Survival Comparisons for Breast Conserving Surgery and Mastectomy Revisited: Community Experience and the Role of Radiation Therapy

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1 Clncal Medcne & Research Volume 13, Number 2: Marshfeld Clnc Health System clnmedres.org Orgnal Research Survval Comparsons for Breast Conservng Surgery and Mastectomy Revsted: Communty Experence and the Role of Radaton Therapy Adedayo A. Ontlo, MD, PhD, MSCR, FACP; Jessca M. Engel, DNP, RN; Rachel V. Stankowsk, PhD; and Suhal A.R. Do, MBBS, FRCP, PhD Objectves: Evdence suggests superorty of breast conservng surgery (BCS) plus radaton over mastectomy alone for treatment of early stage breast cancer. Whether the superorty of BCS plus radaton s related to the surgcal approach tself or to the addton of adjuvant radaton therapy followng BCS remans unclear. Materals and Methods: We conducted a retrospectve cohort study of women wth breast cancer dagnosed from Data regardng patent and tumor characterstcs and treatment specfcs were captured electroncally. Kaplan-Meer survval analyses were performed wth nverse probablty of treatment weghtng to reduce selecton bas effects n surgcal assgnment. Results: Data from 5335 women were ncluded, of whch two-thrds had BCS and one-thrd had mastectomy. Surgcal decson trends changed over tme wth more women undergong mastectomy n recent years. Women who underwent BCS versus mastectomy dffered sgnfcantly regardng age, cancer stage/grade, adjuvant radaton, chemotherapy, and endocrne treatment. Overall survval was smlar for BCS and mastectomy. When BCS plus radaton was compared to mastectomy alone, 3-, 5-, and 10-year overall survval was 96.5% vs 93.4%, 92.9% vs 88.3% and 80.9% vs 67.2%, respectvely. Concluson: These analyses suggest that survval beneft s not related only to the surgery tself, but that the prognostc advantage of BCS plus radaton over mastectomy may also be related to the addton of adjuvant radaton therapy. Ths concluson requres prospectve confrmaton n randomzed trals. Keywords: Breast neoplasms/surgery; Breast neoplasms/radotherapy; Mastectomy/statstcs; Breast conservaton; Rsk factors; Survval Early trals demonstrated equvalent long-term survval rates for patents wth early stage nvasve breast cancer treated by mastectomy or breast conservng surgery (BCS). 1 In leu of clncal tral results demonstratng the superorty of BCS wth radaton compared to BCS alone, the default treatment approach for breast conservng therapy ncludes BCS followed by radaton therapy, wth physcans nfrequently optng to perform BCS alone. 2 In randomzed controlled trals, BCS plus radaton has been shown to be at least equvalent, or even superor, to mastectomy. 3,4 What remans unclear s the relatve mportance of the surgcal procedure tself. In other words, s mastectomy a superor procedure n terms of outcomes, or s the extent of surgery overshadowed by other adjuvant therapy? In 1991, a Natonal Insttutes of Health consensus statement recommended BCS plus radaton as an approprate alternatve prmary therapy to mastectomy for the majorty of women wth early stage breast cancer n whom breast conservaton s not contrandcated. 5 Ths approach was Correspondng Author: Adedayo A. Ontlo, MD, PhD, MSCR, FACP; Marshfeld Clnc Weston Center; 3501 Cranberry Blvd; Weston WI 54476; Tel: ; Fax: ; Emal: ontlo.adedayo@ marshfeldclnc.org Receved: Aprl 10, 2014 Revsed: June 27, 2014 Accepted: July 14, 2014 do: /cmr

2 rapdly adopted and largely replaced mastectomy as the ntal surgcal procedure most commonly performed for management of a prmary breast tumor. 6-8 In recent years, however, mastectomy rates appear to have ncreased for a varety of reasons, ncludng larger tumor sze, multcentrc breast cancer, famly hstory, race, younger age at dagnoss, preoperatve magnetc resonance magng utlzaton, socoeconomc status, dstance from a radaton faclty, patent preference, provder preference, surgeon volume and specalty tranng, and avalablty of and advances n reconstructve surgery. 7,9-24 These factors and the lack of a well-accepted dstncton between the effect of the surgcal approach tself and assocated adjuvant therapy on outcomes have resulted n patents recevng wdely varable surgcal approaches, as deas about surgcal mpact may have been merged wth choces regardng use of adjuvant therapes, ncludng radaton therapy, chemotherapy, and endocrne therapy. Expermentally, determnng the effcacy of surgcal approaches n the context of other adjuvant therapes s dffcult. Adjuvant therapy use s closely montored n randomzed controlled trals, and randomzaton of a woman to BCS alone rather than BCS plus radaton n the context of well-establshed gudelnes for radaton use would be unethcal. 25 Instead, well-conducted observatonal studes from communty practce, where patterns of surgcal treatment and adjuvant therapy admnstraton vary wdely, can be used to determne the utlty of these surgcal approaches. A recently publshed populaton-based study by Hwang et al 26 demonstrated that among women wth early stage breast cancer, BCS plus radaton was assocated wth mproved survval compared to mastectomy, but t excluded women who underwent BCS alone (e, wthout radaton) and women who underwent mastectomy and receved radaton. Therefore, t s dffcult to determne whether the advantage observed was related to the surgcal approach tself or to the use of radaton therapy after surgery, promptng us to examne a populaton of women surgcally treated for breast cancer n a communty practce settng to evaluate surgcal outcomes followng BCS or mastectomy, ndependent of subsequent recept of radaton therapy, chemotherapy, or endocrne therapy. Materals and Methods Study desgn and resources We conducted a retrospectve cohort study of women dagnosed wth breast cancer at the Marshfeld Clnc from Marshfeld Clnc s the largest, physcanowned, prvate group medcal practce n Wsconsn and one of the largest n the Unted States, ncludng an extensve regonal oncology practce provdng care to resdents of central, northern, and western Wsconsn and Mchgan s Upper Pennsula n collaboraton wth regonal hosptals. Data were captured electroncally usng the Marshfeld Clnc/St. Joseph s Hosptal Cancer Regstry as the man source of nformaton for breast cancer dagnoss and 66 Breast cancer surgery and survval treatment. Marshfeld Clnc/St. Joseph s Hosptal Cancer Regstry, ntated n 1960, s accredted by the Amercan College of Surgeons Commsson on Cancer, and meets the Assocaton of Communty Cancer Center standards for cancer programs. Data are entered nto the Cancer Regstry manually and verfed for accuracy. Addtonal data were collected electroncally usng the Marshfeld Clnc comprehensve electronc medcal record (EMR), whch ncludes extensve nformaton pertanng to clncal encounters, dagnoses, medcaton use, procedures, laboratory results, and pathology reports. Ths study was approved by the Marshfeld Clnc Insttutonal Revew Board wth waver of nformed consent. Data collecton The Marshfeld Clnc/St. Joseph s Hosptal Cancer Regstry was quered for female patents dagnosed wth stage 0 IV breast cancer at any of the cancer center stes contrbutng data to the Cancer Regstry usng Internatonal Classfcaton of Dseases for Oncology, 3 rd edton (ICD-O-3) codes C50.0-C50.9 wth frst date of dagnoss between January 1, 1994 and December 31, Cancer Regstry data pror to 1994 dd not nclude the specfc type of surgery. Data captured from the Cancer Regstry ncluded age, gender, nsurance type, tumor characterstcs (dagnoss date, morphology, grade, and estrogen receptor [ER], progesterone receptor [PR], and human epdermal growth factor receptor 2 [HER2] expresson), stage of cancer at dagnoss (by tumor sze, nodal status, and presence of metastases), treatment specfcs (type of defntve surgery, endocrne therapy, radaton therapy, and chemotherapy), and date of death. The Cancer Regstry began collectng data for ER and PR status n 2004 and HER2 expresson n Surgcal desgnatons of lumpectomy, excsonal bopsy, partal mastectomy, re-excson, and segmental mastectomy were consdered BCS f they were not followed by an addtonal surgcal desgnaton ndcatve of mastectomy. Surgcal desgnatons of mastectomy, modfed radcal mastectomy, radcal mastectomy, subcutaneous mastectomy, and total (smple) mastectomy, all wth or wthout mplants, reconstructon, or contralateral breast mastectomy, were consdered mastectomy. Statstcal analyss Unvarate analyss of relevant demographc and clncal characterstcs (eg, age, stage) was performed to compare patents who underwent BCS versus mastectomy usng the Wlcoxon rank sum test. Although prevous studes reled on Cox proportonal hazards modelng to compare survval between groups, 26 we found sgnfcant volaton of the proportonal hazards assumpton; therefore, we dd not analyze our data n ths manner. Instead, survval tme was weghted by the nverse probablty of treatment (IPT) generated from a propensty score and took nto account varables related to surgcal decsons or treatment varables that are nfluenced by the surgcal approach. 27 Two separate statstcal analyses were performed. In the frst, we compared BCS to mastectomy (regardless of radotherapy status), and CM&R 2015 : 2 (June)

3 Fgure 1. Surgcal trends over study perod. Lght gray shadng ndcates the proporton of women who underwent mastectomy and dark gray shadng ndcates the proporton of women who underwent breast conservng surgery (BCS). n the second, we compared BCS plus radotherapy wth mastectomy alone (no radotherapy). In survval analyses, women wth stage 0 and stage IV cancers were excluded as radaton therapy s unlkely to alter survval outcomes n such women. The propensty score for the frst analyss (BCS vs mastectomy) was computed as the probablty of recevng a mastectomy and was estmated for each patent by fttng a multple logstc regresson model, ncludng year of dagnoss ( ), stage of breast cancer (I III), age, grade of tumor (1 3), adjuvant treatment (chemotherapy [Y/N], radaton therapy [Y/N] and hormonal therapy [Y/N]), and three nteracton varables (radaton treatment wth age or stage; chemotherapy wth grade). Model dscrmnaton was excellent as assessed wth the c-statstc (c=0.944; P<0.001). To nvestgate the lnk functon for ths model, we generated a covarate equal to the square of the lnear predctor for that model usng the Stata lnktest. A reftted model wth ths new covarate demonstrated ft as the covarate was nsgnfcant. The Hosmer Lemeshow (H-L) statstc was not used to demonstrate ft because as the sample sze gets large, the H-L statstc can fnd smaller and smaller dfferences between observed and model-predcted values to be sgnfcant, as was the case wth ths dataset. A second propensty score was developed for analyss of BCS plus radaton vs mastectomy alone (.e., wthout radaton) to represent the probablty of undergong mastectomy alone and was estmated for each patent by fttng a multple logstc regresson model, ncludng year of dagnoss ( ), stage of breast cancer (I III), age, grade of tumor (1 3) and adjuvant treatment (except radaton therapy) (chemotherapy [Y/N] and hormonal therapy [Y/N]). The model dscrmnaton was good (c=0.634; P<0.001), and the ft as assessed by the square of the lnear predctor was also good, as ths covarate was nsgnfcant. The IPT weghts were computed from these propensty scores by: Z w = e 1 Z + 1 e where Z s the ndcator varable for extent of surgery and e = Pr( Z = 1 X ) s the propensty score condtonal on observed baselne covarates ( X ). 28 The fnal weght was then trmmed by replacng values greater than the 99 th percentle wth the 99 th percentle value n each category (mastectomy [Y/N]). 29 Overall survval curves were estmated usng Kaplan-Meer analyss wth survval tme set usng IPT weghts, 27 whch reduces the effect of observed confoundng n assgnment for extent of surgery (BCS vs. mastectomy) when strong selecton bas exsts. In both analyses (BCS vs mastectomy; BCS plus radaton vs mastectomy alone), patents wth stage I III breast cancer were analyzed and the effects of selecton based on adjuvant therapy use and other covarates were accounted CM&R 2015 : 2 (June) Ontlo et al. 67

4 Table 1. Descrptve statstcs of patents and cancer; women who underwent BCS were sgnfcantly dfferent from those who underwent mastectomy wth respect to all varables examned. BCS (N=3,340) Mastectomy (N=1,995) Total (N=5,335) Patent Characterstcs N (%) N (%) N (%) P value Age a 63 (52-72) 60 (49-73) < Surgery Type 3340 (62.6.2%) 1995 (37.4%) 5335 (100.0%) < Breast Cancer Stage Stage (24.0%) 330 (16.8%) 1124 (21.3%) < Stage I 1762 (53.2%) 675 (34.4%) 2437 (46.2%) Stage II 672 (20.3%) 650 (33.1%) 1322 (25.1%) Stage III 65 (2.0%) 266 (13.5%) 331 (6.3%) Stage IV 18 (0.5%) 43 (2.2%) 61 (1.2%) Chemotherapy 930 (27.9%) 922 (46.3%) 1852 (34.7%) < Endocrne Therapy 2233 (67.4%) 1181 (59.6%) 3414 (64.5%) < Radaton Therapy 2739 (82.2%) 327 (16.4%) 3066 (57.6%) < Grade (24.6%) 324 (16.2%) 1146 (21.5%) < (34.1%) 672 (33.7%) 1810 (33.9%) (26.8%) 765 (38.3%) 1661 (31.1%) NA 484 (14.5%) 234 (11.7%) 718 (13.5%) ER/PR Status Postve 1490 (44.6%) 927 (46.5%) 2417 (45.3%) < Negatve 224 (6.7%) 256 (12.8%) 480 (9.0%) NA 1626 (48.7%) 811 (40.7%) 2437 (45.7%) Deceased 556 (16.6%) 462 (23.2%) 1018 (19.1%) < Medan Follow-up b 74 (33-134) 57 (29-109) < Abbrevatons: BCS, breast conservng surgery; NA, not avalable; IQR, nterquartle range; ER/PR, estrogen receptor/progesterone receptor. a Years (IQR) b Months (IQR) for statstcally usng IPT weghtng. Fnally, a senstvty analyss usng flexble parametrc proportonal hazards modelng 30 was undertaken to confrm the robustness of the weghted analyss. Ths was done usng the stpm module n Stata. Akake Informaton Crteron (AIC) values for several splne survval models were smlar so the default Webull model dstrbuton of survval tmes (wth one degree of freedom wthn stpm) was used. All tests of sgnfcance were two-taled, and a P value of 0.05 was consdered sgnfcant. All statstcal analyses were performed wth Stata software, verson 11 (StataCorp, College Staton, TX). Results A total of 5,737 breast cancer surgeres were dentfed system-wde between 1994 and Of these, 402 represented duplcate patents wth synchronous or metasynchronous prmary breast cancer dagnoses. For such patents, the date of the frst dagnoss was assessed, and the second prmary cancer was excluded from analyss. For analyss purposes, 5,335 women were ncluded n ths study, of whch 62.6% underwent BCS and 37.4% underwent mastectomy. Medan follow-up tme was 67 months (IQR months), wth unweghted mortalty rates of and per 1,000 person-years for the BCS and mastectomy 68 Breast cancer surgery and survval groups, respectvely. From 1994 to 2003, the proporton of women undergong mastectomy decreased. However, a reversal n ths trend and an ncrease n the proporton of women undergong mastectomy was noted from 2004 to 2012 (fgure 1). Adjuvant radaton therapy s routnely recommended followng BCS, 31 but was not receved n 17.8% of patents followng BCS. In contrast, gudelnes for use of adjuvant radaton therapy followng mastectomy vary, 32 and radaton was receved by only 16.4% of women n the mastectomy group. Of women treated wth BCS who dd not receve radaton therapy, most were early stage (43.8% stage 0, 42.6% stage I, 10.3% stage II, 1.7% stage III, and 1.7% stage IV). Of women treated wth mastectomy who receved radaton, 1.8% had stage 0, 5.8% had stage I, 31.1% had stage II, 54.8% had stage III, and 6.5% had stage IV breast cancer. The remanng women who underwent BCS wthout adjuvant radaton therapy dd so based on decson makng that s typcal n the communty practce settng, ncludng consderatons such as tumor sze, age, comorbdty status, patent preference, treatng physcan preference, and the prmary care provder (oncology, radaton oncology consult, or surgery). CM&R 2015 : 2 (June)

5 Fgure 2. Kaplan-Meer curves for (A) unweghted overall survval and (B) nverse probablty of treatment (IPT) weghted overall survval for patents wth locally nvasve (stage I III) breast cancer who underwent breast-conservng surgery (BCS) versus mastectomy. In addton to use of adjuvant radaton therapy, women who underwent BCS were sgnfcantly dfferent from those who underwent mastectomy wth respect to all other varables examned (Table 1). Women who had BCS were sgnfcantly older, more lkely to be dagnosed wth early stage breast cancer (stage 0 II vs III IV) and tumors of lower grade (1 2 vs 3), less lkely to receve chemotherapy, and more lkely to receve hormonal therapy, as ther breast cancer was more lkely to be endocrne receptor postve, compared to those who had mastectomy. We frst compared the effects of surgcal approach on survval n all subjects wth stage I III breast cancer, regardless of adjuvant therapy use. Subjects wth stage 0 and stage IV cancer were excluded as local therapy s unlkely to have any effect on overall survval n such patents. All other covarates, ncludng radaton therapy, were addressed through the use of a propensty score and IPT weghtng, as descrbed n the methods. Kaplan-Meer survval curves were generated for each surgcal category (fgure 2), and Kaplan-Meer survval functons were calculated at 3-, 5-, and 10-years (fgure 3). Wthout IPT weghtng, 3-, 5-, and 10-year overall survval for BCS vs mastectomy was 95.0% vs 90.9%, 90.5% vs 84.2%, and 78.4% vs 62.8%, respectvely (fgure 3A). After IPT weghtng to account for treatment selecton bas, 3-, 5-, and 10-year survval for BCS vs. mastectomy was 90.3% vs 92.8%, 84.7% vs 86.8%, and 72.4% vs 65.1%, respectvely (fgure 3B). The unweghted analyss appears to exaggerate dfferences as tme accrues, but ths was corrected by the weghted analyss. Ths s demonstrated n fgure 2A, where gnorng treatment selecton bas (confoundng) gves the mpresson that BCS has better survval outcomes. However, once the IPT weghts are n place (fgure 2B), there s no sgnfcant dfference across surgcal categores. Results from flexble parametrc proportonal hazards modelng were smlar wth a mastectomy hazard rato (HR) of 0.93 (95% CI ). Fgure 3. Kaplan-Meer survval estmates for (A) unweghted overall survval and (B) nverse probablty of treatment (IPT) weghted overall survval for patents wth locally nvasve (stage I III) breast cancer who underwent breast-conservng surgery (BCS) versus mastectomy at 3-, 5-, and 10-years. CM&R 2015 : 2 (June) Ontlo et al. 69

6 Fgure 4. Kaplan-Meer curves for (A) unweghted overall survval and (B) nverse probablty of treatment (IPT) weghted overall survval for patents wth locally nvasve (stage I III) breast cancer who underwent breast conservng surgery (BCS) plus radaton versus mastectomy alone. We then compared overall survval n women wth stage I III breast cancer who underwent BCS plus radaton vs mastectomy alone by excludng subjects who had BCS and dd not receve radaton therapy, and women who had mastectomy and dd receve radaton therapy, as n the study by Hwang et al. 26 Ths comparson allowed us to take the radaton therapy component of breast conservng therapy nto consderaton. Kaplan-Meer survval curves were generated for each treatment category (fgure 4), and Kaplan-Meer survval functons were calculated at 3-, 5-, and 10-years (fgure 5). Wthout IPT weghtng, 3-, 5-, and 10-year overall survval for BCT vs mastectomy was 96.9% vs 91.6%, 93.5% vs 85.4%, and 82.6% vs 63.5%, respectvely (fgure 5A). After IPT weghtng to account for treatment selecton bas, 3-, 5-, and 10-year survval for BCS plus radaton vs mastectomy was 96.5% vs 93.4%, 92.9% vs 88.3%, and 80.9% vs 67.2%, respectvely (fgure 5B). Even after accountng for factors related to treatment selecton, BCS plus radaton appears to result n better overall survval than mastectomy alone. Agan, flexble parametrc proportonal hazards modelng revealed a mastectomy alone HR of 1.60 (95% CI ) consstent wth the weghted Kaplan- Meer results. Dscusson At least one tral has demonstrated equvalent long-term survval rates for patents wth early stage nvasve breast cancer treated by BCS alone or mastectomy. 1 However, several studes have demonstrated reduced local recurrence and better survval rates wth combnaton BCS and radaton therapy than BCS alone, and current recommendatons for breast conservng therapy nclude lumpectomy followed by radaton therapy. 31 Several groups have demonstrated n randomzed controlled trals that ths approach (BCS plus radaton) s at least equvalent, or even superor, to mastectomy. 3,4 In the communty-treated populaton examned Fgure 5. Kaplan-Meer survval estmates for (A) unweghted overall survval and (B) nverse probablty of treatment (IPT) weghted overall survval for patents wth locally nvasve (stage I III) breast cancer who underwent breast conservng surgery (BCS) plus radaton versus mastectomy alone at 3-, 5-, and 10-years. 70 Breast cancer surgery and survval CM&R 2015 : 2 (June)

7 here, the beneft of breast conservng therapy over mastectomy appears to be related to the combnaton of BCS and adjuvant radaton therapy rather than the surgcal procedure tself. Addtonally, BCS plus radaton appears to be superor to mastectomy alone suggestng that radcal surgery may not provde addtonal beneft to women who have breast cancer wth respect to overall survval. We and others have demonstrated an ncrease n mastectomy utlzaton n recent years. 7,9-22,26,37 Whle randomzed controlled trals and meta-analyses are consdered the gold standard for clncal evdence, results and recommendatons may not always translate or apply n the same way to communty practce where non-selectve patent care occurs n envronments very dfferent from the controlled, clncal tral envronment. Before adjustment, our results were smlar whether we compared BCS and mastectomy or BCS wth radaton and mastectomy wthout radaton, lkely because the BCS group was affected by selecton of adjuvant therapes post-procedure that were consequences of selecton of the surgcal procedure tself. A clear example s the addton of radaton therapy to a greater extent after BCS (82.2%) than after mastectomy (16.4%). In observatonal studes, the lack of random treatment assgnment frequently results n dfferences between treated and untreated subjects. IPTweghtng was performed n our study to remove or mnmze the effects of confoundng due to dfferences n the dstrbuton of observed and measured baselne covarates between treatment groups when estmatng the effects of the treatments. Weghtng by the nverse probablty of treatment markedly reduced the effects of ths confoundng on surgcal outcomes resultng n survval rates that focus on the dfferences due predomnantly to extent of surgery (fgure 2B). A recent populaton-based study by Hwang et al 26 demonstrated that BCS plus radaton resulted n greater dsease-specfc and overall survval n women wth early stage breast cancer compared to those who underwent mastectomy wthout adjuvant radaton therapy. Our fndngs support ths concluson and suggest that the superorty of BCS plus radaton over mastectomy may be more related to the addton of radaton therapy than to surgery extent alone. Adjuvant radaton therapy followng surgery s clearly mportant for prognoss, and ths and other forms of adjuvant therapy, ncludng chemotherapy and endocrne therapy, wll be the focus of subsequent analyses. In women wth early stage breast cancer, mortalty s more often attrbutable to cardovascular dsease than to breast cancer tself. 38 Interestngly, radaton to the chest has known cardac complcatons. 39 However, exposure to radaton appears to have actually reduced overall mortalty n practce suggestng that the cardac rsks posed by radaton therapy are outweghed by the benefts. The patent characterstcs assocated wth a hgher lkelhood of mastectomy n our study were smlar to those prevously descrbed n the communty and n clncal studes. 7,9-11,37 Mastectomy was more often utlzed n younger women wth advanced stage breast cancer and was assocated wth more chemotherapy use, less endocrne therapy use, less radaton use, hgher tumor grade, and hormone receptor negatvty compared to those who had BCS. Dfferences n the use of adjuvant therapy by surgery type s of partcular nterest, as the data presented here suggest that use of adjuvant radaton therapy followng BCS s assocated wth better survval outcomes than mastectomy alone. The mportance of adjuvant therapy and the role of mastectomy n breast cancer treatment n the absence of clear ndcatons may, therefore, warrant further examnaton. Our study has lmtatons nherent to any retrospectve study, namely the use of data as reported and documented. We do not consder ths a major lmtaton n ths partcular study, as our objectve was to descrbe a communty practce experence wth non-selectve care of patents usng nformaton that was not derved from a more controlled clncal tral envronment. We dd not dfferentate between breast cancer-specfc mortalty and overall mortalty, due to lack of accurate data. Fnally, whle many of the factors lkely to contrbute to confoundng (treatment selecton bas) were accounted for va IPT-weghtng, addtonal factors that may have nfluenced selecton of surgery type or radotherapy reman unaccounted for, ncludng patent preference, race, comorbdty, famly hstory of breast cancer, geographcal locaton, nsurance type, surgeon preference and tranng, and the avalablty of a prospectve, multdscplnary care plan through a tumor board, and thus these fndngs requre prospectve confrmaton. However, our multdscplnary care plan developed through a tumor board takes nto consderaton all of these factors for plannng both surgcal treatment and subsequent selecton of adjuvant treatment. Nevertheless, there s no guarantee that these results are not ndeed the consequence of resdual confoundng by ndcaton. Conclusons Evaluaton of the communty practce experence allows examnaton of outcomes followng non-selectve patent care usng nformaton derved from a less-controlled clncal envronment. We found no dfference n overall survval by breast cancer surgery type when the effects of adjuvant radaton therapy and other covarates were elmnated usng statstcal methods. However, comparson of BCS plus radaton to mastectomy alone revealed a sgnfcant survval beneft wth breast conservng therapy, suggestng that the prognostc dfferences reported here and by others may be related to use of adjuvant radaton therapy after BCS rather than to the extent of surgery tself. Gven the lmtatons nherent n ths type of study desgn, prospectve confrmaton of ths fndng s necessary. Acknowledgements The authors would lke to acknowledge the Marshfeld Clnc Tumor Regstry and the Marshfeld Clnc Research Foundaton s Offce of Scentfc Wrtng and Publcaton for assstance wth ths project. CM&R 2015 : 2 (June) Ontlo et al. 71

8 References 1. Fsher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fsher ER, Jeong JH, Wolmark N. Twenty-year follow-up of a randomzed tral comparng total mastectomy, lumpectomy, and lumpectomy plus rradaton for the treatment of nvasve breast cancer. N Engl J Med 2002;347: Recht A, Houlhan MJ. Conservatve surgery wthout radotherapy n the treatment of patents wth early-stage nvasve breast cancer. A revew. Ann Surg 1995;222: Arragada R, Lê MG, Rochard F, Contesso G. Conservatve treatment versus mastectomy n early breast cancer: patterns of falure wth 15 years of follow-up data. Insttut Gustave- Roussy Breast Cancer Group. J Cln Oncol 1996; 14: Lchter AS, Lppman ME, Danforth DN Jr, d Angelo T, Stenberg SM, demoss E, MacDonald HD, Rechert CM, Merno M, Swan SM, et al. Mastectomy versus breastconservng therapy n the treatment of stage I and II carcnoma of the breast: a randomzed tral at the Natonal Cancer Insttute. J Cln Oncol 1992;10: NIH consensus conference. Treatment of early-stage breast cancer. JAMA 1991;2653: Nattnger AB, Gottleb MS, Veum J, Yahnke D, Goodwn JS. Geographc varaton n the use of breast-conservng treatment for breast cancer. N Engl J Med 1992; 326: Habermann EB, Abbott A, Parsons HM, Vrng BA, Al-Refae WB, Tuttle TM. Are mastectomy rates really ncreasng n the Unted States? J Cln Oncol 2010;28: McCahll LE, Prvette A, James T, Sheehey-Jones J, Ratlff J, Majerck D, Krag DN, Stanley M, Harlow S. Qualty measures for breast cancer surgery: ntal valdaton of feasblty and assessment of varaton among surgeons. Arch Surg 2009;144: Morrow M, Jags R, Alderman AK, Grggs JJ, Hawley ST, Hamlton AS, Graff JJ, Katz SJ. Surgeon recommendatons and recept of mastectomy for treatment of breast cancer. JAMA 2009;302: Balch CM, Jacobs LK. Mastectomes on the rse for breast cancer: the tde s changng. Ann Surg Oncol 2009;16: Gomez SL, France AM, Lee MM. Socoeconomc status, mmgraton/acculturaton, and ethnc varatons n breast conservng surgery, San Francsco Bay area. Ethn Ds 2004;14: Nattnger AB, Kneusel RT, Hoffmann RG, Gllgan MA. Relatonshp of dstance from a radotherapy faclty and ntal breast cancer treatment. J Natl Cancer Inst 2001;93: Temple WJ, Russell ML, Parsons LL, Huber SM, Jones CA, Bankes J, Elaszw M. Conservaton surgery for breast cancer as the preferred choce: a prospectve analyss. J Cln Oncol 2006;24: McCahll LE, Prvette AR, Hart MR, James TA. Are mastectomy rates a reasonable qualty measure of breast cancer surgery? Am J Surg 2009;197: Gllgan MA, Kneusel RT, Hoffmann RG, James TA. Persstent dfferences n socodemographc determnants of breast conservng treatment despte overall ncreased adopton. Med Care 2002;40: Katpamula R, Degnm AC, Hoskn T, Boughey JC, Loprnz C, Grant CS, Brandt KR, Pruth S, Chute CG, Olson JE, Couch FJ, Ingle JN, Goetz MP. Trends n mastectomy rates at the Mayo Clnc Rochester: effect of surgcal year and preoperatve magnetc resonance magng. J Cln Oncol 2009;27: Tuttle TM, Rueth NM, Abbott A, Vrng BA. Unted States trends n the surgcal treatment of prmary breast cancer. World J Surg 2012;36: Breast cancer surgery and survval 18. Katz SJ, Lantz PM, Janz NK, Fagerln A, Schwartz K, Lu L, Deapen D, Salem B, Lakhan I, Morrow M. Patent nvolvement n surgery treatment decsons for breast cancer. J Cln Oncol 2005;23: Boscoe FP, Johnson CJ, Henry KA, Goldberg DW, Shahab K, Elkn EB, Ballas LK, Cockburn M. Geographc proxmty to treatment for early stage breast cancer and lkelhood of mastectomy. Breast 2011;20: Dck AW, Sorbero MS, Ahrendt GM, Hayman JA, Gold HT, Schffhauer L, Stark A, Grggs JJ. Comparatve effectveness of ductal carcnoma n stu management and the roles of margns and surgeons. J Natl Cancer Inst 2011;103: McCahll LE, Sngle RM, Aello Bowles EJ, Fegelson HS, James TA, Barney T, Engel JM, Ontlo AA. Varablty n reexcson followng breast conservaton surgery. JAMA 2012;307: Hershman DL, Buono D, Jacobson JS, McBrde RB, Tsa WY, Joseph KA, Neugut AI. Surgeon characterstcs and use of breast conservaton surgery n women wth early stage breast cancer. Ann Surg 2009;249: Albornoz CR, Cemal Y, Mehrara BJ. The mpact of blateral mastectomy on reconstructve rate and method n the Unted States: a populaton based analyss. Plast Reconstr Surg 2012;130: Brde MB, Neal L, Dlaver CA, Sandhu NP, Heken TJ, Ghosh K, Wahner-Roedler DL. Factors assocated wth surgcal decson makng n women wth early-stage breast cancer: a lterature revew. J Womens Health (Larchmt) 2013; 22: Bellon JR, Harrs EE, Arthur DW, Baley L, Carey L, Goyal S, Halyard MY, Horst KC, Moran MS, MacDonald SM, Haffty BG; Amercan College of Radology. ACR Approprateness Crtera conservatve surgery and radaton stage I and II breast carcnoma: expert panel on radaton oncology: breast. Breast J 2011;17: Hwang ES, Lchtensztajn DY, Gomez SL, Fowble B, Clarke CA. Survval after lumpectomy and mastectomy for early stage nvasve breast cancer: The effect of age and hormone receptor status. Cancer 2013;119: Colea SR, Hernán MA. Adjusted survval curves wth nverse probablty weghts. Comput Methods Programs Bomed 2004;75: Austn PC. An ntroducton to propensty score methods for reducng the effects of confoundng n observatonal studes. Multvarate Behav Res 2011;46: Lee BK, Lessler J, Stuart EA. Weght trmmng and propensty score weghtng. PLoS One 2011;6:e Royston P, Parmar MK. Flexble parametrc proportonalhazards and proportonal-odds models for censored survval data, wth applcaton to prognostc modellng and estmaton of treatment effects. Stat Med 2002;21: Bellon JR, Haffty BG, Harrs EE, Arthur DW, Baley L, Carey L, Goyal S, Halyard MY, Horst KC, MacDonald SM, Moran MS. Conservatve surgery and radaton stage I and II breast carcnoma. Amercan College of Radology, ACR Approprateness Crtera. Date of orgn: Last revew date: Avalable from URL: ACR/Documents/AppCrtera/Oncology ConservatveSurgeryAndRadatonStageIandII BreastCarcnoma.pdf [Accessed March 11, 2013]. 32. Horst KC, Haffty BG, Harrs EE, Baley L, Bellon JR, Carey L, Freedman GM, Goyal S, Halyard MY, MacDonald SM, Moran MS, Suh WW. Postmastectomy radotherapy. Amercan College of Radology, ACR Approprateness Crtera. Date of orgn: Last revew date: Avalable from URL: DBD4D414D09BB1070.pdf [Accessed March 11, 2013] CM&R 2015 : 2 (June)

9 33. Clark RM, McCulloch PB, Levne MN, Lpa M, Wlknson RH, Mahoney LJ, Basrur VR, Nar BD, McDermot RS, Wong CS, et al. Randomzed clncal tral to assess the effectveness of breast rradaton followng lumpectomy and axllary dssecton for node-negatve breast cancer. J Natl Cancer Inst 1992;84: Fsher B, Redmond C. Lumpectomy for breast cancer: an update of the NSABP experence. Natonal Surgcal Adjuvant Breast and Bowel Project. J Natl Cancer Inst Monogr 1992;11: Lljegren G, Holmberg L, Adam HO, Westman G, Graffman S, Bergh J. Sector resecton wth or wthout postoperatve radotherapy for stage I breast cancer: fve-year results of a randomzed tral. Uppsala-Orebro Breast Cancer Study Group. J Natl Cancer Inst 1994;86: Verones U, Lun A, Del Veccho M, Greco M, Galmbert V, Merson M, Rlke F, Sacchn V, Saccozz R, Savo T, et al. Radotherapy after breast-preservng surgery n women wth localzed cancer of the breast. N Engl J Med 1993; 328: Fegelson HS, James TA, Sngle RM, Ontlo AA, Aello Bowles EJ, Barney T, Bakerman JE, McCahll LE. Factors assocated wth the frequency of ntal total mastectomy: results of a mult-nsttutonal study. J Am Coll Surg 2013;216: Cho H, Marotto AB, Mann BS, Klabunde CN, Feuer EJ. Assessng non-cancer-related health status of US cancer patents: other-cause survval and comorbdty prevalence. Am J Epdemol 2013;178: Jaworsk C, Maran JA, Wheeler G, Kaye DM. Cardac complcatons of thoracc rradaton. J Am Coll Cardol 2013;61: Author Afflatons Adedayo A. Ontlo, MD, PhD, MSCR, FACP *, ; Jessca M. Engel, DNP, RN ; Rachel V. Stankowsk, PhD ; and Suhal A.R. Do, MBBS, FRCP, PhD * Department of Hematology/Oncology, Marshfeld Clnc- Weston Center, Weston, Wsconsn, USA School of Populaton Health, Unversty of Queensland, Brsbane, Australa Department of Hematology/Oncology, Marshfeld Clnc Cancer Care, Stevens Pont, Wsconsn, USA Marshfeld Clnc Research Foundaton, Marshfeld, Wsconsn, USA CM&R 2015 : 2 (June) Ontlo et al. 73