MOLECULAR AND CLINICAL ONCOLOGY 5: , 2016

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1 MOLECULAR AND CLINICAL ONCOLOGY 5: , 2016 Improvement of survivl with postmstectomy rdiotherpy in ptients with 1-3 positive xillry lymph nodes: A systemtic review nd met-nlysis of the current literture HANNAH HEADON, ABDUL KASEM, REHAM ALMUKBEL nd KEFAH MOKBEL The London Brest Institute, The Princess Grce Hospitl, W1U 5NY London, UK Received December 14, 2015; Accepted Mrch 21, 2016 DOI: /mco Abstrct. In brest cncer with >4 positive xillry lymph nodes, it is common prctice to deliver rdiotherpy to the ffected site following mstectomy. However, less is known regrding the benefits this my confer on women with 1 3 positive lymph nodes. In this met nlysis, we imed to ssess whether post mstectomy rdiotherpy (PMRT) ws beneficil for such ptients. A literture review ws conducted using the PubMed nd Ovid dtbses. Selected studies were nlysed nd dt regrding overll survivl (OS) nd locoregionl recurrence (LRR) rtes were extrcted. Sttisticl nlysis ws then conducted in order to develop combined risk rtio (RR) for both OS nd LRR in the setting of PMRT in women with brest cncer with 1 3 positive lymph nodes. PMRT in women with 1 3 positive lymph nodes significntly reduced the risk of LRR, with RR of 0.3 [95% confidence intervl (CI): ] nd lso showed minor benefit in terms of OS (RR=1.03, 95% CI: ). Therefore, in brest cncer ptients with 1 3 positive lymph nodes, PMRT significntly reduced the risk of LRR nd ws ssocited with minor OS benefit. Until the results of ongoing rndomised controlled trils re published, PMRT should be recommended in this group of ptients following creful multidisciplinry discussion. Introduction In brest cncer, common tretment for chieving locl control is for the ptient to undergo mstectomy in order to remove ny detectble mcroscopic disese. In erly stge disese, this ims to remove the tumour nd, therefore, reduce the incidence of metstsis. However, mstectomy is not lwys ble to remove ll disese foci, which my remin in the Correspondence to: Professor Kefh Mokbel, The London Brest Institute, The Princess Grce Hospitl, Nottinghm Plce, W1U 5NY London, UK E mil: kefhmokbel@hotmil.com Key words: postmstectomy rdiotherpy, xillry lymph nodes, brest cncer locoregionl tissue. This my led to locoregionl recurrence (LRR) nd, subsequently, in some cses, deth from brest cncer. Rdiotherpy, when used s n djuvnt therpy, hs the potentil to remove smll disese foci, thereby reducing the risk of LRR. The use of post mstectomy rdiotherpy (PMRT) hs long been estblished in the tretment of ptients with T3 4 brest cncer nd or those with 4 positive xillry lymph nodes, hving been ssocited with cler survivl benefit nd reduction in locl recurrence, evidence tht hs reched level of 1 (1). Therefore, its use in such ptients is currently recommended by severl ntionl bodies, including the Ntionl Institute for Helth nd Clinicl Excellence (2). The centrl issue currently is the role of PMRT in intermedite risk ptients, mening those with 1 3 positive lymph nodes. A met nlysis published in 2014 demonstrted tht the beneficil effects of PMRT remined pprent in such ptients, who received the sme benefit s those with more positive nodes (3), lthough no dditionl benefit ws observed in those without positive nodes. The im of the present met nlysis ws to build upon the evidence presented previously by focusing on the effect of PMRT on overll survivl (OS) nd LRR in ptients with 1 3 positive xillry lymph nodes, regrdless of the use of systemic therpy, by including dt from more recent studies. Mterils nd methods Types of studies nd prticipnts. Prospective clinicl trils nd retrospective cse series with reported outcomes s function of PMRT in brest cncer ptients with 1 3 positive xillry lymph nodes were considered. All the selected studies included femle dult ptients with primry brest cncer nd positive metstses to 1 3 xillry lymph nodes, nd ll the ptients were treted with mstectomy, with or without PMRT. Outcome mesures. The primry outcome ws OS in ptients treted with PMRT in the setting of primry brest cncer. The secondry endpoint ws LRR, when reported. Serch methods. A computer ided serch through the PubMed nd Ovid dtbses ws performed to identify relevnt literture. The lower limit dte for the serch ws set t 01/04/2015, with no upper limit. The following serch terms were used: post mstectomy rdiotherpy 1 3 lymph nodes

2 430 HEADON et l: META-ANALYSIS OF THE EFFECT OF POST MASTECTOMY RADIOTHERAPY ON SURVIVAL survivl, post mstectomy 1 3 lymph nodes, rdiotherpy post mstectomy <3 lymph nodes nd post mstectomy. The relted rticles function on PubMed ws lso utilised nd the bibliogrphies of relevnt rticles were nlysed in order to identify ll relevnt literture. Dt collection nd nlysis. The uthors independently performed the study selection ccording to the inclusion criteri outlined bove. Studies in full text were selected if they reported: i) Either OS, or LRR, or both, for dult femle brest cncer ptients who were treted with mstectomy nd PMRT compred with ptients undergoing mstectomy without PMRT in the presence of 1 3 positive xillry lymph nodes; nd ii) full text ws vilble for dt extrction. The exclusion criteri were: i) Studies tht did not report OS or LRR; nd ii) cse reports, commentries, letters or reviews. Dt extrction. The uthors extrcted dt independently using the following items: Chrcteristics of included studies (uthor, publiction dte, study design, prticipnts nd interventions), medin ge of the prticipnts nd the forementioned outcomes. Mesure of tretment effect nd sttisticl nlysis. Percentges nd their 95% confidence intervls (CIs) for OS nd or LRR s function of the use of PMRT in ptients with 1 3 positive lymph nodes were retrieved from ech included study. A met nlysis of ech outcome ws then performed, following ssessment for heterogeneity using Cochrne's Q nd I 2 tests. The results of these tests, plus zero effect test, determined the use of either fixed effects or rndom effects model. Potentil publiction bises were evluted with funnel plots for OS nd LRR in order to exmine the reltive symmetry of individul study estimtes round the overll estimte in ddition to Duvl nd Tweedie's trim nd fill method. This ws ccompnied by Begg's nd Egger's tests. P<0.05 ws considered to indicte sttisticlly significnt differences. The results were reported s clssic forest plot, one for ech outcome of OS nd LRR. All the sttisticl nlyses were performed using RevMn 5.1 nd Comprehensive Met Anlysis, version 2 softwre (Comprehensive Met- Anlysis Softwre, Englewood NJ, USA). Results A totl of 943 publictions were identified, 14 of which were included in this review (Tbles I nd IV), incorporting totl of 8,544 ptients. The flow digrm of the study selection process is shown in Fig. 1. A totl of 13 studies were excluded, s they did not include reports of either OS or LRR rtes s prt of their results. All included studies were retrospective cse series. The primry endpoints of either OS or LRR rte, long with 95% CIs were reported, or could be clculted for ll the studies included. The pooled reltive risk rtio (RR) for OS ws 1.03 (95% CI: ) nd for LRR it ws 0.30 (95% CI: ), showing benefit in delivering PMRT to ptients with 1 3 positive lymph nodes. OS. For OS, totl of 9 studies were included (Tble I), incorporting 5,837 ptients with men follow up of 80.4 months Tble I. Studies included in the OS nlysis of the effect of PMRT on brest cncer ptients with 1 3 positive lymph nodes. Number Number Number Medin Overll Overll of in in Type Medin follow-up survivl survivl in First uthor, prticipnts control intervention of ge time in intervention yer (Refs.) Country Study design (totl) group group surgery (yers) (months) controls (%) group (%) P vlue Nordenskjӧld, Sweden Popultion bsed 2,502 1,490 1,012 Mstectomy NR NR (4) Kong, 2013 (5) Kore Retrospective cse series Mstectomy Chitpnrux, Thilnd Retrospective cse series Mstectomy NR (6) Cosr, 2011 (7) Turkey Retrospective cse series Mstectomy Wu, 2010 (8) Chin Retrospective cse series Mstectomy Rgz, 1997 (9) Cnd Rndomised controlled tril Mstectomy NR Su, 2014 (10) Tiwn Retrospective cse series Mstectomy Moo, 2013 (11) USA Retrospective cse series 1, Mstectomy NR Hung, 2012 (12) Chin Retrospective cse series Mstectomy 48.5 (men) OS, overll survivl; PMRT, post-mstectomy rdiotherpy; NR, not reported.

3 MOLECULAR AND CLINICAL ONCOLOGY 5: , Tble II. Heterogeneity tests for overll survivl. Test Null vs. lterntive/thresholds Mesure Df χ 2 Prob level Cochrn's Q H 0 : All studies re evluting the sme effect Risk rtio 8 χ 2 = H : Not ll studies re evluting the sme effect I 2 0 to 40%: My not be importnt Risk rtio I 2 =42 30 to 60%: My represent moderte heterogeneity 50 to 90%: My represent substntil heterogeneity 75 to 100%: Indictes considerble heterogeneity Tests performed with RevMn. Cochrn's Q nd I 2 tests demonstrted tht the null hypothesis my be rejected t 5% level of significnce nd tht the included studies exhibited moderte heterogeneity. Df, degree of freedom. (rnge, months). Informtion collected included totl prticipnts in the tretment nd control rms nd respective OS rtes. The men follow up time ws 80.4 months. First, heterogeneity ws ssessed ccording to Cochrn's Q nd I 2 tests. Cochrn's Q test suggested tht the null hypothesis (tht the tretment effect would be equl to 0) could be rejected, whilst the I 2 ws clculted t 42%, indicting moderte heterogeneity (Tble II). To ccount for this heterogeneity, we clculted summry sttistics using the rndom effects model. RRs were clculted from the results of the studies listed in Fig. 2. The summry RR ws then clculted s 1.03 (95% CI: ). Therefore, ccording to the summry effect, OS is 3% higher following PMRT. When the reltive risk mesure vlue is equl to 1.00, it indictes no difference in OS between intervention nd control groups. As the lower limit of the 95% CI is 1.00, n dditionl zero effect test ws performed, bsed on the nturl logrithms of RRs (Tble III). Both tests chieved sttisticl significnce (set t P<0.05) t the 5% significnce level; therefore, the null hypothesis cn be rejected. Furthermore, we my conclude tht PMRT exerts smll but positive effect on the OS of ptients. The lst item in our nlysis ws to estimte the publiction bis of the included studies by incorporting them into funnel plot. Within the funnel plot, not ll studies re within the 95% CI, nd it is not conclusive whether ll the studies re symmetricl round the combined effect size, indicting bsence of publiction bis. Using Duvl nd Tweedie's trim nd fill method imputes n llegedly omitted study with nturl logrithm RR of The recomputed combined effect estimte remins very close to our initil estimte of 1.03 on the rndom effects model: 1.03 (95% CI: ) vs (95% CI: ), respectively. The Begg nd Mzumdr rnk correltion test lso supported the bsence of publiction bis, showing no correltion between the study size nd the effect size. In conclusion, we my support our estimte of summry RR=1.03, with 95% CI of LRR. The effect of PMRT on LRR ws lso nlysed using 11 studies (5,7,9-17), incorporting 5,399 ptients (Fig. 3, Tble IV). The men follow up time ws clculted s 91.2 months (rnge, months). The effect of the intervention ws gin estimted using the RR mesure. We used the zero effect test, Cochrne's Q nd I 2 tests for heterogeneity, summry effect using forest plot, nd checked for publiction Figure 1. Flow chrt outlining the methodology followed through the process of the literture review. bis using funnel plot, Egger's test of the intercept, nd Begg nd Mzumdr rnk correltion test. Using the zero effect test, we were ble to reject the null hypothesis, in which the effect is equl to 0, corresponding to RR of 1. Hence, it my be predicted tht PMRT should exert sttisticlly significnt effect on LRR (Tble V). Cochrn's Q nd I 2 tests suggest tht ll the studies re evluting the sme effect, nd heterogeneity is not significntly present (Tble VI). Therefore, the fixed effects model my be used to estimte the combined effect. The summry effect ws clculted using fixed effects model, which ws incorported into forest plot (Fig. 3). The combined RR of the effect of PMRT on LRR ws clculted s 0.30 (95% CI: ), indicting tht PMRT considerbly decreses the risk of LRR.

4 432 HEADON et l: META-ANALYSIS OF THE EFFECT OF POST MASTECTOMY RADIOTHERAPY ON SURVIVAL Tble III. Zero effect tests. Test Null vs. lterntive Mesure Df χ 2 Prob level Non directionl H 0 : ll tretment effects re zero ln (RR) H : t lest one is not zero Directionl H 0 : ll tretment effects re zero ln (RR) H : effects re equl to the sme non zero quntity Mnul clcultion of test sttistics bsed on ln (RR) nd SE ln (RR) output from Comprehensive Met Anlysis, version 2.0. Both tests show significnce t the 5% significnce level, so the null hypothesis my be rejected. Df, degree of freedom; RR, risk rtio; SE, stndrd error. Figure 2. Forest plot showing the summry reltive risk rtio of overll survivl in brest cncer ptients with 1 3 positive xillry lymph nodes undergoing post mstectomy rdiotherpy. This forest plot outlines the studies included in the overll survivl nlysis nd demonstrtes the summry reltive risk rtio, which ws clculted t 1.03, therefore fvouring the intervention. CI, confidence intervl. Figure 3. Forest plot showing the summry reltive risk rtio of locoregionl recurrence in brest cncer ptients with 1 3 positive xillry lymph nodes undergoing post mstectomy rdiotherpy. This forest plot outlines the studies included in the locoregionl recurrence nlysis nd demonstrtes summry reltive risk rtio of 0.30, therefore fvouring the intervention by indicting tht post mstectomy rdiotherpy reduces the risk of locoregionl recurrence in these ptients. CI, confidence intervl. To check for publiction bis, funnel plot ws creted using Duvl nd Tweedie's trim nd fill method. Additionlly, Egger's test nd Begg nd Mzumdr rnk correltion test were performed. On the funnel plot, ll estimtes were within the 95% CI nd were plced reltively symmetriclly round the combined effect, indicting no publiction bis. Duvl nd Tweedie's trim nd fill method did not signify ny missing study, generting n unchnged estimte of the combined RR. The results of the Egger's test nd Begg nd Mzumdr tests re outlined in Tble VII. These concluded tht there ws no

5 MOLECULAR AND CLINICAL ONCOLOGY 5: , Tble IV. Studies included in the locoregionl recurrence nlysis of the effect of PMRT on brest cncer ptients with 1 3 positive lymph nodes. Number Number Number Locoregionl Locoregionl of in in Type Medin Medin recurrence recurrence First uthor, prticipnts control intervention of ge follow-up rte, control rte, intervention yer (Refs.) Country Study design (totl) group group surgery (yers) (months) group, n (%) group, n (%) Kong, 2013 (5) Kore Retrospective cse series Mstectomy (12.8) 2 (6.2) Cosr, Turkey Retrospective cse series Mstectomy (17) 2 (3.0) 2011 (7) Rgz,1997 (9) Cnd Rndomised controlled tril Mstectomy NR (16.0) 6 (7.0) Su, 2014 (10) Tiwn Retrospective cse series Mstectomy (11.8) 4 (4.7) Moo, 2013 (11) USA Retrospective cse series 1, Mstectomy NR (4.3) 5 (3.2) Hung, 2012 (12) Chin Retrospective cse series Mstectomy 48.5 (men) (11.0) 5 (3.1) He, 2015 (13) Chin Retrospective cse series Mstectomy NR (10.5) 1 (1.3) Tendulkr, Americ Retrospective cse series Mstectomy (8.9) 0 (0.0) 2012 (14) McBride, USA Retrospective cse series 1, Mstectomy NR (8.9) 11 (4.7) 2014 (15) Hrris, USA Retrospective cse series Mstectomy NR (6.4) 1 (2.2) 2013 (16) Overgrd, Denmrk Rndomised controlled tril 1, Mstectomy NR (30.0) 38 (7.0) 1997 (17) PMRT, post-mstectomy rdiotherpy; NR, not reported.

6 434 HEADON et l: META-ANALYSIS OF THE EFFECT OF POST MASTECTOMY RADIOTHERAPY ON SURVIVAL Tble V. Zero effect test rejecting the null hypothesis. Test Null vs. lterntive Mesure Df χ 2 Prob level Non directionl H 0 : ll tretment effects re zero ln (RR) H : t lest one is not zero Directionl H 0 : ll tretment effects re zero ln (RR) H : effects re equl to the sme non zero quntity Mnul clcultion of test sttistics bsed on ln (RR) nd SE ln (RR) output from Comprehensive Met Anlysis, version 2.0. Df, degree of freedom; RR, risk rtio; SE, stndrd error. Tble VI. Tests of heterogeneity showing non significnt heterogeneity nd tht ll studies re evluting the sme effect (fixed effects model). Test Null vs. lterntive/thresholds Mesure Df χ 2 Prob level Cochrn's Q H 0 : ll studies re evluting the sme effect Risk rtio 10 χ 2 = H : not ll studies re evluting the sme effect I 2 0 to 40%: My not be importnt Risk rtio I 2 =21% 30 to 60%: My represent moderte heterogeneity 50 to 90%: My represent substntil heterogeneity 75 to 100%: Indictes considerble heterogeneity Tests performed in RevMn. Df, degree of freedom. Tble VII. Tests for publiction bis indicting tht there ws no sign of ny missing study nd, therefore, the estimte of the combined risk rtio remined unchnged (no publiction bis). Test Results Egger's test of the intercept Intercept (B0) is , 95% confidence intervl ( , ), with t= , degree of freedom = 9. The 1 tiled P vlue (recommended) is , nd the 2 tiled P vlue is Begg nd Mzumdr rnk correltion test Anlysis performed with Comprehensive Met Anlysis, version 2. Kendll's tu b (corrected for ties, if ny) is , with 1 tiled P vlue (recommended) of or 2 tiled P vlue of (bsed on continuity corrected norml pproximtion) publiction bis. Therefore, we my support the estimte of summry RR of 0.30 (95% CI: ), indicting tht PMRT significntly reduces the risk of LRR in brest cncer. Overll results of the met nlysis. Overll, the results of the met nlysis demonstrted tht PMRT significntly decresed the risk of LRR (RR=0.30, 95% CI: ), wheres there ws non significnt increse in OS (RR=1.03, 95% CI: ). Discussion The met nlysis results demonstrted tht PMRT ppers to significntly reduce the risk of LRR, with minor benefit in terms of OS. These results, therefore, support the use of PMRT to reduce LRR in brest cncer ptients, with smll chnce of incresing OS. The smll, non significnt benefit in OS through using PMRT my be explined by the follow up times used in the studies nlysed. The men follow up time ws 80.4 months (rnge, months). A longer follow up time my llow the significnt benefit seen in LRR to trnslte to n incresed benefit in OS. Additionlly, number of other risk fctors, which were not included in the present study, my lso ffect these outcomes. Tumour fctors, such s receptor sttus nd size, hve lso been found to ffect both LRR nd OS. Other informtion, which my exert n effect on OS, includes comorbidities nd ptient ge. In this met nlysis, we did not control for ny dditionl fctors tht my lso hve n impct on OS nd LRR rtes. However, some of the studies tht were included performed multivrite nlyses in order to identify ny independent prognostic fctors. In terms of OS, younger ge, medil tumour

7 MOLECULAR AND CLINICAL ONCOLOGY 5: , loction, HER2 neu overexpression nd negtive oestrogen receptor sttus were ssocited with poorer outcomes nd reduction in OS (4 6,10,12). Higher grde disese, triple negtive subtype, ge <40 yers, HER2 neu overexpression nd negtive oestrogen receptor sttus were ll identified s independent poor prognostic fctors for LRR (5,6,10,12,13). In order to fully elucidte the effect of these fctors, nd other fctors, such s the use of systemic therpy, on the suggested LRR rtes nd OS when PMRT is used, future prospective rndomised trils re wrrnted. This my enble the identifiction of subgroup of ptients for whom PMRT my be prticulrly beneficil, in terms of reducing LRR nd incresing OS. The Erly Brest Cncer Trilists' Collbortive Group recently conducted met nlysis investigting the effect of PMRT on 10 yer recurrence nd 20 yer brest cncer mortlity. Although not reporting specificlly on women with only 1 3 positive lymph nodes, they did report on the effect of PMRT on LRR within this group, nd demonstrted tht PMRT significntly reduced the risk of LRR, s well s overll recurrence nd brest cncer mortlity (3). However, due to the long follow up used in this tril, the ptients included were treted long time go; therefore, systemic therpy, which ws used dditionlly, would not hve been s effective s the systemic therpy currently used. Therefore, the benefits exclusively from PMRT in modern trils re likely to be smller, due to the use of modern systemic therpy, such s Herceptin, endocrine therpy nd improved chemotherpy regimens. One of the min issues with PMRT is the risk of crdic toxicity cused by chest wll irrdition. Crdic irrdition hs been ssocited with significnt pthologicl dmge to the hert, such s microcircultory dmge, which my led to ischemi, fibrosis, ccelerted therosclerosis, pericrdil effusion nd pericrdil thickening (18). Erlier studies ssocited PMRT with dverse crdic effects, such s myocrdil infrctions, nd significntly incresed number of crdic deths, with the left nterior descending coronry rtery suggested to be prticulrly vulnerble to dmge (19). Despite this, more recent studies hve dispelled these findings, with one prospective tril showing no cliniclly significnt cute or lte crdic dverse events t the 2 yer follow up, nd no difference in left ventriculr ejection frction (18). Although this prticulr tril hd short follow up time, the reduction in the risk of dverse crdic events hs been ttributed to the dvncements in rdiotherpy techniques. For exmple, the use of three dimensionl computed tomogrphy guided plnning in order to minimise the exposure of the hert hs reduced the effects of lte crdic toxicity (19,20). In study by Doyle et l, it ws reported tht the use of rdiotherpy did not increse the risk of myocrdil infrction over period of 10 yers (21). Subsequently, it my be concluded tht, with proper plnning, PMRT does not necessrily increse the risk of crdic dverse effects, lthough it would be useful to conduct tril ssessing this risk in ptients with 1 3 positive lymph nodes, in order to fully estblish whether the benefits regrding LRR incidence outweigh ny risks to the hert. In ddition, the dverse effects of PMRT on brest reconstruction should be considered in the benefit risk nlysis in the context of LRR incidence nd OS benefits. PMRT increses the compliction rte of ny type of reconstruction, utologous or implnt bsed. Most guidelines lso suggest it is better to dely reconstruction if it is known preopertively tht rdiotherpy will be required. However, immedite reconstruction is ssocited with better qulity of life nd reduces the risks of undergoing second surgery (22). Despite this, it hs been suggested tht rdiotherpy performed fter reconstruction my led to higher compliction rte thn if reconstruction is delyed. In previous study investigting the use of djuvnt rdiotherpy in porcine cellulr dermis ssisted brest reconstruction, the rte of totl complictions nd implnt expnder loss ws significntly higher in irrdited brests (23). Likewise, study investigting immedite utologous reconstruction found tht there ws n incresed risk of ft necrosis when the brests were irrdited (24). Therefore, it is importnt to tke this into ccount when plnning the cre of ptients who re likely to require rdiotherpy, in order to minimise the complictions nd optimise the esthetic outcome. There were number of limittions to this met nlysis. All the studies included were retrospective cse series, wheres, idelly, prospective rndomised trils would be useful in order to increse the relibility of the results. Additionlly, reltively limited number of studies were included in ech section. Despite this, mny of the studies were published in the lst 5 yers, indicting tht this is growing re of reserch; therefore, future nlyses my be ble to drw their conclusions from significntly lrger pool of reserch. For exmple, the SUPREMO tril in the UK, which is currently being undertken, ims to determine the effect of PMRT on OS in women t intermedite risk of LRR. However, the results will not be vilble for number of yers, due to miniml 10 yer follow up (25). In conclusion, PMRT in women with brest cncer with 1 3 positive lymph nodes results is ssocited with significnt decrese in LRR nd reltively smll OS benefit. In view of the fct tht the OS benefit is reltively smll t 3%, it would be resonble to recommend PMRT to selected group of ptients with other risk fctors, such s young ge, oestrogen receptor negtive, HER2 positive, lrge, poorly differentited tumours, following detiled multidisciplinry discussion until the results of ongoing, lrge scle rndomised controlled trils become known. In light of the risk of crdic toxicity, the threshold for recommending PMRT will be lower for tumours of the right brest, where there is lower risk of dverse crdic effects. The results of this met nlysis my enhnce the informed consent process for PMRT in brest cncer ptients with 1 3 positive nodes. References 1. Wenz F, Sperk E, Budch W, Dunst J, Feyer P, Fietku R, Hse W, Hrms W, Piroth MD, Sutter Bihl ML, et l; Brest Cncer Expert Pnel of the Germn Society of Rdition Oncology (DEGRO): DEGRO prcticl guidelines for rdiotherpy of brest cncer IV: Rdiotherpy following mstectomy for invsive brest cncer. Strhlenther Onkol 190: , Dewis R nd Gribbin J: Brest Cncer: Dignosis nd tretment. An Assessment of Need. Ntionl Institute for Helth nd Clinicl Excellence Clinicl Guidelines. Ntionl Collborting Centre for Cncer, Crdiff (UK), Februry EBCTCG (Erly Brest Cncer Trilists' Collbortive Group), McGle P, Tylor C, Corre C, Cutter D, Dune F, Ewertz M, Gry R, Mnnu G, Peto R, et l: Effect of rdiotherpy fter mstectomy nd xillry surgery on 10 yer recurrence nd 20 yer brest cncer mortlity: Met nlysis of individul ptient dt for 8135 women in 22 rndomised trils. Lncet 383: , 2014.

8 436 HEADON et l: META-ANALYSIS OF THE EFFECT OF POST MASTECTOMY RADIOTHERAPY ON SURVIVAL 4. Nordenskjöld AE, Fohlin H, Albertsson P, Arnesson LG, Chmlidou C, Einbeigi Z, Holmberg E, Nordenskjöld B nd Krlsson P; Swedish Western nd Southestern Brest Cncer Groups: No cler effect of postopertive rdiotherpy on survivl of brest cncer ptients with one to three positive nodes: A popultion bsed study. Ann Oncol 26: , Kong M nd Hong SE: Which ptients might benefit from postmstectomy rdiotherpy in brest cncer ptients with T1 2 tumor nd 1 3 xillry lymph nodes metstsis? Cncer Res Tret 45: , Chitpnrux I, Thrvichitkul E, Jkrbhndu S, Klunklin P, Onchn W, Srikwin J, Puknhphn N, Tristhit P nd Vongtm R: Rel world outcomes of postmstectomy rdiotherpy in brest cncer ptients with 1 3 positive lymph nodes: A retrospective study. J Rdit Res 55: , Cosr R, Uzl C, Toktli F, Denizli B, Synk M, Turn N, Uzunoglu S, Ozen A, Sezer A, Ibis K, et l: Postmstectomy irrdition in brest in brest cncer ptients with T1 2 nd 1 3 positive xillry lymph nodes: Is there role for rdition therpy? Rdit Oncol 6: 28, Wu SG, He ZY, Li FY, Wng JJ, Guo J, Lin Q nd Gun XX: The clinicl vlue of djuvnt rdiotherpy in ptients with erly stge brest cncer with 1 to 3 positive lymph nodes fter mstectomy. Chin J Cncer 29: , Rgz J, Jckson SM, Le N, Plenderleith IH, Spinelli JJ, Bsco VE, Wilson KS, Knowling MA, Coppin CM, Prdis M, et l: Adjuvnt rdiotherpy nd chemotherpy in node positive premenopusl women with brest cncer. N Engl J Med 337: , Su YL, Li SH, Chen YY, Chen HC, Tng Y, Hung CH, Chou FF, Wu SC nd Ru KM: Post mstectomy rdiotherpy benefits subgroups of brest cncer ptients with T1 2 tumor nd 1 3 xillry lymph node(s) metstsis. Rdiol Oncol 48: , Moo TA, McMilln R, Lee M, Stempel M, Ptil S, Ho A nd El Tmer M: Selection criteri for postmstectomy rdiotherpy in t1 t2 tumors with 1 to 3 positive lymph nodes. Ann Surg Oncol 20: , Hung CJ, Hou MF, Chung HY, Lin SL, Hung MY, Chen FM, Fu OY nd Lin SF: Comprison of clinicl outcome of brest cncer ptients with T1 2 tumor nd one to three positive nodes with or without postmstectomy rdition therpy. Jpn J Clin Oncol 42: , He ZY, Wu SG, Zhou J, Li FY, Lin Q, Lin HX nd Sun JY: Postmstectomy rdiotherpy improves disese free survivl of high risk of locoregionl recurrence brest cncer ptients with T1 2 nd 1 to 3 positive nodes. PLoS One 10: e , Tendulkr RD, Rehmn S, Shukl ME, Reddy CA, Moore H, Budd GT, Dietz J, Crowe JP nd Mcklis R: Impct of postmstectomy rdition on locoregionl recurrence in brest cncer ptients with 1 3 positive lymph nodes treted with modern systemic therpy. Int J Rdit Oncol Biol Phys 83: e577 e581, McBride A, Allen P, Woodwrd W, Kim M, Kuerer HM, Drink EK, Shin A, Strom EA, Buzdr A, Vlero V, et l: Locoregionl recurrence risk for ptients with T1,2 brest cncer with 1 3 positive lymph nodes treted with mstectomy nd systemic tretment. Int J Rdit Oncol Biol Phys 89: , Hrris EE, Freilich J, Lin HY, Chuong M nd Acs G: The impct of the size of nodl metstses on recurrence risk in brest cncer ptients with 1 3 positive xillry nodes fter mstectomy. Int J Rdit Oncol Biol Phys 85: , Overgrd M, Hnsen PS, Overgrd J, Rose C, Andersson M, Bch F, Kjer M, Gdeberg CC, Mouridsen HT, Jensen MB nd Zedeler K: Postopertive rdiotherpy in high risk premenopusl women with brest cncer who receive djuvnt chemotherpy. Dnish Brest Cncer Coopertive Group 82b Tril. N Engl J Med 337: , Khn M, Gupt M nd Sem R: Anlysis of crdic dverse events following postmstectomy hypofrctionted rdiotherpy. Chin Clin Oncol 3: 47, Kunkler IH: Rdiotherpy of the regionl lymph nodes: Shooting t the sheriff? Brest 18 (Suppl 3): S112 S120, Hrris EE: Crdic mortlity nd morbidity fter brest cncer tretment. Cncer Control 15: , Doyle JJ, Neugut AI, Jcobson JS, Wng J, McBride R, Grnn A, Grnn VR nd Hershmn D: Rdition therpy, crdic risk fctors nd crdic toxicity in erly stge brest cncer ptients. Int J Rdit Oncol Biol Phys 68: 82 93, Berbers J, vn Brdwijk A, Houben R, Heuts E, Smidt M, Keymeulen K, Bessems M, Tuinder S nd Boersm LJ: Reconstruction: Before or fter postmstectomy rdiotherpy? A systemtic review of the literture. Eur J Cncer 50: , Mitchell RE: Porcine cellulr dermis ssisted brest reconstruction: Influence of djuvnt rdiotherpy on complictions nd outcomes. Plst Reconstr Surg Glob Open 1: e77, Rochlin DH, Jeong AR, Goldberg L, Hrris T, Mohn K, Sel S, Cnner J nd Scks JM: Postmstectomy rdition therpy nd immedite utologous brest reconstruction: Integrting perspectives from surgicl oncology, rdition oncology, nd plstic nd reconstructive surgery. J Surg Oncol 111: , Kunkler IH, Cnney P, vn Tienhoven G nd Russell NS; MRC/ EORTC (BIG 2 04) SUPREMO Tril Mngement Group: Elucidting the role of chest wll irrdition in intermedite risk brest cncer: The MRC/EORTC SUPREMO tril. Clin Oncol (R Coll Rdiol) 20: 31 34, 2008.

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