Dose and Dose Intensity of Adjuvant Chemotherapy for Stage II, Node-Positive Breast Carcinoma
William C. Wood, Daniel R. Budman, Ann H. Korzun, M. Robert Cooper, Jerry Younger, Ronald D. Hart, Anne Moore, John A. Ellerton, Larry Norton, Carolyn R. Ferree, Anita Colangelo Ballow, Emil Frei, and I. Craig Henderson
Background Adjuvant chemotherapy is widely used for breast cancerand is known to extend survival. Some clinicians seek a greatersurvival benefit by increasing the intensity of the dose, whereasothers lower it to diminish toxicity.
Methods The Cancer and Leukemia Group B (CALGB) conducted arandomized trial of different levels of doses and dose intensity(dose per unit of time) of adjuvant chemotherapy in 1572 womenwith node-positive, stage II breast cancer who were assignedto three treatment groups. One group received 400 mg of cyclophosphamideper square meter of body-surface area and 40 mg of doxorubicinper square meter once every 28 days and 400 mg of fluorouracilper square meter twice every 28 days, for six cycles. Anothergroup received 50 percent higher doses of the three drugs (600mg, 60 mg, and 600 mg, respectively) but for only four cycles,so that the total dose was identical in these two groups butthe dose intensity was higher in the second. The third groupof women received half the total dose used in the other twogroups and at half the dose intensity used in the second group.
Results After a median of 3.4 years of follow-up, the womentreated with a high or moderate dose intensity had significantlylonger disease-free survival (P<0.001) and overall survival(P = 0.004) than those treated with a low dose intensity, inthree-way log-rank comparisons. However, the difference in survivalbetween the two groups treated with a moderate or high doseintensity was not significant. These results are consistentwith either a dose-response effect or a threshold level of thedose or dose intensity.
Conclusions The doses of chemotherapy used to treat breast cancer,especially early breast cancer, should not be reduced if themaximal benefit is to be achieved. .
Randomized clinical trials have established that adjuvant chemotherapyincreases the survival of patients with breast cancer1,2,3.As a result of these studies, large numbers of women with breastcancer now receive adjuvant chemotherapy. However, it is notclear whether the dose and intensity (dose per unit of time)of the treatment affect the outcome. These variables are importantbecause escalating the dose and intensity of chemotherapy addsto its acute toxicity and costs.
Chemotherapeutic agents can have steep dose-response curvesin studies of animal tumors and in in vitro models of humantumors, yet there is no clear evidence that variations in thedose of adjuvant chemotherapy improve survival in women withbreast cancer4. Bonadonna and Valagussa examined this questionin a retrospective analysis of two of their clinical trialswith cyclophosphamide, methotrexate, and fluorouracil5. Theyfound that disease-free survival was longer in the patientswho received a higher percentage of the intended dose of chemotherapythan in those who received a lower percentage. This result mayhave been due to a dose-response effect, or the patients whowere able to tolerate higher doses of chemotherapy may havebeen more likely to survive longer. It is also possible thatthe women who survived longer had a smaller tumor burden ora better host response to the tumor than those who survivedfor a shorter period.
Other retrospective analyses have either supported or contestedthe benefit of high-dose adjuvant chemotherapy, as comparedwith low-dose therapy6. A small randomized trial by Abeloffet al. compared cyclophosphamide, methotrexate, and fluorouracilin the doses used by Bonadonna and Valagussa with the same drugsgiven in doses reduced by more than 50 percent7. There was nosignificant difference in the rate of relapse between the twotreatment groups. A retrospective analysis of randomized trialsby the Cancer and Leukemia Group B (CALGB 8082) and the LudwigBreast Cancer Study Group (trial I) revealed significant differencesin the dose intensity of the chemotherapy delivered, yet therewere no differences in disease-free or overall survival8,9.
This paper reports the results of a prospective, randomizedtrial of adjuvant cyclophosphamide, doxorubicin, and fluorouracilin three groups of patients. Conducted by the CALGB (see theAppendix), the trial was designed to test the hypothesis thatincreases in the dose and dose intensity would lead to improveddisease-free and overall survival. Group 1 received chemotherapyat twice the dose and dose intensity of the regimen used ingroup 3. Group 2 received the same total dose as that used ingroup 1 but over a 50 percent longer period, resulting in alower dose intensity (Table 1). We report the initial resultsof this trial at a median of 3.4 years of follow-up.
Table 1. Drug Regimens Used as Adjuvant Chemotherapy in Three Groups of Patients with Stage II Breast Cancer.
Methods
Patient Selection
CALGB 8541, which began in January 1985, was for women withhistologically confirmed unilateral stage II adenocarcinomaof the breast (T1 or T2N1M0)10. To be eligible, patients hadto be at least 16 years of age and not pregnant, with a performancescore of 0 or 1 (no symptoms or minimal symptoms), no previousor concomitant cancer, and no serious medical or psychiatricillness that would prevent informed consent or intensive treatment.Primary therapy consisted of a radical or modified radical mastectomyor breast-conservation therapy with excision of the tumor tothe extent of clear margins, dissection of levels 1 and 2 axillarylymph nodes, and irradiation after chemotherapy. Breast-conservationtherapy, with stratification for this method of treatment, wasadded to the original protocol eight months after the studyhad begun. When breast-conserving therapy was used, radiationat a dose of 5040 cGy was delivered to the entire breast bytangential fields in 28 fractions. An electron-beam boost of1504 cGy was administered to the area of excision in eight fractions.
In 1988, an addendum to the protocol required the addition oftamoxifen after the administration of cyclophosphamide, doxorubicin,and fluorouracil in patients who were perimenopausal or postmenopausaland positive for estrogen receptors. This change was based onemerging evidence of the effectiveness of antiestrogen therapyin such women3. Patients already participating in the studywho met one or more of these criteria could be given tamoxifenat a time decided on by their treating physicians. All chemotherapywas begun within six weeks after definitive surgical treatment.All drugs were administered intravenously, and no dose reductionswere scheduled. White-cell and platelet counts were obtainedweekly, and treatment on day 1 of a cycle was delayed if thewhite-cell count was less than 3500 per cubic millimeter orif the platelet count was less than 100,000 per cubic millimeter.Chemotherapy doses were calculated on the basis of actual, notideal, body weight.
The patients were stratified according to primary treatment(mastectomy or breast conservation), menopausal status (before,during, or after menopause), number of positive lymph nodes(one to three, or more than three), and estrogen-receptor status(positive or negative). The patients were randomly assignedto receive chemotherapy at a dose intensity that was high (group1), moderate (group 2), or low (group 3).
Statistical Analysis
The primary objective was to compare the disease-free survivalof patients randomly assigned to group 1 with the survival ofthose randomly assigned to group 3. Disease-free survival wasdefined as the time from randomization to a documented relapseor death without a relapse. Data on patients who were stillalive and free of disease were censored at the date of the lastcontact. Overall survival was defined as the time from randomizationto death from any cause.
Differences in disease-free and overall survival were evaluatedwith the proportional-hazards model11 for multivariate analysesand the log-rank test and stratified log-rank test12 for univariateanalyses. Differences in patient characteristics were evaluatedwith the chi-square test,13 for categorical variables, and Wilcoxon'srank-sum test,13 for continuous variables. Median survival andtime-to-event curves were calculated by the Kaplan-Meier method14.
Multivariate analyses of disease-free survival were performedevery four to six months after a median of one year of follow-up.These analyses were reported to an independent protocol-monitoringcommittee responsible for deciding to terminate the trial earlyif statistical differences emerged on the basis of group sequentialmethods15 for evaluating disease-free and overall survival.Patient-enrollment goals were increased twice, first to 1150women, to allow for the inclusion of patients treated with breast-conservationtherapy, and then to 1570, to accommodate the anticipated diminishedrate of failure with the addition of tamoxifen in perimenopausalor postmenopausal women who were positive for estrogen receptors.The second of these revised goals was reached in March 1991,and the trial was closed. The next scheduled analysis demonstrateda significant difference in survival between treatment groups,with the nominal P value by multivariate analysis (P<0.001)crossing the truncated O'Brien-Fleming boundary (approximatelyP = 0.0026). Physicians of patients in group 3 were notified,and the patients were given the option of receiving an increaseddose and dose intensity.
According to the a priori study design, data on the patientswho had undergone breast-conservation therapy and on those receivingtamoxifen were to be analyzed in separate strata. A subgroupanalysis was to be performed for each of the stratified subgroups.Data for all groups were analyzed by intention-to-treat methods.
All clinical information and surgical and pathology reportswere reviewed by the study cochairs to verify the eligibilityof the patients and their tumor and nodal characteristics. Membersof the CALGB Data Audit Committee made site visits to all theparticipating institutions to verify compliance with federalregulations and protocol requirements, including those regardingeligibility, treatment, toxic effects, and outcome. Such anon-site review of medical records was performed for a randomlyselected subgroup of 376 patients (24 percent) from all theparticipating institutions.
Results
A total of 1572 patients from 26 institutions and their affiliateswere enrolled in the study. Twenty-two patients withdrew fromthe study before they received treatment, and follow-up datawere inadequate for 21 patients. The results reported here arefor 1529 patients, with a median follow-up of 3.4 years. Sixty-eightpatients (4 percent) did not meet one or more eligibility criteria,most often because of a tumor size that exceeded 5 cm. However,no randomized patients were excluded if follow-up data wereavailable and they had received treatment. Analyses of the datawith and without these 68 patients revealed no differences inoutcome. The clinical characteristics of the patients are shownin Table 2.
Table 2. Characteristics of Patients at the Time of Enrollment in the Study.
Outcome
Both disease-free and overall survival were longer in patientswho were treated with a high dose at a moderate or high intensity(groups 1 and 2) than in those treated with a low dose at alow intensity (group 3), and a three-way comparison was significantby a log-rank analysis (Figure 1). Paired comparisons demonstratedsignificant differences between groups 1 and 3 and groups 2and 3 in terms of both disease-free and overall survival (Table 3).
Figure 1. Actuarial Disease-free and Overall Survival According to Dose Intensity of Chemotherapy in Women with Stage II Breast Cancer.
The numbers under the left panel refer to the number of women in each treatment group who were free of disease or had recurrent disease at the time of the last analysis. The numbers under the right panel refer to the number of women in each group who were alive or dead at the time of the last analysis.
Table 3. Disease-free and Overall Survival in the Three Treatment Groups at Three Years.
The large size of this trial allowed an analysis of a priorisubgroups. Table 4 lists the hazard ratios and univariate Pvalues for these subgroups. The difference in survival betweengroups 1 and 3 was remarkably uniform across all subgroups inwhich there was a sufficient number of events to allow an analysisof differences. The survival difference in smaller subgroups,such as postmenopausal women who were negative for estrogenreceptors, or subgroups with few treatment failures, such aswomen with tumors less than 2 cm in diameter and those withone to three positive nodes, was not significant.
Table 4. Hazard-Rate Ratios and Pairwise Comparisons of Disease-free Survival in Subgroups of Patients with Various Clinical Characteristics.
The effect of the two higher-dose regimens of adjuvant chemotherapyon disease-free survival was as great in postmenopausal womenas it was in premenopausal women (Figure 2). The differencein overall survival, according to the chemotherapy dose, betweenpremenopausal and postmenopausal women is shown in Figure 3.The difference had a P value of 0.03 by the log-rank test.
Figure 2. Actuarial Disease-free Survival According to Menopausal Status.
The numbers under the panels refer to the number of women in each treatment group who were free of disease or had recurrent disease at the time of the last analysis.
Figure 3. Actuarial Overall Survival According to Menopausal Status.
The numbers under the panels refer to the number of women in each treatment group who were alive or dead at the time of the last analysis.
Table 5 provides data on initial relapses in each treatmentgroup. Patients in group 3 had a significantly higher numberof relapses at all sites than did patients in group 1 or group2. Among the patients in group 3, local relapses were more frequentthan distant relapses. This raises the possibility that thedose may be more effective in controlling local disease thanin controlling distant metastases. When patients who first hada relapse at a local site were excluded from the analysis, disease-freesurvival was still longer in the patients given the higher doses(P = 0.04 for a three-way comparison; P = 0.01 for a two-waycomparison between groups 1 and 3). However, this analysis assumesthat local and distant failures were independent events, whichwas not likely16. For this reason, data on all local relapses,not just the first relapse, are being collected to perform aproper analysis of the question of dose in relation to localand distant disease.
Table 5. Sites of Recurrent Disease in the Three Treatment Groups.
Toxicity
Toxicity was directly related to dose intensity. According tostandard CALGB grading criteria, grade III or IV leukopenia(grade III: 1000 to 1999 cells per cubic millimeter; grade IV:<1000 cells per cubic millimeter) occurred in 65 percentof the patients in group 1, in 16 percent of those in group2, and in less than 5 percent of those in group 3. Grade IIIor IV thrombocytopenia (grade III: 25,000 to 49,999 cells percubic millimeter; grade IV: <25,000 cells per cubic millimeter)occurred in 18 percent of the women in group 1 but in less than2 percent of those in groups 2 and 3. Nausea affected 39 percent,35 percent, and 20 percent of the patients in groups 1, 2, and3, respectively. Grade III or IV stomatitis (grade III: painfulerythema, edema, ulcers, and inability to eat; grade IV: painfulerythema, edema, ulcers, and requirement of enteral or parenteralnutrition) occurred in 10 percent of the patients in group 1.There were two treatment-related deaths: one patient in group3 died of septic shock and one patient in group 1 died of cardiomyopathythree years after treatment. Ninety-one patients were withdrawnfrom the study before completion of all the assigned cyclesof chemotherapy. Consent to continue in the study was withdrawnby 36 women; 27 withdrew because of excessive toxicity, 11 becauseof a relapse during treatment, and 17 for various other reasons.Virtually all the assigned doses were actually delivered. Over95 percent of the patients received at least 90 percent of theirassigned dose. Intravenous administration of drugs ensured complianceand distinct differences in dose intensity among the three treatmentgroups.
Body weight did not influence disease-free or overall survival;when patients were divided into four groups according to bodyweight (<60 kg, 60 to 67 kg, 68 to 79 kg, and 80 kg), theP values by log-rank analysis were 0.53 for disease-free survivaland 0.89 for overall survival. The administration of dexamethasoneas an antinausea medication also did not affect the outcome.
Discussion
Dose
This randomized trial of adjuvant chemotherapy for stage IIbreast cancer demonstrates a difference in survival resultingfrom the use of different doses of chemotherapy given at differentlevels of intensity, even though the doses were within the conventionalrange. The original chemotherapy regimen was 400 mg of cyclophosphamideper square meter of body-surface area and 40 mg of doxorubicinper square meter, both given on day 1 in a 28-day cycle, and400 mg of fluorouracil per square meter given on days 1 and8 of the cycle17. This protocol approximates the regimen ofa high dose given at a moderate level of intensity in group2 in our study. The protocol for group 1 represents a 50 percentincrease over the original regimen. In a pilot study, the degreeof toxicity associated with the administration of a high doseat a high level of intensity was judged to be the maximum thatcould be accepted in a large, multi-institutional trial of adjuvantchemotherapy for stage II breast carcinoma18. Group 3 receivedhalf the dose received in the other two groups and at half theintensity of that received in group 1.
The dose-response effect refers to a relation in which the effectof a drug increases proportionally with increasing doses. Thisis different from the dose threshold, which is a dose belowwhich there is no discernible effect. The results of our trialdemonstrated at least a threshold effect of a regimen of cyclophosphamide,doxorubicin, and fluorouracil used as adjuvant chemotherapyfor patients with early breast cancer.
The results also provide some evidence of a dose-intensity response.The dose rates for cyclophosphamide, doxorubicin, and fluorouracilwere 150 mg, 15 mg, and 150 mg per square meter, respectively,per week in group 1; 100 mg, 10 mg, and 100 mg per square meterin group 2; and 75 mg, 7.5 mg, and 75 mg per square meter ingroup 3. Thus, the rate in group 1 was 50 percent higher thanthat in group 2, and the rate in group 3 was 50 percent of thatin group 1. Although the overall and disease-free survival ratesin group 3 were higher than those in group 2, the differenceswere not significant.
The use of bone marrow-stimulating factors and bone marrow transplantationmakes further escalation of the dose intensity possible. Suchtreatments are currently being evaluated in national, cooperativegroup trials. However, the results of our trial cannot be usedto justify a higher dose intensity than that used in group 1.The increase from a moderate to a high dose intensity was associatedwith an increase in morbidity. The white-cell nadir was consideredto be in the life-threatening range (<1000 cells per cubicmillimeter) in 21 percent of the patients in group 1 but inonly 1 percent of those in group 2. Nevertheless, only 4 percentof the patients in group 1 required hospitalization. This increasein morbidity in group 1, as compared with group 2, was not accompaniedby a significant increase in either disease-free or overallsurvival.
Menopausal Status
It has been difficult to demonstrate survival benefits fromadjuvant chemotherapy in postmenopausal women. In a 1988 overviewof all trials of adjuvant therapy, the reduction in the oddsof death was 14 percent in 3746 women who received combinationchemotherapy, as compared with those given no adjuvant treatment3.Ten percent of the women over 50 years of age in these studieswere premenopausal. In an earlier study, the National SurgicalAdjuvant Breast and Bowel Project found that patients 50 yearsof age or older survived longer when treated with a combinationof doxorubicin and tamoxifen, as compared with those treatedwith tamoxifen alone. However, others have not demonstrateda similar benefit from doxorubicin-containing regimens for postmenopausalwomen19.
Our results provide evidence that a reduction in chemotherapydoses below the levels that have been shown in large clinicaltrials to improve outcomes in patients with breast cancer reducesthe benefit of such adjuvant therapy. In this study, postmenopausalwomen treated with higher doses of adjuvant chemotherapy hada significantly longer survival than those given lower doses.Our data provide no evidence that an additional benefit willaccrue from doses that are even higher than those employed inthis trial. However, we believe that our results provide a rationalefor randomized clinical trials of high-dose chemotherapy combinedwith autologous bone marrow transplantation or treatment withperipheral stem cells or hematopoietic growth factors.
Supported by grants (CA-12449, CA-35279, CA-33601, CA-03927,CA-07968, CA-35421, and CA-31946) from the National Cancer Institute.
Source Information
From the Winship Cancer Center, Emory University, Atlanta (W.C.W.); North Shore University Hospital, Manhassett, N.Y. (D.R.B.); the Department of Biostatistics, Harvard School of Public Health, Boston (A.H.K.); the Bowman Gray School of Medicine, Winston-Salem, N.C. (M.R.C., C.R.F.); Massachusetts General Hospital, Boston (J.Y.); St. Luke's Medical Center, Milwaukee (R.D.H.); New York Hospital and Cornell Medical Center, New York (A.M.); the S. Nevada Cancer Research Foundation, Las Vegas (J.A.E.); the Memorial Sloan-Kettering Cancer Center, New York (L.N.); the Frontier Science Technology and Research Foundation, Amherst, N.Y. (A.C.B.); the Dana-Farber Cancer Institute, Boston (E.F.); and the University of California, San Francisco, School of Medicine, San Francisco (I.C.H.).
Address reprint requests to Dr. Wood at the Department of Surgery, Emory University School of Medicine, 1364 Clifton Rd., N.E., Atlanta, GA 30322.
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Appendix
The following members of the Cancer and Leukemia Group B participatedin this study: R. Cooper, Bowman Gray School of Medicine, Winston-Salem,N.C.; G. Canellos, Dana-Farber Cancer Institute, Boston; M.Green, University of California, San Diego; R.T. Silver, NewYork Hospital-Cornell Medical Center, New York; R.W. Carey,Massachusetts General Hospital, Boston; J.F. Holland, MountSinai Hospital, New York; J. Aisner, University of MarylandCancer Center, Baltimore; A. Gottlieb, Upstate Medical Center,Syracuse, N.Y.; K. Rai, Long Island Jewish Medical Center, NewHyde Park, N.Y.; M. Perry, University of Missouri, Columbia;A.P. Lyss, Washington University Medical Center, St. Louis;R. Weiss, Walter Reed Army Medical Center, Washington, D.C.;R.C. Bast, Duke University Medical Center, Durham, N.C.; L.Leone, Rhode Island Hospital, Providence; A.M. Mauer, Universityof Tennessee, Memphis; M. Costanza, Central Massachusetts OncologyGroup, Worcester; N. Vogelzang, University of Chicago MedicalCenter, Chicago; B. Cooper, McGill Cancer Center, Montreal;R.R. Ellison, Columbia University, New York; S. Kopel, MaimonidesMedical Center, Brooklyn, N.Y.; G. Omura, University of Alabama,Birmingham; B. Peterson, University of Minnesota, Minneapolis;G. Cornwell, Dartmouth Medical School-Norris Cotton Cancer Center,Hanover, N.H.; E.S. Henderson, Roswell Park Memorial Institute,Buffalo, N.Y.; H. Ozer, University of North Carolina, ChapelHill; O. Martello, University of Cincinnati College of Medicine,Cincinnati; R. Frelick, Delaware Cancer Network, Wilmington;and G. Clamon, University of Iowa, Iowa City.
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80 kg), the P values by log-rank analysis were 0.53 for disease-free survival and 0.89 for overall survival. The administration of dexamethasone as an antinausea medication also did not affect the outcome. 
