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Abstract

Background:

Contrast-enhanced mammography (CEM) is an emerging breast imaging modality. Clinical data is scarce.

Objectives:

To summarize clinical evidence on the use of iopromide in CEM for the detection or by systematically analyzing the available literature on efficacy and safety.

Design:

Systematic review and meta-analysis.

Data sources and methods:

Iopromide-specific publications reporting its use in CEM were identified by a systematic search within Bayer’s Product Literature Information (PLI) database and by levering a recent review publication. The literature search in PLI was performed up to January 2023. The confirmatory-supporting review publication was based on a MEDLINE/EMBASE + full text search for publications issued between September 2003 and January 2019. Relevant literature was selected based on pre-defined criteria by 2 reviewers. The comparison of CEM vs traditional mammography (XRM) was performed on published results of sensitivity and specificity. Differences in diagnostic parameters were assessed within a meta-analysis.

Results:

Literature search: A total of 31 studies were identified reporting data on 5194 patients. Thereof, 19 studies on efficacy and 3 studies on safety. Efficacy: in 11 studies comparing iopromide CEM vs XRM, sensitivity was up to 43% higher (range 1%-43%) for CEM. Differences in specificity were found to be in a range of −4% to 46% for CEM compared with XRM. The overall gain in sensitivity for CEM vs XRM was 7% (95% CI [4%, 11%]) with no statistically significant loss in specificity in any study assessed. In most studies, accuracy, positive predictive value, and negative predictive value were found to be in favor of CEM. In 2 studies comparing CEM with breast magnetic resonance imaging (bMRI), both imaging modalities performed either equally well or CEM tended to show better results with respect to sensitivity and specificity. Safety: eight cases of iopromide-related adverse drug reactions were reported in 1022 patients (0.8%).

Conclusions:

Pertinent literature provides evidence for clinical utility of iopromide in CEM for the detection or confirmation of breast cancer. The overall gain in sensitivity for iopromide CEM vs XRM was 7% with no statistically significant loss in specificity.

Keywords

Iopromide contrast-enhanced mammography

Introduction

X-ray mammography (XRM) today represents the primary diagnostic tool for breast cancer (BC) screening and for the evaluation of patients with suspected lesions in the breast. XRM visualizes breast pathologies by measuring attenuation differences between tumors and lesions and the physiologic fibro-glandular breast tissue. The sensitivity of XRM is limited particularly in women with dense breasts.¹ Contrast-enhanced breast magnetic resonance imaging (bMRI) features higher sensitivity than XRM.^2
-4 Contrast-enhanced bMRI visualizes lesions by enhancing the tumor’s neo-angiogenesis and the leakage of contrast into the tumor tissue.⁵ Like MRI, contrast-enhanced mammography (CEM) is able to assess both imaging principles by visualizing tumor morphology as well as its vascularization.⁶ CEM is an advancement of digital XRM providing 2 images at 2 energy levels which are subsequently combined electronically to highlight the areas of enhancement. CEM requires intravenous administration of an iodine-based contrast medium prior to image acquisition.

According to the American College of Radiology (ACR) Appropriateness Criteria, CEM may be appropriate for supplemental BC screening of intermediate- and high-risk women with non-dense breasts and average- and intermediate-risk women with dense breasts. So far ACR does not recommend CEM for other clinical settings, eg, palpable breast masses, initial workup and surveillance for local recurrence and distant metastases in asymptomatic women.⁷ However, in 2022, ACR acknowledged in a supplement to ACR BI-RADS^® Mammography 2013 that CEM has been shown to be more sensitive than mammography or ultrasound for the detection of malignancy.⁸

The European Society of Breast Imaging (EUSOBI) discussed 3 studies^9
-11 and concluded that based on preliminary results, CEM can be considered as an alternative to bMRI in the case of contraindications to MRI in general or to gadolinium-based contrast injection.⁵ Most recently, EUSOBI recommended supplemental screening in women with extremely dense breasts to be performed preferably with bMRI, because for the time being, level I evidence is available only for bMRI.¹² The recent EUSOBI recommendation, however, mentions that other imaging modalities, like CEM, may eventually offer practical advantages over bMRI.¹²

The Royal College of Radiologists’ Guidance on screening and symptomatic breast imaging (fourth edition) stated that CEM may also be used in the symptomatic setting, where available.¹³ Along that line, also the German Guideline Program in Oncology (GGPO) stated that CEM is an option if MRI is not feasible, especially for dense breasts. The guideline quoted a number of studies showing comparable diagnostic accuracy for CEM vs bMRI.¹⁴

Jochelson et al¹⁵ excellently summarized that CEM is an emerging breast imaging modality that helps improve diagnostic accuracy when routine breast imaging produces inconclusive findings and that may serve as an alternative to bMRI.

Iopromide (Ultravist^TM) is a low osmolar non-ionic X-ray contrast medium (LOCM) with iodine as active ingredient.¹⁶ Initially approved in February 1985, iopromide features a clinical track record of more than 37 years. As of June 30, 2022, more than 324 million have been administered to patients in more than 118 countries.¹⁷ Numerous studies have documented the overall safety profile^18
-24 in a wide range of indications (including but not limited to computed tomography, angiography, urography, cholangiopancreatography, and arthrography).

On January 20, 2023, iopromide received the European Union approval for CEM. The approved indication is “for use in adult women in CEM to evaluate and detect known or suspected lesions of the breast, as an adjunct to XRM (with or without ultrasound) or as an alternative to MRI when MRI is contraindicated or unavailable.”

The objective of this article was to summarize clinical evidence on the use of iopromide in CEM for the detection or confirmation of BC by systematically analyzing the available literature on efficacy and safety.

Data Sources and Methods

Databases

As a first step, iopromide-specific publications were searched in Bayer’s Product Literature Information (PLI) database up to January 2023.

As a second step, additional iopromide-specific publications were retrieved from Zanardo et al,²⁵ who published a systematic review on CEM based on a MEDLINE/EMBASE + full-text search from September 2003 to January 2019 (Figure 1). Full texts with the search term CEM were evaluated by 2 reviewers.

Figure 1.

Literature search strategy—identification of studies in databases and literature. CEM indicates contrast-enhanced mammography; CESM, contrast-enhanced spectral mammography; LOCM, low osmolar non-ionic X-ray contrast medium; PLI, product literature information; XRM, traditional mammography.

The PLI automatically (in rare cases also manually) imports data containing information from biomedical journals dealing with Bayer Pharma and Consumer Health (CH) products from 4 large, commercially and publicly available databases: MEDLINE and EMBASE (until today), Derwent Drug File and BIOSIS (until December 2019). In addition, search hits from Reactions Weekly (case reports) or Medmeme (conference abstracts) complemented PLI. The scientific areas of interest were as follows: clinical pharmacology, efficacy and pharmacokinetics, adverse effects in case reports, clinical adverse effects, pre-clinical toxicology, and pharmacokinetics. Duplicate records and reviews were deleted manually.

The search strategy is shown in Figure 1.

Statistics

Sensitivity and specificity of CEM and XRM and the respective numbers of patients with malignant/benign lesions (N) were extracted from 11 papers (Table 4). The number of patients correctly classified (m) were derived by multiplying N with the given sensitivity or specificity.

The risk difference per publication was computed using the N’s and m’s as basis for a generalized linear model with identity link and a binomial distribution. In case of sensitivities or specificities of 100%, a small value (.0001) was subtracted from m to make computations feasible. SAS Version 9.4 was used for this analysis step.

A meta-analysis based on the data for sensitivity and specificity was computed per method (CEM or XRM) and for the computed risk-differences using the R-package “meta.”²⁶

Results

Results of the literature search

Twenty-four publications reporting data specifically on iopromide were identified by the company’s PLI database (Figure 1). In addition, 7 papers were found in the full-text literature search by Zanardo et al.²⁵ In total, 31 studies were included (Figure 1).

Nineteen studies reported efficacy results for the detection or confirmation of BC (Tables 1 and 4), 3 studies reported safety results (Table 2), and 11 studies reported other findings, not relevant for efficacy or safety analysis (Table 3). 2 studies provided data for efficacy and safety analysis^27,28 (Figure 1).

Table 1.

Efficacy studies on CEM using iopromide for the detection or confirmation of BC.

Author country (n = 19)	Study population/indication	N (n = 2920)	Study design	Image evaluation
Amato et al²⁹/IT	Proven ILC	31	Retrospective	Not specified
Bicchierai et al³⁰/IT/Zan	Biopsy B3 lesions	40	Retrospective	Not specified
Bicchierai et al³¹/IT	Biopsy proven BC	326	Retrospective	5 blinded readers
Chalabi et al³²/Egypt	Various indications	123	Retrospective	Not specified
Diekman et al³³/DE	Known or suspicious findings	21	Prospective	Not specified
Diekmann et al²⁷/DE	Suspicious lesion	70	Prospective	3 unblinded readers
Houben et al³⁴/NL	Suspicious calcifications	147	Retrospective	1 blinded reader
Lalji et al³⁵/NL/Zan	Screening recalls	199	Retrospective	10 blinded readers
Lobbes et al²⁸/UK	Screening recall	113	Retrospective	2 blinded readers
Lobbes et al³⁶/NL	Suspicious/confirmed findings	368	Retrospective	3 blinded readers
Luczynska et al³⁷/PL/Zan	Suspected BC	152	Prospective	6 unblinded readers
Luczynska et al³⁸/PL/Zan	Suspicious lesions	102	Retrospective	2 blinded readers
Luczynska et al³⁹/PL	Suspicion of BC	116	Prospective	Not specified
Mohamed et al⁴⁰/Egypt	Dense breast, lump	25	Prospective	Unblinded
Richter et al⁴¹/DE	Confirmed/suspicious findings	118	Retrospective	2 blinded readers
Rudnicki et al⁴²/PL/Bay	Suspicious lesions	167	Retrospective	3 unblinded readers
Rudnicki et al⁴³/PL	Breast abnormalities	121	Retrospective	Not specified
Tsigginou et al⁴⁴/GR	Known findings	216	Prospective	2 blinded readers
Travieso-Aja et al⁴⁵/ES	Known malignant or benign lesions	465	Retrospective	3 blinded readers

Abbreviations: BC, breast cancer; CEM, contrast-enhanced mammography.

Table 2.

Safety studies on CEM using iopromide.

Author/country	Study population/indication	N (n = 1022)	Study design	Image evaluation
Diekmann et al²⁷/DE	Known BC	70	Prospective	3 unblinded readers
Houben et al⁴⁶/NL	Suspected or known findings	839	Retrospective	1 blinded reader
Lobbes et al²⁸/UK	Suspected BC	113	Retrospective	2 blinded readers

Abbreviations: BC, breast cancer; CEM, contrast-enhanced mammography.

Table 3.

Studies on CEM using iopromide, not specifically reporting efficacy or safety (=reason for exclusion).

Author/country (N = 11)	Study population/indication	N (n = 1435)	Study design	Image evaluation
Bicchierai et al⁴⁷/IT	Known BC findings	348	Retrospective	Not specified
Gluch et al⁴⁸/AU	Known or suspected BC	6	Retrospective	Not specified
Houben et al⁴⁹/NL	Screening recall	351	Not specified	Unblinded
Jeukens et al⁵⁰/NL	Not specified	47	Not specified	Unblinded
Lobbes et al⁵¹/NL/Zan	Screening recall	87	Retrospective	Not specified
Lobbes et al⁵²/NL	Suspicious/known findings	85	Retrospective	Not specified
Luczynska et al⁵³/PL/Zan	Known findings	174	Retrospective	1 blinded reader
Luczynska et al⁵⁴/PL/Zan	Suspicious lesions	82	Retrospective	3 blinded readers
Rudnicki et al⁵⁵/PL/Bay	Suspicious histology	94	Retrospective	2 unblinded readers
Rudnicki et al⁵⁶/PL/Bay	BIRADS 4, 5 or 0	151	Prospective	1 readers, unblinded
Schmitzberger et al⁵⁷/DE	Known malignant lesions	10	Prospective	4 blinded readers

Abbreviations: BC, breast cancer; CEM, contrast-enhanced mammography.

Patient population

Mean age of patients was specified in 24 of the 31 studies, covering 4348 of 5194 patients (84%). Considering the respective patient counts for the 24 studies, the mean age of the included patients was 57.2 years (the average of the specified mean ages without correction for the patient numbers was 56.1 years). Patients were referred to imaging for screening purposes and for characterization of suspicious clinical findings.

Efficacy

A total of 19 studies reported efficacy of iopromide in contrast-enhanced mammography. Six had a prospective and 13 a retrospective design. Nine studies were read by blinded readers and 4 by unblinded readers. The other studies did not specify reading procedure (Table 1).

CEM vs XRM

Eleven studies reported efficacy results of iopromide CEM vs XRM. Sensitivity was always higher for CEM, ranging from 62% to 100%. The advantage ranged from 1%⁴⁴ up to 44%⁴⁰ (Table 4, Figure 2). Overall, CEM provided a gain in sensitivity of 7% (95% CI [4%, 11%]) in the meta-analysis. No hints for heterogeneity were found for the difference in sensitivities for the studies included (P = .06) (Figure 3).

Table 4.

Efficacy results—CEM vs XRM, bMRI and uncontrolled.

Author	Indication	N (n = 2,920)	Sensitivity %	Specificity %	Accuracy %	PPV %	NPV %
			CEM vs XRM
Chalabi et al³²	Suspicious lesion(s)	123	92.782.9	82.476.5	89.781.0	92.789.5	82.465
Diekmann et al²⁷	Suspicious lesion(s)	70	6243	6570
Houben et al³⁴	Suspicious lesion(s)	147	93.890.8	36.639.0		54.054.1	88.284.2
Lalje et al³⁵	Screening recall	199	96.993.0	69.735.9
Lobbes et al²⁸	Screening recall	113	100.096.9	87.742.0		76.239.7	100.097.1
Luczynska et al³⁷	Suspicious lesion(s)	152	10091	4115	8065	7768	10047
Luczynska et al³⁹	Suspicious lesion(s)	116	10090	2722	7869	7063	87
Mohamed et al⁴⁰	Suspicious lesion(s)	25	100^a 56^a	63.6^a 66.6^a	8460	77.875.0	10046
Richter et al⁴¹	Suspicious lesion(s)	118	98.889.2	54.636.4		94.391.4	85.730.8
Travieso-Aja et al⁴⁵	Suspicious lesion(s)	465	92.382.5	86.068.6	90.274.4	93.065.5	84.884.4
Tsigginou et al⁴⁴	BIRADS 3-5	216	93.992.9	71.359.4	8173.9
			CEM vs bMRI
Luczynska et al³⁸	Suspicious lesion(s)	102	10093		7973	7774	10065
Rudnicki et al⁴³	Suspicious lesion(s)	121	100100	3323	7774	7572	100100
			CEM uncontrolled
Amato et al²⁹	Invasive lobular carcinoma	31	25-100^b	0-100^b	40-85^b
Bicchierai et al³⁰	BIRADS 3	40	33.3-66.7	74.4-87.2		16.7-18.2	94.4-96.7
Bicchierai et al³¹	Staging	326	93.0	98	97	90	98
Diekmann et al³³	Suspicious lesion(s)	21	62.5	90	73.1	90.1	60
Lobbes et al³⁶	Suspicious lesion(s)	368	92.9	79.3
Rudnicki et al⁴²	Suspicious lesion(s)	167	49-59	61-88	60-61

Abbreviations: BC, breast cancer; BIRADS, Breast Imaging Reporting & Data System; bMRI, breast magnetic resonance imaging; CEM, contrast-enhanced mammography; NPV, negative predictive value; PPV, positive predictive value; XRM, traditional mammography.

For Figure 3, we recalculated the number of true positives for sensitivity. This resulted in differences of 43% for sensitivity and −4% for specificity.

Values given for detection of index lesion, identification of adjunctive lesions and correct determination of extension for masses, non-mass enhancement and masses associated with non-mass enhancement.

Figure 2.

Sensitivities of CEM vs XRM. CEM indicates contrast-enhanced mammography; XRM, traditional mammography.

Figure 3.

Differences of sensitivities of CEM vs XRM. CEM indicates contrast-enhanced mammography; CI, confidence interval; XRM, traditional mammography.

A similar diagnostic advantage of CEM was seen for specificity in most studies. The differences were found to be in a range of −3%⁴⁰ to 46%²⁸ (Table 4, Figures 4 and 5). Overall, CEM was found to provide a gain in specificity of 16% (95% CI [6%, 26%]). However, a hint for heterogeneity was found for the difference in specificities (P < .01). Therefore, no clear pattern on the advantage was found. Nevertheless, at least no disadvantage of CEM vs XRM can be concluded based on the study-level differences (Figure 5).

Figure 4.

Specificities of CEM vs XRM. CEM indicates contrast-enhanced mammography; XRM, traditional mammography.

Figure 5.

Differences of specificities of CEM vs XRM. CEM indicates contrast-enhanced mammography; CI, confidence interval; XRM, traditional mammography.

Accuracy, and positive and negative predictive values (PPV, NPV) were not recorded by all authors. However, those who did record found more favorable results for CEM (Table 4). Three cases with intra-individual comparison of both modalities are shown on Figure 6.

Figure 6.

Cases showing intra-individual comparison of iopromide CEM and XRM. CEM indicates contrast-enhanced mammography; DCIS, Ductal carcinoma in situ; XRM, traditional mammography.

Four case studies with intra-individual comparisons of XRM vs CEM images are shown on Figure 6.

CEM vs bMRI

2 studies reported efficacy results of iopromide CEM vs bMRI. Sensitivity was similar⁴³ or higher for CEM.³⁸ Specificity was higher⁴³ or not reported.³⁸ Accuracy, PPV, and NPV were in favor of CEM in both studies (Table 4).

CEM uncontrolled

Six efficacy studies presented uncontrolled findings. Sensitivity was in the range of 25% to 100%,²⁹ specificity from 61%⁴² to 98%³⁰ (Table 4).

Safety

Adverse events (AEs)/adverse drug reactions (ADRs) related to iopromide administration were reported in 3 of the 31 studies (Table 2). In total, 8 adverse drug reactions were reported from 7 patients: 1 case of severe allergic reaction that required intensive care and led to discontinuation of the procedure,²⁷ 1 moderate⁴⁶ and 5 mild cases of urticaria,^28,46 and 1 moderate shortness of breath.⁴⁶ In relation to the total number of 1022 patients examined in these studies, this corresponds to 0.8% (Table 5).

Table 5.

Safety results of studies on contrast-enhanced mammography using iopromide.

Author (year)	N	Related adverse drug reactions	%
Diekmann et al²⁷	70	1 severe allergic reaction	1.4
Houben et al⁴⁶	839	4 mild urticaria1 moderate urticaria^a 1 shortness of breath^a	0.7
Lobbes et al²⁸	113	1 mild urticaria	0.9
	1022	8 (in 7 patients)	0.8

Same patient.

In the remaining 28 studies, no AEs or ADRs to iopromide were reported. However, in 11 studies, patients with known risk of allergic reactions or CIN were excluded upfront, in another 15 studies exclusion criteria to known risks of allergic reactions, CIN or renal insufficiency were not explicitly mentioned. 1 study excluded patients for other reasons than known risk of allergic reactions or CIN.

Most of the AEs were reported in context of hypersensitivity reactions and are in line with the well-established safety profile of iopromide. No new safety concerns were identified during this analysis. The benefit risk profile remains favorable and unchanged.

Discussion

We systematically analyzed the usage of iopromide for CEM for detection or confirmation of BC and found strong evidence for higher diagnostic performance compared with XRM and similar performance compared with bMRI.

The PLI database is a robust source as it aggregates data from 4 leading international literature databases. The PLI retrieved more publications than MEDLINE/EMBASE alone (applied by Zanardo et al²⁵) as this system is specifically designed for the company’s global pharmacovigilance department (PV). As PV is obliged to report any ADR all over the world, also country-specific journals are utilized, identifying publications in other languages apart from English. This ensures a high degree of completeness of the literature search (Figure 1).

All 31 studies on iopromide included at total of 5194 patients, 2920 and 1022 patients in the efficacy and safety analysis, respectively (2 studies reported efficacy and safety). In 11 studies (n = 1435 patients) neither efficacy nor safety was reported so they were excluded from the analysis. All patients were included either for screening or for characterization of suspicious findings.

Tagliafico et al⁹ published a similar review and meta-analysis focusing on sensitivity and specificity on 8 studies including 920 patients presenting 994 lesions. Unfortunately, the type of LOCM was not specified. Zanardo et al²⁵ included 14 012 patients from 84 studies looking at a large range of LOCMs. However, Zanardo et al²⁵ investigated primarily technique, protocols, and adverse reactions, while this analysis put emphasis on efficacy and safety.

In 11 studies, sensitivity and specificity of CEM vs XRM were almost always in favor of CEM with an overall gain of 7% in sensitivity and no hints for a loss in specificity. This held also true for accuracy, PPV, and NPV (Table 4). These findings support results from other groups on other LOCMs.

Tennant et al¹⁰ performed a review of 100 CEM examinations (LOCM not specified) vs low-energy images and reported CEM showing increased sensitivity (95% vs 84%, P < .025) and specificity (81% vs 63%, P < .025). They conclude that CEM provides improved efficacy in BC screening and staging as primary mammographic investigation.

Likewise, Mori et al⁵⁸ focused on 72 women with dense breasts who underwent CEM with iohexol and XRM. Sensitivity was 86.2% for CEM and 53.4% for XRM (<.001), and specificity 94.1% and 85.9% (<.016), respectively. They concluded that CEM offers superior clinical performance compared with XRM and may decrease false negatives especially for women with dense breasts.

Kim et al⁵⁹ compared both imaging modalities in BC screening on 64 cases. Median sensitivity and specificity improved with the addition of CEM (iohexol). Sensitivity: from 86% (XRM alone) to 100% (XRM + CEM), specificity, from 85% to 88%.

While other publications point in the same direction,^11,60 Lorek et al⁶¹ criticized that CEM overestimates the tumor size on average by 5 mm.

The 2 studies on efficacy of iopromide CEM vs bMRI showed similar⁴³ or higher sensitivity for CEM³⁸ while accuracy, PPV and NPV were in favor of CEM (Table 4).

Three intra-individual comparison studies of CEM with other LOCMs vs bMRI are of interest in this context.^62
-64 1 retrospective study by Xing et al⁶⁴ on 235 patients administered iohexol and 2 prospective studies, 1 on 178 patients by Fallenberg (iobitridol)⁶² and 1 on 84 patients by Kim (iohexol)⁶³ reported a similar trend: Almost identical sensitivities for both modalities and a slightly higher specificity for CEM. In contrast, Pötsch et al⁶⁵ found in a meta-analysis of 7 studies investigating 1137 lesions higher sensitivity for bMRI (97%) vs CEM (91%), however, at the cost of lower sensitivity, 69% vs 74%.

The 6 uncontrolled studies on iopromide showed a sensitivity of 25% to 100%²⁹ and a specificity of 61%⁴² to 98%⁴⁷ (Table 4).

A recent systematic review and meta-analysis comprising a total of 945 patients of 8 studies using 5 different LOCMs by Suter et al⁶⁶ calculated a sensitivity of 85% and a specificity of 77%. Tagliafico et al⁹ found a sensitivity of 98% and a sensitivity of 58% in a meta-analysis of 8 studies with 920 patients. Although the range is quite broad, our results seem to corroborate these findings.

A total of 8 AEs of iopromide-related AEs/ADRs were reported in 7 patients from three studies comprising 1022 patients. This corresponds to a reporting rate of 0.8%. Skin reactions like urticaria, erythema, rash, and pruritus are usually the most frequent events. The most severe AEs are hypersensitivity reactions.⁶⁷ The safety findings reported here in patients receiving iopromide-enhanced CEM are well in line with other studies focusing on AEs/ADRs after intravenous iopromide administration for other indications, ie, 1.5%,¹⁸ 0.7%,¹⁹ and 2.8%.²⁰ These are also comparable with results of studies on a broad spectrum of different LOCMs, 0.37%,²² 0.34%,⁶⁸ and 0.97%.⁶⁹ The reported AEs/ADRs related to contrast media administration are expected to be independent of the imaged region of the body.

A frequently raised concern about CEM is the increased radiation dose compared with XRM. James et al⁷⁰ retrospectively compared the radiation dose of CEM using high- and low-energy projections with the radiation dose received during XRM in 173 patients with varying breast thickness and density. At a mean breast thickness of 63 mm, the average glandular dose was 3.0 and 2.1 mGy for CEM and XRM, respectively. They conclude that this increase of 0.9 mGy falls below the dose limit of 3 mGy set by Mammography Quality Standards Act regulations (MQSA). Similarly, Gennaro et al⁷¹ reported that the dose for CEM is about 30% higher compared with standard XRM, an increase close to that of digital tomosynthesis, but it is the upper limit according to MQSA.

CEM is assumed to become an emerging new imaging modality providing higher diagnostic efficacy compared with XRM and similar efficacy compared with bMRI in BC screening and diagnostic work up. In addition, CEM also offers the opportunity for CEM-guided biopsy, a new technique that can be successfully used as an alternative to MRI-guided breast biopsy.⁷² As CEM requires only limited technical upgrades of the broadly available XRM equipment and can be implemented easily into the current XRM workflow, it might be a cost-effective alternative to bMRI, in particular as there is some evidence that patients prefer CEM over bMRI.^73,74 CEM might also be a good option when MRI technique is not available.

Limitations

Some limitations need to be addressed:

This review was not based on the patient individual data of the original studies but published results.

As for any literature review, the retrospective nature of the data and the variability of information collected and reported is a major limitation.

As this review focused on studies on iopromide, the full picture regarding use of LOCMs in CEM is not reflected.

Each study only provided 1 pair of sensitivity/specificity results, so that the meta-analyses for the diagnostic parameters might be biased due to, eg, reader experience and selection of readers. In addition, the data sources with regard to prospective and retrospective data and blinding of readers did vary across studies, which increases uncertainty and heterogeneity in the results (Table 1).

Except for 3 studies, all other were performed in Europe.

Studies included mostly women with a high-risk predisposition for BC. It is not clear if this might impact the rate of AEs related to iopromide administration.

No long-term safety data after repetitive administrations were reported.

Studies using iopromide for other imaging modalities (eg, breast CT) were not included.

No dose-finding studies were found.

Potentially varying diagnostic performances between different commercially available mammography systems were not assessed. An impact of the mammography system on diagnostic performance cannot be excluded.

Conclusions

Pertinent literature supports iopromide to be an effective and safe agent for CEM for the detection or confirmation of BC. The overall gain in sensitivity for iopromide CEM vs XRM was 7% without compromising specificity.

Footnotes

Acknowledgements

Not applicable.

Declarations

References

Wanders

Holland

Veldhuis

, et al. Volumetric breast density affects performance of digital screening mammography. Breast Cancer Res Treat. 2017;162:95-103. doi:10.1007/s10549-016-4090-7.

Kuhl

Strobel

Bieling

Leutner

Schild

Schrading

. Supplemental breast MR imaging screening of women with average risk of breast cancer. Radiology. 2017;283:361-370. doi:10.1148/radiol.2016161444.

Sardanelli

Newstead

Putz

, et al. Gadobutrol-enhanced magnetic resonance imaging of the breast in the preoperative setting: results of 2 prospective international multicenter phase III studies. Invest Radiol. 2016;51:454-461. doi:10.1097/RLI.0000000000000254.

Mann

Kuhl

Moy

. Contrast-enhanced MRI for breast cancer screening. J Magn Reson Imaging. 2019;50:377-390. doi:10.1002/jmri.26654.

Sardanelli

Fallenberg

Clauser

, et al. Mammography: an update of the EUSOBI recommendations on information for women. Insights Imaging. 2017;8:11-18. doi:10.1007/s13244-016-0531-4.

Patel

Lobbes

MBI

Lewin

. Contrast enhanced spectral mammography: a review. Semin Ultrasound CT MR. 2018;39:70-79. doi:10.1053/j.sult.2017.08.005.

American College of Radiology. ACR appropriateness criteria. https://acsearch.acr.org/docs/3158166/Narrative/.

ACR. BIRADS CEM. https://www.acr.org/-/media/ACR/Files/RADS/BI-RADS/BIRADS_CEM_2022.pdf.

Tagliafico

Bignotti

Rossi

, et al. Diagnostic performance of contrast-enhanced spectral mammography: systematic review and meta-analysis. Breast. 2016;28:13-19. doi:10.1016/j.breast.2016.04.008.

10.

Tennant

James

Cornford

, et al. Contrast-enhanced spectral mammography improves diagnostic accuracy in the symptomatic setting. Clin Radiol. 2016;71:1148-1155. doi:10.1016/j.crad.2016.05.009.

11.

Tardivel

Balleyguier

Dunant

, et al. Added value of contrast-enhanced spectral mammography in postscreening assessment. Breast J. 2016;22:520-528. doi:10.1111/tbj.12627.

12.

Mann

Athanasiou

Baltzer

PAT

, et al. Breast cancer screening in women with extremely dense breasts recommendations of the European Society of Breast Imaging (EUSOBI). Eur Radiol. 2022;32:4036-4045. doi:10.1007/s00330-022-08617-6.

13.

RCR. Royal College of Radiologists Guidance on screening and symptomatic breast imaging Fourth edition. https://www.rcr.ac.uk/publication/guidance-screening-and-symptomatic-breast-imaging-fourth-edition.

14.

GGPO. German guideline program in oncology evidence-based guideline for the early detection, diagnosis, treatment and follow-up of breast cancer 032/045OL. https://www.verwaltung.awmf.org/fileadmin/user_upload/Leitlinien/032_D_Krebsgesellschaft/032-045OLeng_S3_Guideline_Breast_Cancer_2021-11.pdf.

15.

Jochelson

Lobbes

MBI

. Contrast-enhanced mammography: state of the art. Radiology. 2021;299:36-48. doi:10.1148/radiol.2021201948.

16.

Goldstein

Jacob

Wiggins

. New clinical trial experience with iopromide. Invest Radiol. 1994;29:S208-S210.

17.

Bayer

. Periodic Benefit-Risk Evaluation Report—Periodic Safety Update Report Ultravist® 150/240/300/370 BAY—No.86-4877 (Iopromide) No. 28.0 01 JUL 2020 to 30 JUN 2021. No 260. Leverkusen: Bayer AG, 2021.

18.

Kopp

Mortele

Cho

Palkowitsch

Bettmann

Claussen

. Prevalence of acute reactions to iopromide: postmarketing surveillance study of 74,717 patients. Acta Radiol. 2008;49:902-911. doi:10.1080/02841850802282811.

19.

Mortelé

Oliva

Ondategui

Ros

Silverman

. Universal use of nonionic iodinated contrast medium for CT: evaluation of safety in a large urban teaching hospital. AJR Am J Roentgenol. 2005;184:31-34. doi:10.2214/ajr.184.1.01840031.

20.

Palkowitsch

Lengsfeld

Stauch

, et al. Safety and diagnostic image quality of iopromide: results of a large non-interventional observational study of European and Asian patients (IMAGE). Acta Radiol. 2012;53:179-186. doi:10.1258/ar.2011.110359.

21.

Dillman

Strouse

Ellis

Cohan

Jan

. Incidence and severity of acute allergic-like reactions to i.v. nonionic iodinated contrast material in children. AJR Am J Roentgenol. 2007;188:1643-1647. doi:10.2214/AJR.06.1328.

22.

Jung

Kwon

, et al. Differences in adverse reactions among iodinated contrast media: analysis of the KAERS database. J Allergy Clin Immunol Pract. 2019;7:2205-2211. doi:10.1016/j.jaip.2019.02.035.

23.

Seong

Choi

Lee

, et al. Comparison of the safety of seven iodinated contrast media. J Korean Med Sci. 2013;28:1703-1710. doi:10.3346/jkms.2013.28.12.1703.

24.

Palkowitsch

Bostelmann

Lengsfeld

. Safety and tolerability of iopromide intravascular use: a pooled analysis of three non-interventional studies in 132,012 patients. Acta Radiol. 2014;55:707-714. doi:10.1177/0284185113504753.

25.

Zanardo

Cozzi

Trimboli

, et al. Technique, protocols and adverse reactions for contrast-enhanced spectral mammography (CESM): a systematic review. Insights Imaging. 2019;10:76. doi:10.1186/s13244-019-0756-0.

26.

Schwarzer

. Meta: an R package for meta-analysis. R News. 2007;7:40-45.

27.

Diekmann

Freyer

Diekmann

, et al. Evaluation of contrast-enhanced digital mammography. Eur J Radiol. 2011;78:112-121. doi:10.1016/j.ejrad.2009.10.002.

28.

Lobbes

Lalji

Houwers

, et al. Contrast-enhanced spectral mammography in patients referred from the breast cancer screening programme. Eur Radiol. 2014;24:1668-1676. doi:10.1007/s00330-014-3154-5.

29.

Amato

Bicchierai

Cirone

, et al. Preoperative loco-regional staging of invasive lobular carcinoma with contrast-enhanced digital mammography (CEDM). Radiol Med. 2019;124:1229-1237. doi:10.1007/s11547-019-01116-7.

30.

Bicchierai

Nori

De Benedetto

, et al. Role of contrast-enhanced spectral mammography in the post biopsy management of B3 lesions: preliminary results. Tumori. 2019;105:378-387. doi:10.1177/0300891618816212.

31.

Bicchierai

Tonelli

Piacenti

, et al. Evaluation of contrast-enhanced digital mammography (CEDM) in the preoperative staging of breast cancer: large-scale single-center experience. Breast J. 2020;26:1276-1283. doi:10.1111/tbj.13766.

32.

Chalabi

NAM

AbuElMaati

Elsadawy

MEI

. Contrast-enhanced spectral mammography: successful initial clinical institute experience. Egypt J Radiol Nucl Med. 2021;52:1-18.

33.

Diekmann

Jeunehomme

Muller

Hamm

Bick

. Digital mammography using iodine-based contrast media: initial clinical experience with dynamic contrast medium enhancement. Invest Radiol. 2005;40:397-404. doi:10.1097/01.rli.0000167421.83203.4e.

34.

Houben

Vanwetswinkel

Kalia

, et al. Contrast-enhanced spectral mammography in the evaluation of breast suspicious calcifications: diagnostic accuracy and impact on surgical management. Acta Radiol. 2019;60:1110-1117. doi:10.1177/0284185118822639.

35.

Lalji

Houben

Prevos

, et al. Contrast-enhanced spectral mammography in recalls from the Dutch breast cancer screening program: validation of results in a large multireader, multicase study. Eur Radiol. 2016;26:4371-4379. doi:10.1007/s00330-016-4336-0.

36.

Lobbes

MBI

Hecker

Houben

IPL

, et al. Evaluation of single-view contrast-enhanced mammography as novel reading strategy: a non-inferiority feasibility study. Eur Radiol. 2019;29:6211-6219. doi:10.1007/s00330-019-06215-7.

37.

Luczyńska

Heinze-Paluchowska

Dyczek

Blecharz

Rys

Reinfuss

. Contrast-enhanced spectral mammography: comparison with conventional mammography and histopathology in 152 women. Korean J Radiol. 2014;15:689-696. doi:10.3348/kjr.2014.15.6.689.

38.

Luczynska

Heinze-Paluchowska

Hendrick

, et al. Comparison between breast MRI and contrast-enhanced spectral mammography. Med Sci Monit. 2015;21:1358-1367. doi:10.12659/MSM.893018.

39.

Luczyńska

Heinze

Adamczyk

Rys

Mitus

Hendrick

. Comparison of the mammography, contrast-enhanced spectral mammography and ultrasonography in a group of 116 patients. Anticancer Res. 2016;36:4359-4366.

40.

Mohamed

SAS

Moftah

Chalabi

NAEM

Salem

MAAW

. Added value of contrast-enhanced spectral mammography in symptomatic patients with dense breasts. Egypt J Radiol Nucl Med. 2021;52:2-10.

41.

Richter

Hatterman

Preibsch

, et al. Contrast-enhanced spectral mammography in patients with MRI contraindications. Acta Radiol. 2018;59:798-805. doi:10.1177/0284185117735561.

42.

Rudnicki

Heinze

Niemiec

, et al. Correlation between quantitative assessment of contrast enhancement in contrast-enhanced spectral mammography (CESM) and histopathology-preliminary results. Eur Radiol. 2019;29:6220-6226. doi:10.1007/s00330-019-06232-6.

43.

Rudnicki

Piegza

Rozum-Liszewska

, et al. The effectiveness of contrast-enhanced spectral mammography and magnetic resonance imaging in dense breasts. Pol J Radiol. 2021;86:e159-e164. doi:10.5114/pjr.2021.104834.

44.

Tsigginou

Gkali

Chalazonitis

, et al. Adding the power of iodinated contrast media to the credibility of mammography in breast cancer diagnosis. Br J Radiol. 2016;89:20160397. doi:10.1259/bjr.20160397.

45.

Travieso-Aja

MDM

Maldonado-Saluzzi

Naranjo-Santana

, et al. Diagnostic performance of contrast-enhanced dual-energy spectral mammography (CESM): a retrospective study involving 644 breast lesions. Radiol Med. 2019;124:1006-1017. doi:10.1007/s11547-019-01056-2.

46.

Houben

IPL

Van de Voorde

Jeukens

CRLPN

, et al. Contrast-enhanced spectral mammography as work-up tool in patients recalled from breast cancer screening has low risks and might hold clinical benefits. Eur J Radiol. 2017;94:31-37. doi:10.1016/j.ejrad.2017.07.004.

47.

Bicchierai

Amato

Vanzi

, et al. Which clinical, radiological, histological, and molecular parameters are associated with the absence of enhancement of known breast cancers with Contrast Enhanced Digital Mammography (CEDM). Breast. 2020;54:15-24. doi:10.1016/j.breast.2020.08.009.

48.

Gluch

LSM

Jones

. The brilliance of contrast enhanced spectral mammography. J Gen Surg. 2020;3:1-5.

49.

Houben

IPL

van Berlo

CJLY

Bekers

Nijssen

Lobbes

MBI

Wildberger

. Assessing the risk of contrast-induced nephropathy using a finger stick analysis in recalls from breast screening: the CINFIBS explorative study. Contrast Media Mol Imaging. 2017;2017:5670384. doi:10.1155/2017/5670384.

50.

Jeukens

Lalji

Meijer

, et al. Radiation exposure of contrast-enhanced spectral mammography compared with full-field digital mammography. Invest Radiol. 2014;49:659-665. doi:10.1097/RLI.0000000000000068.

51.

Lobbes

Lalji

Nelemans

, et al. The quality of tumor size assessment by contrast-enhanced spectral mammography and the benefit of additional breast MRI. J Cancer. 2015;6:144-150. doi:10.7150/jca.10705.

52.

Lobbes

MBI

Mulder

HKP

Rousch

Backes

Wildberger

Jeukens

CRLPN

. Quantification of enhancement in contrast-enhanced spectral mammography using a custom-made quantifier tool (I-STRIP): a proof-of-concept study. Eur J Radiol. 2018;106:114-121. doi:10.1016/j.ejrad.2018.07.021.

53.

Luczynska

Niemiec

Ambicka

, et al. Correlation between blood and lymphatic vessel density and results of contrast-enhanced spectral mammography. Pol J Pathol. 2015;66:310-322. doi:10.5114/pjp.2015.54965.

54.

Luczynska

Niemiec

Heinze

, et al. Intensity and pattern of enhancement on CESM: prognostic significance and its relation to expression of podoplanin in tumor stroma—a preliminary report. Anticancer Res. 2018;38:1085-1095. doi:10.21873/anticanres.12327.

55.

Rudnicki

Heinze

Piegza

Pawlak

Kojs

Luczynska

. Correlation between enhancement intensity in contrast enhancement spectral mammography and types of kinetic curves in magnetic resonance imaging. Med Sci Monit. 2020;26:e920742. doi:10.12659/MSM.920742.

56.

Rudnicki

Heinze

Popiela

Kojs

Luczynska

. Quantitative assessment of contrast enhancement on contrast enhancement spectral mammography (CESM) and comparison with qualitative assessment. Anticancer Res. 2020;40:2925-2932. doi:10.21873/anticanres.14270.

57.

Schmitzberger

Fallenberg

Lawaczeck

, et al. Development of low-dose photon-counting contrast-enhanced tomosynthesis with spectral imaging. Radiology. 2011;259:558-564. doi:10.1148/radiol.11101682.

58.

Mori

Akashi-Tanaka

Suzuki

, et al. Diagnostic accuracy of contrast-enhanced spectral mammography in comparison to conventional full-field digital mammography in a population of women with dense breasts. Breast Cancer. 2017;24:104-110. doi:10.1007/s12282-016-0681-8.

59.

Kim

Phillips

Cole

, et al. Comparison of contrast-enhanced mammography with conventional digital mammography in breast cancer screening: a pilot study. J Am Coll Radiol. 2019;16:1456-1463. doi:10.1016/j.jacr.2019.04.007.

60.

Lalji

Jeukens

Houben

, et al. Evaluation of low-energy contrast-enhanced spectral mammography images by comparing them to full-field digital mammography using EUREF image quality criteria. Eur Radiol. 2015;25:2813-2820. doi:10.1007/s00330-015-3695-2.

61.

Lorek

Steinhof-Radwanska

Barczyk-Gutkowska

, et al. Retrospective comparison of contrast-enhanced spectral mammography with digital mammography in assessing tumor size in 668 cases of breast cancer. Med Sci Monit. 2020;26:e926977. doi:10.12659/MSM.926977.

62.

Fallenberg

Schmitzberger

Amer

, et al. Contrast—enhanced spectral mammography vs. Mammography and MRI—clinical performance in a multi-reader evaluation. Eur Radiol. 2017;27:2752-2764. doi:10.1007/s00330-016-4650-6.

63.

Kim

Youn

Lee

, et al. Diagnostic value of contrast-enhanced digital mammography versus contrast-enhanced magnetic resonance imaging for the preoperative evaluation of breast cancer. J Breast Cancer. 2018;21:453-462. doi:10.4048/jbc.2018.21.e62.

64.

Xing

Sun

, et al. Diagnostic value of contrast-enhanced spectral mammography in comparison to magnetic resonance imaging in breast lesions. J Comput Assist Tomogr. 2019;43:245-251. doi:10.1097/RCT.0000000000000832.

65.

Pötsch

Vatteroni

Clauser

Helbich

Baltzer

PAT

. Contrast-enhanced mammography versus contrast-enhanced Breast MRI: a systematic review and meta-analysis. Radiology. 2022;305:94-103. doi:10.1148/radiol.212530.

66.

Suter

Pesapane

Agazzi

, et al. Diagnostic accuracy of contrast-enhanced spectral mammography for breast lesions: a systematic review and meta-analysis. Breast. 2020;53:8-17. doi:10.1016/j.breast.2020.06.005.

67.

Endrikat

Michel

Kolbach

Lengsfeld

Vogtlander

. Risk of hypersensitivity reactions to iopromide after intra-arterial versus intravenous administration: a nested case-control analysis of 133,331 patients. Invest Radiol. 2020;55:38-44. doi:10.1097/RLI.0000000000000611.

68.

Chen

Zhang

, et al. Clinical observation of the adverse drug reactions caused by non-ionic iodinated contrast media: results from 109,255 cases who underwent enhanced CT examination in Chongqing, China. Br J Radiol. 2015;88:20140491. doi:10.1259/bjr.20140491.

69.

Lee

Kang

Kim

, et al. Incidence and risk factors of immediate hypersensitivity reactions associated with low-osmolar iodinated contrast media: a longitudinal study based on a real-time monitoring system. J Investig Allergol Clin Immunol. 2019;29:444-450. doi:10.18176/jiaci.0374.

70.

James

Pavlicek

Hanson

Boltz

Patel

. Breast radiation dose with CESM compared with 2D FFDM and 3D tomosynthesis mammography. AJR Am J Roentgenol. 2017;208:362-372. doi:10.2214/AJR.16.16743.

71.

Gennaro

Cozzi

Schiaffino

Sardanelli

Caumo

. Radiation dose of contrast-enhanced mammography: a two-center prospective comparison. Cancers (Basel). 2022;14(7):1174. doi:10.3390/cancers14071774.

72.

James

. Contrast-enhanced spectral mammography (CESM)-guided breast biopsy as an alternative to MRI-guided biopsy. Br J Radiol. 2022;95:20211287. doi:10.1259/bjr.20211287.

73.

Hobbs

Taylor

Buzynski

Peake

. Contrast-enhanced spectral mammography (CESM) and contrast enhanced MRI (CEMRI): patient preferences and tolerance. J Med Imaging Radiat Oncol. 2015;59:300-305. doi:10.1111/1754-9485.12296.

74.

Phillips

Miller

Mehta

, et al. Contrast-enhanced spectral mammography (CESM) versus MRI in the high-risk screening setting: patient preferences and attitudes. Clin Imaging. 2017;42:193-197. doi:10.1016/j.clinimag.2016.12.011.

Iopromide for Contrast-Enhanced Mammography: A Systemic Review and Meta-Analysis of Pertinent Literature

Abstract

Background:

Objectives:

Design:

Data sources and methods:

Results:

Conclusions:

Keywords

Introduction

Data Sources and Methods

Databases

Statistics

Results

Results of the literature search

Patient population

Efficacy

CEM vs XRM

CEM vs bMRI

CEM uncontrolled

Safety

Discussion

Limitations

Conclusions

Footnotes

Acknowledgements

Declarations

References