High-Dose Chemotherapy with Hematopoietic Stem-Cell Rescue for High-Risk Breast Cancer
Sjoerd Rodenhuis, M.D., Marijke Bontenbal, M.D., Louk V.A.M. Beex, M.D., John Wagstaff, M.D., Dick J. Richel, M.D., Marianne A. Nooij, M.D., Emile E. Voest, M.D., Pierre Hupperets, M.D., Harm van Tinteren, M.Sc., Hans L. Peterse, M.D., Elisabeth M. TenVergert, Ph.D., Elisabeth G.E. de Vries, M.D., for the Netherlands Working Party on Autologous Transplantation in Solid Tumors
Background The use of high-dose adjuvant chemotherapy for high-riskprimary breast cancer is controversial. We studied its efficacyin patients with 4 to 9 or 10 or more tumor-positive axillarylymph nodes.
Methods Patients younger than 56 years of age who had undergonesurgery for breast cancer and who had no distant metastaseswere eligible if they had at least four tumor-positive axillarylymph nodes. Patients in the conventional-dose group receivedfluorouracil, epirubicin, and cyclophosphamide (FEC) every threeweeks for five courses, followed by radiotherapy and tamoxifen.The high-dose treatment was identical, except that high-dosechemotherapy (6 g of cyclophosphamide per square meter of body-surfacearea, 480 mg of thiotepa per square meter, and 1600 mg of carboplatinper square meter) with autologous peripheral-blood hematopoieticprogenitor-cell transplantation replaced the fifth course ofFEC.
Results Of the 885 patients, 442 were assigned to the high-dosegroup and 443 to the conventional-dose group. After a medianfollow-up of 57 months, the actuarial 5-year relapse-free survivalrates were 59 percent in the conventional-dose group and 65percent in the high-dose group (hazard ratio for relapse inthe high-dose group, 0.83; 95 percent confidence interval, 0.66to 1.03; P=0.09). In the group with 10 or more positive nodes,the relapse-free survival rates were 51 percent in the conventional-dosegroup and 61 percent in the high-dose group (P=0.05 by the log-ranktest; hazard ratio for relapse, 0.71; 95 percent confidenceinterval, 0.50 to 1.00).
Conclusions High-dose alkylating therapy improves relapse-freesurvival among patients with stage II or III breast cancer and10 or more positive axillary lymph nodes. This benefit may beconfined to patients with HER-2/neu-negative tumors.
A number of relatively small, uncontrolled studies have suggestedthat adjuvant high-dose chemotherapy with hematopoietic progenitor-cellinfusion could be of benefit for high-risk breast cancer.1 Thelargest of these studies suggested that high-dose chemotherapydramatically prolongs progression-free survival as comparedwith survival among historical controls who had received conventionaltherapy.2 We and others were not able to reproduce this result.3Clearly, much larger prospective, controlled studies were requiredto ascertain the efficacy of this treatment.
The Dutch randomized study reported here was designed in 1993,and the original protocol included fewer than 300 patients.When the study had been under way for two years, we recognizedthat a much larger trial would be required to detect a truerelapse-free survival benefit of 15 to 20 percent. The studyprotocol was amended, but the funding agency stipulated thatthe results in the first 284 patients would be reported in 2000.4,5In addition, the larger study had specifically to address whetherhigh-dose therapy would also be useful in patients with an intermediaterisk of relapse (as defined by the presence of four to ninetumor-positive axillary lymph nodes). Thus, separate analysesof the intermediate-risk (4 to 9 nodes) and high-risk (10 ormore nodes) categories were planned. Here, we report the outcomeof the study after a median follow-up of 57 months and a maximalfollow-up of more than 8 years.
Methods
Patients
The study was designed to enroll women younger than 56 yearsof age who had undergone surgery for breast cancer. Patientswere eligible if they had at least four axillary lymph nodeswith metastases but no distant metastases. The results of chestroentgenography, an ultrasonographic examination of the liver,and a bone scan had to be negative. If the results of bone scanningwere equivocal, normal findings on magnetic resonance imaging(MRI) of the involved area were required to resolve the issue.Other eligibility criteria included an Eastern Cooperative OncologyGroup–Zubrod performance status of 0 or 1, a white-cellcount of at least 4000 per cubic millimeter, a platelet countof at least 100,000 per cubic millimeter, a creatinine clearancerate of at least 60 ml per minute, and a serum bilirubin levelof 1.46 mg per deciliter (25 µmol per liter) or less.The chemotherapy had to begin within six weeks after the lastsurgery. No other cancers were allowed except adequately treatedin situ carcinoma of the cervix or basal-cell carcinoma of theskin. Informed consent was obtained from all patients, and thestudy was approved by the institutional review committees ateach of the participating centers.
Eligible patients underwent randomization before treatment andwere stratified according to age (younger than 50 years of agevs. 50 years or older), menopausal status (premenopausal vs.postmenopausal), the number of lymph-node metastases (4 to 9nodes or 10 or more) and tumor size (pT1, pT2, or pT3).
The conventional-treatment group received five courses of fluorouracil,epirubicin, and cyclophosphamide (FEC), radiotherapy, and tamoxifen.Treatment in the high-dose group was identical, except thatthe fifth course of FEC was replaced by high-dose alkylatingchemotherapy.
Treatment
The conventional chemotherapy consisted of intravenous injectionsof fluorouracil (500 mg per square meter of body-surface area),epirubicin (90 mg per square meter), and cyclophosphamide (500mg per square meter) every three weeks. In the high-dose group,peripheral-blood progenitor cells were mobilized by administeringgranulocyte colony-stimulating factor (filgrastim) at a doseof 300 µg daily subcutaneously for 10 days starting theday after the third course of FEC. Peripheral-blood progenitorcells were collected by leukocytapheresis until at least 3 millionCD34+ cells per kilogram of body weight had been harvested.6The high-dose chemotherapy regimen consisted of cyclophosphamide(6 g per square meter), thiotepa (480 mg per square meter),and carboplatin (1600 mg per square meter) divided over a four-dayperiod and given in daily infusions of 30 to 60 minutes.6,7The peripheral-blood progenitor cells were administered 48 hoursafter the last dose of chemotherapy and were followed by dailytreatment with filgrastim. Details of supportive care beforeand after transplantation have been published elsewhere.6
The original protocol included treatment with tamoxifen, 40mg daily for two years, after the completion of chemotherapy.During the course of the trial, however, it became clear thatfive years of tamoxifen was more efficacious than two years.8Patients with hormone-receptor–positive cancer thereforecontinued to receive tamoxifen for three more years after completingthe first two years of tamoxifen prescribed in the protocol.
Patients were evaluated at the beginning of every chemotherapycourse and at the beginning and end of the radiation therapy.Patients were subsequently seen at least every four months.To monitor patients' menopausal status, the date of the lastmenstruation was noted and follicle-stimulating hormone and17-estradiol levels were determined at least every year duringtamoxifen therapy and after the discontinuation of tamoxifenif any uncertainty regarding postmenopausal status remained.Yearly mammography and chest roentgenography were performed.
Pathological Review
A centralized review of pathological specimens was performedin a blinded fashion by one investigator. Classification includedtumor type according to the criteria of the World Health Organization,histologic tumor grade,9 mitotic activity index,10 and the presenceor absence of carcinoma in situ and angioinvasion.
Formalin-fixed, paraffin-embedded tissue samples were stainedwith antibodies against estrogen receptor (1D5; dilution, 1:150;Dako); progesterone receptor (involving standard antigen retrieval,followed by incubation with progesterone-receptor polyclonalantibody [Dako]), HER2/neu (3B5; dilution, 1:10,000),11 andp53 (D07; dilution, 1:8000; Dako). Immunohistochemical resultswere scored semiquantitatively. Tumors were considered positivefor hormone receptors if at least 10 percent of the tumor cellsshowed nuclear staining. Staining for HER2/neu was scored asfollows: a score of 0, no staining; a score of 1, more than10 percent of cells were weakly positive; a score of 2, moderatehomogeneous staining; and a score of 3, strong homogeneous staining.
Statistical Analysis
The main end points for the comparison of the two treatmentswere relapse-free survival and overall survival. Relapse-freesurvival was calculated from randomization to the initial appearanceof a relapse of disease or to death from any cause; data onpatients known to be alive and without a relapse at the timeof an analysis were censored at the time of their last follow-upvisit. The occurrence of second breast cancers or other cancerswas not counted as an event. Overall survival was calculatedfrom randomization to death from any cause; data on patientsknown to be alive at the time of an analysis were censored atthe time of their last follow-up visit. All treatment comparisonsare based on the intention-to-treat principle. The Kaplan–Meiermethod was used to estimate curves for relapse-free and overallsurvival, and comparisons were made with use of the log-ranktest. Cox proportional-hazards models were fitted in order toestimate hazard ratios and confidence intervals. Differencesin the overall treatment comparison and the treatment comparisonwithin the two groups on the basis of the number of nodes areexpressed in terms of hazard ratios with 95 percent confidenceintervals. The relative benefit of high-dose treatment withrespect to relapse-free survival was further investigated insubgroups of potential prognostic variables by means of forestplots, which showed the hazard ratio with 99 percent confidenceintervals. To evaluate whether there were differences in therelative size of the effect in different subgroups, we useda 2 test for interaction or, when appropriate, a 2 test fortrend. All P values are based on two-sided tests. Analyses wereperformed with use of SAS system version 8.2 and S-Plus version2000.
Results
Characteristics of the Patients
Between August 1993 and July 1999, 885 patients from 10 centerswere enrolled and underwent randomization. Thirty-seven patientswere found to be ineligible for the following reasons: priorradiation therapy for unrelated disease (4 patients), evidenceof distant metastases (2), prior cervical cancer (1), and abnormalitiesin laboratory values (30). All 37 stayed in the study, and allpatients were included in the intention-to-treat analysis. Pertinentcharacteristics of the patients are listed in Table 1, as arethe results of the pathological review.
Table 1. Characteristics of the Patients and Tumors.
FEC Chemotherapy
Two patients (one in each group) declined chemotherapy afterrandomization. The median dose intensities were equal in bothgroups, but the absence of a fifth course of conventional chemotherapymade the cumulative doses of epirubicin and fluorouracil 20percent lower in the high-dose group. Clinically significantadverse effects included 50 episodes of fever and neutropeniarequiring antibiotics (1 percent), grade 3 (moderate) or grade4 (severe) nausea and vomiting in 388 courses (10 percent),and grade 3 or 4 mucositis in 14 courses (less than 1 percent).Fourteen days after the third course of FEC, one patient inthe high-dose group died of cardiac arrhythmia during an emergencyhospital admission for diarrhea and an electrolyte imbalance.
Mobilization and Harvest of Peripheral-Blood Progenitor Cells
A total of 402 patients in the high-dose group received filgrastimafter the third or fourth course of FEC and underwent leukocytapheresisto obtain peripheral-blood progenitor cells. A median of twosessions (range, one to four) was required to obtain at least3 million CD34+ cells per kilogram of body weight in 394 patients(median yield, 8.9 million; range, 3.0 million to 51.0 million).In seven patients (2 percent), less than the target number ofcells was harvested (median yield, 2.6 million; range, 1.3 millionto 2.9 million). In a single patient, no CD34+ cells could bemobilized into the peripheral blood.
High-Dose Chemotherapy
Of the 442 patients in the high-dose group, 397 received theplanned course of high-dose alkylating therapy after four coursesof FEC. Reasons for canceling high-dose therapy in the 45 otherpatients were the withdrawal of informed consent in the caseof 15 patients, severe psychological problems in 5 patients,medical complications in 9 patients, early progression in 6patients, venous access problems in 1 patient, early death in1 patient, inability to harvest sufficient numbers of peripheral-bloodprogenitor cells in 1 patient, and unknown reasons in 7 patients.Thirty-four of the 45 patients received a fifth course of FECinstead of the high-dose alkylating therapy. None of the 443patients who were randomly assigned to the conventional-dosechemotherapy group crossed over to high-dose treatment or receivedhigh-dose therapy elsewhere.
In six patients, the high-dose course was terminated early becauseof high fever (four patients), cardiac arrhythmia (one patient),or possible heart failure (one patient). All other patientsreceived the full course without dose reductions. All patientsgiven high-dose chemotherapy had nausea and vomiting and becametransfusion-dependent. There were four deaths within 100 daysafter the reinfusion of peripheral-blood progenitor cells, twofrom septicemia and two from cardiac causes.
Radiation Therapy
Radiotherapy was administered to 776 patients. Radiation-inducedpneumonitis requiring therapy with corticosteroids occurredin 25 patients, 7 of whom were in the conventional-dose groupand 18 of whom were in the high-dose group. The condition ofall but one patient improved; severe lung fibrosis developedin this patient, who was in the high-dose group, and the patientdied of pulmonary complications 18 months after randomization.
Tamoxifen
The durations of tamoxifen therapy are given in Table 1. Morepatients became postmenopausal after high-dose chemotherapythan after conventional-dose treatment (Table 1).
Survival Analysis
At the time of the analysis, the median follow-up of the survivingpatients was 57 months. A total of 319 events (36 percent) hadbeen reported. The five-year relapse-free survival rates were59 percent (range, 54 to 64) in the conventional-dose groupand 65 percent (range, 60 to 70) in the high-dose group. Thehazard ratio for relapse in the high-dose group was 0.83 (95percent confidence interval, 0.66 to 1.03; P=0.09) (Figure 1A).At the time of the last follow-up, a total of 235 patients haddied, and there was no significant difference in overall survivalbetween the two groups (Figure 1B).
Figure 1. Relapse-free Survival (Panel A) and Overall Survival (Panel B) among all 885 Patients, According to an Intention-to-Treat Analysis, and Relapse-free Survival among Patients with 4 to 9 Tumor-Positive Axillary Lymph Nodes (Panel C) and Patients with 10 or More Tumor-Positive Axillary Lymph Nodes (Panel D).
P values were calculated with use of the log-rank test.
The only planned subgroup analyses were for patients at intermediaterisk (those with 4 to 9 tumor-positive axillary lymph nodes)(Figure 1C) and patients at high risk (those with 10 or morepositive nodes) (Figure 1D). Patients with 10 or more axillarylymph nodes had a significantly longer relapse-free survivalafter high-dose therapy than after conventional therapy (P=0.05by the log-rank test; hazard ratio for relapse, 0.71; 95 percentconfidence interval, 0.50 to 1.00), but in both subgroups, high-dosetherapy had no significant effect on overall survival. Furthersubgroup analyses were performed for a range of predictive factors(data not shown). Younger age (P=0.05), negativity for HER2/neuexpression (P=0.02), and lower grade (P=0.002) were associatedwith a significant positive effect of high-dose therapy on relapse-freesurvival.
HER2/neu-Negative and HER2/neu-Positive Tumors
A total of 620 patients had tumors that were negative for HER2/neu(as defined by a score of 0, 1+, or 2+) and 181 had tumors thatexpressed HER2/neu (as defined by a score of 3+). Since patientswith HER2/neu-positive tumors derived no benefit from high-dosetherapy, we performed a subgroup analysis of the patients withHER2/neu-negative tumors. In this subgroup, relapse-free survivalwas significantly longer after high-dose therapy than afterconventional therapy (Figure 2A) (hazard ratio for relapse,0.66; 99 percent confidence interval, 0.46 to 0.94; P=0.002).There was also a trend toward an overall survival benefit afterhigh-dose chemotherapy (P=0.07) (Figure 2B).
Figure 2. Recurrence-free Survival (Panel A) and Overall Survival (Panel B) among the 620 Patients with HER2/neu-negative Tumors and Relapse-free Survival among 181 Patients with HER2/neu-Positive Tumors (Panel C).
For these analyses, scores of 0, 1+, or 2+ were considered to be HER2/neu-negative, and scores of 3+ to be HER2/neu-positive. P values were calculated with use of the log-rank test.
Patients with HER2/neu-positive tumors in the high-dose grouphad a higher frequency of relapses than did such patients inthe conventional-dose group, although the difference was notstatistically significant (Figure 2C). Subgroup analyses ofthe HER2/neu-negative group are shown in Figure 3. As was truefor the group as a whole, in this subgroup, younger age (P=0.02)and a low histologic grade (P=0.01) were strong indicators ofrelapse-free survival after high-dose therapy.
Figure 3. Characteristics of the Patients (Panel A) and Tumors (Panel B) in Subgroup Analyses for Potential Predictive Factors among 620 Patients with HER2/neu-Negative Tumors.
Higher scores for the mitotic activity index indicate more aggressive disease. The Elston–Ellis histologic grades range from I to III, with III indicating more aggressive disease. HER2/neu-negative disease was defined by a score of 0, 1+, or 2+. These forest plots show the effect of high-dose therapy on the hazard ratio for recurrence (or death) and the 99 percent confidence interval. The size of the solid squares corresponds to the size of the subgroups. Subgroups for which the line representing the 99 percent confidence interval lies to the left of the vertical line represent subgroups for which high-dose chemotherapy may offer a significant benefit over conventional therapy with respect to relapse-free survival. All subgroup analyses except those associated with the number of lymph nodes were unplanned. The diamonds correspond to the 95 percent confidence intervals. Data were missing for some patients.
Long-Term Adverse Effects and Second Cancers
The main long-term adverse effect was the induction of menopause,which was more frequent in the high-dose chemotherapy groupthan in the conventional-dose group (Table 1). Second cancersalso occurred slightly more often in the high-dose chemotherapygroup (Table 2).
This randomized study was designed to determine whether high-dosechemotherapy with cyclophosphamide, thiotepa, and carboplatincould improve relapse-free survival among patients with node-positivebreast cancer. All patients received the regimen of adjuvanttherapy that was considered optimal when the study was designed:radiotherapy, chemotherapy, and tamoxifen. The only differencebetween the groups was that one group received high-dose chemotherapyafter four courses of anthracycline-based chemotherapy (FEC).To ensure that any advantage of the high-dose therapy couldnot simply be ascribed to a difference in the duration of treatmentbetween the groups, a fifth course of FEC was given to the patientsin the conventional-dose group.
One potential drawback of our study was that the high-dose alkylatingchemotherapy was expected to induce amenorrhea in nearly allpatients, whereas a substantial proportion of women in the conventionalgroup would remain premenopausal, creating an imbalance withregard to ovarian function. However, this imbalance proved tobe relatively minor, and we have no evidence that chemotherapy-inducedamenorrhea contributed heavily to the relapse-free survivalbenefit of high-dose therapy.
The high-dose chemotherapy regimen caused five deaths (1 percent)and considerable reversible morbidity. This rate is, however,less than the rate of 7.4 percent reported for the regimen ofcisplatin, cyclophosphamide, and carmustine in the AmericanIntergroup Study,12 and one year after high-dose therapy therewere no significant differences in the quality of life betweenthe treatment groups (unpublished data).
The relapse-free survival curve for all the 885 patients showsa mean (±SD) reduction of 17±10 percent in thehazard ratio for relapse in the high-dose group as comparedwith the conventional-dose group (P=0.09), a degree of improvementfor which even a study involving 885 patients is underpowered,but that could be clinically important. The respective reductionin the hazard ratio in the subgroup with 10 or more tumor-positivelymph nodes was 29±15 percent (P=0.05). Since this subgroupanalysis was planned, the result is statistically significant.The overall survival benefit was not statistically significant,but 5 to 10 years of additional follow-up may be required beforea definitive conclusion about overall survival can be made.
We found a significant interaction between HER2/neu status andtreatment (P<0.05). Although unplanned, the subgroup analysesof HER2/neu-positive disease and HER2/neu-negative disease areimportant, since the amplification of HER2/neu characterizesa breast-cancer subtype with a distinct molecular signature,13and the sensitivity to alkylating agents and to anthracyclinesmay differ markedly between HER2/neu-negative and HER2/neu-positivetumors.14,15,16
Patients with HER2/neu-positive disease had a higher relapserate after high-dose therapy than after conventional-dose therapy,but this difference was not statistically significant. Retrospectiveanalyses of uncontrolled studies of high-dose chemotherapy,both as adjuvant chemotherapy and in patients with metastases,have consistently shown that patients with HER2/neu-positivetumors have a very poor response to this approach.17,18,19,20,21,22,23Since staining for HER2/neu is often among the strongest adversepredictive factors for relapse or survival after high-dose alkylatingchemotherapy, high-dose therapy may be inappropriate in suchpatients.24
In our study, patients in the high-dose group who had HER2/neu-negativetumors had a relapse rate of 30 percent after five years, ascompared with a rate of 42 percent among such patients in theconventional-dose group (P=0.002). This value corresponds toa 34±11 percent reduction in the hazard ratio. In thissubgroup, there is also a trend toward a survival benefit withhigh-dose therapy.
High-dose chemotherapy significantly decreased the relapse rate,as compared with conventional therapy, among patients youngerthan 40 years of age (P for interaction, <0.05). This heldtrue for patients with HER2/neu-negative tumors (P for interaction<0.02) but not for those with HER2/neu-positive tumors (datanot shown). The effect of high-dose therapy was particularlyevident among patients with low-grade tumors, as defined bya low mitotic activity index or a low histologic grade (P forinteraction = 0.01). Clearly, the results of these retrospectivesubgroup analyses should be interpreted with caution, but thesubgroups are relatively large and the tests for statisticalsignificance indicate that the results are reliable. These findingscould have important consequences if they are confirmed, becauseit has long been assumed that high-dose chemotherapy shouldbe particularly effective in patients with prognostically unfavorablefeatures of the disease. Another study of conventional adjuvantchemotherapy plus high-dose chemotherapy and autologous stem-celltransplantation in high-risk breast cancer is also reportedin this issue.25
Supported by a grant (OG 94-051) from the Dutch Health InsuranceCouncil.
We are indebted to A. Goldhirsch, M.J. Piccart, and M.K. Parmarfor serving on the independent data-monitoring committee, toO. Dalesio for her help in the statistical design and her criticalevaluation of the analysis, to K.H. Antman for critically readingthe manuscript, and to the following persons for registeringpatients and making important contributions to patient care:W.T.A. van der Graaf, N.H. Mulder, P.H.B. Willemse, B.E. Oosterhuis,and J. Dijkstra at University Hospital, Groningen; J.H. Schornagel,J.W. Baars, and M. Holtkamp at the Netherlands Cancer Institute,Amsterdam; E. van der Wall and K. Hoekman at Free UniversityHospital, Amsterdam; J.G.M. Klijn, R. de Wit, and C. Seynaeveat Erasmus Medical Center–Daniel den Hoed Cancer Center,Rotterdam; A.M. Westermann at the Academic Medical Center, Amsterdam;W.M. Smit and T. Duyts at the Medical Center, Enschede; C.P.Vendrik and E.J. Petersen at the University Medical Center,Utrecht; Q.C.G.M. van Hoesel and P.H.M. de Mulder at UniversityHospital, Nijmegen; and H.C. Schouten and M. Janssen at UniversityHospital, Maastricht.
Source Information
From the Netherlands Cancer Institute, Amsterdam (S.R., H.T., H.L.P.); the Erasmus Medical Center–Daniel den Hoed Cancer Center, Rotterdam (M.B.); University Hospital Nijmegen, Nijmegen (L.V.A.M.B.); Free University Medical Center, Amsterdam (J.W.); University Hospital Maastricht, Maastricht (J.W., P.H.); Academic Medical Center, Amsterdam, and Medical Center Enschede, Enschede (D.J.R.); University Medical Center Leiden, Leiden (M.A.N.); University Medical Center Utrecht, Utrecht (E.E.V.); and University Hospital Groningen, Groningen (E.M.V., E.G.E.V.) — all in the Netherlands.
Address reprint requests to Dr. Rodenhuis at the Netherlands Cancer Institute, Department of Medical Oncology, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands, or at sroden{at}nki.nl.
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High-Dose Chemotherapy for Breast Cancer
Wheatley K., Gray R. G., Ives N. J., Tartarone A., Iodice G., Di Renzo N., Mangano M. M., Dazzi C., Cariello A., Rodenhuis S., van Tinteren H., de Vries E. G.E., Tallman M. S., Robert N. J., Lazarus H. M., Elfenbein G. J.
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19: 861-870
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Somlo, G., Frankel, P., Chow, W., Leong, L., Margolin, K., Morgan, R. Jr, Shibata, S., Chu, P., Forman, S., Lim, D., Twardowski, P., Weitzel, J., Alvarnas, J., Kogut, N., Schriber, J., Fermin, E., Yen, Y., Damon, L., Doroshow, J. H.
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Gratwohl, A., Baldomero, H., Demirer, T., Rosti, G., Dini, G., Ladenstein, R., Urbano-Ispizua, A.
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Colleoni, M., Rotmensz, N., Martinelli, G., Gelber, R., Coates, A., Goldhirsch, A.
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Wheatley, K., Gray, R. G., Ives, N. J., Tartarone, A., Iodice, G., Di Renzo, N., Mangano, M. M., Dazzi, C., Cariello, A., Rodenhuis, S., van Tinteren, H., de Vries, E. G.E., Tallman, M. S., Robert, N. J., Lazarus, H. M., Elfenbein, G. J.
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-estradiol levels were determined at least every year during tamoxifen therapy and after the discontinuation of tamoxifen if any uncertainty regarding postmenopausal status remained. Yearly mammography and chest roentgenography were performed. 
2 test for interaction or, when appropriate, a 
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