Partial breast irradiation for early breast cancer

  • Review
  • Intervention

Authors


Abstract

Background

Breast conserving therapy for women with breast cancer consists of local excision of the tumour (achieving clear margins) followed by radiation therapy (RT). RT is given to sterilize tumour cells that may remain after surgery to decrease the risk of local tumour recurrence. Most true recurrences occur in the same quadrant as the original tumour. Whole breast RT may not protect against the development of a new primary cancer developing in other quadrants of the breast. In this Cochrane Review, we investigated the role of delivering radiation to a limited volume of the breast around the tumour bed (partial breast irradiation: PBI) sometimes with a shortened treatment duration (accelerated partial breast irradiation: APBI).

Objectives

To determine whether PBI/APBI is equivalent to or better than conventional or hypofractionated WBRT after breast conservation therapy for early-stage breast cancer.

Search methods

We searched the Cochrane Breast Cancer Group Specialised Register (07 November 2013), CENTRAL (2014, Issue 3), MEDLINE (January 1966 to 11 April 2014), EMBASE (1980 to 11 April 2014), CINAHL (11 April 2014) and Current Contents (11 April 2014). Also we searched the International Standard Randomised Controlled Trial Number Register, the World Health Organization's International Clinical Trials Registry Platform (07 November 2013) and US clinical trials registry (www.clinicaltrials.gov) (22 April 2014). We searched for grey literature: Open Grey (23 April 2014), reference lists of articles, a number of conference proceedings and published abstracts, and did not apply any language restrictions.

Selection criteria

Randomised controlled trials (RCTs) without confounding and evaluating conservative surgery plus PBI/APBI versus conservative surgery plus whole breast RT. We included both published and unpublished trials.

Data collection and analysis

Three review authors (ML, DF and BH) performed data extraction and resolved any disagreements through discussion. We entered data into Review Manager for analysis. BH and ML assessed trials, graded the methodological quality using Cochrane's Risk of Bias tool and resolved any disagreements through discussion.

Main results

We included four RCTs that had 2253 women. Two older trials examined RT techniques which do not reflect current practice and one trial had a short follow-up. We downgraded the quality of the evidence for our key outcomes due to risk of bias. Taken together with other GRADE recommendations, the quality of evidence for our outcomes was very low to low. For the comparison of partial breast irradiation/accelerated breast irradiation (PBI/APBI) with whole breast irradiation (WBRT), local recurrence-free survival appeared worse (Hazard Ratio (HR) 1.74, 95% confidence interval (CI) 1.23 to 2.45; three trials, 1140 participants, very low quality evidence). Cosmesis appeared improved with PBI/APBI in a single trial (OR 0.40, 95% CI 0.23 to 0.72; one trial, 241 participants, very low quality evidence), but late toxicity (telangiectasia OR 4.41, 95% CI 3.21 to 6.05; very low quality evidence, 708 participants) and subcutaneous fibrosis (OR 4.27, 95% CI 3.04 to 6.01; one trial, 710 participants, very low quality evidence) appeared increased in another trial. We found no clear evidence of a difference for the comparison of PBI/APBI versus WBRT for the outcomes of: overall survival (HR 0.99, 95% CI 0.83 to 1.18; three trials, 1140 participants, very low quality evidence), cause-specific survival (HR 0.95, 95% CI 0.74 to 1.22; two trials, 966 participants, low evidence quality), distant metastasis-free survival (HR 1.02, 95% CI 0.81 to 1.28; 1140 participants, low quality evidence), subsequent mastectomy rate (OR 0.20, 95% CI 0.01 to 4.21; 258 participants, low quality evidence) and relapse-free survival (HR 0.99, 95% CI 0.53 to 1.85; 258 participants, low quality evidence). We found no data for the outcomes of acute toxicity, new ipsilateral breast primaries, costs, quality of life or consumer preference.

Authors' conclusions

The limitations of the data currently available mean that we cannot make definitive conclusions about the efficacy and safety or ways to deliver of PBI/APBI. We await completion of ongoing trials.

Résumé scientifique

Irradiation partielle du sein pour un cancer du sein au stade précoce

Contexte

Le traitement conservateur du sein chez les femmes atteintes d'un cancer du sein est constitué de l'exérèse locale de la tumeur (avec des marges saines) suivie d'une radiothérapie (RT). La RT est administrée afin de stériliser les cellules tumorales éventuellement restantes après la chirurgie pour réduire le risque de récidive locale de la tumeur. La plupart des cas de récidives véritables se produisent dans le même quadrant que la tumeur primitive. La RT de l'ensemble du sein peut ne pas protéger contre le développement d'un nouveau cancer primaire dans d'autres quadrants du sein. Dans cette revue systématique Cochrane, nous avons examiné le rôle de l'administration de rayonnements à un volume limité du sein autour du lit de la tumeur (irradiation partielle du sein : IPS), parfois avec une durée de traitement raccourcie (irradiation partielle du sein accélérée : IPSA).

Objectifs

Déterminer si l'IPS/l'IPSA est équivalente voire plus efficace que la RTSE conventionnelle ou hypofractionnée après un traitement conservateur du sein pour le cancer du sein au stade précoce.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre spécialisé du groupe Cochrane sur le cancer du sein (7 novembre 2013), CENTRAL (2014, numéro 3), MEDLINE (de janvier 1966 au 11 avril 2014), EMBASE (de 1980 au 11 avril 2014), CINAHL (11 avril 2014) et Current Contents (11 avril 2014). Nous avons également effectué des recherches dans le registre ISRCTN (International Standard Randomised Controlled Trial Number Register), le système d'enregistrement international des essais cliniques (ICTRP) de l'Organisation mondiale de la Santé (7 novembre 2013) et le registre des essais cliniques américain (www.clinicaltrials.gov) (22 avril 2014). Nous avons effectué des recherches dans la littérature grise : Open Grey (23 avril 2014), les références bibliographiques des articles, un certain nombre d'actes de conférence et de résumés publiés, sans aucune restriction de langue.

Critères de sélection

Essais contrôlés randomisés (ECR) sans variables parasites évaluant la chirurgie conservatrice plus IPS/IPSA versus la chirurgie conservatrice plus RT du sein entier. Nous avons inclus les essais publiés et non publiés.

Recueil et analyse des données

Trois auteurs de la revue (ML, DF et BH) ont effectué l'extraction des données et résolu les désaccords par la discussion. Nous avons saisi les données dans Review Manager pour l'analyse. BH et ML ont évalué les essais, ainsi que leur qualité méthodologique à l'aide de l'outil Cochrane d'évaluation du risque de biais, et résolu les désaccords par la discussion.

Résultats principaux

Nous avons inclus quatre ECR qui incluaient 2 253 femmes. Deux essais plus anciens examinaient des techniques de RT qui ne reflètent pas la pratique actuelle, et un essai avait un suivi de courte durée. Nous avons abaissé la qualité des données pour nos principaux critères de jugement en raison du risque de biais. En appliquant d'autres recommandations GRADE, la qualité des données pour nos critères de jugement était très faible à faible. Pour la comparaison de l'irradiation partielle du sein / l'irradiation partielle du sein accélérée (IPS/IPSA) avec la radiothérapie du sein entier (RTSE), la survie sans récidive locale semblait moins bonne (rapport des risques instantanés (hazard ratio ou HR) 1,74, intervalle de confiance (IC) à 95 % 1,23 à 2,45 ; trois essais, 1 140 participants, preuves de très faible qualité). L'aspect esthétique semblait meilleure avec l'IPS/l'IPSA dans un essai unique (RC 0,40, IC à 95 % 0,23 à 0,72 ; un essai, 241 participants, preuves de très faible qualité), mais la toxicité tardive (télangiectasie : RC 4,41, IC à 95 % 3,21 à 6,05 ; preuves de très faible qualité, 708 participants, et fibrose sous-cutanée : RC 4,27, IC à 95 % 3,04 à 6,01 ; un essai, 710 participants, preuves de très faible qualité) semblait augmentée dans un autre essai. Nous n'avons trouvé aucune preuve probante d'une différence dans la comparaison de l'IPS/l'IPSA versus RTSE pour les critères de jugement suivants : survie globale (HR 0,99, IC à 95 % 0,83 à 1,18 ; trois essais, 1 140 participants, preuves de très faible qualité), survie spécifique à la maladie (HR 0,95, IC à 95 % 0,74 à 1,22 ; deux essais, 966 participants, preuves de faible qualité), survie sans métastases distantes (HR 1,02, IC à 95 % 0,81 à 1,28 ; 1 140 participants, preuves de faible qualité), taux de mastectomie subséquente (RC 0,20, IC à 95 % 0,01 à 4,21 ; 258 participants, preuves de faible qualité) et survie sans récidive (HR 0,99, IC à 95 % 0,53 à 1,85 ; 258 participants, preuves de faible qualité). Nous n'avons pas trouvé de données pour les critères de jugement de la toxicité aiguë, les nouvelles tumeurs primaires du sein ipsilatéral, les coûts, la qualité de vie ou la préférence des usagers.

Conclusions des auteurs

En raison des limitations des données actuellement disponibles, nous ne pouvons pas tirer de conclusions définitives concernant l'efficacité et l'innocuité de l'IPS/l'IPSA ou ses moyens d'administration. Nous attendons l'achèvement des essais en cours.

摘要

早期乳癌的局部性乳房放射治療

背景

乳癌女性患者的乳房保留治療 (breast conserving therapy),包括局部切除腫瘤 (達組織邊緣乾淨 [clear margin] 的程度) 和後續的放射線治療 (radiation therapy, RT)。RT的目的是消滅外科手術後可能殘留體內的腫瘤細胞,以降低局部腫瘤復發的風險。大部分的真正復發 (true recurrence) 會出現在與原腫瘤相同的象限。全乳房RT無法預防乳房的其他象限出現新的原位癌。此次考科藍文獻回顧探討針對腫瘤床周圍的部分乳房組織,進行放射線治療的作用 (局部性乳房放射治療 [partial breast irradiation, PBI]),有時會採用治療時間較短的方式 (加速局部性乳房放射治療 [accelerated partial breast irradiation, APBI])。

目的

判斷在早期乳癌的乳房保留治療後,PBI/APBI的療效等同或優於傳統或低分次全乳房放射線治療 (hypofractionated WBRT)。

搜尋策略

我們搜尋考科藍乳癌群組專業註冊 (Cochrane Breast Cancer Group Specialised Register) (2013年11月7日)、CENTRAL (2014年第3次發行)、MEDLINE (1966年1月至2014年4月11日)、EMBASE (1980年至2014年4月11日)、 CINAHL (2014年4月11日) 和 Current Contents (2014年4月11日)。我們不但搜尋國際標準隨機對照試驗編號登錄 (International Standard Randomised Controlled Trial Number Register)、世界衛生組織國際臨床試驗註冊平台 (World Health Organization's International Clinical Trials Registry Platform) (2013年11月7日),和美國臨床試驗註冊 (US clinical trials registry) (www.clinicaltrials.gov) (2014年4月22日),也搜尋灰色文獻:Open Grey (2014年4月23日)、論文的參考文獻清單、一些研討會會議記錄和已發表的摘要,但並未進行任何語言限制。

選擇標準

本次文獻回顧收錄無混淆的隨機對照試驗 (randomized controlled trial, RCT),評估保留手術加PBI/APBI和保留手術加全乳房RT的療效。我們收錄已發表和未發表的試驗。

資料收集與分析

由3位文獻回顧作者 (ML、DF和BH) 進行資料萃取,並透過討論解決任何歧見。我們將資料輸入Review Manger進行分析。由BH和ML負責評估試驗、利用考科藍偏差風險工具區分方法學品質的等級,並透過討論解決任何歧見。

主要結果

本次文獻回顧收錄4篇RCT,涵蓋2253名女性。有2篇檢驗RT技術的舊試驗,並未反映目前的實務狀況,有1篇試驗追蹤期很短。基於偏差風險,我們將本次文獻回顧所得重要結果的證據品質等級向下調降。將其他GRADE建議併入考慮後,我們所得結果的證據品質範圍介於極低和偏低之間。比較局部性乳房放射治療 (PBI)/加速乳房放射治療 (APBI) 和全乳房放射治療 (WBRT),結果發現局部無復發存活期 (local recurrence-free survival) 較差 (風險比 [HR] 為1.74,95%信賴區間 [CI] 為1.23至2.45;3篇試驗,1140名受試者,證據品質極低)。只有1篇試驗顯示PBI/APBI可改善患者的外觀 (OR為0.40,95% CI為0.23至0.72;1篇試驗,241名受試者,證據品質極低),但另1篇試驗則指出晚期毒性 (微血管擴張症候群 [telangiectasia] OR為4.41,95% CI為3.21至6.05;證據品質極低,708名受試者) 和皮下組織纖維化 (subcutaneous fibrosis) (OR為4.27,95% CI為3.04至6.01;1篇試驗,710名受試者,證據品質極低) 會增加。比較PBI/APBI和WBRT並未發現此2種治療對下列結果具有明顯差異:整體存活期 (HR為0.99,95% CI為0.83至1.18;3篇試驗,1140名受試者,證據品質極低)、特定原因存活期 (cause-specific survival) (HR為0.95,95% CI為0.74至1.22;2篇試驗,966名受試者,證據品質低)、無遠處轉移存活期 (distant metastasis-free survival) (HR為1.02,95% CI為0.81至1.28;1140名受試者,證據品質低)、後續乳房切除術 (mastectomy) 發生率 (OR為0.20,95% CI為0.01至4.21;258名受試者,證據品質低),以及無復發存活期 (relapse-free survival) (HR為0.99,95% CI為0.53至1.85;258名受試者,證據品質低)。我們並未發現急性毒性、同側乳房發生新原位癌、費用、生活品質或患者偏好等結果的資料。

作者結論

目前可取得的資料有限,表示我們無法針對PBI/APBI的療效和安全性或遞送方式提出明確結論。我們正靜待進行中的試驗結束。

譯註


翻譯者:臺北醫學大學實證醫學研究中心
本翻譯計畫由衛生福利部補助經費,臺北醫學大學實證醫學研究中心、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行。

Plain language summary

Partial breast irradiation for early breast cancer

For women with early breast cancer, removal of the tumour followed by radiation therapy (RT) allows the breast to be kept (breast conserving therapy). A tumour occurring again within the breast can be either a true recurrence (arising in the same area of the breast as the original cancer) or a new primary cancer (another breast cancer arising in another part of the breast). RT reduces the risk of a true recurrence but does not prevent the development of a new primary cancer.

RT usually involves treating the whole breast (WBRT) in four to six weeks of daily treatments. This can be costly and inconvenient for women and their families. This can mean women choose mastectomy (removal of the breast) to avoid RT. RT delivered only to the area of the breast from which the tumour was removed (partial breast irradiation: PBI) offers the potential for preservation of the breast if the tumour then occurs in a previously untreated part of the breast. If RT is also delivered over a shorter period of time (accelerated partial breast irradiation: APBI) than WBRT, fewer visits to the RT department are required, reducing inconvenience for the woman who is treated.

In this Cochrane Review, we investigated the role of PBI and APBI against WBRT.

We included four completed trials: one had a short follow-up so the information is not mature enough yet, two trials involved RT techniques that do not meet today's standards, and the other trial stopped early. The evidence is current to April 2014. We found local relapse-free survival appeared worse with PBI/APBI than WBRT. When PBI/APBI was compared with WBRT the rates of overall survival were similar, but we could not exclude potentially important differences between treatment groups. This was also the case for the effects of PBI/APBI on cause-specific survival, distant metastasis-free survival, subsequent mastectomy rate and relapse-free survival when PBI/APBI was compared with WBRT. We found no data for: acute toxicity, costs, quality of life or consumer preference. Breast appearance was better with PBI/APBI in a single trial but late adverse events were increased in another trial.

The quality of the evidence (low to very low) means we cannot make any recommendations about the benefit of or best way to deliver PBI/APBI. We would only advise the use of PBI/APBI in a trial. We found seven ongoing trials which do reflect modern RT practice and await their completion; it may be possible to answer these questions in a future update of this review.

Résumé simplifié

Irradiation partielle du sein pour un cancer du sein au stade précoce

Pour les femmes atteintes d'un cancer du sein au stade précoce, l'ablation de la tumeur suivie de radiothérapie (RT) permet de garder le sein (traitement conservateur du sein). Une tumeur qui apparaît à nouveau dans le sein peut être soit une véritable récidive (survenant dans la même partie du sein que le cancer primaire) ou un nouveau cancer primaire (un autre cancer du sein survenant dans une autre partie du sein). La RT réduit le risque de récidive véritable, mais ne permet pas de prévenir le développement d'un nouveau cancer primaire.

La RT implique généralement le traitement du sein entier (RTSE) pendant quatre à six semaines de traitements quotidiens. Cela peut être onéreux et peu pratique pour les patientes et leurs familles, et peu conduire des femmes à choisir la mastectomie (ablation du sein) pour éviter la RT. La RT administrée seulement à la zone du sein dont la tumeur a été retirée (irradiation partielle du sein : IPS) offre le potentiel pour la préservation du sein si une tumeur survient ensuite dans une partie du sein non traitée préalablement. Si la RT est également administrée sur une plus courte période de temps (irradiation partielle du sein accélérée : IPSA) que la RTSE, moins de visites au service de RT sont nécessaires, ce qui réduit le désagrément pour la patiente.

Dans cette revue systématique Cochrane, nous avons examiné le rôle de l'IPS et de l'IPSA par rapport à la RTSE.

Nous avons inclus quatre essais achevés : un d'entre eux avait un suivi de courte durée, de sorte que les informations ne sont pas encore suffisamment matures, deux essais portaient sur des techniques de RT qui ne remplissent pas les critères actuels, et le dernier essai a été arrêté prématurément. Les preuves sont à jour en avril 2014. Nous avons découvert que la survie sans récidive locale semblait moins bonne avec l'IPS/l'IPSA qu'avec la RTSE. Lorsque l'IPS/l'IPSA était comparée à la RTSE, les taux de survie globale étaient similaires, mais nous n'avons pas pu exclure des différences potentiellement importantes entre les groupes de traitement. Ceci était également le cas pour les effets de l'IPS/l'IPSA sur la survie spécifique à la maladie, la survie sans métastases distantes, le taux de mastectomie subséquente et la survie sans récidive, lorsque l'IPS/l'IPSA était comparée à la RTSE. Nous n'avons pas trouvé de données pour la toxicité aiguë, les coûts, la qualité de vie ou la préférence des usagers. L'apparence du sein était meilleure avec l'IPS/l'IPSA dans un essai unique, mais les événements indésirables tardifs étaient augmentés dans un autre essai.

En raison de la qualité des preuves (faible à très faible), nous ne pouvons pas émettre de recommandations concernant le bénéfice de l'IPS/l'IPSA ou la meilleure manière de l'administrer. Nous recommandons l'utilisation de l'IPS/l'IPSA seulement dans le contexte d'essais. Nous avons trouvé sept essais en cours qui reflètent effectivement les pratiques modernes en matière de RT et qui sont en attente d'achèvement ; ainsi, il pourrait être possible de répondre à ces questions dans une prochaine mise à jour de cette revue.

Notes de traduction

Traduit par: French Cochrane Centre 27th August, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

淺顯易懂的口語結論

早期乳癌的局部性乳房放射治療

對於罹患早期乳癌的女性而言,先摘除腫瘤再進行放射線治療 (radiation therapy, RT) 可保留乳房 (乳房保留治療)。罹癌的乳房內再度出現腫瘤可能是真正復發 (發生於乳房原腫瘤的相同部位),也可能是新的原位癌 (另一個乳房腫瘤,發生於乳房的其他部位)。RT可降低真正復發的風險,但無法預防新原位癌的發生。

RT通常針對整個乳房進行治療 (WBRT),患者必須每日接受治療持續4至6週。此種治療相當昂貴,而且對患者和家屬都會造成不便。因此女性患者可能為了避免接受RT,而選擇接受乳房切除術 (切除乳房)。若採取僅針對摘除腫瘤的乳房部位進行RT (局部性乳房放射治療,PBI),則當腫瘤出現在先前未接受治療的乳房部位時,或許可以保留乳房。若RT的進行時間短於WBRT (加速局部性乳房放射治療,APBI),患者到放射線治療科回診的次數就不需要那麼頻繁,可以減少接受治療女性患者的不便。

此次考科藍文獻回顧乃相對於WBRT,探討PBI和APBI的療效。

我們納入4篇已完成的試驗:其中有1篇試驗的追蹤期很短,因此所得資訊不夠周延;有2篇探究RT技術的試驗,並未符合目前的標準;而另1篇試驗則提前結束。最新資料可追溯至2014年4月。我們發現PBI/APBI對局部無復發存活期的療效劣於WBRT。雖然PBI/APBI和WBRT的整體存活率相似,但無法排除治療組之間可能具有重要差異。比較PBI/APBI和WBRT後發現,PBI/APBI對特定原因存活期、無遠處轉移存活期、後續乳房切除術發生率,和無復發存活期的療效亦出現相同狀況。我們並未發現下列資訊:急性毒性、費用、生活品質或患者偏好。有1篇試驗指出PBI/APBI較不會影響乳房外觀,但另1篇試驗則指出PBI/APBI的晚期不良事件會增加。

基於證據品質 (偏低極低),我們無法就PBI/APBI的效益或最佳治療方式,提出任何建議,僅建議在某項試驗中使用PBI/APBI。我們發現有7項進行中的試驗,確實可反映現代的RT實務,並靜待這些試驗完成;未來在更新此篇文獻回顧時,或許可以解決這些問題。

譯註


翻譯者:臺北醫學大學實證醫學研究中心
本翻譯計畫由衛生福利部補助經費,臺北醫學大學實證醫學研究中心、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行。

Laički sažetak

Parcijalno zračenje dojke kod ranog raka dojke

Za žene s ranim rakom dojke, uklanjanje tumora nakon kojeg slijedi radioterapija (RT) omogućuje očuvanje dojke (poštedno liječenje dojke). Tumor koji se ponovno javlja u dojci može biti ili pravi recidiv (nastao u istom području dojke kao izvorni rak) ili novi primarni rak (drugi rak dojke koji nastane u drugom dijelu dojke). RT smanjuje rizik od pravog recidiva, ali ne sprječava razvoj novog primarnog raka.

RT obično uključuje zračenje cijele dojke tijekom 4 do 6 tjedana dnevnih primjena. To može biti skupo i nezgodno za žene i njihove obitelji. To može značiti da će žene odabrati mastektomiju (uklanjanje dojke) kako bi se izbjegla RT. RT primjenjena samo na područje dojke iz kojeg je uklonjen tumor dojke (parcijalno zračenje dojke; PZD) pruža mogućnost očuvanja dojke ako se tumor javio u prethodno neliječenom dijelu dojke. Ako se RT primjeni i u kraćem vremenskom razdoblju (akcelerirano parcijalno zračenje dojke; APZD) nego RT cijele dojke, potrebno je manje posjeta odjelu RT-a, čime se smanjuje nelagoda za ženu koja se liječi.

U ovom Cochrane sustavnom pregledu, istražena je uloga parcijalnog zračenja dojke i akceleriranog parcijalnog zračenja dojke nasuprot RT cijele dojke.

Uključena su 4 završena istraživanja: jedno je imalo kratko praćenje te podaci još nisu dovoljno zreli, dva su istraživanja uključivala RT tehnike koje ne zadovoljavaju današnje standarde, a drugo je istraživanje prerano prekinuto. Uključene su studije objavljene do travnja 2014. godine. Pronađeno je da se preživljenje bez lokalnog relapsa činilo lošije s PZD/APZD nego s RT cijele dojke. Kad je PZD/APZD uspoređeno s RT cijele dojke stope ukupnog preživljenja su bile slične, ali nismo mogli isključiti potencijalno važne razlike između liječenih skupina. To je također bio slučaj za učinke PZD/APZD na preživljenje od specifičnog uzroka, preživljenje bez udaljenih metastaza, stopu naknadne mastektomije i preživljenje bez recidiva kada je PZD/APZD uspoređeno s RT cijele dojke. Autori nisu pronašli podatke za: akutnu toksičnost, troškove, kvalitetu života i preferencije bolesnica. Izgled dojki je bio bolji sa PZD/APZD u jednom istraživanju, ali su kasni štetni događaji bili povećani u drugom istraživanju.

Kvaliteta dokaza (niska do vrlo niska) znači da ne možemo dati nikakve preporuke o koristi ili najboljem načinu primjene parcijalnog zračenja dojke/akceleriranog parcijalnog zračenja dojke. Savjetuje se samo primjena parcijalnog zračenja dojke/akceleriranog parcijalnog zračenja dojke u sklopu istraživanja. Pronađeno je 7 istraživanja koja su u tijeku, koja odražavaju suvremenu RT praksu, i čeka se njihov završetak; možda bude moguće odgovoriti na postavljena istraživačka pitanja u budućem ažuriranju ovog pregleda.

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

Summary of findings(Explanation)

Summary of findings for the main comparison. Partial breast irradiation or accelerated partial breast irradiation for early breast cancer
  1. 1 Mammography was performed at pre-specified intervals in Dodwell 2005 and Polgár 2007.
    2 Over 50% of domains were at high risk of bias (blinding of outcome reporting- both subjective and objective, incomplete outcome reporting and selective reporting).
    3 The applicability of the findings is uncertain because in two of the three trials RT and surgical techniques used do not reflect current practice and would be considered inadequate today.
    4 Downgraded because with few events the data is imprecise.
    5 Harvard cosmetic four point scoring system used: cosmetic outcome scored as poor, fair, good or excellent.
    6 The women unsuitable for interstitial brachytherapy were treated with conventional fractionation. Current PBI practice would mean the use of hypofractionated (> 2 Gy pre fraction RT) and interstitial brachytherapy is variably used depending on local practice and operator skills.
    7 The CIs include both a clinically significant benefit or harm.
    8 One trial used RT and surgical techniques which do not reflect current practice and would not be considered adequate today.
    9 For control risk for distant metastasis-free survival, we chose the trials with the highest risk and the lowest risk.

Partial breast irradiation or accelerated partial breast irradiation for early breast cancer
Patient or population: patients with early breast cancer
Settings: district hospitals or cancer centres
Intervention: partial breast irradiation or accelerated partial breast irradiation
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Partial breast irradiation/accelerated partial breast irradiation
Local recurrence-free survival
Determined using mammography and clinical examination1
Follow-up: median 66 to 122.4 months
Study population HR 1.74
(1.23 to 2.45)
1140
(3 trials)
⊕⊝⊝⊝
very low 2,3,4
The local relapse rate in a modern PBI series with low risk patients in 11.9 per 1000 (Vicini 2011)
106 per 1000 177 per 1000
(129 to 240)
Moderate
45 per 1000 77 per 1000
(55 to 107)
High
144 per 1000 237 per 1000
(174 to 317)
Cosmesis
Global cosmetic score5
Follow-up: median 122.4 months
371 per 1000 191 per 1000
(119 to 298)
OR 0.4
(0.23 to 0.72)
241
(1 trial)
⊕⊝⊝⊝
very low 4,6
-
Overall survival
Follow-up: median 66 to 122.4 months
Study population HR 0.99
(0.83 to 1.18)
1140
(3 trials)
⊕⊝⊝⊝
very low 2,3,7
-
317 per 1000 314 per 1000
(271 to 362)
Moderate
240 per 1000 238 per 1000
(204 to 277)
High
380 per 1000 377 per 1000
(328 to 431)
Late toxicity - Subcutaneous breast fibrosis
Unvalidated three point scale
Follow-up: median 122.4 months
180 per 1000 484 per 1000
(401 to 569)
OR 4.27
(3.04 to 6.01)
710
(1 trial)
⊕⊝⊝⊝
very low 4,6
This is a late toxicity endpoint of relevance to patients.
Subsequent mastectomy
Follow-up: median 122.4 months
Study population OR 0.20
(0.01 to 4.21)
258
(1 trial)
⊕⊝⊝⊝
very low 4,6
-
15 per 1000 3 per 1000
(0 to 62)
Moderate
"-" 
Cause-specific survival
Follow-up: median 8.4 to 10 years
Study population HR 0.95
(0.74 to 1.22)
966
(2 trials)
⊕⊕⊝⊝
low 2,6,8
-
252 per 1000 241 per 1000
(193 to 298)
Low
7 per 1000 7 per 1000
(5 to 9)
Distant metastasis-free survival
Follow-up: median 66 to 122.4 months
Study population9 HR 1.02
(0.81 to 1.28)
1140
(3 trials)
⊕⊕⊝⊝
low 2,3,6
-
261 per 1000 265 per 1000
(217 to 321)
Low9
100 per 1000 102 per 1000
(82 to 126)
High9
310 per 1000 315 per 1000
(260 to 378)
*The basis for the assumed risk (e.g. the median control group risk across trials) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio; HR: Hazard ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Breast cancer is the most common cancer occurring in women. One in eight women living in the United States and the United Kingdom has a lifetime risk of being diagnosed with breast cancer; while one in nine women living in Australia are at risk (AIHW 2012; Howlader 2009; ONS 2010). Breast cancer is the second most common cause of cancer death in women.

Historically, mastectomy was the recommended therapeutic option for all stages of breast cancer. However, large randomised controlled trials (RCTs) have demonstrated equivalent survival for women with early-stage disease (Stages I, II) whether they are treated with breast conserving therapy or mastectomy (EBCTCG 1995; Fisher 1995; Fisher 2002; Jacobson 1995; Poggi 2003; van Dongen 2000; Veronesi 1995; Veronesi 2002). Consequently, breast conservation has become the preferred management option for these patients.

Breast conserving therapy consists of local excision of the tumour (achieving clear margins) followed by radiation therapy (RT). RT is given to sterilize tumour cells that may remain after surgery. This practice is supported by data from detailed pathological examination of mastectomy specimens where residual tumour was found more than two centimetres from the original tumour in 41% of patients (Holland 1985). Conventional RT delivers 45 to 50 Gray (Gy) to the whole breast over five weeks followed by a boost to the tumour bed (the most likely site of residual tumour cells) of 10 to 16 Gy over one to two weeks. This prolonged duration of treatment negatively impacts on quality of life (Whelan 2000) and contributes to the higher mastectomy rates observed in women residing in rural and remote areas who wish to avoid being away from home and family for extended periods (Schroen 2005).

Hypofractionated whole breast RT regimens, in which 40 to 42.5 Gy is delivered to the whole breast over three to four weeks using a larger radiation dose with each treatment have been investigated. Compared to conventional whole breast radiotherapy (WBRT), hypofractionated WBRT results in no difference in breast recurrence rates at five and ten years, no difference in overall survival and an improvement in cosmetic outcomes (START 2008; START B 2008; Whelan 2002).

RCTs have shown that addition of conventional or hypofractionated whole breast RT to local excision decreases ipsilateral breast (same breast) recurrence rates from 30 to 40% (Fisher 1995; Fisher 2002; Freeman 1981; Lagios 1983; Montgomery 1978) to 10 to 20% with 10 to 15 years of follow-up (Fisher 1995; Fisher 2002). An ipsilateral recurrence can either be a true recurrence of the original cancer (typically arising in the same quadrant as the original tumour and known as local recurrence) or a second primary tumour developing elsewhere in that same breast. Studies evaluating ipsilateral breast tumour recurrence patterns show that new primaries increasingly contribute to the rate of recurrence after five to eight years while true recurrence rates stabilise (Krauss 2004; Smith 2000). If radiation given to the whole breast (whole breast RT) was successful in preventing the recurrence of new primary cancer, the rate of such cancers in the treated breast should be lower than the rate of development of cancers in the other breast (contralateral breast cancer). This has not been found in studies of ipsilateral breast tumour recurrence patterns (Krauss 2004; Smith 2000). Furthermore, more recent studies examining primary and re-excision pathological specimens removed at the time of breast conserving surgery revealed residual tumour less than 10 and 15 mm from the primary tumour in 81% and 91% of the specimens, respectively (Wallner 2004).

Thus, as most true recurrences occur in the same quadrant as the original tumour and as whole breast RT does not appear to protect against the development of new primary cancer, investigators have begun to examine the role of partial breast irradiation (PBI).

Description of the intervention

Partial breast irradiation (PBI; also known as less than whole breast RT) refers to irradiation of a limited volume of breast tissue around the tumour bed. It may be achieved by any of the following techniques:

  1. Intracavitary brachytherapy or MammoSite® (applying radioactive sources directly into the cavity left after surgical removal of the tumour either at the time of surgery or at a later date, the latter requiring a second procedure);

  2. Interstitial brachytherapy (inserting catheters into the surgical cavity and surrounding tissue to temporarily deliver radioactive sources);

  3. Intra-operative techniques using electrons or X-rays at 50 kVp (using a dedicated machine to deliver a very localised radiation dose to the surgical cavity in the operating room or by moving the patient with an open wound to the radiation machine, which may be in a different part of the hospital);

  4. External beam RT using either three-dimensional conformal RT (external beam RT delivered in the post-operative setting to a volume of breast tissue around the tumour cavity using a standard linear accelerator in a radiation oncology department) or other methods.

Conventional RT typically delivers a radiation dose of 2 Gy with each treatment. Some partial breast irradiation techniques deliver a larger than standard dose of radiation with each treatment, allowing the overall duration of treatment to be shortened. This is termed accelerated partial breast radiation (APBI).

How the intervention might work

PBI/APBI will only be of benefit if it confers the same local control benefit as standard whole breast RT with acceptable toxicity and cosmesis. Currently, some authorities consider PBI/APBI to be an experimental therapy (Clinical Evidence). The NCCN 2012 state: "Preliminary studies of APBI suggest rates of local control in patients with early stage breast cancer may be comparable to those treated with WBRT. Follow-up, however is limited and studies are ongoing". Because this technique has been widely adopted outside the context of clinical trials, published guidelines exist which identify women with early breast cancer for whom this technique may be safe. For those women ineligible for a trial, carefully selected women with early breast cancer may be offered PBI/APBI (Bellon 2011; Polgár 2010; Smith 2009).

The use of PBI/APBI has a number of potential advantages including:

  1. a reduction in treatment-related toxicities, as a smaller volume of breast tissue is irradiated;

  2. increased utilisation of breast conservation;

  3. a reduction in RT waiting times; a reduction in the overall treatment duration of a common malignancy has the potential to substantially impact on RT waiting times in countries with strained resources (including the UK, Canada, Australia and New Zealand);

  4. a greater chance of preserving the breast should a recurrence occur elsewhere in the breast;

  5. easier integration with chemotherapy schedules because RT time will be shorter, thus avoiding delays.

The use of PBI/APBI has a number of potential disadvantages including:

  1. an increased risk of local recurrence due to geographic miss. This is either because treatment is delivered before full pathological examination is obtained or because of difficulty in reproducing the target volume (the tissue which needs to be treated with RT) daily;

  2. increased late toxicity. The late effects of radiation are dependent on the dose of radiation given at each treatment and as PBI/APBI delivers a large radiation dose per fraction, late toxicity may be increased with resultant poor cosmetic outcome or breast appearance (cosmesis);

  3. more patient inconvenience as some techniques may require a second anaesthetic or a further invasive procedure;

  4. a number of techniques (e.g. interstitial and intracavitary brachytherapy) require operator expertise and specialized equipment which may not be available in all centres;

  5. invasive techniques of delivering PBI/APBI (e.g. interstitial and intracavitary brachytherapy) may be associated with toxicity such as infection and delays in wound healing. Scarring post-insertion of interstitial brachytherapy catheters can negatively impact on cosmetic appearance.

Why it is important to do this review

PBI/APBI has the potential to change the pattern of practice for a common malignancy and thereby impact on resource utilisation, patient satisfaction and quality of life. However as PBI/APBI is currently an experimental therapy, it must be thoroughly evaluated before being adopted as the new standard of care for early-stage breast cancer. PBI/APBI can be recommended if it is as effective or better than conventional or hypofractionated WBRT for cancer-related outcomes (local-relapse-free survival, survival, breast cancer-specific survival and metastasis-free survival) as well as patient-orientated outcomes (cosmesis, quality of life and consumer preference). We found a systematic review which concluded: "The data on PBI/APBI compared to whole-breast irradiation are insufficient to draw any conclusions about the relative effectiveness of these modalities" (Blue Cross Shield). The fact that the benefit versus risk profile of PBI/APBI is currently unknown makes it an ideal topic for a systematic review.

Objectives

To determine whether PBI/APBI is equivalent to or better than conventional or hypofractionated WBRT after breast conservation therapy for early-stage breast cancer.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) evaluating conservative surgery plus PBI/APBI versus conservative surgery plus whole breast RT. The comparisons had to be unconfounded (that is treatments given to the randomised groups must differ only in relation to the volume of the breast radiated). Trials incorporating the use of adjuvant treatments, such as chemotherapy, monoclonal antibodies or hormonal therapy, were eligible if these other treatments were applied in exactly the same way to both groups in the RCT. Published and unpublished studies were eligible.

We did not consider studies in which partial breast irradiation was used as a boost following conventional external beam RT for inclusion.

Types of participants

Women with histologically confirmed early-stage breast cancer who had conservative surgery. Early breast cancer included tumours classified as AJCC stage T1-2N0-1M0 (Fleming 1997). Surgery could include lumpectomy and wide local excision or quadrantectomy, with or without axillary dissection, axillary sampling or sentinel node biopsy. Women with a previous diagnosis of breast cancer were not eligible for inclusion.

Types of interventions

Radiation delivered to the partial breast (PBI) and PBI using larger than standard radiation dose per fraction such that the overall treatment time is reduced (APBI). We considered any method of PBI/APBI delivery including, but not limited to, intracavitary brachytherapy or MammoSite®, interstitial brachytherapy, intra-operative techniques such as electrons or X-rays at 50 kVp or external beam RT using either three-dimensional conformal therapy or other methods. Conventional breast RT is delivered to the whole breast ± the supra-clavicular fossa and axilla, using standard fractionation (1.8 to 3.0 Gy per fraction) to deliver a total of 40 to 61 Gy at the reference point. Treatment could include a boost (using electrons, interstitial therapy, external beam or new techniques).

Types of outcome measures

Primary outcomes
  1. Local recurrence in the ipsilateral breast. We defined local recurrence as a recurrence of the same histological type of cancer within the same quadrant of the breast as the primary cancer;

  2. Cosmesis (cosmetic outcome or breast appearance).

Secondary outcomes
  1. Overall survival (time from date of randomisation to death from any cause, or number of deaths from any cause);

  2. Toxicity (including acute and late effects of RT, chemotherapy-related toxicity and surgical toxicity; individual protocol-based definitions);

  3. New primary tumours in ipsilateral breast. We defined a new primary as a lesion arising in a quadrant of the breast that is different from the original cancer or a tumour of a different histological subtype occurring anywhere within the breast;

  4. Cause-specific survival (deaths due to breast cancer at five years);

  5. Distant metastases, in isolation or at the same time as local recurrence (the occurrence of metastases at five years);

  6. Relapse-free survival (length of time after treatment during which no recurrence is found). Recurrence referred to breast cancer in the ipsilateral breast or elsewhere in the body, excluding a new breast cancer in the contralateral breast;

  7. Locoregional control;

  8. Subsequent mastectomy (ipsilateral partial mastectomy, modified radical mastectomy or radical mastectomy);

  9. Compliance, defined as the number of women who commenced treatment with PBI/APBI or conventional external beam RT (EBRT) and completed the treatment course;

  10. Costs (monetary costs of PBI versus EBRT) to women, government and insurance companies;

  11. Quality of life (using trial-specific instruments). The effects of PBI/APBI and EBRT on global quality of life and the physical, emotional and psychological domains;

  12. Consumer preference, that is, did women prefer PBI/APBI or WBRT given the advantages and disadvantages of each approach.

Search methods for identification of studies

Electronic searches

Electronic databases

We searched the Cochrane Breast Cancer Group Specialized Register (07 November 2013), CENTRAL (2014, Issue 3), MEDLINE (January 1966 to 11 April 2014), EMBASE (1980 to 11 April 2014), CINAHL (11 April 2014) and Current Contents (11 April 2014). Regarding the Cochrane Breast Cancer Specialized Register, details of search strategies used to identify 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). We extracted studies on the specialised register with keywords 'early breast cancer', 'radiotherapy', 'partial breast irradiation', 'whole breast irradiation', 'whole breast radiotherapy', 'brachytherapy', 'high-dose-rate brachytherapy', 'accelerated partial breast irradiation', 'tumour bed boost', 'sole tumour bed irradiation', 'MammoSite', 'radiotherapy', 'PBI', 'APBI' and 'interstitial brachytherapy' for consideration. We modified the MEDLINE search strategy (Appendix 1) to search the other databases named above, without language restrictions.

Unpublished literature

We searched following registers for ongoing clinical trials:

  • the International Standard Randomised Controlled Trial Number Register (www.controlled-trials.com/isrctn) (22 April 2014);

  • the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) search portal (http://apps.who.int/trialsearch/Default.aspx) (07 November 2013; see Appendix 2);

  • US clinical trials registry (www.clinicaltrials.gov) (22 April 2014; see Appendix 3).

Grey literature

We checked Open Grey (www.opengrey.eu/) up to 23 April 2014.

Searching other resources

We contacted researchers located from the grey literature and unpublished literature to ask if they were aware of any other trials on this topic. We contacted the Barcelona authors on 15 October 2012 for more information. We contacted the IRMA authors on 02 October 2012 and they supplied us with the trial protocol. We contacted the authors of Polgár 2007 and Ribeiro 1993 on 24 August 2013; we gratefully received and incorporated data from the authors of Ribeiro 1993 and Polgár 2007 in November 2013.

Handsearching

We handsearched a number of conference proceedings and published abstracts including:

  • Adjuvant Therapy for Primary Breast Cancer International Conference (2001);

  • Primary Therapy of Early Breast Cancer (2001 and 2003);

  • 6th and 7th Nottingham International Breast Cancer Meeting Conference Report;

  • 23rd and 24th Congress of the International Association for Breast Cancer Research;

  • 3rd and 4th Perspectives in Breast Cancer Conference Report;

  • 26th and 27th Annual San Antonio Breast Cancer Symposium;

  • 4th European Breast Cancer Conference;

  • 94th and 95th American Association of Cancer Research;

  • American Society for Clinical Oncology (1995 to 2005);

  • European Society for Therapeutic and Radiation Oncology (1990, 1993, 2000 to 2010, 2012);

  • 5th and 6th Milan Breast Cancer Conference;

  • Australian Breast Cancer Conference (2004);

  • 27th and 28th Annual Symposium of the American Society of Breast Disease;

  • CDC Cancer Conference (2003);

  • International Journal of Radiation Oncology Biology Physics: proceedings of ASTRO 2011 to S581;

  • Radiotherapy and Oncology: Proceedings of World Congress of Brachytherapy 2012;

  • American Society of Clinical Oncology (ASCO) from 1995 to 2010.

Data collection and analysis

Selection of studies

Three review authors (ML, BH and DF) checked the titles and abstracts retrieved by the searches. Each review author independently assessed the full text of the studies thought relevant to the review and we resolved any differences in assessment by discussion. We performed trial assessments with the results masked. In cases where data were limited or information on trial methods was limited, we requested further information from the trial authors.

Data extraction and management

Three authors (ML, DF and BH) performed data extraction and resolved disagreements through discussion. We entered data into Review Manager for analysis. Where possible we extracted data on tumour stage, nodal status, margin status, receptor status, hormonal manipulation, treatment allocation and surgery performed. The information extracted on RT included overall treatment time, radiation dose, dose per fraction and method of PBI. We extracted outcome data on local recurrence, deaths (all-cause and breast cancer deaths), new ipsilateral primaries, mastectomy rate, distant metastases, treatment-related toxicity (including that related to acute and late effects of RT and to surgery), cosmesis, costs of treatment, consumer preference and quality of life.

We derived data for overall survival, local recurrence-free survival, distant metastasis-free survival, disease-free survival and cause-specific survival from information in the text (Dodwell 2005) and data received from trial authors (Polgár 2007; Ribeiro 1993). Trial authors of Polgár 2007 and Ribeiro 1993 provided the HR, 95% CI and P values, together with the number of events with further follow-up. This allowed us to use the spreadsheet developed by Matthew Sydes (Tierney 2007) to derive O-E and variance using method three. One trial, TARGIT, had inadequate follow-up for inclusion in the analysis, but we were able to report the compliance in this trial.

We derived data for local recurrence, overall survival, cause-specific survival, metastasis-free survival and relapse-free survival from a spreadsheet developed by Matthew Sydes (Tierney 2007).

We converted the radiation doses to the equivalent dose in 2 Gy fractions (EQD2 ) (Maciejewski 1986; Withers 1983), using the formula: EQD2 = D (d + alpha/beta/2 + alpha/beta), where D = total dose, d = dose per fraction and alpha/beta = 4 Gy (Owen 2006). This was to facilitate comparison of radiation doses given at differing dose per fraction. We converted brachytherapy (radiation sources applied directly to the body) to the biological equivalent dose (BED) using the method of Stitt 1992.

Assessment of risk of bias in included studies

BH and ML assessed trials to check they met the inclusion criteria and independently assessed methodological quality. DF resolved any discrepancies. BH undertook 'Risk of bias' tables assessments, which were checked by ML, and reported them in the text and as a figure.

We described the risk of bias for each included trial. BH and ML judged risk of bias in eight specific domains, and resolved any differences through discussion. The eight domains were:

  1. random sequence generation;

  2. allocation concealment;

  3. blinding of participants and personal;

  4. blinding of outcome assessors for objective outcomes;

  5. blinding of outcome assessors for subjective outcomes;

  6. incomplete outcome data;

  7. selective outcome reporting;

  8. other sources of bias (i.e. early stopping and differences in follow-up examinations).

We will perform sensitivity analyses on the basis of trial quality when more trials are available. We plan to perform the analysis both with and without trials at low risk of bias to assess the effect of bias on the results when more trials are available to examine.

Measures of treatment effect

We presented results for dichotomous outcomes as hazard ratios (HR) for time-to-event data and odds ratios (OR) with 95% confidence intervals (CI) where this was not possible (Deeks 2004).

For future updates, if results for continuous variables (such as quality of life) are available, we will summarise them using the mean difference or the standardised mean difference when different measurement scales are used (Deeks 2004).

Unit of analysis issues

Because the unit of analysis is the individual patient, we did not anticipate any unit of analysis issues.

Dealing with missing data

If data are missing in future updates, we will contact the original investigators (by written correspondence).

We will make explicit what assumptions we make, for example, if we assume the data missing is missing at random, or if we make the assumption that missing data were assumed to have a particular value such as a poor outcome. We will, if necessary, perform a sensitivity analysis to see how sensitive results are the assumptions we have made. We will address the potential implications of this in the discussion.

Assessment of heterogeneity

We assessed heterogeneity both visually and statistically using the Chi2 test of heterogeneity (Altman 1992; Walker 1988) and I2 statistic (Higgins 2002; Higgins 2003). The criterion for identification of heterogeneity is a P value less than 0.10 for the Chi2 test (acknowledging the limitations of this process) and an I2 statistic value of greater than 50%. Where we identified significant heterogeneity, we explored the reasons for it and made a cautious attempt to explain the heterogeneity.

Assessment of reporting biases

We acknowledge that there are multiple potential sources of reporting biases, including, but not limited to publication bias, time-lag bias, duplicate publication bias and selective outcome reporting. By searching multiple sources including trial registries, we hope to minimize publication bias. We note the early reporting for the TARGIT is an example of time-lag bias. We planned to use funnel plots to evaluate funnel plot asymmetry, but took into account that visual interpretation is subjective and that statistical methods to evaluate funnel plot asymmetry are unlikely to be valid if there are fewer than 10 included trials.

Data synthesis

We applied the intention-to-treat principle in analysing data from the trials and determined a weighted average treatment effect using the fixed-effect model to combine results (Mantel 1959) with Review Manager software.

We used the Mantel-Haenszel methods to calculate pooled results (Greenland 1985; Mantel 1959) when there was no significant heterogeneity, or if otherwise, the random-effects model of Der Simonian and Laird (DerSimonian 1986).

Subgroup analysis and investigation of heterogeneity

In future updates if data are available, we may perform subgroup analyses to investigate whether the effects of using PBI/APBI or conventional breast RT differ depending on nodal status, margin status, receptor status, hormonal manipulation or tumour stage. If heterogeneity is identified in future updates, we will assess it both statistically and visually using the Chi2 test of heterogeneity (Altman 1992; Walker 1988) and I2 statistic (Higgins 2002; Higgins 2003). If we do identify significant heterogeneity, we will explore the reasons for it and attempt to explain it.

Sensitivity analysis

We performed sensitivity analysis by excluding the trials which use RT techniques that do not reflect current practice (Dodwell 2005; Ribeiro 1993) and by excluding the trials at high risk of bias (see 'Risk of Bias' tables; Polgár 2007; Ribeiro 1993). In future updates, if adequate data are available, we will perform a sensitivity analysis to assess the robustness of the results by excluding unpublished trials.

We created a 'Summary of findings' table using the following outcomes:

  1. Local recurrence-free survival;

  2. Cosmesis;

  3. Overall survival;

  4. Late toxicity: late subcutaneous breast fibrosis;

  5. Subsequent mastectomy;

  6. Cause-specific survival;

  7. Distant metastasis-free survival.

The population included women with early breast cancer and the intervention was PBI/APBI versus WBRT. We used GRADEpro and the GRADE approach to evaluate the strength of the evidence (GRADE Working Group 2004).

Results

Description of studies

Results of the search

Based on our search strategy, we identified and screened a total of 3193 references and identified 43 references from other sources. After exclusion of duplicates and screening of references (by title or abstract), we evaluated 166 full-text references. We found 58 potentially eligible studies and excluded eleven (see Characteristics of excluded studies). Twenty-five reports referred to five completed studies (Dodwell 2005; ELIOT; Polgár 2007; Ribeiro 1993; TARGIT). ELIOT was published while this Cochrane Review was in peer review; we will incorporate their results in an update. Although TARGIT was eligible, the report (at five years' follow-up) contained data with five years' follow-up on 35% of those women randomised. This length of follow-up is too short for assessment of the relevant breast cancer outcomes. Therefore, we did not included it in either the qualitative or quantitative analysis, but reported their compliance. We found seven ongoing trials (GEC-ESTRO; IMPORT; IRMA; Livi; NSABP-B39/RTOG; RAPID; SHARE) and interim reports for Barcelona and RAPID. Two trials await classification (Barcelona; ELIOT). See Figure 1.

Figure 1.

Study flow diagram.

Included studies

Design

1140 women were enrolled in three RCTs (Dodwell 2005; Polgár 2007; Ribeiro 1993), which enrolled women from July 1986 to June 1990 (Dodwell 2005), July 1998 to May 2004 (Polgár 2007) and November 1982 to December 1987 (Ribeiro 1993).

Sample size

Dodwell 2005 enrolled 174 women, Ribeiro 1993 enrolled 708 women and Polgár 2007 enrolled 258 women of a planned sample size of 570 participants.

Setting

All three included trials were single institution trials from tertiary institutions: two in the United Kingdom (Dodwell 2005; Ribeiro 1993) and one in Hungary (Polgár 2007).

Participants

Polgár 2007 included women with invasive breast cancer after wide local excision of tumour and negative pathological margins, T1N0-N1miM0, grade I or II. In Dodwell 2005: women with pT1-2pN0-1 tumours considered suitable for local excision. All participants had local excision (with clear margins) and level II axillary dissection. Ribeiro 1993 included women with a single, mobile lump less than 4 cm treated with breast conserving surgery (BCS) and no axillary dissection but clinically negative axillae. See Characteristics of included studies.

Interventions

Experimental arm: partial breast irradiation using either:

  1. High-dose rate (HDR) brachytherapy: 7 X 5.2 Gy high-dose rate (HDR) multi-catheter brachytherapy for 88/128 women (Polgár 2007);

  2. EBRT to partial breast. PBI delivered via EBRT was delivered in conventional fractionation (2 Gy per fraction) in 50 Gy/25 fraction electron beam RT to partial breast for 40/128 women (Polgár 2007), or at greater than 2 Gy per fraction (55 Gy/20 fractions) (Dodwell 2005) or 40 to 42 Gy/8 fractions (Ribeiro 1993). As these fractionation schemes differed both in dose as well as dose per fraction, we cannot simply order them by dose.

Control arm: WBRT using either conventional fractionation: 50 Gy/25 fractions whole breast irradiation (Polgár 2007), or at greater than 2 Gy per fraction (40 Gy/15 fractions (Dodwell 2005; Ribeiro 1993).

Co-interventions (chemotherapy and hormonal manipulation): all women had chemotherapy with cyclophosphamide, methotrexate, 5-fluorouracil (CMF) and vincristine. Node-positive pre-menopausal women had five cycles of CMF and all women received five years of tamoxifen (Dodwell 2005). In Polgár 2007 women received systemic therapy according to institutional protocol (see Characteristics of included studies for further details).

Outcomes
Primary outcomes

Two trials reported local recurrence in the ipsilateral breast as a discrete outcome (Dodwell 2005; Polgár 2007) but Ribeiro 1993 reported it as first event data. Polgár 2007 reported a global cosmetic result, using the Harvard Cosmetic score (see Table 1). The results were dichotomised into good/excellent and fair/poor.

Table 1. Harvard cosmetic score
Cosmetic score
Excellent
Good
Fair
Poor
Secondary outcomes
  1. Overall survival was reported in Dodwell 2005 and Polgár 2007, but Ribeiro 1993 reported it as first event data;

  2. Toxicity: (a) acute toxicity was not reported; (b) late toxicity (telangiectasia and subcutaneous fibrosis) was dichotomised and measured annually using an unvalidated three-point scale (see Table 2; Ribeiro 1993). Polgár 2007 reported the incidence of any fat necrosis at four years according to an institutional scale (Table 3);

    Table 2. Toxicity scale (Ribeiro 1993)
    Score
    Minimal
    Moderate
    Marked
    Table 3. Fat necrosis
    GradeFindings
    0No fat necrosis
    1Asymptomatic fat necrosis (only radiologic, or
    cytologic findings, or both)
    2Symptomatic fat necrosis not requiring medication
    (palpable mass with or without mild pain)
    3Symptomatic fat necrosis requiring medication
    (palpable mass with significant pain)
    4Symptomatic fat necrosis requiring surgical
    intervention
  3. New primary tumours in ipsilateral breast were not reported;

  4. Cause-specific survival was reported in Polgár 2007;

  5. Distant metastases was reported in Dodwell 2005 and Polgár 2007;

  6. Relapse-free survival was reported in Polgár 2007;

  7. Subsequent mastectomy was reported in Polgár 2007;

  8. Compliance with RT was reported in Dodwell 2005; Ribeiro 1993; Polgár 2007; and TARGIT;

  9. Costs were not reported;

  10. Quality of life was not reported;

  11. Consumer preference was not reported (see Characteristics of included studies).

The three RCTs differed in several ways:

  1. Population included: Dodwell 2005 included women with pT1-2pN0-1 tumours considered suitable for local excision. All had local excision (with clear margins) and level II axillary dissection. Polgár 2007 included wide excision with negative margins, unifocal tumour, tumour size < 20 mm, clinically or pathologically N0, or single microscopic nodal metastasis (> 0.2 mm and < 2.0 mm), i.e. pT1N0-1miM0, grade I or II. Ribeiro 1993 included women with a single, mobile breast carcinoma, less than 4 cm treated with BCS, a clinically negative axilla and no axillary dissection;

  2. Surgery performed: margins were negative for women in Dodwell 2005; Polgár 2007; and TARGIT, but 20% of women studied in Ribeiro 1993 had positive or "unknown" margins;

  3. Target volume definition varied between the trials. In the two earlier trials, definition of the target volume was less accurate: in Dodwell 2005 it was defined "according to pre-operative information, scar position and patient recollection"; in Ribeiro 1993 RT was delivered "to the affected quadrant"; and in Polgár 2007, the cavity was clipped and the planning target volume (PTV) was comprised of the cavity plus a 1 to 2 cm margin isotropically (in all directions three dimensionally) for those women treated with interstitial therapy. If electrons were used, 6 to 15 MeV were used to treat the cavity with a 2 cm margin;

  4. Radiation dose prescribed differed greatly not only between the trials but also between the two trial arms in Dodwell 2005 and Ribeiro 1993 (see Table 4);

    Table 4. RT doses prescribed
    1. APBI: accelerated partial breast irradiation
      Gy: Gray
      PBI: partial breast irradiation

    TrialPBI/APBI doseEQD2 PBI/APBIControl doseEQD2 Control
    Dodwell 200555 Gy/20# (PBI)61.8 Gy

    40 Gy/15#

    + 15 Gy boost

    44 + 15.2 Gy = 59.2 Gy
    Ribeiro 199340 to 42 Gy/8# (APBI)60 to 64.7 Gy40 Gy/15#66.6 Gy
    Polgár 2007

    7 X 5.2 Gy HDR (APBI)

    or 50 Gy/25# (PBI)

    53.6 Gy or 50 Gy50 Gy/25#50 Gy
    TARGIT

    20 Gy at surface cavity

    7 Gy at 1 cm (APBI)

    80 Gy at cavity surface

    12.8 at 1 cm

    40 to 56 Gy/ 20-28#

    ± 10 to 16 Gy boost

    40 to 56 Gy ± 10 to 16 Gy
  5. The trials differed in fractionation used; in Dodwell 2005 PBI was delivered at greater than 2.0 Gy per fraction (hypo-fractionation), while in Polgár 2007 most women (88/128) received accelerated RT and women in Ribeiro 1993 were treated with APBI at 5 Gy per fraction;

  6. RT technique for PBI/APBI delivery differed. Dodwell 2005 used three techniques: a direct cobalt field or caesium (for 47/84 women), electron field (for 13/84 women) or "mini-tangents" using MV photons (for 24/84 women). Ribeiro 1993 used 8 to 14 MeV. In Polgár 2007, most women (88/128) in the PBI/APBI arm were treated using interstitial brachytherapy, but 40/128 women were treated with EBRT, as they were not suitable for brachytherapy (Table 5);

    Table 5. RT techniques
    1. EBRT: external beam radiation therapy; RT: radiation therapy

    TrialRT technique
    Dodwell 2005EBRT (using cobalt, caesium, electrons, mini-tangents)
    Polgár 2007

    Interstitial brachytherapy (88/128)

    EBRT using photons (40/128)

    Ribeiro 19938 to 14 MeV
  7. Dodwell 2005 and Ribeiro 1993 did not mention quality assurance. Quality assurance for APBI using electrons or WBRT was not mentioned (Polgár 2007);

  8. Time period of accrual: both Dodwell 2005 and Ribeiro 1993 (which accrued women in the 1980s) are older trials, and used RT and surgical techniques which do not represent current practice;

  9. Two trials did not accrue the full sample size: Dodwell 2005 stopped early because of poor accrual, and Polgár 2007 stopped early because a competing multi-centred RCT was started.

Excluded studies

We excluded eleven studies (see Characteristics of excluded studies).

Risk of bias in included studies

Allocation

The risk of bias for random sequence generation and allocation concealment in Dodwell 2005 was unclear. Dodwell 2005 was randomised (though no details of sequence generation were given) and no details of treatment allocation were given. Polgár 2007, Ribeiro 1993 and TARGIT were at low risk of bias for sequence generation. Polgár 2007 was randomised, the method (sealed envelopes) described and allocation was done by the chief investigator: however this trial was at high risk of bias. Ribeiro 1993 was at low risk of bias as treatment was randomised, the method of sequence generation was described, and allocation was concealed. TARGIT was at low risk of bias for allocation concealment.

Blinding

1. Objective outcomes

Blinding of participants was not mentioned. It would have been difficult to do so with this intervention, but the lack of blinding is unlikely to have introduced bias (Dodwell 2005; Polgár 2007; Ribeiro 1993). Participants in TARGIT were not blinded to treatment arm, but this was unlikely to introduce bias.

Blinding of physicians was not mentioned in the included trials. It would have been difficult to do so with this intervention, but failure to do so is less likely to have introduced bias because mammographic screening interval was prespecified (Dodwell 2005). Polgár 2007 had a prespecified follow-up protocol with pre-determined interval for mammographic evaluation and any local recurrence required biopsy confirmation. This served to make the objective outcomes at low risk of bias. Blinding was not mentioned and probably not done in Ribeiro 1993, but this is probably not associated with high risk of bias. in TARGIT, physicians were not blinded to treatment allocation, this is unlikely to have been a source of bias.

Blinding of outcome assessors was not mentioned, and probably not done in the trial of Dodwell 2005. Polgár 2007 did not mention blinding, but the predetermined mammographic follow-up protocol and requirement for biopsy confirmation of local recurrence would have reduced the risk of bias. The lack of blinding for outcome assessors in Ribeiro 1993 is at high risk of introducing bias, particularly in view of the lack of a pre-specified protocol for mammographic follow-up. Outcome assessors were not blinded in TARGIT, but the prespecified follow-up protocol minimised the risk of bias. The analyses in TARGIT were reported to be done blinded, which reduced the risk of bias.

2. Subjective outcomes

Blinding of participants: no subjective outcomes were reported (Dodwell 2005). Blinding of participants for subjective outcomes was not reported, but it is unlikely to have introduced bias because no patient-related outcomes were reported (Polgár 2007; Ribeiro 1993; TARGIT).

Blinding of physicians: no subjective outcomes were reported (Dodwell 2005). Polgár 2007, Ribeiro 1993 and TARGIT did not mention blinding of physicians and this may have introduced bias.

Blinding of outcome assessors: no subjective outcomes were reported (Dodwell 2005). As Polgár 2007 and Ribeiro 1993 did not mention blinding of outcome assessors, it is unlikely to have been done and is potentially a source of bias and therefore at high risk of bias. The authors of the TARGIT did not report blinding of outcome assessors, so it seems unlikely that they were. However the use of a predetermined data collection form for toxicity would have reduced the risk of bias, because data was collected for all women studied.

Incomplete outcome data

In Dodwell 2005, no women were excluded, none were lost to follow-up and no attrition was reported. Thus this trial was at unclear risk of bias. In Polgár 2007, no women were excluded and attrition was reported by arm (without providing reasons). Ribeiro 1993 reported exclusions (with reasons provided) but not by arm. They documented that no patient was lost to follow-up (Ribeiro 1993). For these aforementioned trials, the risk of bias was unclear. TARGIT trial authors reported on < 20% of randomised patients because the follow-up duration was restricted to four years. This makes this outcome at high risk of bias, so we did not include it in the analysis.

Selective reporting

For Dodwell 2005 and Polgár 2007, the trial protocols were not available for review and were at 'unclear' risk of bias. Ribeiro 1993 had a high risk of selective outcome reporting (see Characteristics of included studies). The outcomes pre-specified in the protocol have not all been reported on in TARGIT, putting it at high risk of bias.

Other potential sources of bias

Regarding other potential sources of bias, Dodwell 2005 had unclear risk of bias and Polgár 2007 had low risk of bias. Dodwell 2005stopped the trial early because of problems with recruitment. Polgár 2007 stopped the trial early because a competing trial started recruiting (GEC-ESTRO). In Ribeiro 1993, mammograms were performed in 25% of women studied (from a single institution). For other women enrolled, mammography was only done to investigate symptoms, giving a high risk of bias (Ribeiro 1993; see Figure 2). TARGIT has a short follow-up, which puts it at high risk of bias (see Figure 2).

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included trials.

Effects of interventions

See: Summary of findings for the main comparison Partial breast irradiation or accelerated partial breast irradiation for early breast cancer

Primary outcomes

1. Local recurrence-free survival in the ipsilateral breast

There were 104 local recurrences in the 1140 women studied.

Local recurrence-free survival appeared worse with PBI/APBI (HR 1.74, 95% CI 1.23 to 2.45; three trials, 1140 participants, Analysis 1.1; Figure 3). There was some evidence of heterogeneity on visual inspection and statistical testing (P = 0.10, I2 statistic = 56%).

Figure 3.

Forest plot of comparison: 1 PBI/APBI versus WBI, outcome: 1.1 Local recurrence-free survival.

Sensitivity analysis was based on:

  1. excluding the trials which used RT techniques which do not reflect current practice (Dodwell 2005; Ribeiro 1993). This left a single trial (Polgár 2007). We found no clear evidence of a difference with PBI/APBI (HR 1.09, 95% CI 0.63 to 1.89; Polgár 2007). Testing for heterogeneity was not appropriate with data from a single trial.

  2. excluding a trial at high risk of bias, which did not pre-specify interval for follow-up mammograms (Ribeiro 1993). We found no clear evidence of a difference with PBI (HR 1.31, 95% CI 0.79 to 2.15; two trials, 432 participants). There appeared to be some evidence of heterogeneity both on visual inspection and statistical testing (P = 0.14, I2 statistic = 55%).

2. Cosmesis

In Polgár 2007, cosmesis at five years (OR 0.49, 95% CI 0.28 to 0.86; one trial, 258 participants) and 10 years (OR 0.40, 95% CI 0.23 to 0.72; one trial, 258 participants) appeared improved in the group treated with PBI/APBI.

Secondary outcomes

There were 363 deaths of the 1140 women studied.

1. Overall survival

We found no clear evidence of a difference in overall survival with the use of PBI/APBI (HR 0.99, 95% CI 0.83 to 1.18; three trials, 1140 participants, Analysis 1.2; Figure 4). There was no heterogeneity on either visual inspection or statistical testing (P = 0.76, I2 statistic = 0%).

Figure 4.

Forest plot of comparison: 1 PBI/APBI versus WBI, outcome: 1.2 Overall survival.

2. Toxicity

There was no data on acute skin toxicity.

Regarding late toxicity:

  • telangiectasia appeared worse with APBI (OR 4.41, 95% CI 3.21 to 6.05; one trial, 708 participants) as seen in Ribeiro 1993.

  • subcutaneous fibrosis appeared worse with APBI (OR 4.27, 95% CI 3.04 to 6.01; one trial, 708 participants) as reported in Ribeiro 1993.

  • we found no clear evidence that symptomatic fat necrosis differed with PBI/APBI (OR 1.20, 0.56 to 2.58; one trial, 256 participants evaluated Polgár 2007). This was also the case for the presence of any fat necrosis (OR 0.76, 95% CI 0.48 to 1.23, figures from the text in Polgár 2007). There was more fat necrosis when HDR brachytherapy was used for PBI/APBI compared with WBRT (using electrons) (OR 0.42, 95% CI 0.18 to 0.94, figures from the text in Polgár 2007).

3. New primary tumours in ipsilateral breast

Data were not reported or available.

4. Cause-specific survival

We found no clear evidence that cause-specific survival differed with the use of PBI/APBI versus WBRT (HR 0.95, 95% CI 0.74 to 1.22; two trials, 966 participants, Analysis 1.3; Figure 5). We found no evidence of heterogeneity on either visual inspection or statistical testing: P = 0.70, I2 statistic = 0%.

Figure 5.

Forest plot of comparison: 1 PBI/APBI versus WBI, outcome: 1.3 Cause-specific survival.

5. Distant metastases

We found no clear evidence that distant metastasis-free survival differed with PBI/APBI versus WBRT (HR 1.02, 95% CI 0.81 to 1.28; three trials, 1140 participants, Analysis 1.4; Figure 6). We found no heterogeneity with either visual inspection or statistical testing: P = 0.90, I2 statistic = 0%.

Figure 6.

Forest plot of comparison: 1 PBI/APBI versus WBI, outcome: 1.4 Distant metastasis-free survival.

6. Relapse-free survival

We found no clear evidence that relapse-free survival differed in Polgár 2007 (HR 0.99, 95% CI 0.53 to 1.85; one trial, 258 participants). With data from a single trial, testing for heterogeneity was not appropriate.

7. Locoregional control

We found no data.

8. Subsequent mastectomy

Subsequent mastectomy rate did not appear to differ between the two groups (OR 0.20, 95% CI 0.01 to 4.21; one trial, 258 participants) in Polgár 2007 (these results are imprecise). Salvage surgery was possible in 86% of those treated with APBI and 90% of those women treated with EBRT (denominators not available) in Ribeiro 1993.

9. Compliance

More than 90% of the women randomised to PBI/APBI received it (Dodwell 2005; Ribeiro 1993; Polgár 2007). Eighty-nine percent of women in TARGIT received PBI/APBI.

For those women randomised to receive WBRT, over 90% received the planned RT (Dodwell 2005; Ribeiro 1993; Polgár 2007; TARGIT).

10. Costs

There was no data on this outcome.

11. Quality of life

There was no data on this outcome.

12. Consumer preference

There was no data on this outcome.

Discussion

Summary of main results

Local recurrence-free survival appeared worse with the use of PBI/APBI (Analysis 1.1). PBI/APBI appeared to be associated with improved cosmesis (Polgár 2007). We found no clear evidence of a difference in overall survival when PBI/APBI was used (Analysis 1.2) but we could not exclude potentially important differences between the treatment groups. We found no data for the effect of PBI/APBI on acute toxicity. Late toxicity appeared increase with APBI (Ribeiro 1993). We found no data on the effect of PBI/APBI on the development of new tumours in treated breast.

We found no clear evidence of a difference in cause-specific survival (Analysis 1.3), distant metastasis-free survival (Analysis 1.4) and relapse-free survival (Polgár 2007) with the use of PBI/APBI but we could not exclude potentially important differences between the treatment groups. We found no data for the effect of PBI/APBI on loco-regional control. The mastectomy rate did not appear affected by the use of PBI/APBI (Polgár 2007) but the results were imprecise. Compliance with allocated treatment was high: greater than 80% for all women studied. There were no data found for the effects of PBI/APBI on costs, quality of life and consumer preference.

Based on these findings, it seems that PBI/APBI appears associated with worse local relapse-free survival in comparison with WBRT. We still have significant reservations about both the quantity and the quality of these data. The limitations of the applicability of these data to current RT practice mean there is still significant uncertainty about the efficacy of this intervention even though there is little evidence that the use of PBI/APBI is associated with increased toxicity. We will discuss this further under 'Overall completeness and applicability of evidence'.

Overall completeness and applicability of evidence

There were limitations in completeness and applicability of evidence due to:

1. Out-moded surgical and RT technique

Two of the four completed trials (which accrued women in the 1980s) used RT techniques which do not reflect current RT practice (Dodwell 2005; Ribeiro 1993). The high rate of positive pathological margins in Ribeiro 1993 would not be acceptable today; a negative surgical margin would be deemed essential.

2. Clinical heterogeneity between the trials

The PBI/APBI delivered was heterogenous in dose, technique, fractionation and target delineation:

  • The RT doses varied between the trials and differed between the two treatment arms in Dodwell 2005 and Ribeiro 1993 (Table 4);

  • The RT techniques used to deliver PBI/APBI varied (see Table 5);

  • The trials differed in fractionation used; in Dodwell 2005 PBI was delivered using > 2 Gy per fraction (hypo-fractionation), while in Polgár 2007 most women (88/128) received accelerated RT and women in Ribeiro 1993 were treated with APBI at 5 Gy per fraction. In the earlier two trials, target definition was less rigorous. Dodwell 2005 defined the tumour bed according to pre-operative information, scar position and patient recollection, Ribeiro 1993 treated the "affected quadrant", using a mean eight by 10 cm field and 10 MeV. In Polgár 2007, a clipped surgical cavity plus 1 cm margin defined the PTV for the women treated with HDR. For women unsuitable for HDR, the clipped cavity was treated plus a 2 cm margin using 6 to 15 MeV. The technique used for target definition in Dodwell 2005 and Ribeiro 1993 would not be acceptable in current practice because of the likelihood of a geographic miss (failing to accurately treat the tumour) with these methods.

Avoiding geographic miss is imperative in RT. Delivery of RT is a technical exercise. Peters 2010 demonstrated the extremely important role that quality assurance plays in the delivery of high quality RT. Poor quality RT (a non-compliant plan) for locally advanced head and neck cancer was associated with a 20% detriment in survival and a 29% detriment to loco-regional control (Peters 2010). Quality assurance was not mentioned in two (Dodwell 2005; Ribeiro 1993) of the three completed trials. Although Polgár 2007 assessed implant quality, less than 20% of the implants had post-implant CT to document PTV coverage (see Characteristics of included studies).

The lack of precision in target definition, the variety of methods used to deliver PBI/APBI (even within the experimental arm of the trials; see Table 5) and the omission of robust quality assurance mean that the RT delivered in the trials is not reproducible. We cannot be certain of the dose delivered and the volume of breast treated. These trials do not meet the technological precision and accuracy of current practice.

3. Duration of follow-up

The length of follow-up in three of the included trials (eight years, 66 months and 65 months in Dodwell 2005, Polgár 2007 and Ribeiro 1993, respectively) was adequate to detect local recurrences. While local recurrences do continue (at about 1% per year), any effect on breast cancer-specific survival related to local control requires much longer follow-up. None of the included trials have long enough follow-up to report overall survival results. There are data from one trial with a median survival of 10.2 years (Polgár 2007).

4. There is little or no useful information available for all outcome measures

The authors of TARGIT (completed, but with short follow-up) indicate that cosmesis, patient satisfaction, health economics, patient preference will be the subject of a sub-protocol and information with respect to these outcomes will be available in the future. The seven ongoing trials we found are likely to address these outcomes (GEC-ESTRO; IMPORT; IRMA; Livi; NSABP-B39/RTOG; RAPID; SHARE; see Characteristics of ongoing studies).

Quality of the evidence

We have evidence from two low quality trials (Dodwell 2005; Ribeiro 1993) (one at high risk of bias) using outmoded RT techniques which have little relevance to current practice. We have evidence from a single trial (Polgár 2007) of moderate quality (but at high risk of bias) suggesting that the use of PBI/APBI (using the technique of brachytherapy) may result in similar local control and survival as WBRT, but little or no evidence with respect to associated toxicity. There is no good mature data for 3D conformal or intra-operative RT (IORT) PBI/APBI. Many of the endpoints we wished to explore and report were not reported. The overall quality of the evidence (using GRADE) is very low, with the exceptions of cause-specific survival and distant metastasis-free survival, which are both low.

Potential biases in the review process

We think that we have identified all the relevant completed RCTs. The age of the trials means that data have little relevance to current practice of RT.

Agreements and disagreements with other studies or reviews

We found one meta-analysis (Valachis 2010) which included the same three trials in our systematic review and recruited 1140 women (Dodwell 2005; Polgár 2007; Ribeiro 1993). They found no difference for death (OR 0.91, 95% CI 0.67 to 1.23; P = 0.55) and distant metastasis (OR 0.74, 95% CI 0.51 to 1.08; P = 0.12) for the comparison of PBI/APBI versus WBRT. PBI/APBI was associated with increased local recurrence (OR 2.15, 95% CI 1.40 to 3.31; P = 0.001) and axillary recurrence (OR 3.43, 95% CI 2.06 to 5.71; P < 0.0001) when compared with whole breast-radiation. They conclude that partial breast irradiation does not seem to jeopardize survival and may be used as an alternative to whole breast-radiation (Valachis 2010). The authors pooled the data from the trials (see Data synthesis section).

We found one systematic review with a search date in 2010 (Blue Cross Shield). They included two RCTs (Polgár 2007; Ribeiro 1993) and seven non-RCTs. They concluded that "the body of evidence on interstitial PBI/APBI compared to conventional whole-breast irradiation is weak, and it is extremely weak (i.e. no comparative studies) for balloon brachytherapy, intraoperative PBI/APBI, and external-beam PBI/APBI. The data on PBI/APBI compared to whole-breast irradiation are insufficient to draw any conclusions about the relative effectiveness of these modalities. Furthermore, it is becoming increasingly clear that each type of PBI/APBI should be judged on its own merits, and studies comparing different PBI/APBI techniques to each other as well as to whole-breast irradiation are needed" (Blue Cross Shield).

The review in Clinical Evidence (search date April 2009) compared intraoperative RT versus standard postoperative RT in women receiving breast-conserving surgery, and found no fully published RCTs (see comment, ASERNIP-S 2002). The review concluded "Studies are currently attempting to address the question as to whether partial breast irradiation may be sufficient treatment for some sub-groups of breast cancer. Until those studies are complete and the follow-up data mature, it is not possible to recommend partial breast irradiation as an appropriate treatment for breast cancer outside of a properly conducted trial" (Clinical Evidence).

Several guidelines have been published on the use of PBI/APBI. The American Society of Therapeutic Radiology and Oncology (ASTRO) consensus evolved because it was clear that many women are treated in the United States with PBI/APBI outside clinical trials (over 32,000 women have had treatment using Mammosite®; Cytec). They indicated a patient population "suitable" for PBI/APBI outside the context of a clinical trial: women ≥ 60 years old, with pT1N0(i-, i+)M0, margins > 2 mm, unifocal disease, oestrogen receptor-positive, who have had no neoadjuvant therapy. They also described women deemed unsuitable for PBI/APBI. They state that "patients who choose treatment with PBI/APBI should be informed that whole-breast irradiation (WBI) is an established treatment with a much longer track record that has documented long-term effectiveness and safety" (Smith 2009). This statement provides guidance in selecting patients who may be appropriate for PBI/APBI outside the context of a clinical trial, but the Task Force strongly endorsed enrolment of all eligible patients considering PBI/APBI onto NSABP-B39/RTOG and encouraged enrolment of other patients considering PBI/APBI, particularly those not in the "suitable" group, into prospective clinical studies to address many of the unanswered questions in PBI/APBI" (Smith 2009).

In the absence of an available trial, the Americal College of Radiology (ACR) Appropriateness Criteria® panel recommends following the consensus guidelines of the ASTRO (Bellon 2011).

The GEC-ESTRO Breast Cancer Working Group recommends three categories guiding patient selection for PBI/APBI:

  1. a low-risk group for whom PBI/APBI outside the context of a clinical trial is an acceptable treatment option; including patients ageing at least 50 years with unicentric, unifocal, pT1–2 (< 30 mm) pN0, non-lobular invasive breast cancer without the presence of an extensive intraductal component (EIC) and lympho-vascular invasion (LVI) and with negative surgical margins of at least 2 mm;

  2. a high-risk group, for whom PBI/APBI is considered contraindicated; including patients ageing ≤ 40 years; having positive margins, and/or any of the following pathological features (multicentric or large (> 30 mm) tumours, EIC positive or LVI positive tumours, four or more positive lymph nodes, unknown axillary status (pNx)); and

  3. an intermediate-risk group, for whom PBI/APBI is considered acceptable only in the context of prospective clinical trials (Polgár 2010).

Authors' conclusions

Implications for practice

The limitations of the currently available data mean that we are unable to draw any definitive conclusions about the efficacy, safety or best technique for delivery of PBI/APBI. We await completion of the ongoing trials for inclusion in a review update.

Implications for research

The ongoing trials will address relevant clinical outcomes. PBI/APBI is a highly technical intervention that is operator dependent and requires careful quality assurance. Interpretation of these trials will require consideration of the quality of the RT delivered, with respect to target definition and treatment verification.

Acknowledgements

We thank the Princess Alexandra Hospital Cancer Collaborative Group.

Data and analyses

Download statistical data

Comparison 1. PBI/APBI versus WBI
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Local recurrence-free survival31140Hazard Ratio (95% CI)1.74 [1.23, 2.45]
2 Overall survival31140Hazard Ratio (95% CI)0.99 [0.83, 1.18]
3 Cause-specific survival2966Hazard Ratio (95% CI)0.95 [0.74, 1.22]
4 Distant metastasis-free survival31140Hazard Ratio (95% CI)1.02 [0.81, 1.28]
Analysis 1.1.

Comparison 1 PBI/APBI versus WBI, Outcome 1 Local recurrence-free survival.

Analysis 1.2.

Comparison 1 PBI/APBI versus WBI, Outcome 2 Overall survival.

Analysis 1.3.

Comparison 1 PBI/APBI versus WBI, Outcome 3 Cause-specific survival.

Analysis 1.4.

Comparison 1 PBI/APBI versus WBI, Outcome 4 Distant metastasis-free survival.

Appendices

Appendix 1. Search strategy: Medline (Ovid) (1966 to present)  

1.RANDOMIZED CONTROLLED TRIAL.pt
2. CONTROLLED CLINICAL TRIAL.pt
3. RANDOMIZED CONTROLLED TRIALS.sh
4. RANDOM ALLOCATION.sh
5. DOUBLE BLIND METHOD.sh
6. SINGLE BLIND METHOD.sh
7. or/1-6
8. (ANIMALS not HUMANS).sh
9. 7 not 8
10. CLINICAL TRIAL.pt
11. exp CLINICAL TRIALS/
12. (clin$ adj25 trial$).ti,ab
13. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab
14. PLACEBOS.sh
15. placebo$.ti,ab
16. random$.ti,ab
17. RESEARCH DESIGN.sh
18. or/10-16
19. 18 not 8
20. 19 not 9
21. 9 or 20
22. exp breast neoplasms/
23. exp "neoplasms, ductal, lobular, and medullary"/
24. exp breast/
25. exp neoplasms/
26. 24 AND 25
27 (breast$ adj5 (neoplasm$ or cancer$ or tumo?r$ or carcinoma$ or adenocarcinoma$ or sarcoma$ or dcis or ductal or infiltrat$ or intraductal$ or lobular or medullary)).mp.
28 exp mammary neoplasms/
29 (mammar$ adj5 (neoplasm$ or cancer$ or tumo?r$ or carcinoma$ or adenocarcinoma$ or sarcoma$ or dcis or ductal or infiltrat$ or intraductal$ or lobular or medullary)).mp
30. or/22, 23,26-29
31. partial breast irradiation.sh,kw,ti,ab
32. partial breast.sh,kw,ti,ab
33. whole breast irradiation.sh,kw,ti,ab
34. whole breast radiotherapy.mp
35. less than whole breast rad$.mp
36. brachytherapy.sh,kw,ti,ab
37. high-dose-rate brachytherapy.sh,kw,ti,ab
38. accelerated partial breast irradiation.sh,kw,ti,ab
39. tumour bed boost.sh.kw.ti.ab
40. sole tumour bed irradiation.sh,kw,ti,ab
41. MammoSite.sh.kw.ti.ab
42. Breast Neoplasms/ rt.sh
43. Radiotherapy, Conformal/adverse events.sh
44. Radiotherapy, Conformal/methods.sh
45. Brachytherapy.sh
46. Balloon dilation.sh
47. Radiotherapy/.sh
48. or/31-47
49. 48 AND 30
50. 49 AND 21

Appendix 2. Search strategy: WHO ICTRP

Basic search:

  1. Partial irradiation for early breast cancer

  2. Early breast cancer AND partial irradiation

  3. Early breast cancer AND partial breast irradiation

  4. Early breast cancer AND Mammosite

  5. Early breast cancer AND Intracavitary brachytherapy

  6. Early breast cancer AND Interstitial brachytherapy

  7. Early breast cancer AND accelerated partial breast irradiation

  8. Early breast cancer and less than whole breast radiotherapy

Advanced search:

1. Title: Partial irradiation for early breast cancer

Recruitment status: all

2. Condition: early breast cancer

Intervention: partial breast irradiation OR Mammosite OR intracavitary brachytherapy OR interstitial brachytherapy OR accelerated partial breast irradiation OR less than whole breast radiotherapy

Recruitment status: all

Appendix 3. ClinicalTrials.gov

Basic searches:

  1. Partial irradiation for early breast cancer

  2. Early breast cancer AND partial irradiation

  3. Early breast cancer AND partial breast irradiation

  4. Early breast cancer AND Mammosite

  5. Early breast cancer AND Intracavitary brachytherapy

  6. Early breast cancer AND Interstitial brachytherapy

  7. Early breast cancer AND accelerated partial breast irradiation

  8. Early breast cancer and less than whole breast radiotherapy

Advanced searches:

1. Search terms: Partial irradiation for early breast cancer

Recruitment: All studies

Study type: All studies

Gender: All studies

2. Condition: Early breast cancer

Intervention: Partial breast irradiation OR Mammosite OR intracavitary brachytherapy OR interstitial brachytherapy OR accelerated partial breast irradiation OR less than whole breast radiotherapy

Recruitment: All studies

Study type: All studies

Gender: All studies

History

Protocol first published: Issue 2, 2008
Review first published: Issue 6, 2014

DateEventDescription
15 May 2008AmendedConverted to new review format.

Contributions of authors

ML, BH and DF wrote the protocol. BH extracted data, created 'Risk of bias' tables and 'Characteristics of included studies' tables, analysed the data, wrote the results section and discussion, and responded to editorial and peer review (in consultation with ML). ML checked the analyses, risk of bias tables, collaborated with writing the results, discussion and conclusion sections. AS checked the extracted data and ran the search strategy.

Declarations of interest

We have no known conflicts of interest.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Princess Alexandra Cancer Collaborative Group, Australia.

Differences between protocol and review

We added locoregional control as a secondary endpoint; in view of two changes in breast cancer management. Firstly, the emergence of axillary sampling means that fewer women have axillary dissection, and partial breast irradiation means that there is no chance of "inadvertent" upper axillary RT being delivered (as we know happens when tangential beams are used to irradiate the entire breast). The effect of these two changes in management have the potential to affect locoregional control adversely in the PBI/APBI group.

We initially indicated that we would convert doses to their biological equivalent (BED), but have in fact used equivalent dose in 2 Gy fractions (EQD2 ). Tthis allows numerical addition of separate components of a treatment and is more readily understood by clinical radiation oncologists because it results in numbers which can be directly related to clinical experience.

We added APBI as well as PBI: modern RT techniques which reduce the treated volume allow the use of high dose per fraction to the smaller treated volume. The ongoing studies tend to use APBI, which reflects modern RT practice, making the review results more applicable.

We added blinding to assessment of risk of bias, because the lack of blinding for the primary outcome of cosmesis would be a significant cause of bias. We searched an additional database (i.e. EMBASE.com) and trial registry (WHO ICTRP) to our search strategy, and also handsearched other resources. This ensured that our searches were as comprehensive as possible, and complied with Cochrane search requirements.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Dodwell 2005

MethodsRCT
Single centre trial in UK tertiary referral centre
Accrual dates: July 1986 to June 1990
Median follow-up: eight years
ParticipantsN = 174 women with pT1-2pN0-1 tumours considered suitable for local excision. All had local excision (with clear margins) and level II axillary dissection. All women had chemotherapy with cyclophosphamide, methotrexate, 5-fluorouracil (CMF) and vincristine, node positive pre-menopausal women had five cycles of CMF. All women received five years of tamoxifen.
Interventions

Experimental arm: tumour bed defined according to pre-operative information, scar position and patient recollection. Dose: 55 Gy in 20 fractions over 28 days. Techniques used: direct cobalt, caesium (47/84) or electron field (13/84), or "mini-tangents" using MV photons (24/84). Margin for PBI/APBI volume not specified.

Control arm: target volume (breast tissue plus one cm margin) was defined clinically. Dose: 40 Gy in 15 fractions over 21 days plus 15 Gy boost (delivered using cobalt, caesium or electron fields).

OutcomesLocal recurrence (position recorded as tumour bed or in remainder of breast)
Arm oedema assessed at six months
Compliance
Locoregional recurrence
Distant metastases
Survival
NotesAssessed clinically three monthly for 12 months then every six months. Biennial mammography. Trial closed early because of poor accrual.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

"174 women were randomised" (Abstract of Dodwell 2005)

"referred by seven surgeons were randomised", page 619, paragraph 5. No details given about method, therefore is uncertain whether it was a source of bias.

Allocation concealment (selection bias)Unclear riskNo details given, therefore the risk of bias is unclear.
Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Participants: No details given about blinding, but both groups were treated equally in follow-up.

Physicians: No details given, this is unlikely to introduce bias.

Blinding of outcome assessment (detection bias)
Objective outcomes
Low risk

Participants: Blinding of patients was not mentioned, and would have been difficult given the type of intervention, but as the outcomes reported were objective, it was unlikely to have been a source of bias.

Physicians: blinding of physicians was not mentioned, therefore probably was not done. This could potentially be a source of bias.

Assessors: Blinding of assessors could have been done. It may be a source of bias in reporting of treatment related morbidity, although described in the text, they were not reported in the results.

"The protocol determined that participants were to be followed up every three months...thereafter. Bilateral annual surveillance mammography was carried out", page 619, paragraph 3.

The follow-up protocol would reduce the risk of bias ensuring women in each arm are seen at the same intervals for follow-up. As mammograms were performed biennially for women in each arm of the trial, (presumably by personnel uninvolved in the trial, although this is not stated), there appears little risk of bias associated with the outcome of local recurrence.

Blinding of outcome assessment (detection bias)
Subjective outcomes
Low risk

Participants: No subjective outcomes reported

Physicians: No subjective outcomes reported

"Assessment of the presence of (any) arm or breast oedema was intended at six months", page 619, paragraph 4

Assessors: No subjective outcomes reported, blinding of assessors could have been done. It may be a source of bias in reporting of treatment related morbidity, although described in the text, they were not reported in the results.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo women excluded, and none reported lost to follow-up. No attrition reported.
Selective reporting (reporting bias)Unclear risk

Outcomes described in text of methods:

Primary: Local-regional recurrence

Secondary: Rx related morbidity

Distant recurrence

Survival

Outcomes reported in paper:

Primary: Local-regional recurrence

Secondary:

Local recurrence

Distant recurrence

Survival

Protocol was not available for review

Other biasUnclear riskTrial stopped early, because of problems with recruitment, not for benefit.

Polgár 2007

MethodsRCT
Single centre trial
Accrual dates July 1998 to May 2004
Median follow-up: 10.2 years
Participants

N = 258 women with invasive breast cancer treated in Hungary.

Inclusion criteria: wide excision with negative margins, unifocal tumour, tumour size < 20 mm, clinically or pathologically N0, or single microscopic nodal metastasis (> 0.2 mm and < 2.0 mm), i.e. pT1N0-1miM0, grade I or II.

Exclusion criteria: bilateral breast cancer, prior uni or contralateral breast cancer, concomitant or previous other malignancies, invasive lobular cancer, pure ductal or lobular cancer in situ (pTis). After 2001, women < 40 years excluded.

Mean age 58 to 59 years (given for each arm)

Interventions

Experimental arm: partial breast irradiation; 88/128 women had 7 X 5.2 Gy high-dose rate (HDR) multi-catheter brachytherapy and 40/128 women unsuitable for HDR had 50 Gy/25# electron beam RT to partial breast

Control arm: 50 Gy/25# whole breast irradiation (N = 130)

Surgery: wide excision (resection of tumour with at least 1 cm macroscopic free margin). Cavity marked with titanium clips.

Central pathology review performed.

Systemic therapy given according to institutional protocol.

Baseline mammography was performed at six months after RT then annually. Women were seen every three months in the first year, then once every six months.

Outcomes

Primary outcomes
Local recurrence in the ipsilateral breast at five years

Cosmetic outcome (using the Harvard cosmetic score; Table 1)

Secondary outcomes

  1. Overall survival

  2. Toxicity - late toxicity will be reported elsewhere

  3. Cause-specific mortality (deaths due to breast cancer at five years)

  4. Distant metastasis-free survival at five years

  5. Relapse-free survival at five years

  6. Subsequent mastectomy (ipsilateral partial mastectomy, modified radical mastectomy or radical mastectomy)

  7. Compliance, defined as the number of women who commence treatment with PBI/APBI or conventional EBRT and complete the treatment course.

Notes

Early stopping at N = 258 because another multi-centred trial commenced.

Local recurrence (LR) defined as any detection of cancer in the treated breast, proven histologically. An "elsewhere breast failure" defined as ipsilateral (LR) at least 2 cm from the clips. All other LR classified as true recurrence or marginal miss.

Cosmetic score Harvard criteria, scored by treating radiation oncologist and chief investigator at analysis date (June to August 2006). In case of discrepancy, worst score used for analysis.

Event-free intervals defined as time between date of surgery and date of event or last follow-up.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

"were randomised". Polgár 2007 page 694, para 3.

"randomly allocated to treatment options by a sealed envelope system in blocks of 10". Randomisation was done by the main investigator (C.P.) Polgár 2007, page 695, paragraph 2.

The trial is likely to have been randomised.

Allocation concealment (selection bias)High risk

"randomly allocated to treatment options by a sealed envelope system in blocks of 10". Polgár 2007, page 695, paragraph 2.

Allocation concealment appears to have been done, although the description is incomplete, which contributed to the judgement of high bias risk.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Participants: not mentioned, unlikely to have been done.

"Blinding of physicians performing treatments and follow-up of patients was not possible for technical reasons". Polgár 2007, page 695, paragraph 2.

Physicians: Not done.

"Blinding of physicians performing treatments and follow-up of patients was not possible for technical reasons". Polgár 2007, page 695, paragraph 2.

Blinding of outcome assessment (detection bias)
Objective outcomes
Low risk

Participants: not mentioned, unlikely to have been done.

"Blinding of physicians performing treatments and follow-up of patients was not possible for technical reasons". Polgár 2007, page 695, paragraph 2.

Physicians: Not done, but in view of prespecified follow-up protocol, with regular mammography, unlikely to have introduced bias.

"Patients were seen every three months in the first two years after RT and every six months thereafter. Baseline mammography was performed six months after completion of RT and yearly thereafter". Polgár 2007, page 697, paragraph six.

"Blinding of physicians performing treatments and follow-up of patients was not possible for technical reasons". Polgár 2007, page 695, paragraph 2.

"Local recurrence...proved by histological confirmation in every case". Polgár 2007, page 697, paragraph 6.

Assessors: Not done

Unlikely to be a source of bias in view of the prespecified schedule for follow-up visits and investigations. Local recurrence required biopsy confirmation, which would reduce the risk of bias in evaluation of this outcome.

Blinding of outcome assessment (detection bias)
Subjective outcomes
High risk

Participants: Not mentioned, unlikely to have introduced bias

Physicians: Not mentioned, may be a source of bias

Assessors: Not mentioned, unlikely to have been done, this is potentially a source of bias.

"Cosmetic outcome scored independently by treating radiation oncologist and the main investigator…in the case of discrepancy, the worse cosmetic score was used for analysis." Polgár 2007, page 697, paragraph 5

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Exclusions : nil

Attrition:

Experimental N = 0

Control N = 2 (declined follow-up at 18 and 22 months post op)

Selective reporting (reporting bias)Unclear risk

Outcomes in methods section:

Primary: local recurrence at five years

Differences in cosmetic outcome

Outcomes reported in paper:

Local recurrence

LR-free survival at five years

Five year actuarial LR rate, true recurrence and marginal miss

Overall survival at five years

Cancer-specific survival at five years

DM-free survival at five years

Disease-free survival at five years

Probability of developing contralateral cancer at five years

Salvage therapy

MRM rate

Cosmetic outcome

Outcomes in methods and protocol: protocol not reviewed

Other biasLow riskTrial stopped early because 258/ planned 570 patients) of competing trial GEC-ESTRO starting recruiting.

Ribeiro 1993

MethodsRCT
Accrual: November 1982 to December 1987
Median follow-up: 8.7 years
ParticipantsSetting: tertiary referral hospital in UK. N = 708 women aged < 70 years (mean age 53 years in experimental arm, 52 years in control arm). Single, mobile lump < 4 cm treated with BCS and no axillary dissection. Breast carcinoma, clinically negative axilla.
Interventions

Experimental arm: limited field (LF) RT to tumour bed only, using 8 to 14 MeV, 40 to 42 Gy in eight fractions over 10 days.

Control arm: Wide field (WF) radiation to whole breast, ipsilateral axilla and supraclavicular fossa (SCF) to 40 Gy in 15 fractions over 21 days using 4 Mv. Unwedged tangents used to treat breast, with anterior field matched to treat axilla and SCF.

Outcomes

Survival, local or regional recurrence, breast recurrence, axillary recurrence (all reported as first event data). Annual physician assessment of late effects of RT (telangiectasia, fibrosis, fat necrosis, breast oedema, rib fractures, pneumonitis, match-line fibrosis). A un-validated three-point scale was used by the treating physician. Fat necrosis was diagnosed when a biopsy was performed. Rib fractures were recorded when the patient gave a history of acute pain, but not confirmed radiologically.

Scoring system three point scale; minimal, moderate or marked.

NotesFollowed every three months for two years, then every six months. Mammography not part of protocol.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

"randomly assigned", Ribeiro 1993 page 278, paragraph 9.

"They were then allocated to one of the two groups, which had been randomised using a balanced block design, where each block size in sequence was chosen at random from a given range of six-16", Ribeiro 1993 page 279, paragraph 4.

"were randomly allocated", Ribeiro 1990, page 27, abstract.

Allocation concealment (selection bias)Low risk"Patients entered into the trial by direct phone call to the statistics department", page 279, paragraph 4. Allocation concealment described and likely to have occurred.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk

Participants: Not mentioned, probably not done.

Phyicians: Not mentioned, probably not done.

Risk of bias unclear.

Blinding of outcome assessment (detection bias)
Objective outcomes
High risk

Participants: Not mentioned, probably not done.

Physicians: Not mentioned, probably not done.

Assessors: Not mentioned, probably not done.

Reporting of local recurrence is at high risk of bias, as follow-up mammography was not performed at pre-prescribed intervals, thus allowing high risk of bias in evaluation of this outcome.

Blinding of outcome assessment (detection bias)
Subjective outcomes
High risk

Participants: Not mentioned, probably not done.

Physicians: Not mentioned, probably not done.

Assessors: Not mentioned, probably not done.

Risk of bias high, because clinicians in favour of the intervention could potentially under-report toxicity in this arm of the trial.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Exclusions: N = 5 (two had palpable nodes, one had angiosarcoma, two had bone metastases).

Not reported according to group.

Attrition: None documented, "no patients lost to follow up", Ribeiro 1990, page 28, paragraph 8

Selective reporting (reporting bias)High risk

Outcomes indicated in methods:

Local control

Factors governing local recurrence

Axillary recurrence

Survival

RT sequelae

Outcome reported in paper:

Overall survival: reported by tumour size, and not by group

Actuarial breast-cancer specific survival: at 3, 5 and 7 years.

Local recurrence (reported as first event data)

Axillary recurrence

Fibrosis (not reported for all in cohort)

Telangiectasia (not reported for all in cohort)

Occurrence of fat necrosis, breast oedema, rib fractures and pneumonitis reported when detected.

Cosmesis: assessed annually)

Other biasHigh risk

Mammograms performed in 25% (women from a  particular institution).

Follow-up mammography only if symptoms or signs of recurrence.

TARGIT

MethodsMulticentre international randomised non-inferiority phase III trial, accrual from March 2000 - data lock 02 May 2010.
ParticipantsN = 1113 women ≥ 45 years, with T1 and small T2N0-1M0 invasive breast cancer, suitable for BCS, available for 10 years' follow-up.
Interventions

Experimental arm: a single fraction of RT given intraoperatively (using Intrabeam).

Control arm: standard post-operative RT (40 to 56 Gy ± 10 to 16 Gy boost).

Outcomes

Primary: pathologically confirmed local relapse within the treated breast.

Secondary: Site of relapse within the breast, relapse-free survival and overall survival, local toxicity and local morbidity.

Notes

Intrabeam uses low Kv X-rays to deliver 20 Gy at the surface of the tumour bed, attenuating to 5 to 7 Gy at 1 cm. Quality assurance: training and auditing by member of ISC required before centre could join.

NCT00983684, ISCTN 34086741, ISRCTN 34086741, REC No. 99/0307, UKCRN.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

"prospective, randomised, non-inferiority trial", Abstract, paragraph 2, page 1.

"patients were randomly assigned in a 1:1 ratio", Abstract, paragraph 2, page 1.

"patients were randomly allocated", Abstract, paragraph 3, page 1.

"TARGIT –A was a …randomised, phase three trial", Methods, paragraph 4, page 2.

"Patients were randomly assigned in a 1:1 ratio"

This trial appears to have been randomised.

Allocation concealment (selection bias)Low risk

"patients were randomly assigned in a 1:1 ratio…with blocks stratified by centre." Abstract, paragraph 2, page 1.

"The randomisation schedules were generated centrally by computer (securely kept in trial centres in Perth for Australian centres, and London, UK for all other centres). Requests for randomisation were via telephone or fax to the trials office (Perth or London), where a trained member of staff checked patient eligibility. Treatment was allocated from a pre-printed randomisation schedule available to authorised staff only. Written confirmation of randomisation was sent by fax to the site". Methods, paragraph 1, page 4.

This is trial is likely to have had adequate allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Participants: "Neither patients nor investigators or their teams were masked to treatment assignment". Abstract, paragraph 2, page 1.

Physicians: "Neither patients nor investigators or their teams were masked to treatment assignment". Abstract, paragraph 2, page 1.

"Individual centres were unblinded to treatment given in their own centres, but they were not given access to these data for other sites". Methods, paragraph 3, page 4.

"Patient assessments were scheduled at entry".

Because of the nature of the intervention, it was not possible to blind the women participating or the personnel involved in their care, this is not likely to have resulted in bias. Because the patient assessments were scheduled at trial entry with pre-specified times for follow-up visits this is likely to have reduced the risk of bias from the lack of blinding of personnel.

Blinding of outcome assessment (detection bias)
Objective outcomes
Low risk

Participants: not relevant.

Physicians: not relevant.

Assessors: "Patient's assessments were scheduled at entry, 3 months and 6 months", page 94, paragraph 4. This means the risk of lead time bias is reduced.

"We recommend that mammography of the ipsilateral breast occurs annually and of the contralateral breast at least every three years". TARGIT protocol, 7.1 page 25.

"Confidential unblinded reports for the DMC, and blinded reports for the ISC were produced by the trial statistician. Unblinded analyses were done according to a prespecified statistical analysis plan". Methods, paragraph 3, page 4.

If there were prespecified time intervals for mammography, this would have reduced the risk of bias for detection of the primary endpoint: local relapse.

Blinding of outcome assessment (detection bias)
Subjective outcomes
Low risk

"The secondary outcome measure of local toxicity, or morbidity was assessed from data recorded on the complications form which contained a  prespecified checklist", Page 94, paragraph 3.

It is not stated who assessed the subjective outcomes, however, we know:

"Neither patients nor investigators or their teams were masked to treatment assignment", Abstract, paragraph 2, page 1.

The blinding of outcome assessors was not reported, this does mean that there is risk of bias with assessment of toxicity however the use of a prespecified form would help to reduce bias because the data would be collected for all women.

Incomplete outcome data (attrition bias)
All outcomes
High risk

"All randomised patients were included in the intention-to-treat analysis", Abstract, paragraph 2, page 1.

"When displaying the results, we restricted the duration of follow up to four years...since fewer than 420 (< 20%) patients had follow up beyond this point", page 95, paragraph 4.

Because the outcomes were reported with a follow-up duration of four years, this does mean there is a high risk of bias because they report on < 20% of the patients.

Selective reporting (reporting bias)High risk

Outcomes specified in the protocol:

Local tumour control

Site of relapse within the breast

Relapse-free survival

Overall survival

Local toxicity and morbidity

Cosmesis, patient satisfaction, health economics, patient preference will be the subject of a sub-protocol.

Outcomes specified in methods:

Primary: "pathologically confirmed local relapse within the treated breast", page 94, paragraph 5

Secondary: prospectively collected local toxicity or morbidity (checklist included haematoma, seroma, wound infection, skin breakdown, delayed wound healing), RTOG Grade III/IV dermatitis, telangiectasia, pain in irradiated field or other. "To assess extent of local surgery we analysed specimen weight, margin status and re-operation for margins", page 95, paragraph 1.

Outcomes reported in paper:

Median amount of tissue resected

Re-excision rates

Any complication

Clinically significant complications

RTOG toxicity score of III/IV

Major toxicity rate

Axillary recurrences

Uncontrolled local recurrences

Local recurrences at four years

The authors state that "no changes were made to trial outcomes after commencement of the trial".

The outcomes prespecified in the protocol have not all been reported, this probably reflects the short follow-up duration, so does put this outcome at high risk of bias.

Other biasHigh riskShort duration of follow-up puts the outcomes reported at high risk of bias.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Flynn 2003Not a RCT.
Hannoun-Levi 2008Not a RCT.
NCT00892814Phase II RCT.
NCT01185132PBI used in both study arms.
NCT01928589PBI used in both study arms.
Ott 2007Not a RCT.
Polgar 2004Not a RCT.
Sher 2008Not a RCT.
Suh 2005Not a RCT.
TARGIT-BWBRT used in both study arms.
TROGFeasibility study and not a RCT.

Characteristics of studies awaiting assessment [ordered by study ID]

Barcelona

MethodsPhase III RCT
ParticipantsWomen with early stage breast cancer (T1-2NO MO)
Interventions

Experimental arm: accelerated partial breast irradiation (PBI/APBI) delivered by three dimensional

conformal external beam RT (3D-CRT)

Control arm: conventional whole-breast RT (WBRT).

OutcomesLocal control, dosimetry and toxicity (using RTOG CTC)
Notes-

ELIOT

MethodsPhase III RCT
ParticipantsWomen aged 48 to 75 with early breast cancer, maximum tumour diameter 2.5 cm, suitable for breast conservation
Interventions

Experimental arm: intraoperative electron therapy to deliver 21 Gy at the 90% isodose delivered at the time of surgery after tumour excision

Control arm: post-operative external beam RT (50 Gy/25 fractions plus 10 Gy/5 fraction boost using electrons)

OutcomesIpsilateral in breast local recurrence (IBTR) which includes both local recurrence and new ipsilateral breast primaries, overall survival, regional nodal failure, distant metastases, late toxicity (measured using LENT-SOMA)
Notes-

Characteristics of ongoing studies [ordered by study ID]

GEC-ESTRO

Trial name or titleInterstitial Brachytherapy Alone Versus External Beam Radiation Therapy After Breast Conserving Therapy for Low-Risk Invasive Carcinoma and Low-Risk Ductal Carcinoma in Situ (DCIS) of the Female Breast
MethodsRandomized, phase III, open label trial
ParticipantsWomen > 40 years with Stage 0, I or II breast cancer (including DCIS), no lymph or vascular invasion, lesions < 3 cm in diameter, pN0/pNmi, DCIS alone, sentinel node biopsy optional. Clear margin (at least 2 mm), unifocal or unicentric disease.
Interventions

Experimental arm: accelerated partial breast irradiation

Control arm: external beam whole breast irradiation

Outcomes

Primary: local control

Secondary: incidence and severity of acute and late side effects, differences in cosmetic results, distant metastases disease-free survival, survival rates (overall survival, disease-free survival), contralateral breast cancer rate, quality of life.

Starting dateNovember 2004
Contact informationO Ott oliver.ott@strahlen.imed.uni-erlangen.de
NotesNCT00402519

IMPORT

Trial name or titleRandomized Trial testing Intensity Modulated and Partial Organ Radiotherapy After Breast Conservation Surgery for Early Breast Cancer
MethodsRandomized, phase III multi centre trial
ParticipantsWomen > 50 years, with invasive breast cancer pT1-2pN0, who have had BCS with negative margins (≥ 2 mm) who have < 1% annual risk of local recurrence.
Interventions

Experimental arm 1: reduced whole breast RT and standard partial breast Rt once daily on days 1 to 5 for three weeks

Experimental arm 2: Partial breast RT daily on days 1 to 5 for three weeks

Control: Standard whole breast RT day 1 to 5 for three weeks

Outcomes

Primary: Local tumour control in the ipsilateral breast

Secondary: Location of tumour relapse, contralateral primary breast cancer, regional or distant metastases, late adverse effects in normal tissues, (photographic, physician and patient assessments), quality of life, cost-effectiveness

Starting dateOctober 2006
Contact informationJ Yarnold Royal Marsden, Surrey
Notes

NCT00814567

CSDR0000629765, ICR-IMPORT-LOW, ICR-CTSU/2006/10001, ISCTN12852634, EU-20896

IRMA

Trial name or titleIRMA
MethodsMulticentre phase III controlled randomised, unblinded study of non-inferiority.
ParticipantsWomen aged ≥ 49, ECOG 0-2, undergoing conservative breast surgery for invasive
breast cancer, pT 1-2 (< 3 cm in diameter) pN0-N1 M0, unifocal, resection margins
histologically negative ( 2 mm) at first intervention or after subsequent widening.
InterventionsTrial arm 38.5 Gy total in 10 fractions (3.85 Gy per fraction), twice a day with an interval of
at least six hours between the two fractions, for five consecutive working days of the sole cavity.
Control arm 50.0 Gy in 25 fractions (2 Gy per fraction), once a day for five days in the week RT of the entire breast.
OutcomesPrimary: survival free of local ipsilateral recurrence as prime event.
Secondary: global survival, locoregional recurrence-free, distant recurrence-free, acute
and late toxicity (RTOG) and cosmetic result.
Starting date-
Contact informationData Center Office,
Clinical Trials Office, Integrated Department of Oncology and Hematology,
Polyclinic Hospital, University of Modena and Reggio Emilia
R. D’Amico, G. Jovic, R. Vicini
Tel. 059 4223865
Roberto.damico@unimore.it
NotesStudy currently accruing patients.

Livi

Trial name or titleLivi
MethodsRCT, single centre
ParticipantsWomen > 40 years, wide local excision or quadrantectomy for invasive breast cancer, negative margins, tumour size ≤ 25 mm
InterventionsPBI/APBI (using IMRT) versus WBI (conventional RT)
OutcomesNot specified in report
Starting date-
Contact information-
NotesStudy has not completed accrual (target 520)

NSABP-B39/RTOG

Trial name or titleA randomised phase II study of conventional whole breast irradiation (WBI) versus Partial Breast Irradiation (PBI) for Women with Stage 0, I, or II Breast Cancer
MethodsRandomized, multicentre phase III trial
ParticipantsWomen > 18 years with histologically confirmed DCIS or invasive adenocarcinoma of the breast, negative histological margins, no more than 3 axillary nodes involved, must have had BCS.
Interventions

Experimental arm: Partial breast irradiation five days per week for five to seven weeks,

Control arm: Whole breast irradiation bd on five days over five to 10 days) 50 Gy in 25 fractions at 1.8 to 2 Gy per fraction, optional boost to 60 to 66 Gy).

Outcomes

Primary: In-breast tumour recurrence.

Secondary: Survival , event-free survival , distant disease-free survival, quality of life and patient-reported cosmesis, physician-reported cosmesis and toxicity.

Starting dateMarch 2005
Contact information

Study chair: F Vicini, WIlliam Beaumont Hospital- Royal Oak Campus

J White, Medical College of Wisconsin

Notes

NCT00103181

NSABP B-39/RTOG 0413, SWOG-NSABP-B-39

Collaborators: SWOG, NCI, RTOG, NSABP

RAPID

Trial name or titleRAPID: Randomised Trial of Accelerated Partial Breast Irradiation. Official title: A Multi-Centered Randomized Trial to determine if Accelerated Partial Breast Irradiation, utilizing 3D CRT, is as effective as whole breast irradiation following breast conserving surgery in women with ductal carcinoma in situ or invasive breast cancer with negative axillary nodes.
MethodsRandomised phase III trial; stratified for age, tumour histology, tumour size, adjuvant hormonal therapy and clinical centre.
ParticipantsWomen ≥ 40 years with new diagnosis of DCIS or with microscopically clear margins after BCS of non-invasive or invasive disease (or no residual disease on re-excision). Negative axillary nodal involvement including micrometastasis (> 0.2 mm or positive cells only identified on IHC as determined by 1) sentinel node biopsy; 2) axillary node dissection; or 3) clinical exam for DCIS only.
Interventions

Experimental arm: Accelerated partial breast irradiation (3D CRT: 38.5 Gy in 10 fractions, bd over five to eight days. Six to eight hour gap between doses required).

Control arm: whole breast irradiation (42.5 Gy in 16 fractions daily over 22 days). Women with large breast size: 50 Gy in 25 fractions over 25 days. Boost 10 Gy in four to five fractions over four to seven days is permitted for those women deemed at moderate to high risk of local recurrence as per local cancer centre guidelines.

Outcomes

Primary: ipsilateral breast tumour recurrence (defined as recurrent invasive or in situ cancer in the ipsilateral breast including the axillary tail).

Secondary: adverse cosmetic outcome, disease-free survival, event-free survival, overall survival , radiation toxicity, quality of life, cost effectiveness.

Starting dateJanuary 2006
Contact information

Brandy Cochrane bcochrane@mcmaster.ca

Lornal Holmes lholmes@mcmaster.ca

NotesNCT00282035

SHARE

Trial name or titleStandard or Hypofractionated Radiotherapy Versus Accelerated Partial Breast Irradiation (PBI/APBI) for Breast Cancer (SHARE) Phase III Multicentric Trial Comparing Accelerated Partial Breast Irradiation (PBI/APBI) Versus Standard or Hypofractionated Whole Breast Irradiation in Low Risk of Local Recurrence of Breast Cancer
MethodsMulticentre RCT
Participants Inclusion criteria:
Women aged ≥ 50 years
Menopausal status confirmed
Pathology confirmation of invasive carcinoma (all types)
Complete tumour removal and conservative surgery
Pathologic tumour size of invasive carcinoma ≤ 2 cm (including the in situ component) pT1
All histopathologic grades
Clear lateral margins for the invasive and in situ disease (> 2mm)
pN0 or pN(i+)
No metastasis
RT should be started more than four weeks and less than 12 weeks after last surgery
Surgical clips (four to five clips in the tumour bed)
No prior breast or mediastinal RT
ECOG 0-1
Information to the patient and signed informed consent
Exclusion criteria:
Multifocal invasive ductal carcinoma defined as the presence of at least two distinct tumours that are separated by normal tissue or when the distance between the two lesions does not permit conservative surgery
Bilateral breast cancer
No or less than four surgical clips in the tumour bed
Nodal involvement : pN1 (including micrometastasis, mi+), pN2, pN3
Metastatic disease
internal mammary node involvement or supraclavicular lymph node involvement
Indication of chemotherapy or trastuzumab
Involved or close lateral margins for the invasive and /or in situ components (< 2 mm) AND impossibility to re-operate or impossible to perform another conservative surgery
Patients with known BRCA1 or BRCA2 mutations
Previous mammoplasty
Previous homolateral breast or mediastinal irradiation, or both
Previous invasive cancer (except basocellular epithelioma or in situ carcinoma of the cervix)
No geographical, social or psychologic reasons that would prevent study follow
InterventionsRadiation: Accelerated partial breast irradiation
Tumor bed 40 Gy in 10 fractions, two fractions of 4 Gy per day in five to seven days. PBI/APBI using 3D CRT technique, in five days, 40 Gy to the tumour bed.
Outcomes Primary outcome measures:
Rate of local recurrence
Secondary outcome measures:
Ipsilateral breast recurrence-free survival
Nodal regional recurrence-free survival
Distant recurrence-free survival
Disease-specific survival
Overall survival
Toxicities: Measurement of the rate and type of toxicity (acute and late toxic effects)
Cosmetic: comparison of the cosmetic result (according to both the physician and the patient)
Quality of life and satisfaction
Medico-economic study
Starting dateOctober 2010
Contact informationJerome LEMONNIER, PhD+33 1 7193 6702j-lemonnier@unicancer.fr
Notes 

Ancillary