Reanalysis and Results after 12 Years of Follow-Up in a Randomized Clinical Trial Comparing Total Mastectomy with Lumpectomy with or without Irradiation in the Treatment of Breast Cancer
Bernard Fisher, M.D., Stewart Anderson, Ph.D., Carol K. Redmond, Sc.D., Norman Wolmark, M.D., D. Lawrence Wickerham, M.D., and Walter M. Cronin, M.P.H.
Background Previous findings from a clinical trial (ProtocolB-06) conducted by the National Surgical Adjuvant Breast andBowel Project (NSABP) indicated the worth of lumpectomy andbreast irradiation for treating breast cancer. After the discoveryby NSABP staff members of falsified information on patientsenrolled in the study by St. Luc Hospital in Montreal, separateaudits were conducted at St. Luc Hospital and other participatinginstitutions. We report the results of both audits and updatethe study findings through an average of 12 years of follow-up.
Methods Patients with either negative or positive axillary nodesand tumors 4 cm or less in diameter were randomly assigned toone of three treatments: total mastectomy, lumpectomy followedby breast irradiation, or lumpectomy without irradiation. Threecohorts of patients were analyzed. The first cohort includedall 2105 randomized patients, who were analyzed according tothe intention-to-treat principle. The second cohort consistedof 1851 eligible patients in the first cohort with known nodalstatus who agreed to be followed and who accepted their assignedtherapy (among those excluded were 6 patients from St. Luc Hospitalwho were declared ineligible because of falsified biopsy dates).The third cohort consisted of the patients in the second cohortminus the 322 eligible patients from St. Luc Hospital (total,1529 patients).
Results Regardless of the cohort, no significant differenceswere found in overall survival, disease-free survival, or survivalfree of disease at distant sites between the patients who underwenttotal mastectomy and those treated by lumpectomy alone or bylumpectomy plus breast irradiation. After 12 years of follow-up,the cumulative incidence of a recurrence of tumor in the ipsilateralbreast was 35 percent in the group treated with lumpectomy aloneand 10 percent in the group treated with lumpectomy and breastirradiation (P<0.001).
Conclusions Our findings continue to indicate that lumpectomyfollowed by breast irradiation is appropriate therapy for womenwith either negative or positive axillary nodes and breast tumors4 cm or less in diameter.
Findings from a clinical trial (Protocol B-06) conducted bythe National Surgical Adjuvant Breast and Bowel Project (NSABP)to evaluate lumpectomy in the treatment of breast cancer havebeen reported previously in the Journal.1,2 Life-table estimatesfive and eight years after surgery indicated that 90 percentof women who underwent lumpectomy followed by breast irradiationremained free of cancer in the ipsilateral breast. The ratesof disease-free survival, survival free of disease at distantsites, and overall survival were not significantly differentfrom those among patients who underwent either total mastectomyor lumpectomy alone. As a consequence of these and other findings,lumpectomy and breast irradiation have become accepted in thesurgical approach to the treatment of breast cancer.3
In February 1991, staff members at the NSABP headquarters verifiedthat St. Luc Hospital in Montreal, one of the centers participatingin the study, had submitted falsified information on patients.These findings were immediately reported to the appropriategovernmental agencies. The Office of Research Integrity supervisedpersonnel from the NSABP and the National Cancer Institute (NCI)in an audit of St. Luc's records.4,5 In March 1994, the NCIbegan a special audit of 37 of the 89 institutions participatingin Protocol B-06 to assess the quality of data submitted. Theresults of this audit are reported elsewhere in this issue ofthe Journal.6
In the current report, we present information from both auditsand update the Protocol B-06 findings through an average of12 years of postrandomization follow-up. We have also analyzedthe data after excluding all St. Luc patients with falsifieddata and all St. Luc patients.
Methods
Study Design and Eligibility of Patients
Eligibility requirements, the design of the study, surgicaland radiation techniques used, characteristics of the patientsand tumors, and the distribution of patients among treatmentgroups have been described previously.1,2,5 Patients with eithernegative or positive axillary nodes and tumors 4 cm or lessin diameter (stage I and II breast cancer) were randomly assignedto one of three treatments: total mastectomy, lumpectomy followedby breast irradiation, or lumpectomy without irradiation. Theprotocol specified that the lower two levels of axillary nodesbe removed regardless of the treatment assignment.
Patients were enrolled between April 8, 1976, and January 27,1984. A prerandomization procedure was implemented in January1978; according to this procedure, patients were randomly assignedto treatment before consent was obtained. After the treatmentassignment had been made by the NSABP Biostatistical Center,the protocol was discussed with the patient, who gave writtenconsent if she accepted the assigned treatment or agreed tobe followed. Of the 2163 patients who entered the study, 1573(73 percent) were assigned to treatment through the prerandomizationprocedure.
Patients who had undergone a lumpectomy and in whom the marginsof the resected specimen were not tumor-free were to undergoa total mastectomy. However, they remained in the group to whichthey had originally been assigned. Tumor was evident in thespecimen margins in approximately 10 percent of patients treatedwith lumpectomy, 78 percent of whom subsequently had a mastectomy.
Patients who had had a total mastectomy as treatment for a recurrenceof tumor in the ipsilateral breast after lumpectomy remainedin the group to which they had originally been assigned. Mastectomywas performed in 81 percent of these patients. The remainderunderwent a second lumpectomy, either because they refused toundergo mastectomy or because a medical problem precluded mastectomy.Patients who underwent mastectomy because of a recurrence ofthe tumor were considered to have had a "cosmetic" failure butnot a treatment failure, unless the tumor was so extensive thatit could not be completely removed by mastectomy.
The events used in the analyses of disease-free survival werefirst recurrences of disease, second cancers, and death withoutrecurrence of cancer. Recurrence of tumor in the ipsilateralbreast was not designated an event in determining disease-freesurvival, since the patients who initially underwent total mastectomywere not at risk for such a recurrence. Events used in the analysisof distant disease were distant metastasis as the first recurrence,distant metastasis after a local or regional recurrence, anda second cancer, including a tumor in the contralateral breast.Overall survival refers to survival with or without recurrenceof disease.
Distribution of Patients
The distribution of the patients among the three treatment groupsin the various cohorts used for the analyses is shown in Table 1.Of the 2163 patients randomized, 2105 agreed to be studiedand had follow-up data available. These 2105 patients were includedin the intention-to-treat analyses, and are hereafter referredto as cohort A.
Table 1. Distribution of Patients among Treatment Groups in the Various Cohorts Used in the Analyses of Data from Protocol B-06.
Of the 2105 women included in the intention-to-treat analyses,254 were removed from the analyses for various reasons (Table 1),leaving 1851 patients (the current-update cohort, or cohortB). Data on these 1851 patients formed the basis of our updatedanalysis. Among the 254 women excluded were 170 who consentedto be followed in the study but who were not included in cohortB because they refused the assigned therapy; 152 of these womenwere randomly assigned to treatment before they had signed consentforms (prerandomization), and 18 after they had signed. CohortB also excludes six patients from St. Luc Hospital who weredeclared ineligible because the dates of the first positivebiopsy had been falsified. Two patients in cohort B were notused in a previous analysis of this protocol2 because they withdrewconsent after participating in the study. The patients are includedin this analysis up to the time of their withdrawal. CohortC comprised all the patients in cohort B minus 322 patientsenrolled in the study by St. Luc Hospital. These 322 patientswere eligible, had known nodal status, accepted the assignedtreatment, and were followed.
Statistical Analysis
Life tables were computed by the actuarial method.7 The lengthof time to treatment failure was calculated from the time ofthe initial operation. The summary chi-square test was usedto compare the distributions of the time to treatment failureafter adjustment for the number of positive nodes.9,10,11 AllP values relate to two-sided log-rank tests. Tests for heterogeneityof outcomes among the three treatments were performed for eachcohort throughout the entire follow-up (referred to in thisreport as the global P value). Numbers and statistics (event-freerates, relative odds ratios and their 95 percent confidenceintervals, and P values) for pairwise comparisons in summarytables are cumulative through the end of 12 years of observation.In comparisons of the group treated by total mastectomy witheach of the groups treated by lumpectomy, relative odds withvalues greater than 1 indicate a better outcome for patientstreated by lumpectomy, whereas relative odds less than 1 indicatea better outcome for those treated by total mastectomy. Testswere adjusted for the number of nodes involved (0, 1 to 3, 4to 9, 10). In accordance with recently recommended statisticalmethods12,13 for estimating the probability of a recurrenceof tumor in the ipsilateral breast in the presence of competingrisks — that is, recurrences at other sites or death —cumulative incidence curves are used. This differs from ourprevious reports8,14 in which life-table estimates and cumulativehazard rates were used to present such information.
Information on survival, disease-free survival, and distant-disease–freesurvival is presented for cohorts A, B, and C. Information onthe recurrence of tumor in the ipsilateral breast after lumpectomywith breast irradiation and without it has been obtained fromall cohorts but is presented only for the 1851 women in cohortB.
Falsifications of Data on Patients from St. Luc Hospital
Of the 354 patients enrolled in the trial by St. Luc Hospital,118 were assigned to total mastectomy, 119 to lumpectomy, and117 to lumpectomy and breast irradiation. Descriptions of thefalsifications have been reported previously.4,5 False biopsydates were submitted for six patients (1.7 percent), or 0.3percent of all patients who underwent randomization: three treatedby total mastectomy, two treated by lumpectomy, and one treatedby lumpectomy and breast irradiation. As of the cutoff datefor this report, September 30, 1993, all six patients had up-to-datefollow-up information. Five of the six were node-negative, andall six were alive on the cutoff date. One had distant metastasis,which was reported after the publication of our 1989 report.2Two had a recurrence of tumor in the ipsilateral breast andwere included in previously published analyses.1,2
The NCI Audit
Between March 28 and July 20, 1994, on-site audits of the recordsof 1554 randomized patients in protocol B-06 (86 percent ofthe randomized patients excluding those enrolled at St. LucHospital) were carried out to ascertain whether additional falsificationscould be identified and to verify patients' eligibility andoutcome end points.6 In addition, the National Death Index wassearched to identify deaths not previously found. The data basefor the current reanalysis was obtained by merging the NSABPsummary file with the audited NCI data base. The file for thecurrent analysis was closed on March 19, 1995, although at thattime, there was a discrepancy between the audit findings andthe NSABP records for six patients. In one of the six cases,follow-up information was available to the NSABP BiostatisticalCenter but not to the auditors. The NCI audit used clinicalinformation on the site of the first treatment failure in theother five cases. However, histologic confirmation was not available.NCI audit findings were used in this reanalysis, except forthe six cases with discrepant findings, when NSABP records wereused. The results did not change, regardless of whether NSABPrecords or NCI audit findings were used for these six patients.
The audit did not change the number of patients included inthe current update (cohort B). Although one additional patientwas found to be ineligible, she had never been included in publishedanalyses because she had refused her assigned treatment.
Results
Survival
When overall survival in the three treatment groups was examinedin each of the three cohorts, no significant differences werefound (Figure 1). The overall survival estimates at 12 yearswere similar in the three cohorts for patients treated withlumpectomy and breast irradiation: 62 percent in both cohortA (patients analyzed according to the intention to treat) andcohort B (the current-update cohorts, consisting of the patientsin cohort A minus the 254 excluded for the reasons listed inTable 1) and 63 percent in cohort C (consisting of the patientsin cohort B minus all patients enrolled by St. Luc Hospital)(Table 2). In all three cohorts, overall survival among patientstreated by lumpectomy and breast irradiation was the same asor slightly greater than that among patients treated by totalmastectomy. Overall survival in all three cohorts was similarfor patients who had undergone a total mastectomy and patientstreated by lumpectomy.
Figure 1. Life-Table Analysis Showing Overall Survival among Patients in the Three Cohorts Who Were Treated by Total Mastectomy, Lumpectomy, or Lumpectomy and Breast Irradiation.
The number of deaths includes those occurring after 12 years.
Table 2. Survival Estimates for All Treatment Groups after 12 Years of Follow-up.
When survival was analyzed according to nodal status, therewas no significant heterogeneity among the three treatment groupsfor either patients with node-negative cancer or patients withnode-positive cancer in any of the cohorts (data not shown).
Disease-Free Survival and Distant-Disease–Free Survival
As with overall survival, when disease-free survival was analyzedin each of the cohorts, the outcome was similar among the threetreatment groups (Figure 2). The estimates of disease-free survivalat 12 years for patients treated by lumpectomy and breast irradiationwere 50 percent in cohorts A and C and 49 percent in cohortB (Table 3).
Figure 2. Life-Table Analysis Showing Disease-free Survival among patients in the Three Cohorts Who Were Treated by Total Mastectomy, Lumpectomy, or Lumpectomy and Breast Irradiation.
The number of events includes those that occurred after the 12-year follow-up period.
Table 3. Estimates of Disease-free Survival for All Treatment Groups after 12 Years of Follow-up.
When overall distant-disease–free survival was analyzedin each cohort, no significant differences were found amongthe three treatment groups (Figure 3). When pairwise comparisonswere made in each of the cohorts between the group treated bytotal mastectomy and each of the lumpectomy-treated groups,there were no significant differences in overall distant-disease–freesurvival during the 12 years of follow-up (data not shown).
Figure 3. Life-Table Analysis Showing Distant-Disease–free Survival among Patients in the Three Cohorts Who Were Treated by Total Mastectomy, Lumpectomy, or Lumpectomy and Breast Irradiation.
The number of events includes those that occurred after the 12-year follow-up period.
When disease-free survival and distant-disease–free survivalwere analyzed for patients with node-negative cancer in thethree cohorts, significant or nearly significant differenceswere observed among the treatment groups (data not shown). Significantlyor nearly significantly higher percentages of patients withnode-negative cancer treated by total mastectomy or lumpectomyand breast irradiation remained free of disease and free ofdistant disease than of patients with node-negative cancer treatedby lumpectomy. However, in patients with node-positive cancer,there were no significant differences in disease-free and distant-disease–freesurvival in any of the three cohorts.
Tumor in the Ipsilateral Breast after Lumpectomy with or without Breast Irradiation
The likelihood of the recurrence of tumor in the ipsilateralbreast was evaluated in a total of 1137 patients treated withlumpectomy whose specimen margins were histologically free oftumor (Figure 4). Radiation therapy resulted in a marked decreasein the rate of recurrence of tumor in the ipsilateral breast.For the 12 years of follow-up, the cumulative incidence of tumorrecurrence was 35 percent in the group treated by lumpectomyalone and 10 percent in those treated by lumpectomy and breastirradiation (P<0.001). In patients with node-negative cancer,the cumulative incidence was 32 percent and 12 percent, respectively.Among the patients with node-positive cancer, all of whom alsoreceived chemotherapy, the decrease in the likelihood of recurrenceof tumor in the ipsilateral breast was more evident after lumpectomyand breast irradiation than after lumpectomy alone (5 percentvs. 41 percent).
Figure 4. Life-Table Analysis Showing the Cumulative Incidence of Recurrence of Tumor in the Ipsilateral Breast after Lumpectomy or Lumpectomy and Breast Irradiation in 1137 Patients in the Current-Update Cohort (Cohort B) Who Had either Negative or Positive Nodes and Tumor-Negative Specimen Margins.
The P values were calculated from average annual rates of recurrence in the ipsilateral breast. The number of recurrences includes those that occurred after the 12-year follow-up period.
Discussion
In planning a strategy for the reanalysis of data in this study,we encountered numerous issues that were difficult to resolve.The literature is sparse regarding how fraudulent or altereddata should best be handled.15 The options available to us fordealing with patients made ineligible because of fraudulentdata ranged from including all data from all patients, regardlessof whether falsified information was submitted, to excludingall data from all patients enrolled by St. Luc Hospital. Anintermediate strategy was to exclude only the patients withfalsified entry information. Findings from St. Luc Hospitalare not presented separately, since examining a subgroup ofa much larger cohort of patients may result in unreliable conclusions.Because of the variations in findings among institutions, thechance of obtaining false positive findings (i.e., type I errors)is increased.
In previous analyses of Protocol B-06,1,2 two analytic componentswere used: the intention-to-treat principle,16,17,18 accordingto which eligibility criteria are ignored and patients are analyzedaccording to their randomized treatment assignment (cohort A),and the "clinically analyzable," or "analysis-per-protocol,"strategy, similar to the one designated in this report as thecurrent update (cohort B). According to the latter strategy,patients who, for example, are ineligible for the protocol,have refused the assigned treatment, have noninvasive cancers,or have unknown nodal status are removed from the cohort usedfor analysis. In our initial report of the results of ProtocolB-06,1 we indicated that these two cohorts were used and that,since the conclusions of the resulting analyses did not differ,the findings presented were those obtained by the analysis-per-protocolstrategy.
In the current report, we have continued to use this strategy.The only difference between the current-update cohort in thispaper and the current-update cohort in our previous reportsis that in this paper six St. Luc patients with data falsificationswere regarded as six additional ineligible patients and werethus deleted from the clinically analyzable cohort of patients.
To allay concern generated by the St. Luc falsifications, wealso analyzed our data after eliminating all patients enrolledby St. Luc Hospital. The outcomes and conclusions did not change.Though the removal of all St. Luc patients from future analysesmight seem appropriate, there are compelling reasons not todo so.15,18 A large-scale removal of data is justifiable ifthe existence of patients is fabricated, randomization is compromised,end-point information is altered, or the number of falsificationsis large. However, the audit of the St. Luc data for ProtocolB-06, in which records from multiple sources were examined forall patients, revealed no evidence of such falsifications.5The false information concerned the eligibility status of asmall number of patients and was altered before the patientsunderwent randomization. Under these circumstances, eliminatingthe 128 St. Luc patients who died, as well as those who arestill alive — all of whom agreed to participate and tocontribute to the study — is antithetical to the appropriateanalysis of large, randomized, multicenter clinical trials.18Furthermore, in principle, the falsifications encountered wouldnot have been expected to bias the outcome. Our findings supportthat contention. Thus, it is appropriate to include all St.Luc patients with follow-up data in future intention-to-treatanalyses.18
The findings and conclusions reported for 12 years of follow-upare in accord with those reported after 5 and 8 years of follow-up.1,2They indicate that there is no significant heterogeneity insurvival, disease-free survival, or distant-disease–freesurvival among the three treatment groups, regardless of whichof the cohorts was used for the analyses.
The value of radiation therapy in reducing the incidence oftumor in the ipsilateral breast after lumpectomy continues tobe an important factor. Current findings show a 10 percent cumulativeincidence of tumor recurrence after 12 years of follow-up amongpatients who underwent irradiation, as compared with 35 percentfor those who underwent no irradiation. These values are lowerthan those previously reported8,14 since they estimate the probabilityof a recurrence of tumor in the ipsilateral breast in the presenceof competing risks — that is, recurrences at other sitesand deaths. Of particular importance are the findings in patientswith node-positive cancer treated by lumpectomy, who also receivedradiation and systemic therapy. The cumulative incidence ofrecurrent tumors in the ipsilateral breast was only 5 percentin this group at 12 years of follow-up. This low incidence precludesone from considering positive axillary nodes as a contraindicationto breast-conserving surgery.
This report should eliminate any remaining uncertainty surroundingProtocol B-06 as a result of the disclosure of data falsificationsat St. Luc Hospital. After 12 years of follow-up, findings continueto indicate that lumpectomy followed by breast irradiation isappropriate therapy for women with stage I or II breast cancer.The safeguards incorporated into the design of the study preventedthe actions of a single person from materially affecting thefindings and conclusions — an assurance that cannot bemade for studies that lack such safeguards. We believe thatthis report confirms the worth of meticulously conducted largemulticenter, prospective, randomized clinical trials and shouldrestore the confidence of physicians and patients in such trials.
Supported by a Public Health Service grant (NCI-U10-CA-12027)from the National Cancer Institute and by a grant (ACS-RC-13)from the American Cancer Society.
Source Information
From the National Surgical Adjuvant Breast and Bowel Project. The authors of this paper are the authors who participated in the current reanalysis. The institutions and principal investigators that participated in this study are listed in the Appendixes of papers previously published in the Journal (1985;312:672-3 and 1989;320:827-8).
Address reprint requests to Dr. Fisher at Rm. 914, Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261.
References
Fisher B, Bauer M, Margolese R, et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med 1985;312:665-673. [Abstract]
Fisher B, Redmond C, Poisson R, et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1989;320:822-828. [Abstract]
Consensus statement: treatment of early-stage breast cancer. NIH Consensus Development Conference, June 18–21, 1990. Vol. 8. No. 6. Bethesda, Md.: National Institutes of Health, 1990:1-19.
Fisher B, Redmond CK. Fraud in breast-cancer trials. N Engl J Med 1994;330:1458-1460. [Free Full Text]
Division of Research investigations report. Washington, D.C.: Office of Research Integrity, 1993. (DHHS publication no. (ORI) 91-08.)
Christian MC, McCabe MS, Korn EL, et al. The National Cancer Institute audit of the National Surgical Adjuvant Breast and Bowel Project Protocol B-06. N Engl J Med 1995;333:1469-1474. [Free Full Text]
Cutler SJ, Ederer F. Maximum utilization of the life table method in analyzing survival. J Chronic Dis 1958;8:699-712. [CrossRef][Medline]
Fisher B, Anderson S. Conservative surgery for the management of invasive and noninvasive carcinoma of the breast: NSABP trials: National Surgical Adjuvant Breast and Bowel Project. World J Surg 1994;18:63-69. [CrossRef][Medline]
Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50:163-170. [Medline]
Peto R, Peto J. Asymptotically efficient rank invariant test procedures. J R Stat Soc [A] 1972;135:185-206.
Hankey BF, Myers MH. Evaluating differences in survival between two groups of patients. J Chronic Dis 1971;24:523-531. [CrossRef][Medline]
Korn EL, Dorey FJ. Applications of crude incidence curves. Stat Med 1992;11:813-829. [Medline]
Dignam JJ, Weissfeld LA, Anderson SJ. Methods for bounding marginal survival distribution. Stat Med 1995;14:1985-1998. [Medline]
Fisher B, Anderson S, Fisher ER, et al. Significance of ipsilateral breast tumour recurrence after lumpectomy. Lancet 1991;338:327-331. [CrossRef][Medline]
Neaton JD, Bartsch GE, Broste SK, Cohen JD, Simon NM. A case of data alteration in the Multiple Risk Factor Intervention Trial (MRFIT). Control Clin Trials 1991;12:731-740. [Medline]
Gail MH. Eligibility exclusions, losses to follow-up, removal of randomized patients, and uncounted events in cancer clinical trials. Cancer Treat Rep 1985;69:1107-1113. [Medline]
Lewis JA, Machin D. Intention to treat -- who should use ITT? Br J Cancer 1993;68:647-650. [Medline]
Collins R, Peto R, Gray R, Parrish S. Large-scale randomized evidence: trials and overviews. In: Weatherall DJ, Ledingham JGG, Warrell DA, eds. Oxford textbook of medicine. 3rd ed. Oxford, England: Oxford University Press, 1996.
Jones, H. A., Antonini, N., Hart, A. A.M., Peterse, J. L., Horiot, J.-C., Collin, F., Poortmans, P. M., Oei, S. B., Collette, L., Struikmans, H., Van den Bogaert, W. F., Fourquet, A., Jager, J. J., Schinagl, D. A.X., Warlam-Rodenhuis, C. C., Bartelink, H.
(2009). Impact of Pathological Characteristics on Local Relapse After Breast-Conserving Therapy: A Subgroup Analysis of the EORTC Boost Versus No Boost Trial. JCO
27: 4939-4947
[Abstract][Full Text]
Kwan, W., Al-Tourah, A. J., Speers, C., Woods, R., Kennecke, H., Olivotto, I. A.
(2009). Does HER2 status influence locoregional failure rates in breast cancer patients treated with mastectomy for pT1-2pN0 disease?. Ann Oncol
0: mdp396v1-mdp396
[Abstract][Full Text]
Anderson, S. J., Wapnir, I., Dignam, J. J., Fisher, B., Mamounas, E. P., Jeong, J.-H., Geyer, C. E. Jr, Wickerham, D. L., Costantino, J. P., Wolmark, N.
(2009). Prognosis After Ipsilateral Breast Tumor Recurrence and Locoregional Recurrences in Patients Treated by Breast-Conserving Therapy in Five National Surgical Adjuvant Breast and Bowel Project Protocols of Node-Negative Breast Cancer. JCO
27: 2466-2473
[Abstract][Full Text]
McCahill, L. E., Privette, A., James, T., Sheehey-Jones, J., Ratliff, J., Majercik, D., Krag, D. N., Stanley, M., Harlow, S.
(2009). Quality Measures for Breast Cancer Surgery: Initial Validation of Feasibility and Assessment of Variation Among Surgeons. Arch Surg
144: 455-462
[Abstract][Full Text]
Connell, P. P., Hellman, S.
(2009). Advances in Radiotherapy and Implications for the Next Century: A Historical Perspective. Cancer Res.
69: 383-392
[Full Text]
Weichselbaum, R. R., Ishwaran, H., Yoon, T., Nuyten, D. S. A., Baker, S. W., Khodarev, N., Su, A. W., Shaikh, A. Y., Roach, P., Kreike, B., Roizman, B., Bergh, J., Pawitan, Y., van de Vijver, M. J., Minn, A. J.
(2008). An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer. Proc. Natl. Acad. Sci. USA
105: 18490-18495
[Abstract][Full Text]
Kim, S. J., Ko, E. Y., Shin, J. H., Kang, S. S., Mun, S. H., Han, B.-K., Cho, E. Y.
(2008). Application of Sonographic BI-RADS to Synchronous Breast Nodules Detected in Patients with Breast Cancer. Am. J. Roentgenol.
191: 653-658
[Abstract][Full Text]
Godinez, J., Gombos, E. C., Chikarmane, S. A., Griffin, G. K., Birdwell, R. L.
(2008). Breast MRI in the Evaluation of Eligibility for Accelerated Partial Breast Irradiation. Am. J. Roentgenol.
191: 272-277
[Abstract][Full Text]
Sanders, M. E., Scroggins, T., Ampil, F. L., Li, B. D.
(2007). Accelerated Partial Breast Irradiation in Early-Stage Breast Cancer. JCO
25: 996-1002
[Abstract][Full Text]
Epstein, A. M.
(2007). Pay for Performance at the Tipping Point. NEJM
356: 515-517
[Full Text]
Ng, T. T., McGory, M. L., Ko, C. Y., Maggard, M. A.
(2006). Meta-analysis in Surgery: Methods and Limitations. Arch Surg
141: 1125-1130
[Abstract][Full Text]
Mandelblatt, J., Schechter, C. B., Lawrence, W., Yi, B., Cullen, J.
(2006). Chapter 8: The SPECTRUM Population Model of the Impact of Screening and Treatment on U.S. Breast Cancer Trends From 1975 to 2000: Principles and Practice of the Model Methods. J Natl Cancer Inst Monogr
2006: 47-55
[Abstract][Full Text]
Potts, M., Prata, N., Walsh, J., Grossman, A.
(2006). Parachute approach to evidence based medicine.. BMJ
333: 701-703
[Full Text]
Hanrahan, E. O., Valero, V., Gonzalez-Angulo, A. M., Hortobagyi, G. N.
(2006). Prognosis and Management of Patients With Node-Negative Invasive Breast Carcinoma That Is 1 cm or Smaller in Size (stage 1; T1a,bN0M0): A Review of the Literature. JCO
24: 2113-2122
[Abstract][Full Text]
DeMets, D. L, Fost, N., Powers, M.
(2006). An Institutional Review Board dilemma: responsible for safety monitoring but not in control. Clin Trials
3: 142-148
[Abstract]
Moss, R. W.
(2006). Should Patients Undergoing Chemotherapy and Radiotherapy Be Prescribed Antioxidants?. Integr Cancer Ther
5: 63-82
[Abstract]
Patt, D. A., Goodwin, J. S., Kuo, Y.-F., Freeman, J. L., Zhang, D. D., Buchholz, T. A., Hortobagyi, G. N., Giordano, S. H.
(2005). Cardiac Morbidity of Adjuvant Radiotherapy for Breast Cancer. JCO
23: 7475-7482
[Abstract][Full Text]
Martin, M., Pienkowski, T., Mackey, J., Pawlicki, M., Guastalla, J.-P., Weaver, C., Tomiak, E., Al-Tweigeri, T., Chap, L., Juhos, E., Guevin, R., Howell, A., Fornander, T., Hainsworth, J., Coleman, R., Vinholes, J., Modiano, M., Pinter, T., Tang, S. C., Colwell, B., Prady, C., Provencher, L., Walde, D., Rodriguez-Lescure, A., Hugh, J., Loret, C., Rupin, M., Blitz, S., Jacobs, P., Murawsky, M., Riva, A., Vogel, C., the Breast Cancer International Research Group 001,
(2005). Adjuvant Docetaxel for Node-Positive Breast Cancer. NEJM
352: 2302-2313
[Abstract][Full Text]
Giordano, S. H., Kuo, Y.-F., Freeman, J. L., Buchholz, T. A., Hortobagyi, G. N., Goodwin, J. S.
(2005). Risk of Cardiac Death After Adjuvant Radiotherapy for Breast Cancer. JNCI J Natl Cancer Inst
97: 419-424
[Abstract][Full Text]
Kim, K. J., Huh, S. J., Yang, J.-H., Park, W., Nam, S. J., Kim, J. H., Lee, J. H., Kang, S. S., Lee, J. E., Kang, M. K., Park, Y. J., Nam, H. R.
(2005). Treatment Results and Prognostic Factors of Early Breast Cancer Treated with a Breast Conserving Operation and Radiotherapy. Jpn J Clin Oncol
35: 126-133
[Abstract][Full Text]
Zablotska, L. B., Chak, A., Das, A., Neugut, A. I.
(2005). Increased Risk of Squamous Cell Esophageal Cancer after Adjuvant Radiation Therapy for Primary Breast Cancer. Am J Epidemiol
161: 330-337
[Abstract][Full Text]
Ahn, P. H., Vu, H. T., Lannin, D., Obedian, E., DiGiovanna, M. P., Burtness, B., Haffty, B. G.
(2005). Sequence of Radiotherapy With Tamoxifen in Conservatively Managed Breast Cancer Does Not Affect Local Relapse Rates. JCO
23: 17-23
[Abstract][Full Text]
Violet, J A, Harmer, C
(2004). Breast cancer: improving outcome following adjuvant radiotherapy. Br. J. Radiol.
77: 811-820
[Abstract][Full Text]
Komenaka, I. K., Bauer, V. P., Schnabel, F. R., Joseph, K.-A., Horowitz, E., Ditkoff, B.-A., El-Tamer, M. B.
(2004). Interpectoral Nodes as the Initial Site of Recurrence in Breast Cancer. Arch Surg
139: 175-178
[Abstract][Full Text]
Arriagada, R., Le, M. G., Guinebretiere, J.-M., Dunant, A., Rochard, F., Tursz, T.
(2003). Late local recurrences in a randomised trial comparing conservative treatment with total mastectomy in early breast cancer patients. Ann Oncol
14: 1617-1622
[Abstract][Full Text]
Davol, P. A., Bagdasaryan, R., Elfenbein, G. J., Maizel, A. L., Frackelton, A. R. Jr.
(2003). Shc Proteins Are Strong, Independent Prognostic Markers for Both Node-Negative and Node-Positive Primary Breast Cancer. Cancer Res.
63: 6772-6783
[Abstract][Full Text]
Mamounas, E. P.
(2003). NSABP Breast Cancer Clinical Trials: Recent Results and Future Directions. Clin Med Res
1: 309-326
[Abstract][Full Text]
Cocquyt, V., Moeremans, K., Annemans, L., Clarys, P., Van Belle, S.
(2003). Long-term medical costs of postmenopausal breast cancer therapy. Ann Oncol
14: 1057-1063
[Abstract][Full Text]
Punglia, R. S., Kuntz, K. M., Lee, J. H., Recht, A.
(2003). Radiation Therapy Plus Tamoxifen Versus Tamoxifen Alone After Breast-Conserving Surgery in Postmenopausal Women With Stage I Breast Cancer: A Decision Analysis. JCO
21: 2260-2267
[Abstract][Full Text]
Foster, R. S. Jr
(2003). Breast Cancer Detection and Treatment: A Personal and Historical Perspective. Arch Surg
138: 397-408
[Full Text]
Mandelblatt, J. S., Edge, S. B., Meropol, N. J., Senie, R., Tsangaris, T., Grey, L., Peterson, B. M. Jr, Hwang, Y.-T., Kerner, J., Weeks, J.
(2003). Predictors of Long-Term Outcomes in Older Breast Cancer Survivors: Perceptions Versus Patterns of Care. JCO
21: 855-863
[Abstract][Full Text]
Sharkis, D. H., Recht, A., Sonpavde, G., Veronesi, U., Mariani, L., Fisher, B., Anderson, S., Bryant, J.
(2003). Breast-Conserving Surgery for Breast Cancer. NEJM
348: 657-660
[Full Text]
Wasserberg, N., Morgenstern, S., Schachter, J., Fenig, E., Lelcuk, S., Gutman, H.
(2002). Risk Factors for Lymph Node Metastases in Breast Ductal Carcinoma In Situ With Minimal Invasive Component. Arch Surg
137: 1249-1252
[Abstract][Full Text]
Fisher, B., Anderson, S., Bryant, J., Margolese, R. G., Deutsch, M., Fisher, E. R., Jeong, J.-H., Wolmark, N.
(2002). Twenty-Year Follow-up of a Randomized Trial Comparing Total Mastectomy, Lumpectomy, and Lumpectomy plus Irradiation for the Treatment of Invasive Breast Cancer. NEJM
347: 1233-1241
[Abstract][Full Text]
Whelan, T.
(2002). A Trial of Two Questions. JCO
20: 4135-4138
[Full Text]
ISHIZAKI, T., IMANAKA, Y., HIROSE, M., KUWABARA, K., OGAWA, T., HARADA, Y.
(2002). A first look at variations in use of breast conserving surgery at five teaching hospitals in Japan. Int J Qual Health Care
14: 411-418
[Abstract][Full Text]
Freedman, G. M., Hanlon, A. L., Fowble, B. L., Anderson, P. R., Nicoloau, N.
(2002). Recursive Partitioning Identifies Patients at High and Low Risk for Ipsilateral Tumor Recurrence After Breast-Conserving Surgery and Radiation. JCO
20: 4015-4021
[Abstract][Full Text]
Hansen, N. M., Grube, B. J., Giuliano, A. E.
(2002). The Time Has Come to Change the Algorithm for the Surgical Management of Early Breast Cancer. Arch Surg
137: 1131-1135
[Abstract][Full Text]
Arriagada, R., Le, M. G., Contesso, G., Guinebretiere, J. M., Rochard, F., Spielmann, M.
(2002). Predictive factors for local recurrence in 2006 patients with surgically resected small breast cancer. Ann Oncol
13: 1404-1413
[Abstract][Full Text]
Morrow, M., Strom, E. A., Bassett, L. W., Dershaw, D. D., Fowble, B., Harris, J. R., O'Malley, F., Schnitt, S. J., Singletary, S. E., Winchester, D. P.
(2002). Standard for the Management of Ductal Carcinoma In Situ of the Breast (DCIS). CA Cancer J Clin
52: 256-276
[Abstract][Full Text]
Morrow, M., Strom, E. A., Bassett, L. W., Dershaw, D. D., Fowble, B., Giuliano, A., Harris, J. R., O'Malley, F., Schnitt, S. J., Singletary, S. E., Winchester, D. P.
(2002). Standard for Breast Conservation Therapy in the Management of Invasive Breast Carcinoma. CA Cancer J Clin
52: 277-300
[Abstract][Full Text]
Tillman, G. F., Orel, S. G., Schnall, M. D., Schultz, D. J., Tan, J. E., Solin, L. J.
(2002). Effect of Breast Magnetic Resonance Imaging on the Clinical Management of Women With Early-Stage Breast Carcinoma. JCO
20: 3413-3423
[Abstract][Full Text]
Whelan, T., MacKenzie, R., Julian, J., Levine, M., Shelley, W., Grimard, L., Lada, B., Lukka, H., Perera, F., Fyles, A., Laukkanen, E., Gulavita, S., Benk, V., Szechtman, B.
(2002). Randomized Trial of Breast Irradiation Schedules After Lumpectomy for Women With Lymph Node-Negative Breast Cancer. JNCI J Natl Cancer Inst
94: 1143-1150
[Abstract][Full Text]
Moon, W. K., Noh, D.-Y., Im, J.-G.
(2002). Multifocal, Multicentric, and Contralateral Breast Cancers: Bilateral Whole-Breast US in the Preoperative Evaluation of Patients. Radiology
224: 569-576
[Abstract][Full Text]
Scarth, H., Cantin, J., Levine, M.
(2002). Clinical practice guidelines for the care and treatment of breast cancer: Mastectomy or lumpectomy? The choice of operation for clinical stages I and II breast cancer (summary of the 2002 update). CMAJ
167: 154-155
[Full Text]
Vallis, K. A., Pintilie, M., Chong, N., Holowaty, E., Douglas, P. S., Kirkbride, P., Wielgosz, A.
(2002). Assessment of Coronary Heart Disease Morbidity and Mortality After Radiation Therapy for Early Breast Cancer. JCO
20: 1036-1042
[Abstract][Full Text]
Goldhirsch, A., Gelber, R. D., Yothers, G., Gray, R. J., Green, S., Bryant, J., Gelber, S., Castiglione-Gertsch, M., Coates, A. S.
(2001). Adjuvant Therapy for Very Young Women With Breast Cancer: Need for Tailored Treatments. J Natl Cancer Inst Monogr
2001: 44-51
[Abstract][Full Text]
Wolmark, N., Wang, J., Mamounas, E., Bryant, J., Fisher, B.
(2001). Preoperative Chemotherapy in Patients With Operable Breast Cancer: Nine-Year Results From National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr
2001: 96-102
[Abstract][Full Text]
Bartelink, H., Horiot, J.-C., Poortmans, P., Struikmans, H., Van den Bogaert, W., Barillot, I., Fourquet, A., Borger, J., Jager, J., Hoogenraad, W., Collette, L., Pierart, M., the European Organization for Research and Treatme,
(2001). Recurrence Rates after Treatment of Breast Cancer with Standard Radiotherapy with or without Additional Radiation. NEJM
345: 1378-1387
[Abstract][Full Text]
Nattinger, A. B., Kneusel, R. T., Hoffmann, R. G., Gilligan, M. A.
(2001). Relationship of Distance From a Radiotherapy Facility and Initial Breast Cancer Treatment. JNCI J Natl Cancer Inst
93: 1344-1346
[Full Text]
Hadley, J., Mitchell, J. M., Mandelblatt, J.
(2001). Medicare Fees and Small Area Variations in Breast-Conserving Surgery among Elderly Women. Med Care Res Rev
58: 334-360
[Abstract]
Harris, S. R
(2001). Challenging Myths in Physical Therapy. ptjournal
81: 1180-1182
[Full Text]
Buchholz, T. A., Tucker, S. L., Erwin, J., Mathur, D., Strom, E. A., McNeese, M. D., Hortobagyi, G. N., Cristofanilli, M., Esteva, F. J., Newman, L., Singletary, S. E., Buzdar, A. U., Hunt, K. K.
(2001). Impact of Systemic Treatment on Local Control for Patients With Lymph Node-Negative Breast Cancer Treated With Breast-Conservation Therapy. JCO
19: 2240-2246
[Abstract][Full Text]
Vicini, F. A., Baglan, K. L., Kestin, L. L., Mitchell, C., Chen, P. Y., Frazier, R. C., Edmundson, G., Goldstein, N. S., Benitez, P., Huang, R. R., Martinez, A.
(2001). Accelerated Treatment of Breast Cancer. JCO
19: 1993-2001
[Abstract][Full Text]
Fisher, B., Dignam, J., Tan-Chiu, E., Anderson, S., Fisher, E. R., Wittliff, J. L., Wolmark, N.
(2001). Prognosis and Treatment of Patients With Breast Tumors of One Centimeter or Less and Negative Axillary Lymph Nodes. JNCI J Natl Cancer Inst
93: 112-120
[Abstract][Full Text]
Tempfer, C., Seifert, M., Brodowicz, T., Auerbach, L., Zielinski, C., Iacopino, P., Palazzo, S., Patrone, F., Stadtmauer, E. A., Goldstein, L. J., Glick, J. H.
(2000). High-Dose Chemotherapy plus Hematopoietic Stem-Cell Rescue for Metastatic Breast Cancer. NEJM
343: 439-441
[Full Text]
van Dongen, J. A., Voogd, A. C., Fentiman, I. S., Legrand, C., Sylvester, R. J., Tong, D., van der Schueren, E., Helle, P. A., van Zijl, K., Bartelink, H.
(2000). Long-Term Results of a Randomized Trial Comparing Breast-Conserving Therapy With Mastectomy: European Organization for Research and Treatment of Cancer 10801 Trial. JNCI J Natl Cancer Inst
92: 1143-1150
[Abstract][Full Text]
Wolff, A. C., Davidson, N. E.
(2000). Primary Systemic Therapy in Operable Breast Cancer. JCO
18: 1558-1569
[Abstract][Full Text]
Schrag, D., Kuntz, K. M., Garber, J. E., Weeks, J. C.
(2000). Life Expectancy Gains From Cancer Prevention Strategies for Women With Breast Cancer and BRCA1 or BRCA2 Mutations. JAMA
283: 617-624
[Abstract][Full Text]
Finlayson, C. A., MacDermott, T. A.
(2000). Ultrasound Can Estimate the Pathologic Size of Infiltrating Ductal Carcinoma. Arch Surg
135: 158-159
[Abstract][Full Text]
Hayman, J. A., Hillner, B. E., Harris, J. R., Pierce, L. J., Weeks, J. C.
(2000). Cost-Effectiveness of Adding an Electron-Beam Boost to Tangential Radiation Therapy in Patients With Negative Margins After Conservative Surgery for Early-Stage Breast Cancer. JCO
18: 287-287
[Abstract][Full Text]
Berg, W. A., Gilbreath, P. L.
(2000). Multicentric and Multifocal Cancer: Whole-Breast US in Preoperative Evaluation1. Radiology
214: 59-66
[Abstract][Full Text]
Temple, L. K.F., Wang, E. E.L., McLeod, R. S.
(1999). Preventive health care, 1999 update: 3. Follow-up after breast cancer. CMAJ
161: 1001-1008
[Abstract][Full Text]
Krishnamurthy, R., Whitman, G. J., Stelling, C. B., Kushwaha, A. C.
(1999). Mammographic Findings after Breast Conservation Therapy. RadioGraphics
19: 53-62
[Abstract][Full Text]
Day, R., Ganz, P. A., Costantino, J. P., Cronin, W. M., Wickerham, D. L., Fisher, B.
(1999). Health-Related Quality of Life and Tamoxifen in Breast Cancer Prevention: A Report From the National Surgical Adjuvant Breast and Bowel Project P-1 Study. JCO
17: 2659-2659
[Abstract][Full Text]
Liljegren, G., Holmberg, L., Bergh, J., Lindgren, A., Tabar, L., Nordgren, H., Adami, H.O.
(1999). 10-Year Results After Sector Resection With or Without Postoperative Radiotherapy for Stage I Breast Cancer: A Randomized Trial. JCO
17: 2326-2326
[Abstract][Full Text]
Mandelblatt, J. S., Ganz, P. A., Kahn, K. L.
(1999). Proposed Agenda for the Measurement of Quality-of-Care Outcomes in Oncology Practice. JCO
17: 2614-2614
[Abstract][Full Text]
Meijer-van Gelder, M. E., Look, M. P., Vries, J. B.-d., Peters, H. A., Klijn, J. G.M., Foekens, J. A.
(1999). Breast-Conserving Therapy: Proteases as Risk Factors in Relation to Survival After Local Relapse. JCO
17: 1449-1449
[Abstract][Full Text]
Esserman, L., Hylton, N., Yassa, L., Barclay, J., Frankel, S., Sickles, E.
(1999). Utility of Magnetic Resonance Imaging in the Management of Breast Cancer: Evidence for Improved Preoperative Staging. JCO
17: 110-110
[Abstract][Full Text]
Esteva, F. J., Hortobagyi, G. N.
(1998). Integration of Systemic Chemotherapy in the Management of Primary Breast Cancer. The Oncologist
3: 300-313
[Abstract][Full Text]
Hellman, S.
(1997). Stopping Metastases at Their Source. NEJM
337: 996-997
[Full Text]
Schrag, D., Kuntz, K. M., Garber, J. E., Weeks, J. C.
(1997). Decision Analysis -- Effects of Prophylactic Mastectomy and Oophorectomy on Life Expectancy among Women with BRCA1 or BRCA2 Mutations. NEJM
336: 1465-1471
[Abstract][Full Text]
Topol, E. J., Califf, R. M., Van de Werf, F., Simoons, M., Hampton, J., Lee, K. L., White, H., Simes, J., Armstrong, P. W.
(1997). Perspectives on Large-Scale Cardiovascular Clinical Trials for the New Millennium. Circulation
95: 1072-1082
[Full Text]
Fisher, B., Anderson, S., Redmond, C. K., Bailar, J. C.
(1996). Surgery for Early Breast Cancer. NEJM
334: 987-988
[Full Text]
Hellman, S.
(1996). Reanalysis of a Trial Comparing Total Mastectomy with Lumpectomy. NEJM
334: 989-989
[Full Text]
(1996). Update on Surgery and Radiotherapy for Breast Cancer. Journal Watch Cardiology
1996: 13-13
[Full Text]
Dixon, J M.
(1995). Surgery and radiotherapy for early breast cancer. BMJ
311: 1515-1516
[Full Text]
(1995). UPDATE ON SURGERY AND RADIOTHERAPY FOR BREAST CANCER. JWatch General
1995: 1-1
[Full Text]
Early Breast Cancer Trialists' Collaborative Group,
(1995). Effects of Radiotherapy and Surgery in Early Breast Cancer -- An Overview of the Randomized Trials. NEJM
333: 1444-1456
[Abstract][Full Text]
Christian, M. C., McCabe, M. S., Korn, E. L., Abrams, J. S., Kaplan, R. S., Friedman, M. A.
(1995). The National Cancer Institute Audit of the National Surgical Adjuvant Breast and Bowel Project Protocol B-06. NEJM
333: 1469-1475
[Abstract][Full Text]
Bailar, J. C.
(1995). Surgery for Early Breast Cancer -- Can Less Be More?. NEJM
333: 1496-1498
[Full Text]
Formenti, S. C., Rosenstein, B., Skinner, K. A., Jozsef, G.
(2002). T1 Stage Breast Cancer: Adjuvant Hypofractionated Conformal Radiation Therapy to Tumor Bed in Selected Postmenopausal Breast Cancer Patients—Pilot Feasibility Study. Radiology
222: 171-178
[Abstract][Full Text]
10). In accordance with recently recommended statistical methods12,13 for estimating the probability of a recurrence of tumor in the ipsilateral breast in the presence of competing risks — that is, recurrences at other sites or death — cumulative incidence curves are used. This differs from our previous reports8,14 in which life-table estimates and cumulative hazard rates were used to present such information. 
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