Mammography in combination with breast ultrasonography versus mammography for breast cancer screening in women at average risk

  • Review
  • Intervention

Authors


Abstract

Background

Breast cancer is the most common malignant disease diagnosed in women worldwide. Screening with mammography has the ability to detect breast cancer at an early stage. The diagnostic accuracy of mammography screening largely depends on the radiographic density of the imaged breasts. In radiographically dense breasts, non-calcified breast cancers are more likely to be missed than in fatty breasts. As a consequence, some cancers are not detected by mammography screening. Supporters of adjunct ultrasonography to the screening regimen for breast cancer argue that it might be a safe and inexpensive approach to reduce the false negative rates of the screening process. Critics, however, are concerned that performing supplemental ultrasonography on women at average risk will also increase the rate of false positive findings and can lead to unnecessary biopsies and treatments.

Objectives

To assess the comparative effectiveness and safety of mammography in combination with breast ultrasonography versus mammography for breast cancer screening for women at average risk of breast cancer.

Search methods

We searched the Cochrane Breast Cancer Group's Specialised Register, MEDLINE (via OvidSP) and EMBASE up until February 2012.

To detect ongoing or unpublished studies, we searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov and the National Cancer Institute's clinical trial database until June 2012. In addition, we conducted grey literature searches using the following sources: OpenGrey; National Institute of Health RePORTER; Health Services Research Projects in Progress (HSRPROJ); Hayes, Inc. Health Technology Assessment; The New York Academy of Medicine’s Grey Literature Index and Conference Papers Index.

Selection criteria

For efficacy, we considered randomised controlled trials (RCTs), with either individual or cluster randomisation, and prospective, controlled non-randomised studies with a low risk of bias and a sample size of at least 500 participants.

In addition to studies eligible for efficacy, we considered any controlled, non-randomised study with a low risk of bias and a study size of at least 500 participants for the assessment of harms.

Our population of interest were women between the ages of 40 and 75 years who were at average risk for breast cancer.

Data collection and analysis

Two review authors screened abstracts and full-text publications against the inclusion criteria. None of the studies met our inclusion criteria.

Main results

Our review did not detect any controlled studies on the use of adjunct ultrasonography for screening in women at average risk for breast cancer. One ongoing randomised controlled trial was identified (J-START, Japan).

Authors' conclusions

Presently, there is no methodologically sound evidence available justifying the routine use of ultrasonography as an adjunct screening tool in women at average risk for breast cancer.

Résumé scientifique

Mammographie combinée à l'échographie du sein versus mammographie, pour le dépistage du cancer du sein chez les femmes présentant un risque moyen

Contexte

Le cancer du sein est, mondialement, le cancer le plus fréquemment diagnostiqué chez les femmes. Le dépistage par mammographie est en mesure de détecter le cancer du sein à un stade précoce. La précision diagnostique du dépistage par mammographie dépend grandement de la densité radiographique des seins examinés. Le risque de manquer la détection d'un cancer du sein non calcifié est plus grande pour des seins radiographiquement denses que pour des seins contenant surtout des tissus adipeux. En conséquence, certains cancers ne sont pas détectés par la mammographie de dépistage. Les partisans de l'ajout de l'échographie à la procédure de dépistage du cancer du sein soutiennent que cela pourrait constituer une façon sûre et peu coûteuse de réduire les taux de faux négatifs du processus de dépistage. D'autres, toutefois, craignent que l'échographie supplémentaire effectuée sur des femmes à risque moyen aura également pour conséquence d'augmenter le taux de faux positifs et de conduire à des biopsies et des traitements inutiles.

Objectifs

Évaluer l'efficacité et l'innocuité comparatives de la mammographie combinée à l'échographie du sein par rapport à la mammographie, pour le dépistage du cancer du sein chez les femmes présentant un risque moyen de cancer du sein.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre spécialisé du groupe Cochrane sur le cancer du sein, MEDLINE (via OvidSP) et EMBASE jusqu'à février 2012.

Afin de repérer des études en cours ou non publiées, nous avons cherché dans le système d’enregistrement international des essais cliniques (ICTRP) de l’Organisation mondiale de la Santé (OMS), ClinicalTrials.gov et la base de données d'essais cliniques du National Cancer Institute jusqu'à juin 2012. Nous avons de plus cherché dans la littérature grise au moyen des sources suivantes : OpenGrey ; National Institute of Health RePORTER ; Health Services Research Projects in Progress (HSRPROJ) ; Hayes, Inc. Health Technology Assessment ; The New York Academy of Medicine’s Grey Literature Index et Conference Papers Index.

Critères de sélection

Pour l'efficacité, nous avons pris en compte des essais contrôlés randomisés (ECR), avec randomisation individuelle ou de groupe, ainsi que des études contrôlées non randomisées prospectives, à faible risque de biais et à effectifs d'au moins 500 participants.

En plus des études éligibles pour l'efficacité, nous avons pris en compte pour l'évaluation des préjudices toute étude contrôlée non randomisée à faible risque de biais qui comprenait au moins 500 participants.

Notre population cible était les femmes âgées de 40 à 75 ans présentant un risque moyen de cancer du sein.

Recueil et analyse des données

Deux auteurs ont passé au crible des résumés et des textes intégraux de publications pour vérifier s'ils répondaient aux critères d'inclusion. Aucune des études ne répondait à nos critères d'inclusion.

Résultats principaux

Notre revue n'a détecté aucune étude contrôlée sur l'utilisation supplémentaire de l'échographie pour le dépistage des femmes présentant un risque moyen de cancer du sein. Un essai contrôlé randomisé en cours a été identifié (J -START, Japon).

Conclusions des auteurs

On ne dispose actuellement d'aucunes données de bonne qualité méthodologique justifiant l'utilisation systématique de l'échographie comme outil de dépistage complémentaire chez les femmes présentant un risque moyen de cancer du sein.

摘要

乳房X光攝影合併乳房超音波檢查與乳房X光攝影對於風險為一般的女性之乳癌篩檢比較

背景

乳癌是全球女性最常被診斷出的惡病。乳房X光攝影篩檢有早期偵測乳癌的能力。乳房X光攝影的診斷準確性主要取決於乳房成像的X光攝影緻密度。X光攝影緻密的乳房相較於脂肪多的乳房,非鈣化性的乳癌很容易被忽略,結果造成部份癌症沒有被乳房X光攝影篩檢偵測出來。乳癌篩檢方法附加乳房超音波的支持者認為,這可能會是降低篩檢程序偽陰性率的一個安全且不昂貴的方式。然而批評者擔心,在風險為一般的女性身上進行追加的乳房超音波檢查也可能提高偽陽性結果,並且可能導致不必要的切片檢查與治療。

目的

評估乳房X光攝影合併乳房超音波檢查相較於乳房X光攝影,對於乳癌風險為一般的女性之乳癌篩檢比較效益與安全。

搜尋策略

截至2012年2月,我們搜尋了Cochrane Breast Cancer Group's Specialised Register、MEDLINE (via OvidSP) 以及EMBASE等資料庫。

為了找出正在進行或尚未發表的研究,截至2012年6月,我們搜尋了世界衛生組織 (WHO) International Clinical Trials Registry Platform (ICTRP)、ClinicalTrials.gov以及National Cancer Institute的臨床試驗資料庫。此外,我們利用下列資源進行灰色文獻搜尋:OpenGrey、National Institute of Health RePORTER、Health Services Research Projects in Progress (HSRPROJ)、Hayes, Inc. Health Technology Assessment、The New York Academy of Medicine’s Grey Literature Index以及Conference Papers Index。

選擇標準

為求研究效力,我們選擇不論是以個體或群體為單位隨機分派的隨機對照試驗(RCTs),以及預期的、低偏誤風險且樣本數至少有500位受試者的非隨機對照研究。

除了對效力合適的研究之外,我們選擇任何低偏誤風險且研究樣本數至少有500位受試者的非隨機對照研究來評估危害。

我們對於研究族群的偏好是40至75歲,乳癌風險為一般的女性。

資料收集與分析

兩位作者將摘要及出版物全文與納入標準對照審查。沒有研究符合我們的納入標準。

主要結果

我們的文獻沒有發現任何乳癌風險為一般的女性使用附加乳房超音波檢查來做篩檢的對照研究。有找出1個正在進行中的隨機對照試驗(J-START,日本)。

作者結論

目前,沒有研究方法健全的證據可以證明,常規地將乳房超音波檢查用來做為對乳癌風險為一般的女性之附加篩檢工具是正當的。

譯註

翻譯者:臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

Plain language summary

Mammography followed by ultrasonography compared to mammography alone for breast cancer screening in women at average risk of breast cancer

Worldwide, breast cancer is the most common malignancy in women. Evidence shows that mammography in healthy women 50 to 70 years of age can detect breast cancer early and reduce the risk of dying from breast cancer. Mammography, however, is not a perfect tool to detect breast cancer and misses some tumours in some women, particularly in women who have dense breasts. In women with dense breasts, the normal breast tissue and the tumour are difficult to distinguish from each other on the mammogram. Because of this, some supporters feel that the addition of ultrasonography screening of these women in addition to the mammography screening will detect those tumours that are missed by mammography alone. Others feel that this will increase the rate of false positive tumours and increase the number of biopsies and unnecessary treatment.

The benefit of ultrasound as an additional examination for women who do not have especially dense breasts and who have normal mammographies is uncertain. This review sought to examine the evidence for and against adding ultrasonography screening to mammograms for women at average risk for breast cancer. It is important to weigh positive and negative sides of screening because the detection of more tumours by screening does not necessarily mean that more women will have their lives saved. We need to assess whether the few additional cancers that may be detected by ultrasonography lead to a real decrease in mortality from breast cancer and then balance any benefit against the harm caused by many women being incorrectly alarmed or diagnosed.

We did not find any trials that addressed our review question. One randomised controlled trial is currently underway in Japan (called J-START). Because it is unclear whether ultrasonography in women with normal mammographies can reduce the risk of dying from breast cancer, they should not be used on a routine basis. If screening with ultrasonography is performed it should be as part of a clinical trial designed to test the effect of additional screening on mortality and the harms experienced by women who have a positive ultrasonography screening test.

Résumé simplifié

Comparaison de la mammographie suivie d'une échographie du sein à la seule mammographie pour le dépistage du cancer du sein chez les femmes présentant un risque moyen de cancer du sein

Le cancer du sein est, mondialement, le cancer le plus fréquent chez les femmes. Les données montrent que, chez les femmes en bonne santé de 50 à 70 ans, la mammographie peut détecter le cancer du sein à un stade précoce et réduire le risque de mourir d'un cancer du sein. La mammographie n'est cependant pas un outil parfait pour détecter le cancer du sein et elle rate des tumeurs chez certaines femmes, en particulier chez celles qui ont des seins denses. Chez les femmes ayant des seins denses, il est difficile de distinguer, sur la mammographie, la tumeur du tissu mammaire normal. C'est pourquoi certains partisans estiment que pour ces femmes l'ajout à la mammographie du dépistage par échographie pourrait permettre de détecter des tumeurs qui sont manquées par la seule mammographie. D'autres pensent que cela augmenterait le taux de tumeurs fausses positives ainsi que le nombre de biopsies et de traitements superflus.

On n'est pas sûr du bénéfice de l'échographie en tant qu'examen complémentaire pour les femmes qui n'ont pas les seins spécialement denses et dont les mammographies sont normales. Cette revue visait à examiner les données en faveur ou contre l'ajout à la mammographie du dépistage par échographie pour les femmes présentant un risque moyen de cancer du sein. Il est important de peser les aspects positifs et négatifs du dépistage, car la détection d'un plus grand nombre de tumeurs à l'aide du dépistage ne ​​signifie pas nécessairement que la vie de plus de femmes sera sauvée. Nous devons évaluer si les quelques cancers supplémentaires qui peuvent être détectées par échographie conduisent à une réelle diminution de la mortalité par cancer du sein, puis mettre en balance l'éventuel bénéfice avec les préjudices découlant du fait que de nombreuses femmes seront inquiétées pour rien ou mal diagnostiquées.

Nous n’avons pas trouvé d'essais qui se soient portés sur la question de notre revue. Un essai contrôlé randomisé est actuellement en cours au Japon (dénommé J-START). Comme il est difficile de savoir si, chez les femmes dont la mammographie est normale, l'échographie peut réduire le risque de mourir d'un cancer du sein, celle-ci ne devrait pas être utilisée de manière systématique. Si un dépistage par échographie est effectué, cela devrait être dans le cadre d'un essai clinique visant à examiner l'effet du dépistage supplémentaire sur la mortalité, ainsi que les préjudices subis par les femmes dont le dépistage par échographie est positif.

Notes de traduction

Traduit par: French Cochrane Centre 17th May, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Laički sažetak

Mamografija praćena ultrazvukom u usporedbi sa samom mamografijom za probir na rak dojke kod žena sa prosječnim rizikom od raka dojke

Diljem svijeta, rak dojke je najčešći zloćudni tumor u žena. Dokazi pokazuju da mamografija može kod zdravih žena starosti 50-70 godina rano otkriti rak dojke i smanjiti rizik od smrti od raka dojke. Međutim, mamografija nije savršena pretraga za otkrivanje raka dojke i ne otkrije pojedine tumore kod nekih žena, osobito u žena koje imaju gušće tkivo dojki. U žena s gušćim tkivom dojki, teško je na mamogramu razlikovati normalno tkivo dojke od tumora. Zbog toga, neki zagovornici smatraju da će dodatni pregled ultrazvukom kod tih žena nakon mamografskog probira otkriti i one tumore koji nisu otkriveni samom mamografijom. Drugi smatraju da će to povećati stopu lažno pozitivnih nalaza tumora i povećati broj biopsija i nepotrebnog liječenja.

Nije jasna prednost ultrazvuka kao dodatnog pregleda za žene koje nemaju osobito gusto tkivo dojki i koje imaju normalne mamografske nalaze. Ovaj pregled nastojao je ispitati dokaze koji govore u prilog i protiv dodatnog pregleda ultrazvukom nakon mamografije za žene s prosječnim rizikom za rak dojke. Važno je odvagnuti pozitivne i negativne strane probira jer ne znači nužno da će otkrivanje više tumora probirom i spasiti život više žena. Moramo procijeniti hoće li nekoliko dodatnih karcinoma koji bi se mogli otkriti ultrazvukom dovesti i do stvarnog smanjenja smrtnosti od raka dojke, a potom ocijeniti omjer postojeće koristi i štete uzrokovane time što će se mnoge žene nepotrebno uznemiriti ili pogrešno dijagnosticirati.

Nismo pronašli istraživanja vezana za pitanje kojim se bavi naš pregled. Trenutno je u tijeku jedno randomizirano kontrolirano istraživanje u Japanu (naziva J-START). Budući da nije jasno može li ultrazvuk u žena s normalnim mamografskim nalazom smanjiti rizik od smrti od raka dojke, ne bi se trebao rutinski koristiti. Ako se provodi probir s ultrazvukom, trebao bi biti dio kliničkog istraživanja dizajniranog za ispitivanje učinka ovog dodatnog pregleda na smrtnost i štetne učinke koji se javljaju kod žena s pozitivnim nalazom nakon ultrazvuka u svrhu probira.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Katarina Vučić
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

淺顯易懂的口語結論

乳房X光攝影之後接著進行乳房超音波檢查與只進行乳房X光攝影,對於乳癌風險一般的女性之乳癌篩檢比較

乳癌是全世界女性最常被診斷出的惡病。證據顯示對50至70歲女性進行乳房X光攝影,能夠在早期偵測乳癌並降低死於乳癌的風險。然而乳房X光攝影不是偵測乳癌最好的工具,並且在某些女性身上可能會忽略部份腫瘤的存在,特別是那些乳房緻密度高的女性。在乳房緻密度高的女性身上,乳房X光攝影片很難分辨一般的乳房組織與腫瘤。因此,部份支持者認為對於這些女性,在乳房X光攝影篩檢之外再做額外的乳房超音波篩檢,將能偵測出那些被只做乳房X光攝影忽略的腫瘤。其他人認為這將會提高偽陽性腫瘤率以及增加切片檢查與不必要的治療次數。

對於乳房緻密度不特別高以及乳房X光攝影片為一般的女性來說,將乳房超音波做為額外檢查的益處是不明確的。本文獻企圖檢視支持與反對對於乳癌風險為一般的女性,在乳房X光攝影之外增加乳房超音波篩檢的證據。衡量篩檢正向與負向的一面是重要的,因為透過篩檢而偵測出較多的腫瘤,不一定表示能拯救更多女性的生命。我們需要評估那些可能被乳房超音波偵測出來的附加癌症,是否導致乳癌死亡率真正地降低,於是能將益處與許多女性因為被錯誤地提醒或診斷而造成的傷害平衡。

我們沒有發現任何處理本文獻問題的試驗。目前有1個隨機對照試驗正在日本進行(稱為J-START)。對於乳房X光攝影片為一般的女性來說,乳房超音波是否能降低死於乳癌的風險還不明確,因此不應該常規地使用。假如篩檢是以乳房超音波進行,它應被視為設計用來測試額外篩檢對死亡率的影響以及對於乳房超音波篩檢為陽性的女性之危害的臨床試驗一部分。

譯註

翻譯者:臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

Background

Description of the condition

Breast cancer is the most common malignant disease diagnosed in women worldwide, comprising 16% of all female cancers (World Health Organization 2011). The risk of developing breast cancer increases with age and certain risk factors such as dense breasts, family history of breast or ovarian cancer, or familial breast cancer gene mutations of BRCA1 (BReast CAncer 1, early onset) and BRCA2 (BReast CAncer 2, susceptibility protein).

Screening with mammography has the ability to detect breast cancer at an early stage. Subsequent effective diagnostic pathways and treatment regimens can reduce the burden of disease of breast cancer, most importantly mortality in women aged 50 to 70 years (USPSTF). A Cochrane review estimated a relative reduction of mortality from breast cancer of 15%, corresponding to an absolute risk reduction of 0.05 per cent in women aged 50 and older (Gøtzsche 2011). In addition to a reduction in mortality, studies evaluating the efficacy of mammographic screening have repeatedly reported a reduction in breast cancer morbidity (Griffin 2010). The sensitivity of mammography ranges between 77% and 95% and the specificity ranges between 94% and 97% (Nelson 2009). The diagnostic accuracy of mammography screening largely depends on the radiographic density of the imaged breasts (Carney 2003). In radiographically dense breasts, non-calcified breast cancers are more likely to be missed than in fatty breasts. As a consequence, some cancers are not detected by mammography screening.

Ultrasonography of the breast is currently not recommended in screening of women at average risk for breast cancer (Elmore 2005; Griffin 2010). Most clinical practice guidelines specify ultrasonography of the breast as a supplementary examination for further clarification of ambiguous findings (Albert 2009). The European Guidelines on Quality Assurance in Breast Cancer Screening and Diagnosis state that ultrasonography should be carried out in the presence of a discrete clinical mass even if negative on mammography (Perry 2008).

Supporters of supplemental ultrasonography to the screening regimen for breast cancer argue that it might be a safe and inexpensive approach to reduce the false negative rates of the screening process. Critics, however, are concerned that performing supplemental ultrasonography on women at average risk will also increase the rate of false positive findings and can lead to unnecessary biopsies and treatments. Authors of a 2009 systematic review of six observational studies in ultrasonography noted the increased biopsy rate in women at intermediate risk, finding a mean positive predictive value of 15% (range 2% to 28%) from four of the six studies, that is, the percentage of positively classified findings for which no carcinoma was subsequently found ranged from 72% to 98% (Nothacker 2009).

Description of the intervention

The intervention entails any form of mammography screening (for example one view, two views, digital, etc) that meets the technical standards of the European Guidelines for Quality Assurance in Breast Cancer Screening and Diagnosis (Perry 2008) with adjunct breast ultrasonography used as a sequential screening test (that is breast ultrasonography that is conducted in women with negative screening mammograms). Breast ultrasonography as a diagnostic test following a positive mammogram is not of interest for this systematic review. We draw this distinction because only ultrasonographies conducted in women with negative mammograms are true screening tests because their goal is to increase the sensitivity of the screening procedure.

To be eligible for this report, ultrasonography needs to be performed with a high-frequency transducer of 7.5 MHz or higher.

How the intervention might work

To increase either sensitivity or specificity, two or more screening tests may be applied in the same individuals. These tests can be used sequentially or simultaneously. Sequential screening tests are applied in a proportion of the population with a specific result of the first screening test. In sequential screening the post-test probability of the first screening test becomes the pre-test probability of the second screening test. The goal of sequential screening is usually to increase sensitivity. By contrast, simultaneous screening applies two (or more) tests to the screened individuals without knowledge of the results of each individual test. Therefore, the pre-test probability remains the same for all tests.

Breast ultrasonography is used routinely as a diagnostic measure to distinguish benign from malignant lesions because it can differentiate between cysts and solid tumours and thus lowers the number of indeterminate mammographical findings. A 2008 study found an increase in diagnostic accuracy when using breast ultrasonography in addition to mammography (accuracy of 0.78 (95% confidence interval (CI) 0.67 to 0.87) for mammography alone compared with 0.91 (95% CI 0.84 to 0.96) when mammography is combined with ultrasonography) (Berg 2008). Thus, breast ultrasonography as an adjunct screening tool to mammography might also be able to detect cancer lesions that mammography screening misses. We consider adjunct breast ultrasonography a sequential screening test because it is administered as an add-on test in women with a negative mammogram. Women with a positive mammogram will also receive breast ultrasonography, but for this population ultrasonography is a diagnostic test.  

In women at increased risk for breast cancer, defined by high breast density or other risk factors, several studies have demonstrated that supplemental screening with ultrasonography can increase the detection rates of cancer, particularly in women with dense breasts (Berg 2008; Nothacker 2009). Mammographically dense breast tissue is an independent risk factor for breast cancer and is associated with a high risk of interval cancers, that is cancers that become clinically apparent between screening tests (Boyd 2007). Ultrasonography, therefore, has the potential to detect mammographically occult cancers at an earlier stage and to improve surrogate outcomes such as tumour size and lymph node status, which have been linked to a poor prognosis of breast cancer (Michaelson 2002; Michaelson 2003).

Why it is important to do this review

In women at increased risk for breast cancer, adjunct ultrasonography can improve the diagnostic yield of breast cancer screening (Berg 2008). Based on these findings, ultrasonography is sometimes used routinely as an adjunct screening tool in women at average risk. It is unclear whether the use of ultrasonography as an adjunct screening tool in women at average risk corresponds to a reduction in mortality and morbidity (the ultimate goal of any screening programme) or to an increase in screening-related harms.

Objectives

To assess the comparative effectiveness and safety of mammography in combination with breast ultrasonography versus mammography for breast cancer screening for women at average risk of breast cancer. Figure 1 depicts the analytic pathway of the research question.

Figure 1.

Analytic pathway of the comparative efficacy and risk of harms of mammography screening with and without supplemental ultrasonography

Methods

Criteria for considering studies for this review

Types of studies

For efficacy we considered RCTs with either individual or cluster randomisation and prospective, controlled non-randomised studies with a low risk of bias and a sample size of at least 500 participants.

In addition to studies eligible for efficacy, we considered any controlled, non-randomised study with a low risk of bias and a study size of at least 500 participants for the assessment of harms.

Studies needed to have a follow-up period of at least one year and had to include at least one relevant outcome.

Types of participants

Women between the age of 40 and 75 years who are at average risk for breast cancer, have not previously had breast cancer, and who participate in a breast cancer screening program or undergo mammography screening.

We define women at average risk as those who have a lifetime risk of less than 15% or who have dense breasts without any additional risk factors for breast cancer.

Types of interventions

Any form of mammography screening (for example one view, two views, digital, etc) that meets the technical standards of the European Guidelines for Quality Assurance in Breast Cancer Screening and Diagnosis (Perry 2008) with additional breast ultrasonography compared with mammography screening without breast ultrasonography.

Types of outcome measures

Primary outcomes
  • Breast cancer mortality

Secondary outcomes
  • All-cause mortality

  • Incremental cancer detection rate

  • Incremental detection rate of invasive cancers

  • Rate of interval cancers

  • Lymph node status

  • Size of detected cancers

  • Health-related quality of life

  • False positive rate

  • False negative rate

  • Rate of biopsies

  • Screening associated harm (psychological distress, adverse effects caused by subsequent diagnostic or therapeutic interventions, others)

Search methods for identification of studies

Electronic searches

We searched the following databases:

  1. The Cochrane Breast Cancer Group (CBCG) searched their Specialised Register. Details of the search strategies used by the Group for the identification of studies and the procedure used to code references are outlined in the Group's module: http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/BREASTCA/frame.html.

  2. MEDLINE (via OvidSP) (from July 2008 to February 2012). See Appendix 1 for the full search strategy.

  3. EMBASE (via Embase.com) (2008 to February 2012). See Appendix 2 for the full search strategy.

  4. The WHO International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/AdvSearch.aspx) for all prospectively registered and ongoing trials to January 2012. See Appendix 3 for the search strategy.

Searching other resources

We manually searched reference lists of pertinent reviews and relevant background articles on this topic to look for any relevant citations that our searches might have missed.

We searched for grey literature (through June 2012) in the following databases:

  1. OpenGrey;

  2. ClinicalTrials.gov;

  3. National Cancer Institute's clinical trial database;

  4. National Institute of Health RePORTER;

  5. Health Services Research Projects in Progress (HSRPROJ);

  6. Hayes Inc. Health Technology Assessment;

  7. The New York Academy of Medicine’s Grey Literature Index; and

  8. Conference Papers Index.

Data collection and analysis

Selection of studies

We developed and pilot-tested literature review forms for abstract and full-text reviews. Two authors (AC, AK, DB, GG, KT, THH, MvN) independently reviewed abstracts. We retrieved full-text copies of all studies that potentially met the inclusion criteria based on the abstract review. Studies marked for possible inclusion by either review author underwent a full-text review. For studies that lacked adequate information to determine inclusion or exclusion, we retrieved the full text and then made the determination. If the necessary information in the full-text articles was unclear or missing, we contacted authors of the publications. Two trained members of the research team (GG, KT) independently reviewed each full-text article for inclusion or exclusion based on the eligibility criteria described above. If both review authors agreed that a study did not meet the eligibility criteria, we excluded it. If the review authors disagreed, they resolved conflicts by discussion and consensus or by consulting a third member of the review team. All results were tracked in an EndNote X5 database.

Data extraction and management

We designed, pilot-tested and used structured data extraction forms to gather pertinent information from relevant articles; this included characteristics of study populations, settings, interventions, comparators, study designs, methods and results.

Assessment of risk of bias in included studies

We planned to assess the risk of bias of included randomised trials using the Cochrane 'Risk of bias' tool as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The tool includes assessment of: sequence generation; allocation sequence concealment; blinding of participants, personnel and outcome assessors; incomplete outcome data; selective outcome reporting and other potential threats to validity. In addition, we planned to assess whether all relevant outcomes for the trial were reported in the published articles. We intended to rate each domain as high risk of bias, low risk of bias or unclear risk of bias.

For non-randomised studies, we planned to use criteria involving selection of cases or cohorts and controls, adjustment for confounders, methods of outcomes assessment, length of follow-up and statistical analysis (Higgins 2011).

Measures of treatment effect

We planned to use extracted data from the original studies to construct 2 x 2 tables. Where multiple studies would have allowed for quantitative analysis, we planned to calculate the risk ratio or odds ratio with 95% confidence intervals for each outcome. In addition, we planned to pool continuous data using the mean difference or standardised mean difference. For time-to-event data, we planned to calculate a pooled hazard ratio where this was available or to dichotomise data at multiple time points into response/no response (e.g. at one week, two weeks, four weeks, etc).

Unit of analysis issues

The unit of our analyses was intended to include women (not cancer lesions).

Dealing with missing data

We intended to use intention-to-treat analysis where data were missing from participants who dropped out of trials before completion. Where data regarding an outcome of interest were not reported, we planned to contact authors of publications to obtain missing results.

Assessment of heterogeneity

We planned to use the Cochran Chi2 test (Q-test) to assess heterogeneity. We intended to use the I2 statistic to estimate the degree of heterogeneity. This measure describes the percentage of total variation across studies that results from heterogeneity rather than chance. We would have interpreted the importance of any heterogeneity in terms of its magnitude and the direction of effects. We would not have used thresholds; instead we would have adopted the overlapping bands suggested in the Cochrane Handbook. For example, we planned to consider an I2 of between 0% and 40% as probably not important, between 30% and 60% as representing moderate heterogeneity, between 50% and 90% as substantial heterogeneity, and between 75% and 100% as considerable heterogeneity (Higgins 2011).

Assessment of reporting biases

We checked trial registries (for example WHO ICTRP and www.clinicaltrials.gov) to detect completed but unpublished trials.

Data synthesis

We planned to analyse data using Review Manager 5.1 (RevMan 5.1). We would have pooled data for meta-analysis where the participant groups were similar and the studies assessed the same treatments with the same comparator and had similar definitions of outcome measures over a similar duration of treatment. We planned to use a fixed-effect model where heterogeneity was low and a random-effects model where the presence of heterogeneity resulted in a higher I2 unless too few studies were included in the analysis. We planned to rate the strength of the evidence based on the system developed by the GRADE Working Group.

Subgroup analysis and investigation of heterogeneity

We planned to perform subgroup analyses based on breast density.

Sensitivity analysis

We had planned to conduct sensitivity analyses excluding small studies, studies with a high risk of bias and studies published in abstract form.

Results

Description of studies

Results of the search

We identified 2731 citations from searches and reviews of reference lists. Overall, we did not find any completed studies that met our eligibility criteria. Figure 2 depicts the numbers of search results and the flow of the literature for this report.

Figure 2.

Study flow diagram.

Included studies

We did not find any controlled studies assessing the incremental benefits and harms of adjunct screening ultrasonography in women at average risk for breast cancer. Our searches in clinical trial registries detected one ongoing RCT in Japan that is potentially relevant. This trial, termed J-START (Japan-Strategic Anti-cancer Randomized Trial), is a large-scale study that will randomly assign 100,000 Japanese women aged 40 to 49 years to either mammography or mammography with adjunct ultrasonography (Ohuchi 2011). The primary endpoints of this trial are sensitivity and specificity; the secondary endpoint is the accumulated incidence rate of advanced cancers during the four-year follow-up period.

Excluded studies

Overall, we excluded 45 studies. The main reasons for exclusion were study populations that did not meet the eligibility criteria (e.g. women with high risk of breast cancer) or study designs that ascertained only the diagnostic yield of adjunct ultrasonography without taking screening-relevant health outcomes into consideration. Reasons for excluding studies after full-text review are summarised under Characteristics of excluded studies.

Risk of bias in included studies

We did not include any studies.

Allocation

We did not include any studies.

Blinding

We did not include any studies.

Incomplete outcome data

We did not include any studies.

Selective reporting

We did not include any studies.

Other potential sources of bias

We did not include any studies.

Effects of interventions

We did not include any studies.

Discussion

Summary of main results

Overall, our review did not detect any controlled studies that provided evidence for (or against) the use of adjunct ultrasonography for screening in women at average risk for breast cancer. The only available evidence regarding adjunct breast ultrasonography in women at average risk is limited to one uncontrolled observational study of women with normal screening mammograms who received sequential ultrasonography screening (Buchberger 2000). This study, conducted in Tyrol, Austria, reported an incremental diagnostic yield of 2.6 cancers per 1000 women without a personal history of breast cancer. Although this study provides some information regarding the performance of adjunct ultrasonography as a sequential screening test, i.e. how well it diagnoses illness, it cannot provide information on the overall usefulness as a screening test, i.e. whether adjunct ultrasonography results in a reduction of morbidity and mortality. Simply diagnosing more cases of illness does not necessarily result in lower mortality or less morbidity. Screening for neuroblastoma in children in Japan in the late 1990s provides a dramatic historical example of how inferences on the usefulness of cancer screening, when based solely on incremental cancer detection rates, can result in a screening programme that causes more harm than benefits (Soderstrom 2005).

Overall completeness and applicability of evidence

Despite extensive searches of the grey literature, we did not find any eligible studies. A separate publication will extrapolate findings of results from women at elevated risk for breast cancer to estimate the false positive rates in women at average risk who were recalled because of positive ultrasonographies (Gartlehner 2013).

Quality of the evidence

We did not include any studies.

Potential biases in the review process

Publication bias is a threat for any systematic review. Although we have conducted extensive searches of grey literature, we cannot be sure that we have detected each study conducted in this field. We have identified one study that has been registered but has not yet been published (Ohuchi 2011).

Agreements and disagreements with other studies or reviews

We did not find any other studies that addressed the research question. A systematic review of adjunct ultrasonography in women at high risk for breast cancer, defined by increased breast density or other risk factors, demonstrated that supplemental screening with ultrasonography can increase the detection rates of cancer at the cost of a high false positive rate (Nothacker 2009).

Authors' conclusions

Implications for practice

The majority of women undergoing breast cancer screening do not have dense breasts and are at average risk. Presently, no methodologically sound evidence is available justifying the routine use of ultrasonography as an adjunct screening tool in such a population. The prevalence (pre-test risk) of breast cancer in a population with radiographic BI-RADS (Breast Imaging Reporting and Data System) breast density grades 1 or 2 is low (1.0/1000 women in an Italian cohort) (Corsetti 2011). Even if only a small proportion of screened women will be recalled because of positive ultrasonography findings, the rate of false positive results and unnecessary harm caused by subsequent investigations may be unacceptably high given the lack of evidence supporting a gain in health benefits. The conclusion that adjunct ultrasonography should not be used in women at average risk for breast cancer is in line with the World Health Organization's recommendation that no screening programme should be implemented without sound evidence of a reduction in morbidity and mortality (Wilson 1968).

Implications for research

The lack of evidence clearly indicates the need for well-conducted, controlled studies. Ideally, a methodologically sound RCT of screening would assess the comparative benefits and risks of mammography only and mammography with adjunct ultrasonography. The outcomes of such a study have to look beyond the incremental diagnostic yield and assess interval cancer rates, morbidity, screening-related harms and mortality, although for mortality to be included this would require a long follow-up period.

Acknowledgements

We would like to acknowledge Evelyn Auer from the Danube University for superb administrative support during this review.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. MEDLINE (via OVID) search strategy February 2012

# ▲Searches
1exp Breast Neoplasms/
2breast cancer.mp.
31 or 2
4exp Diagnosis/
5diagnosis.ab,ti,tw.
6screening.ab,ti,tw.
7exp Mass Screening/
8mass screening.ab,ti,tw.
9exp "Early Detection of Cancer"/
104 or 5 or 6 or 7 or 8 or 9
113 and 10
12exp Mammography/
13mammograph*.ab,ti,tw.
14mammogram.ab,ti,tw.
1512 or 13 or 14
16exp Ultrasonography/
17exp Ultrasonography, Mammary/
18breast ultrasonography.mp.
19mammary ultrasonography.mp.
2016 or 17 or 18 or 19
21mammary.ab,ti,tw.
22breast.ab,ti,tw.
2321 or 22
2420 and 23
2511 and 15 and 24
26limit 25 to humans
27limit 26 to (clinical trial, all or clinical trial, phase i or clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or clinical trial or comparative study or controlled clinical trial or evaluation studies or meta analysis or multicenter study or randomized controlled trial or "review" or validation studies)
28("Single Blind Method" or "Double Blind Method" or "Case Control Study" or "Cohort Study" or "Epidemiologic Study" or "Cross Sectional Study" or "Cross Over Study" or "Follow Up Study" or "Longitudinal Study" or "Prospective Study" or "observational study").mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]
2926 and 28
3027 or 29

Appendix 2. EMBASE (via Embase.com) search strategy

#25

#24 AND [humans]/lim AND [embase]/lim AND [2008-2012]/py

#24

#8 AND #12 AND #23

#23

#21 AND #22

#22

'breast cancer screening'

#21

#18 OR #20

#20

#18 AND #19

#19

#15 OR #16 OR #17

#18

#13 OR #14

#17

'breast'/de OR breast AND ultrasonograph*

#16

'breast ultrasonography'/exp OR 'breast ultrasonography'

#15

'ultrasonography'/exp OR ultrasonography

#14

mammograph*

#13

'mammography'/exp OR mammography

#12

#9 OR #10 OR #11

#11

'breast cancer risks'

#10

'breast cancer risk'

#9

'breast neoplasm'

#8

#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7

#7

groups:ab

#6

trial:ab

#5

randomly:ab

#4

placebo:ab

#3

randomi*ed:ab

#2

controlled AND clinical AND trial

#1

randomised AND controlled AND trial

Appendix 3. WHO ICTRP search strategy

Advanced search:

1. Title: mammography in combination with breast ultrasonography versus mammography for breast cancer screening

Recruitment Status: ALL

2. Condition: breast AND (cancer% OR carcinoma% OR neoplas% OR tumour% OR tumor%)

Intervention: (breast mammograph% OR breast ultrasonograph%) AND breast screening

Recruitment Status: ALL

Contributions of authors

  1. Draft the protocol: GG, KT

  2. Study selection: GG, KT, AC, AK, TH, DB, MvN

  3. Extract data from studies: GG, KT, AC, AK

  4. Enter data into RevMan: AC, MvN

  5. Carry out the analysis: GG, KT

  6. Interpret the analysis: GG, KT, TH

  7. Draft the final review: GG, KT

  8. Disagreement resolution: TH

  9. Update the review: GG, KT

Declarations of interest

None known.

Sources of support

Internal sources

  • No sources of support, Not specified.

External sources

  • Ministry of Health, Austria.

    A larger underlying report will be funded by the Austrian Ministry of Health

Differences between protocol and review

None.

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Benson 2004Ineligible population (women with breast cancer)
Berg 2008Ineligible population (women with elevated risk)
Brancato 2007Ineligible study design (retrospective cohort study)
Buchberger 1999Ineligible study design, ineligible outcome (uncontrolled prospective cohort study assessing diagnostic yield)
Buchberger 2000Ineligible study design, ineligible outcome (uncontrolled prospective cohort study assessing diagnostic yield)
Chan 2008Ineligible population (women with breast cancer)
Cho 2010Ineligible population (women with breast cancer)
Corsetti 2006Ineligible study design (retrospective cohort study)
Corsetti 2008Ineligible study design (retrospective cohort study)
Corsetti 2011Ineligible study design (retrospective cohort study)
Crystal 2003Ineligible population (high-risk women)
De Felice 2007Ineligible study design (uncontrolled prospective cohort study)
Dilhuydy 2008Ineligible study design (retrospective analysis of data of the Women's Health Initiative)
Duijm 1997Ineligible population (symptomatic patients)
Flobbe 2003Ineligible population (symptomatic patients)
Grady 2011Ineligible population (high-risk women)
Hellquist 2011No sonography screening
Honjo 2007Ineligible study design (uncontrolled cohort study)
Hou 2002Ineligible population (high-risk women)
Kaplan 2001Ineligible study design (retrospective cohort study)
Kelly 2010aIneligible study design (uncontrolled cohort study)
Kelly 2010bIneligible study design (uncontrolled cohort study)
Kolb 1998Ineligible study design (uncontrolled retrospective cohort study)
Kolb 2002Ineligible study design (uncontrolled cohort study)
Leconte 2003Ineligible population (symptomatic patients)
Madjar 1994Ineligible study design (uncontrolled prospective cohort study)
Madjar 2010Ineligible study design (uncontrolled retrospective cohort study)
Maestro 1998Ineligible study design (uncontrolled prospective cohort study)
Marini 2003Ineligible population (women with microcalcifications)
McCavert 2009Ineligible population (symptomatic patients)
Meden 1995Ineligible population (symptomatic patients)
Moon 2000Ineligible population (women with microcalcifications)
Moss 1999Ineligible population (symptomatic patients)
Najafi 2010Published as abstract only
Ohlinger 2006Ineligible outcome (diagnostic yield)
Rahbar 1999Ineligible population (symptomatic patients)
Richter 1997Ineligible population (symptomatic patients)
Richter 1998Ineligible population (symptomatic patients)
Tohno 2009Ineligible study design (uncontrolled retrospective cohort study)
Uchida 2008Ineligible study design, ineligible outcome (uncontrolled, retrospective cohort study comparing the diagnostic yield of mammography, ultrasonography and physical examination)
Vercauteren 2008Ineligible population (symptomatic patients)
Weining 2005Ineligible population (symptomatic patients)
Youk 2011Ineligible population (symptomatic patients)
Zanello 2011Ineligible population (symptomatic patients)
Zonderland 1999Ineligible population (symptomatic patients)

Characteristics of ongoing studies [ordered by study ID]

Ohuchi 2011

  1. a

    RCT: randomised controlled trial

Trial name or titleRandomized controlled trial on effectiveness of ultrasonography screening for breast cancer in women aged 40-49 (J-START)
MethodsRCT
ParticipantsWomen ages 40 to 49 years
InterventionsMammography versus mammography plus ultrasonography
OutcomesSensitivity, specificity, false positive rates
Starting date2011
Contact informationYoko Narikawa at narikawayoko@gmail.com
NotesTrial information: http://apps.who.int/trialsearch/Trial.aspx?TrialID=JPRN-UMIN000000757

Ancillary