Background Adjuvant combination chemotherapy with cyclophosphamide,methotrexate, and fluorouracil was administered after radicalmastectomy for primary breast cancer with histologically positiveaxillary lymph nodes to assess whether it would improve treatmentoutcome as compared with surgery alone. Here we report a 20-yearfollow-up of this investigation.
Methods In 1973 we began a trial involving 386 women who wererandomly assigned to receive either no further treatment afterradical mastectomy (179 women) or 12 monthly cycles of adjuvantcombination chemotherapy (207 women). All patients were admittedto the Istituto Nazionale Tumori in Milan, Italy. Adjuvant chemotherapywas delivered in the outpatient clinic of the Division of MedicalOncology.
Results After a median follow-up of 19.4 years, the patientsgiven adjuvant combination chemotherapy had significantly betterrates of relapse-free survival (unadjusted relative risk ofrelapse, 0.71; 95 percent confidence interval, 0.56 to 0.90;P = 0.004; adjusted relative risk, 0.65; 95 percent confidenceinterval, 0.51 to 0.83; P<0.001) and total survival (unadjustedrelative risk of death, 0.78; 95 percent confidence interval,0.62 to 0.99; P = 0.04; adjusted relative risk, 0.76; 95 percentconfidence interval, 0.60 to 0.97; P = 0.03). With the exceptionof postmenopausal women, a benefit from adjuvant chemotherapywas evident in all subgroups of patients.
Conclusions The long-term results of this trial of adjuvantcombination chemotherapy confirm our preliminary observationsof the effectiveness of the treatment in women with node-positivebreast cancer.
In 1975 we presented our first report on the efficacy of cyclophosphamide,methotrexate, and fluorouracil (CMF) as adjuvant treatment fornode-positive breast cancer.1 A subsequent report in the Journal,2along with the results of the National Surgical Adjuvant Breastand Bowel Project,3 published in 1975, raised hopes that chemotherapycould have a more central role in the primary management ofthis common cancer. The ease of administration and the virtualabsence of severe acute toxicity made CMF the most frequentlyused combination of drugs in clinical practice in oncology,as well as the regimen against which all new systemic adjuvanttreatments were tested.4
In this paper we report the results of 20 years of follow-upof our original series of women who had had a radical mastectomyand who were randomly assigned to receive no further treatmentor CMF chemotherapy for 12 monthly cycles. The long-term resultscontinue to show a significant overall benefit for adjuvantchemotherapy. The findings support the strategy of early systemictreatment of patients at high risk of micrometastases.
Methods
Selection of Patients
The study group consisted of patients admitted to the IstitutoNazionale Tumori in Milan, Italy. All women 75 years of ageor younger who had had a radical mastectomy (conventional orextended) for unilateral carcinoma of the breast and who hadhistologic evidence of involvement of one or more axillary nodeswere considered for inclusion in the study. Patients with locallyadvanced or metastatic breast cancer, those whose tumors werefixed to the underlying pectoral fascia or muscle, those witha history of cancer, and those with concomitant severe nonmalignantsystemic disease were not eligible for the study. The patientswere told that they would be receiving either combination chemotherapyor no further treatment after mastectomy. The protocol designwas approved by members of the institute's research and ethicscommittees.
Study Design
The patients were stratified according to age (<49 yearsand 50 to 75 years), the number of axillary nodes involved (oneto three and four or more), and the type of radical mastectomy(conventional or extended). The patients were then randomlyassigned to receive either CMF for 12 cycles or no further treatment.No additional therapy was planned beyond that allowed in theprotocol without documented evidence of treatment failure. Inparticular, no postoperative irradiation and no adjuvant endocrinetherapy were administered.
From June 1, 1973, to September 11, 1975, a total of 391 patientswere enrolled. Randomization was carried out by the centraloperations office; assignment was based on random-number tablesand was balanced with a permuted-block design according to stratification.The median age of the control group was 52 years (range, 29to 75), and of the CMF group, 51 years (range, 26 to 73). Ofthe original group of 391 patients, 5 patients could not beevaluated. One patient in each group died of cardiovasculardisease within a few months of mastectomy, without evidenceof treatment failure. The other three patients had protocolviolations: one patient in each group was found to have hadbone metastases at the time of mastectomy, and one patient (assignedto receive CMF) had had involvement of supraclavicular nodesat mastectomy. Interim analyses to verify the accrual of patientsand drug tolerance were planned every four months. We initiallydecided that patients who declined to complete 12 cycles ofCMF or who completed treatment with serious deviations fromthe protocol were to be considered unable to be evaluated andthat we would rebalance the groups after excluding these patients.However, no such patients were excluded. Twenty-three womendeclined to complete all 12 cycles of CMF (median number ofcycles completed, 5; range, 2 to 11), and six additional patientstemporarily discontinued treatment with CMF for more than onemonth.
Treatment failure was considered to have occurred with the firstdocumented evidence of new manifestations of disease in locoregionalareas (including homolateral supraclavicular adenopathy), distantsites, the contralateral breast, or any combination of thesesites. Neither second primary cancers nor deaths due to causesother than breast cancer were considered treatment failures.
Adjuvant Treatment
CMF treatment consisted of the cyclic administration of cyclophosphamide(100 mg per square meter of body-surface area orally from day1 to 14), methotrexate (40 mg per square meter intravenouslyon days 1 and 8), and fluorouracil (600 mg per square meterintravenously on days 1 and 8). Each cycle was followed by atwo-week rest period (day 15 to 28). The total dose of cyclophosphamidewas adjusted upward or downward to the nearest 25 mg, sincefractions of tablets could not be administered. In patientsolder than 60 years of age, the initial dose of methotrexatewas reduced to 30 mg per square meter and that of fluorouracilto 400 mg per square meter. Chemotherapy was started two tofour weeks after mastectomy. The dose was reduced if myelosuppressionwas present.2
Follow-Up Study
Before surgery, all patients underwent a complete physical examination,x-ray study of the chest and skeleton (skull, spine, pelvis,and upper third of femurs), bilateral mammography, a differentialblood count with platelet count, and biochemical tests. In theabsence of symptoms, physical examination was performed every3 weeks during the first year, every 6 months for the next 4years, and every 12 months for the following 10 years. Biochemicaltests, chest roentgenography, and bone roentgenography or bonescanning were performed every six to eight months during thefirst five years and once a year thereafter. Mammography wasplanned once a year. After the 15th year of follow-up, the patientswere examined every 12 to 18 months. In patients with suspiciousor controversial radiologic findings, examinations were performedmore often. Liver ultrasonography was performed only if therewere suspicious clinical or biochemical findings.
Percentage of Optimal Dose Received
The percentage of the optimal dose received was calculated aspreviously reported.5 Briefly, for all patients, the total administereddose of each drug was calculated. For patients who either completedor refused to complete their treatment program, we calculatedthe total planned dose of each drug according to the protocol.In patients who had disease progression while receiving adjuvantchemotherapy, the total planned dose of each drug was calculatedup to the day the last dose was received. For each drug, thetotal dose administered was divided by the total planned dose.The percentage of the optimal dose received represented theaverage of all drugs given.
Statistical Analysis
Relapse-free survival was calculated from the date of surgeryto the first documented evidence of treatment failure, whereasevent-free survival was calculated from the date of surgeryto the occurrence of any of the following: treatment failure,a second cancer, or death during complete clinical remission.Death from all causes was used as the end point for overallsurvival, which was also measured from the date of surgery.The Kaplan–Meier product-limit method6 was adopted toestimate survival. The null hypothesis concerning the differentialeffects of treatment in univariate (unadjusted) analysis orafter adjustment for prognostic factors (adjusted analysis)was tested by means of the log-rank test,7 and all P valueswere two-tailed. In addition, Cox multiple regression analysis8was performed. The regression coefficients were estimated onthe basis of maximum-likelihood criteria, and their significancewas tested by the Wald test.9 The relative risks were estimatedas hazard rate ratios. The median follow-up at the time of thecurrent analysis (August 1994) was 19.4 years. Only one patientin complete clinical remission was lost to follow-up, after15.8 years; the minimal follow-up was 18.1 years.
Results
At the 20-year analysis both relapse-free and overall survivalremained significantly better in patients treated with surgeryplus adjuvant chemotherapy than in patients treated with surgeryalone (Figure 1A and Figure 1B). In the control group the mediantime to relapse was 40 months, as compared with 83 months inthe CMF group; the median lengths of overall survival were 104and 137 months, respectively. It is worth emphasizing that mostrecurrences occurred within the first three years after radicalmastectomy, but in the analysis of survival the two curves starteddiverging only after the seventh year. The median survival afterthe diagnosis of relapse was 36 months in the control group,as compared with 32 months in the CMF group. Eighteen yearsafter relapse, and after receiving a variety of salvage treatments,104 percent of the women in the control group were alive withdisease, as compared with 5 percent of the women in the CMFgroup. Thus, salvage therapy had the same palliative effectregardless of whether the patients received or did not receiveinitial adjuvant chemotherapy. These results reinforce the observationthat the difference in overall survival was due to the adjuvanttreatment and not to salvage therapy.
Figure 1. Relapse-free Survival (Panel A) and Overall Survival (Panel B) According to Treatment Group.
With respect to relapse-free survival, 48 of 179 patients in the control group were disease-free at 20 years, as compared with 74 of 207 patients in the CMF group. With respect to overall survival, 44 of 179 patients in the control group were alive at 20 years, as compared with 70 of 207 patients in the CMF group.
Table 1 outlines the main clinical characteristics of the womenwho entered the study. All medical records were reviewed, andsome of these characteristics have changed slightly since ourfirst report.1,2 Two patients who underwent extended radicalmastectomy — one in each group — were originallyclassified as having four positive axillary nodes, whereas ourreview showed that in each case three were axillary nodes andone was an internal mammary node. In addition, the definitionof premenopausal now includes all perimenopausal patients —that is, women whose last menstrual period was within 12 monthsbefore the diagnosis of breast cancer and women less than 50years of age who had had a hysterectomy before the diagnosisof breast cancer. All these patients were previously consideredpostmenopausal. The main characteristics of the premenopausaland postmenopausal women were similar in the two treatment groups.
Table 1. Relapse-free and Overall Survival at 20 Years in the Two Groups of Patients, According to their Characteristics at Entry into the Study.
Table 1 also shows treatment outcome with respect to the mainsubgroups of patients. In all subgroups except postmenopausalwomen and patients with 4 to 10 positive nodes, a benefit fromadjuvant CMF was evident, as reflected by either a lower rateof unfavorable events or longer survival. The greatest benefitof CMF treatment was among patients with one to three positivenodes (Table 1). Of the 9 women in the control group who presentedwith more than 10 positive lymph nodes, none were alive at 20years, whereas 3 of 18 such patients in the CMF group were aliveat 20 years, albeit with cancer. In this subgroup, the medianlength of relapse-free survival was 7 months in the controlgroup and 36 months in the CMF group; the median lengths ofoverall survival were 27 and 78 months, respectively.
Table 1 shows rates of relapse-free survival and overall survivalat 20 years according to menopausal status. At 20 years, therewas still a sharp difference in the rates of both relapse-freeand overall survival between premenopausal and postmenopausalpatients. After adjuvant chemotherapy with CMF, 47 percent ofthe premenopausal women were alive at 20 years, as comparedwith 22 percent of the postmenopausal women. Table 2 shows thatthe frequency of drug-induced amenorrhea (defined as the cessationof menses for at least three months during or soon after theadministration of CMF) correlated with age. The latest analysisconfirms our previous finding11 that there is no significantdifference in outcome between perimenopausal women, women withdrug-induced amenorrhea, and women without drug-induced amenorrhea.
Table 2. Results of CMF Treatment at 20 Years in Premenopausal Patients According to Whether They Had Drug-Induced Amenorrhea.
Cox regression analysis, including all prognostic variablesreported in Table 1, was carried out by resorting to a backwardprocedure. Relapse-free survival was significantly influencedonly by the extent of nodal involvement and the treatment group.The number of involved nodes remained the most important prognosticfactor (relative risk for women with >3 positive nodes, 1.74;95 percent confidence interval, 1.44 to 2.11; P<0.001), followedby the type of treatment (relative risk with adjuvant chemotherapy,0.65; 95 percent confidence interval, 0.51 to 0.83; P<0.001).The most important variables influencing total survival werethe extent of nodal involvement (relative risk for women with>3 positive nodes, 1.50; 95 percent confidence interval,1.24 to 1.82; P<0.001), the type of treatment (relative riskwith adjuvant chemotherapy, 0.76; 95 percent confidence interval,0.60 to 0.97; P = 0.03), and menopausal status (relative riskfor postmenopausal women, 1.29; 95 percent confidence interval,1.01 to 1.64; P = 0.04).
Figure 2A and Figure 2B shows the outcome according to the percentageof drugs received in the CMF protocol. In the 42 women who receivedat least 85 percent of the planned dose of CMF, the rate ofrelapse-free survival was 49 percent (median survival, 220 months)and the rate of overall survival was 52 percent.
Figure 2. Relapse-free Survival (Panel A) and Overall Survival (Panel B) According to the Percentage of theOptimal Dose Administered.
With respect to relapse-free survival, 48 of 179 patients in the control group were disease-free at 20 years, as compared with 21 of 71 patients given <65 percent of the optimal dose of CMF, 31 of 94 patients given 65 to 84 percent of the optimal dose, and 22 of 42 patients given 85 percent of the optimal dose. With respect to overall survival, 44 of 179 patients in the control group were alive at 20 years, as compared with 18 of 71 patients given <65 percent of the optimal dose of CMF, 30 of 94 patients given 65 to 84 percent of the optimal dose, and 22 of 42 patients given 85 percent of the optimal dose.
Table 3 shows the rates of event-free survival in the two groupsand the cumulative incidence of first relapse according to anatomicalsite. There were no important differences between groups inthe incidence of locoregional relapse and relapse in the contralateralbreast. The main therapeutic effect of adjuvant CMF was to reducethe incidence of distant metastases (10 percentage point differenceat 20 years between patients who received CMF and those whodid not).
Table 3. Cumulative Event-free Survival and the Incidence of First Relapse in the Two Groups of Patients at 5, 10, 15, and 20 Years.
Within 20 years after surgery second cancers were detected in19 patients (5 in the control group and 12 in the CMF group).Various types were found in both groups, but no distinctivepattern prevailed. Similar results were found in 2465 patientstreated with adjuvant CMF with or without doxorubicin.12 Twenty-fourwomen died without clinical or radiologic evidence of tumorrecurrence (10 in the control group; median age at death, 76years; 14 in the CMF group; median age at death, 67 years).
Discussion
Clinical studies2,3 have established that node-positive breastcancer is not simply a localized disorder and that the prognosisof this disease could be improved by the administration of chemotherapyafter surgical removal of the tumor by radical mastectomy. Theeffectiveness of various forms of adjuvant systemic therapyafter 10 years of follow-up has been validated by an internationaloverview.4
This long-term analysis of the trial we started two decadesago demonstrates a significant advantage of combination adjuvantchemotherapy that persists for at least 20 years after surgery.The effect was seen for both relapse-free and overall survival,though the magnitude of the changes differed among various subgroupsof patients. Overall, the benefit translated into a 34 percentreduction in the relative risk of relapse and a 26 percent reductionin the relative risk of death.
As previously reported,13 chemotherapy with CMF, as given inour study, failed to improve outcome significantly in postmenopausalwomen, particularly those older than 60 years of age. Many oncologistsinterpreted these results to mean that the predominant effectof chemotherapy was chemical castration. We have always maintainedthat the difference in the effectiveness of the regimen betweenpremenopausal and postmenopausal women was mainly, if not exclusively,due to the low dose of chemotherapy that many postmenopausalpatients received, either by protocol design or because of protocolviolations, including lack of compliance with the regimen fororal cyclophosphamide.5 Our results after 20 years of follow-upconfirmed our initial observation. A recent study by the Cancerand Leukemia Group B14 showed that both premenopausal and postmenopausalwomen given regimens involving high or moderate doses of cyclophosphamide,doxorubicin, and fluorouracil had significantly better disease-freeand overall survival than those given regimens involving lowdoses. Thus, recent, effective drug programs indicate that treatmentoutcome is very similar in premenopausal and postmenopausalwomen14,15,16,17 and that drug-induced amenorrhea is not animportant predictor of response.18
A recent analysis from the International Breast Cancer StudyGroup19 concluded that adjuvant systemic treatments improvedoutcome mainly by reducing the incidence of first locoregionaland distant soft-tissue relapses, whereas the incidence of firstrecurrences in bones and viscera was influenced much less. Thoughour sample was smaller, we found that treatment with CMF resultedin a moderate suppression of micrometastases regardless of theiranatomical sites. This observation motivated us to try new regimens— namely, one consisting of doxorubicin (Adriamycin) followedby CMF — to improve relapse-free and overall survivalfurther in patients with more than three positive nodes.16 Secondcancers were not a major problem in the present study. In fact,the cumulative 20-year rate of second cancers in the absenceof a relapse of breast cancer was 3 percent in the control groupand 6 percent in the patients treated with CMF. In this studywe did not observe any case of acute leukemia.
Our experience as well as that of other investigators14 underlinesthe importance of avoiding reduced doses of chemotherapy ifmaximal benefit is to be achieved. These long-term results representan important step in the contemporary evolution of breast-cancertreatment, which has expanded to include patients with node-negativecancer; new therapeutic choices, including anthracyclines; andthe use of chemotherapy as the primary treatment.14,20,21
Supported in part by a contract (N01-CM-33714) with the Divisionof Cancer Treatment, National Cancer Institute, National Institutesof Health.
We are indebted to the many clinical associates, in particularthe medical oncologists, surgeons, pathologists, and researchnurses, for their cooperation during the study.
Source Information
From the Division of Medical Oncology, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy, where reprint requests should be addressed to Dr. Bonadonna.
References
Bonadonna G, Brusamolino E, Valagussa P, Veronesi U. Adjuvant study with combination chemotherapy in operable breast cancer. Proc Am Assoc Cancer Res Am Soc Clin Oncol 1975;16:254. abstract.
Bonadonna G, Brusamolino E, Valagussa P, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 1976;294:405-410. [Abstract]
Fisher B, Carbone P, Economou SG, et al. l-Phenylalanine mustard (L-PAM) in the management of primary breast cancer: a report of early findings. N Engl J Med 1975;292:117-122. [Abstract]
Early Breast Cancer Trialists' Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31 000 recurrences and 24 000 deaths among 75 000 women. Lancet 1992;399:1-15, 71. [CrossRef]
Bonadonna G, Valagussa P. Dose-response effect of adjuvant chemotherapy in breast cancer. N Engl J Med 1981;304:10-15. [Abstract]
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81.
Peto R, Peto J. Asymptotically efficient rank invariant test procedures. J R Stat Soc [A] 1972;135:185-207.
Cox DR. Regression models and life-tables. J R Stat Soc [B] 1972;34:187-220.
Miller RG. Survival analysis. New York: John Wiley, 1981.
Valagussa P, Brambilla C, Zambetti M, Bonadonna G. Salvage treatments in relapsing resectable breast cancer. Recent Results Cancer Res 1989;115:69-76. [Medline]
Bonadonna G, Valagussa P, De Palo G. The results of adjuvant chemotherapy are predominantly caused by the hormonal changes such therapy induces. In: Van Scoy-Mosher MB, ed. Medical oncology: controversies in cancer treatment. Boston: G.K. Hall Medical, 1981:100-9, 112-5.
Valagussa P, Moliterni A, Terenziani M, Zambetti M, Bonadonna G. Second malignancies following CMF-based adjuvant chemotherapy in resectable breast cancer. Ann Oncol 1994;5:803-808. [Free Full Text]
Bonadonna G, Rossi A, Valagussa P, Banfi A, Veronesi U. The CMF program for operable breast cancer with positive axillary nodes: updated analysis on the disease-free interval, site of relapse and drug tolerance. Cancer 1977;39:2904-2915. [CrossRef][Medline]
Wood WC, Budman DR, Korzun AH, et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 1994;330:1253-1259. [Free Full Text]
Moliterni A, Bonadonna G, Valagussa P, Ferrari L, Zambetti M. Cyclophosphamide, methotrexate, and fluorouracil with and without doxorubicin in the adjuvant treatment of resectable breast cancer with one to three positive axillary nodes. J Clin Oncol 1991;9:1124-1130. [Abstract]
Bonadonna G, Zambetti M, Valagussa P. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive axillary nodes: ten-year results. JAMA 1995;273:542-547. [Free Full Text]
Fisher B, Brown AM, Dimitrov NV, et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 1990;8:1483-1496. [Abstract]
Goldhirsch A, Gelber RD, Castiglione M. The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients. Ann Oncol 1990;1:183-188. [Free Full Text]
Goldhirsch A, Gelber RD, Price KN, et al. Effect of systemic adjuvant treatment on first sites of breast cancer relapse. Lancet 1994;343:377-381. [CrossRef][Medline]
Henderson IC, Hayes DF, Parker LM, et al. Adjuvant systemic therapy for patients with node-negative tumors. Cancer 1990;65:Suppl:2132-2147. [Medline]
Bonadonna G, Valagussa P, Zucali R, Salvadori B. Primary chemotherapy in surgically resectable breast cancer. CA Cancer J Clin (in press).
Adjuvant Chemotherapy in Breast Cancer
Del Mastro L., Costantini M., Bianco A. R., Newman M. D., Evans R. A., Bonadonna G., Valagussa P., Henderson I. C.
Extract |
Full Text
N Engl J Med 1995;
333:596-597, Aug 31, 1995.
Correspondence
This article has been cited by other articles:
Bretzel, R. L. Jr, Cameron, R., Gustas, M., Garcia, M. A., Hoffman, H. K., Malhotra, R., Miller, K., Prime, J., Favret, A.
(2009). Dose Intensity in Early-Stage Breast Cancer: A Community Practice Experience. J Oncol Pract
5: 287-290
[Abstract][Full Text]
Villamizar, N. R., Darrabie, M. D., Burfeind, W. R., Petersen, R. P., Onaitis, M. W., Toloza, E., Harpole, D. H., D'Amico, T. A.
(2009). Thoracoscopic lobectomy is associated with lower morbidity compared with thoracotomy.. J. Thorac. Cardiovasc. Surg.
138: 419-425
[Abstract][Full Text]
Hershman, D. L., Unger, J. M., Barlow, W. E., Hutchins, L. F., Martino, S., Osborne, C. K., Livingston, R. B., Albain, K. S.
(2009). Treatment Quality and Outcomes of African American Versus White Breast Cancer Patients: Retrospective Analysis of Southwest Oncology Studies S8814/S8897. JCO
27: 2157-2162
[Abstract][Full Text]
Maguire, R., Cowie, J., Leadbetter, C., McCall, K., Swingler, K., McCann, L., Kearney, N.
(2009). The development of a side effect risk assessment tool (ASyMS(C)-SERAT) for use in patients with breast cancer undergoing adjuvant chemotherapy. Journal of Research in Nursing
14: 27-40
[Abstract]
Jenkins, P., Freeman, S.
(2009). Pretreatment haematological laboratory values predict for excessive myelosuppression in patients receiving adjuvant FEC chemotherapy for breast cancer. Ann Oncol
20: 34-40
[Abstract][Full Text]
Olopade, O. I., Grushko, T. A., Nanda, R., Huo, D.
(2008). Advances in Breast Cancer: Pathways to Personalized Medicine. Clin. Cancer Res.
14: 7988-7999
[Abstract][Full Text]
Balducci, L., Al-Halawani, H., Charu, V., Tam, J., Shahin, S., Dreiling, L., Ershler, W. B.
(2007). Elderly Cancer Patients Receiving Chemotherapy Benefit from First-Cycle Pegfilgrastim. The Oncologist
12: 1416-1424
[Abstract][Full Text]
Courneya, K. S., Segal, R. J., Mackey, J. R., Gelmon, K., Reid, R. D., Friedenreich, C. M., Ladha, A. B., Proulx, C., Vallance, J. K.H., Lane, K., Yasui, Y., McKenzie, D. C.
(2007). Effects of Aerobic and Resistance Exercise in Breast Cancer Patients Receiving Adjuvant Chemotherapy: A Multicenter Randomized Controlled Trial. JCO
25: 4396-4404
[Abstract][Full Text]
Petersen, R. P., Pham, D., Burfeind, W. R., Hanish, S. I., Toloza, E. M., Harpole, D. H. Jr, D'Amico, T. A.
(2007). Thoracoscopic Lobectomy Facilitates the Delivery of Chemotherapy after Resection for Lung Cancer. Ann. Thorac. Surg.
83: 1245-1250
[Abstract][Full Text]
Touw, I. P., Bontenbal, M.
(2007). Granulocyte Colony-Stimulating Factor: Key (F)actor or Innocent Bystander in the Development of Secondary Myeloid Malignancy?. JNCI J Natl Cancer Inst
99: 183-186
[Full Text]
Griggs, J. J., Culakova, E., Sorbero, M. E.S., van Ryn, M., Poniewierski, M. S., Wolff, D. A., Crawford, J., Dale, D. C., Lyman, G. H.
(2007). Effect of Patient Socioeconomic Status and Body Mass Index on the Quality of Breast Cancer Adjuvant Chemotherapy. JCO
25: 277-284
[Abstract][Full Text]
Walshe, J. M., Denduluri, N., Swain, S. M.
(2006). Amenorrhea in Premenopausal Women After Adjuvant Chemotherapy for Breast Cancer. JCO
24: 5769-5779
[Abstract][Full Text]
Dittrich, C., Petruzelka, L., Vodvarka, P., Gneist, M., Janku, F., Kysela, T., Melemed, A., Latz, J., Simms, L., Krejcy, K.
(2006). A Phase I Study of Pemetrexed (ALIMTA) and Cyclophosphamide in Patients with Locally Advanced or Metastatic Breast Cancer. Clin. Cancer Res.
12: 7071-7078
[Abstract][Full Text]
Lohrisch, C., Paltiel, C., Gelmon, K., Speers, C., Taylor, S., Barnett, J., Olivotto, I. A.
(2006). Impact on Survival of Time From Definitive Surgery to Initiation of Adjuvant Chemotherapy for Early-Stage Breast Cancer. JCO
24: 4888-4894
[Abstract][Full Text]
Wardley, A.
(2006). Capecitabine: Expanding Options for the Treatment of Patients with Early or Locally Advanced Breast Cancer. The Oncologist
11: 20-26
[Abstract][Full Text]
Roche, H., Kerbrat, P., Bonneterre, J., Fargeot, P., Fumoleau, P., Monnier, A., Clavere, P., Goudier, M.-J., Chollet, P., Guastalla, J.-P., Serin, D., On behalf of the French Adjuvant Study Group,
(2006). Complete hormonal blockade versus epirubicin-based chemotherapy in premenopausal, one to three node-positive, and hormone-receptor positive, early breast cancer patients: 7-year follow-up results of French Adjuvant Study Group 06 randomised trial. Ann Oncol
17: 1221-1227
[Abstract][Full Text]
Neugut, A. I., Matasar, M., Wang, X., McBride, R., Jacobson, J. S., Tsai, W.-Y., Grann, V. R., Hershman, D. L.
(2006). Duration of Adjuvant Chemotherapy for Colon Cancer and Survival Among the Elderly. JCO
24: 2368-2375
[Abstract][Full Text]
Petrek, J. A., Naughton, M. J., Case, L. D., Paskett, E. D., Naftalis, E. Z., Singletary, S. E., Sukumvanich, P.
(2006). Incidence, Time Course, and Determinants of Menstrual Bleeding After Breast Cancer Treatment: A Prospective Study. JCO
24: 1045-1051
[Abstract][Full Text]
Gilbert, S. G., Banna, G. L., Santoro, A., Gounaris, I. G., Katsumata, M., Drebin, J. A., Greene, M. I., Mastrianni, D. M., Mano, M., Cameron, D., Gelber, R. D., the HERA Trial Study Team, , Bryant, J., Romond, E., Perez, E. A., Hortobagyi, G. N., Barron, H.
(2006). Trastuzumab in breast cancer.. NEJM
354: 640-644
[Full Text]
International Breast Cancer Study Group,
(2006). Multicycle Dose-Intensive Chemotherapy for Women With High-Risk Primary Breast Cancer: Results of International Breast Cancer Study Group Trial 15-95. JCO
24: 370-378
[Abstract][Full Text]
Gluck, S.
(2005). Adjuvant Chemotherapy for Early Breast Cancer: Optimal Use of Epirubicin. The Oncologist
10: 780-791
[Abstract][Full Text]
Kris, M. G.
(2005). How Today's Developments in the Treatment of Non-Small Cell Lung Cancer Will Change Tomorrow's Standards of Care. The Oncologist
10: 23-29
[Abstract][Full Text]
Hershman, D., McBride, R., Jacobson, J. S., Lamerato, L., Roberts, K., Grann, V. R., Neugut, A. I.
(2005). Racial Disparities in Treatment and Survival Among Women With Early-Stage Breast Cancer. JCO
23: 6639-6646
[Abstract][Full Text]
Parulekar, W. R., Day, A. G., Ottaway, J. A., Shepherd, L. E., Trudeau, M. E., Bramwell, V., Levine, M., Pritchard, K. I.
(2005). Incidence and Prognostic Impact of Amenorrhea During Adjuvant Therapy in High-Risk Premenopausal Breast Cancer: Analysis of a National Cancer Institute of Canada Clinical Trials Group Study--NCIC CTG MA.5. JCO
23: 6002-6008
[Abstract][Full Text]
Demicheli, R., Miceli, R., Moliterni, A., Zambetti, M., Hrushesky, W. J. M., Retsky, M. W., Valagussa, P., Bonadonna, G.
(2005). Breast cancer recurrence dynamics following adjuvant CMF is consistent with tumor dormancy and mastectomy-driven acceleration of the metastatic process. Ann Oncol
16: 1449-1457
[Abstract][Full Text]
Griggs, J. J., Sorbero, M. E. S., Lyman, G. H.
(2005). Undertreatment of Obese Women Receiving Breast Cancer Chemotherapy. Arch Intern Med
165: 1267-1273
[Abstract][Full Text]
Lyman, G. H., Lyman, C. H., Agboola, O., for the Anc Study Group,
(2005). Risk Models for Predicting Chemotherapy-Induced Neutropenia. The Oncologist
10: 427-437
[Abstract][Full Text]
Pierce, L. J.
(2005). The Use of Radiotherapy After Mastectomy: A Review of the Literature. JCO
23: 1706-1717
[Full Text]
Sano, H. S, Waddell, J A., A Solimando, D. Jr, Doulaveris, P., Myhand, R.
(2005). Study of the effect of standardized chemotherapy order forms on prescribing errors and anti-emetic cost. J Oncol Pharm Pract
11: 21-30
[Abstract]
Bonadonna, G., Moliterni, A., Zambetti, M., Daidone, M. G., Pilotti, S., Gianni, L., Valagussa, P.
(2005). 30 years' follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort study. BMJ
330: 217-
[Abstract][Full Text]
Bonadonna, G., Zambetti, M., Moliterni, A., Gianni, L., Valagussa, P.
(2004). Clinical Relevance of Different Sequencing of Doxorubicin and Cyclophosphamide, Methotrexate, and Fluorouracil in Operable Breast Cancer. JCO
22: 1614-1620
[Abstract][Full Text]
Lyman, G. H., Dale, D. C., Crawford, J.
(2003). Incidence and Predictors of Low Dose-Intensity in Adjuvant Breast Cancer Chemotherapy: A Nationwide Study of Community Practices. JCO
21: 4524-4531
[Abstract][Full Text]
Giordano, S. H.
(2003). Update on Locally Advanced Breast Cancer. The Oncologist
8: 521-530
[Abstract][Full Text]
Weiss, R. B., Woolf, S. H., Demakos, E., Holland, J. F., Berry, D. A., Falkson, G., Cirrincione, C. T., Robbins, A., Bothun, S., Henderson, I. C., Norton, L.
(2003). Natural History of More Than 20 Years of Node-Positive Primary Breast Carcinoma Treated With Cyclophosphamide, Methotrexate, and Fluorouracil-Based Adjuvant Chemotherapy: A Study by the Cancer and Leukemia Group B. JCO
21: 1825-1835
[Abstract][Full Text]
Moliterni, A., Menard, S., Valagussa, P., Biganzoli, E., Boracchi, P., Balsari, A., Casalini, P., Tomasic, G., Marubini, E., Pilotti, S., Bonadonna, G.
(2003). HER2 Overexpression and Doxorubicin in Adjuvant Chemotherapy for Resectable Breast Cancer. JCO
21: 458-462
[Abstract][Full Text]
Fumoleau, P., Kerbrat, P., Romestaing, P., Fargeot, P., Bremond, A., Namer, M., Schraub, S., Goudier, M.-J., Mihura, J., Monnier, A., Clavere, P., Serin, D., Seffert, P., Pourny, C., Facchini, T., Jacquin, J.-P., Sztermer, J.-F., Datchary, J., Ramos, R., Luporsi, E.
(2003). Randomized Trial Comparing Six Versus Three Cycles of Epirubicin-Based Adjuvant Chemotherapy in Premenopausal, Node-Positive Breast Cancer Patients: 10-Year Follow-Up Results of the French Adjuvant Study Group 01 Trial. JCO
21: 298-305
[Abstract][Full Text]
Climent, J., Martinez-Climent, J. A., Blesa, D., Garcia-Barchino, M. J., Saez, R., Sanchez-Izquierdo, D., Azagra, P., Lluch, A., Garcia-Conde, J.
(2002). Genomic Loss of 18p Predicts an Adverse Clinical Outcome in Patients with High-Risk Breast Cancer. Clin. Cancer Res.
8: 3863-3869
[Abstract][Full Text]
Morrow, T., Siegel, M., Boone, S., Lawless, G., Carter, W.
(2002). Chemotherapy Dose Intensity Determination as a Quality of Care Measure for Managed Care Organizations in the Treatment of Early-Stage Breast Cancer. American Journal of Medical Quality
17: 218-224
[Abstract]
Hamilton, A., Love, R. R.
(2002). Ethical Issues Surrounding the Conduct of Off-Shore Clinical Research. JCO
20: 3934-3936
[Full Text]
Niyikiza, C., Baker, S. D., Seitz, D. E., Walling, J. M., Nelson, K., Rusthoven, J. J., Stabler, S. P., Paoletti, P., Calvert, A. H., Allen, R. H.
(2002). Homocysteine and Methylmalonic Acid: Markers to Predict and Avoid Toxicity from Pemetrexed Therapy. Molecular Cancer Therapeutics
1: 545-552
[Abstract][Full Text]
Ferreira Filho, A. F., Di Leo, A., Paesmans, M., Beauduin, M., Vindevoghel, A., Michel, J., Focan, C., Awada, A., Cardoso, F., Dolci, S., Bartholomeus, S., Piccart, M. J.
(2002). The feasibility of classical cyclophosphamide, methotrexate, 5-fluorouracil (CMF) for pre- and post-menopausal node-positive breast cancer patients in a Belgian multicentric trial: a study of consistency in relative dose intensity (RDI) and cumulative doses across institutions. Ann Oncol
13: 416-421
[Abstract][Full Text]
Wilson-Royalty, M., Lawless, G., Palmer, C., Brown, R.
(2001). Predictors for chemotherapy-related severe or febrile neutropenia: a review of the clinical literature. J Oncol Pharm Pract
7: 141-147
[Abstract]
Antman, K. H.
(2001). Overview of the Six Available Randomized Trials of High-Dose Chemotherapy With Blood or Marrow Transplant in Breast Cancer. J Natl Cancer Inst Monogr
2001: 114-116
[Full Text]
Goldhirsch, A., Glick, J. H., Gelber, R. D., Coates, A. S., Senn, H.-J.
(2001). Meeting Highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. JCO
19: 3817-3827
[Full Text]
Menard, S., Valagussa, P., Pilotti, S., Gianni, L., Biganzoli, E., Boracchi, P., Tomasic, G., Casalini, P., Marubini, E., Colnaghi, M. I., Cascinelli, N., Bonadonna, G.
(2001). Response to Cyclophosphamide, Methotrexate, and Fluorouracil in Lymph Node-Positive Breast Cancer According to HER2 Overexpression and Other Tumor Biologic Variables. JCO
19: 329-335
[Abstract][Full Text]
Wolff, A. C., Davidson, N. E.
(2000). Primary Systemic Therapy in Operable Breast Cancer. JCO
18: 1558-1569
[Abstract][Full Text]
Antman, K. H., Heitjan, D. F., Hortobagyi, G. N.
(1999). High-Dose Chemotherapy for Breast Cancer. JAMA
282: 1701-1703
[Full Text]
Antman, K. H.
(1999). Critique of the High-Dose Chemotherapy Studies in Breast Cancer: A Positive Look at the Data. JCO
17: 30-34
[Full Text]
Liberman, L., Cody, H. S. III, Hill, A. D. K., Rosen, P. P., Yeh, S. D. J., Akhurst, T., Morris, E. A., Abramson, A. F., Borgen, P. I., Dershaw, D. D.
(1999). Sentinel Lymph Node Biopsy after Percutaneous Diagnosis of Nonpalpable Breast Cancer. Radiology
211: 835-844
[Abstract][Full Text]
Acuna, L. R., Langhi, M., Perez, J., Acuna, J. R., Machiavelli, M., Lacava, J., Vallejo, C., Romero, A., Fasce, H., Ortiz, E., Grasso, S., Amato, S., Rodriguez, R., Barbieri, M., Leone, B.
(1999). Vinorelbine and Paclitaxel as First-Line Chemotherapy in Metastatic Breast Cancer. JCO
17: 74-74
[Abstract][Full Text]
Basser, R. L., To, L. B., Collins, J. P., Begley, C. G., Keefe, D., Cebon, J., Bashford, J., Durrant, S., Szer, J., Kotasek, D., Juttner, C. A., Russell, I., Maher, D. W., Olver, I., Sheridan, W. P., Fox, R. M., Green, M. D.
(1999). Multicycle High-Dose Chemotherapy and Filgrastim-Mobilized Peripheral-Blood Progenitor Cells in Women With High-Risk Stage II or III Breast Cancer: Five-Year Follow-Up. JCO
17: 82-82
[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]
Foote, M.
(1998). The Importance of Planned Dose of Chemotherapy on Time: Do We Need to Change Our Clinical Practice?. The Oncologist
3: 365-368
[Full Text]
Baker, J. P., Jones, S. E.
(1998). Rationalisation of chemotherapy services in the University Hospital Birmingham National Health Science Trust. J Oncol Pharm Pract
4: 10-14
[Abstract]
Hudis, C. A., Norton, L.
(1997). Adjuvant Drug Treatment for Resectable Breast Cancer. The Oncologist
2: 351-358
[Abstract][Full Text]
Overgaard, M., Hansen, P. S., Overgaard, J., Rose, C., Andersson, M., Bach, F., Kjaer, M., Gadeberg, C. C., Mouridsen, H. T., Jensen, M.-B., Zedeler, K., The Danish Breast Cancer Cooperative Group 82b Tri,
(1997). Postoperative Radiotherapy in High-Risk Premenopausal Women with Breast Cancer Who Receive Adjuvant Chemotherapy. NEJM
337: 949-955
[Abstract][Full Text]
Mayer, R. J., Schnipper, L. E., Broder, S., Hughes-Davies, T.H., Rand, T. S., Cole, P., Rodu, B., Corey, S., Suit, H., Isselbacher, K., Chabner, B., Feldman, A., Atkins, R. N., Arlen, P. A., Noxon, C. L., Wilcken, N., Bailar, J. C., Gornik, H. L.
(1997). Winning the War on Cancer. NEJM
337: 935-938
[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]
Gamel, J. W., Edwards, M. J.
(1996). Parametric Models of Therapeutic Efficacy in Breast Cancer. NEJM
334: 1270-1271
[Full Text]
Carbone, D. P, Minna, J. D
(1995). Chemotherapy for non-small cell lung cancer. BMJ
311: 889-890
[Full Text]
Del Mastro, L., Costantini, M., Bianco, A. R., Newman, M. D., Evans, R. A., Bonadonna, G., Valagussa, P., Henderson, I. C.
(1995). Adjuvant Chemotherapy in Breast Cancer. NEJM
333: 596-597
[Full Text]
(1995). Breast Cancer: Long-Term Follow-up of Adjuvant Chemotherapy . . .. Journal Watch Dermatology
1995: 13-13
[Full Text]
(1995). BREAST CANCER: LONG-TERM FOLLOW-UP OF ADJUVANT CHEMOTHERAPY. JWatch General
1995: 2-2
[Full Text]
Henderson, I. C.
(1995). Paradigmatic Shifts in the Management of Breast Cancer. NEJM
332: 951-952
[Full Text]
85 percent of the optimal dose. With respect to overall survival, 44 of 179 patients in the control group were alive at 20 years, as compared with 18 of 71 patients given <65 percent of the optimal dose of CMF, 30 of 94 patients given 65 to 84 percent of the optimal dose, and 22 of 42 patients given