of an imaging modality.
Three studies reported on disease progression by standard FDG uptake values.21,23,24 All reported that standardized uptake values on initial FDG-PET scans were associated with outcomes, including time to disease progression or skeletal-related event (n=28; median followup 17.5 months),23 response duration (n= 102; median followup=15 months),24 and progression-free survival (n=22; followup was at least 4 years).21
One small study19 (n=30, 27 of which were women) reported use of FES-PET to compare response to estrogen blocking therapy with estrogen depleting therapy in patients with bone metastases undergoing salvage endocrine therapy. These authors found the standardized uptake value of FES declined 54 percent in patients taking estrogen-blocking therapy and declined only 14 percent for patients taking estrogen-depleting agents.19 Finally, one small study11 (n=12) conducted in China compared use of F-FMISO to FDG-PET. While FDG uptake did not correlate with clinical outcomes, F-FMISO-PET showed a fairly strong correlation (r=0.77).11
Positron Emission Tomography/Magnetic Resonance Imaging
Several of our Key Informants mentioned that combination PET/MRI scanners might become important within the next decade and at least one such device has received FDA approval.33 However, we did not find any published or gray literature describing use of this modality to evaluate treatment of metastatic breast cancer. Although a major disadvantage of this technology is that it combines two expensive modalities, it might be ideal for imaging of brain metastases. By combining PET's metabolic imaging capabilities with MRI's excellent tissue contrast, the combination may increase accuracy in evaluating response to therapy for brain metastases. Another advantage is that, unlike PET/CT, it would not involve exposure to as much ionizing radiation from the CT component (although it would still entail some radiation exposure from the tracer).34
- Findings - Imaging Techniques for Treatment Evaluation for Metastatic Breast Can...Findings - Imaging Techniques for Treatment Evaluation for Metastatic Breast Cancer
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