Original Article
Interrupted versus Continuous Chemotherapy in Patients with Metastatic Breast Cancer
N Engl J Med 1991; 325:1342-1348November 7, 1991
- Abstract
- Abstract
Background.
Chemotherapy for metastatic breast cancer is palliative, and the optimal duration of therapy is unknown. We designed a trial to determine whether continuous treatment is superior to stopping treatment after a brief induction period and resuming treatment when the disease progresses.
Methods.
We treated 250 women with metastatic breast cancer with six courses of cyclophosphamide, doxorubicin, and fluorouracil given every three weeks. At the completion of this induction period, women whose disease either regressed or remained stable were randomly assigned to receive either continued treatment with cyclophosphamide, methotrexate, and fluorouracil (maintenance therapy) or no further treatment (observation) followed by treatment with cyclophosphamide, methotrexate, and fluorouracil when disease progression became evident (reinduction).
Results.
The combined rate of complete and partial response after initial therapy was 30 percent (71 of 233 patients who could be evaluated; 95 percent confidence interval, 25 percent to 37 percent). In another 42 percent (98 patients), the disease remained stable. A total of 145 patients were randomized. Seventy-one were randomly assigned to the maintenance-therapy group, and 74 to the observation group. The median time to progression was 9.4 months for patients in the maintenance-therapy group and 3.2 months for patients in the observation group (P<0.001). After reinduction therapy, the median time to progression was 3.5 months. The median length of survival from the time of initial therapy was 14.8 months for all 250 patients; it was 21.1 months for the 71 patients in the maintenance-therapy group and 19.6 months for the 74 patients in the observation group (P = 0.67). Maintenance therapy was the most important determinant of the time before progression (P<0.001), but it was not associated with prolonged survival. The changes in performance status were similar in the patients in both groups, but nausea, vomiting, and mucositis were significantly more frequent in the maintenance-therapy group.
Conclusions.
In patients with breast cancer who received induction chemotherapy for 18 weeks, subsequent continuous chemotherapy was associated with a significant prolongation of the time before progression as compared with those receiving no further therapy; overall survival, however, was not significantly different in the two groups. (N Engl J Med 1991;325:1342–8.)
Media in This Article
Figure 1
Progression-free Survival of Patients in the Maintenance-Therapy and Observation Groups.Figure 2
Survival of Patients in the Maintenance-Therapy Group and Patients in the Observation Group, Including All Patients in the Observation Group in Whom Chemotherapy Was Reinstituted (Reinduction).Article Activity
- Article
METASTATIC breast cancer is an incurable disease. Although endocrine therapy, chemotherapy, or both may produce an objective response, almost all patients subsequently have progressive disease and die of their illness. Objective responses to combination chemotherapy occur in 40 to 70 percent of patients and generally last 6 to 12 months; the median length of survival is approximately 18 months.1 , 2 After the failure of initial chemotherapy, salvage regimens are often used, but the rates of response are poor, the responses are short-lived, and length of survival averages approximately 10 months.1 , 3 Numerous combinations of cytotoxic drugs have been used to treat patients with advanced breast cancer. The response rates are generally higher among patients treated with regimens that include doxorubicin,4 5 6 7 although survival may be no better than that in patients treated with regimens that do not include doxorubicin.8 Even so, many experts consider doxorubicin-containing regimens standard treatment, both as adjuvant therapy and in advanced disease.
Few data are available concerning the optimal duration of chemotherapy for patients with metastatic breast cancer. Most patients with metastases are treated continuously with a number of chemotherapy regimens until shortly before their death. However, for most curable cancers,9 and for the adjuvant treatment of breast cancer, shorter courses of chemotherapy lasting four to six months are as effective as treatment for longer periods.10 11 12
Because the treatment of metastatic breast cancer is palliative and because of the frequent side effects associated with chemotherapy, we designed a trial to determine the effectiveness of continuous chemotherapy after an initial six-course induction regimen. The principal objective of the trial was to determine whether the time before progression and the length of survival in patients treated with six courses of induction chemotherapy with cyclophosphamide, doxorubicin (Adriamycin), and fluorouracil (CAF), followed by observation, were equivalent to those in patients treated with six courses of induction therapy followed immediately by maintenance therapy with cyclophosphamide, methotrexate, and fluorouracil (CMF).
Methods
Study Subjects
We studied 250 women who were more than 18 years of age and who had histologically confirmed carcinoma of the breast, metastatic disease with lesions that could be measured or otherwise evaluated, and a performance status of 0 to 3 (a score of 0 was assigned to patients who were asymptomatic, 1 to those who were ambulatory with minimal symptoms, 2 to those who were ambulatory with moderate symptoms, and 3 to those who were in bed more than 50 percent of their waking hours but capable of self-care). Patients who had received any chemotherapy, either as adjuvant therapy or therapy for advanced disease, were excluded, as were those receiving endocrine therapy, but some who had received endocrine therapy in the past were included. Patients were ineligible if they had a granulocyte count of less than 2.0 × 109 per liter or a platelet count of less than 100×109 per liter, unless myelosuppression was due to tumor. Patients were also excluded if they had a history of congestive heart failure or clinical findings indicating congestive heart failure or had brain metastases as the only evidence of tumor spread. Patients were allowed to undergo concurrent irradiation provided they had assessable or measurable disease outside the field of irradiation. The protocol was approved by the institutional review boards of the Bowman Gray School of Medicine of Wake Forest University and the hospitals of participating Piedmont Oncology Association members; all the women gave informed consent.
Treatment Protocol
Induction chemotherapy consisted of 500 mg of cyclophosphamide per square meter of body-surface area, 50 mg of doxorubicin per square meter, and 500 mg of fluorouracil per square meter; all three drugs were given intravenously at the same time every three weeks. In patients more than 60 years of age, those undergoing concurrent irradiation, those with a performance status of 3, those who had undergone irradiation of the axial skeleton or pelvis during the preceding 12 months, and those with S3 bone lesions on radionuclide bone scanning or skeletal survey, the dose of all study drugs was decreased by 25 percent for the first treatment. Drug doses were modified subsequently if there was granulocytopenia (granulocyte count, <1.5×109 per liter); thrombocytopenia (platelet count, <100×109 per liter); severe mucositis; nausea, vomiting, or diarrhea; hepatic dysfunction (only the dose of doxorubicin was changed); hemorrhagic cystitis (only the dose of cyclophosphamide was changed); or cardiac toxicity (doxorubicin was withheld). After six courses of CAF therapy, patients who did not have disease progression were randomly assigned either to receive continued CMF chemotherapy (maintenance therapy) or to be observed. Patients assigned to the observation group received CMF therapy (reinduction) when their disease progressed.
The CMF maintenance and reinduction regimens were identical. Cyclophosphamide was given daily in an oral dose of 100 mg per square meter for 14 days, and methotrexate and fluorouracil were given intravenously in doses of 40 mg and 500 mg per square meter, respectively, on days 1 and 8. On days 1 through 5 of each cycle, 60 mg of prednisone was given orally each day. The CMF regimen was repeated every four weeks for 12 cycles or for a total of one year, whichever came first. Patients in whom brain metastases developed during the observation, maintenance, or reinduction period were treated with whole-brain irradiation and continued to receive chemotherapy according to the protocol if their extracranial metastatic disease was responding to therapy or was stable. The doses of CMF were modified if myelosuppression, severe mucositis, vomiting, diarrhea, or hemorrhagic cystitis occurred.
Evaluation Procedures
Pretreatment evaluation included a complete history and physical examination, measurement of all palpable lesions, complete blood counts, liver-function tests, renal-function tests, measurements of serum electrolytes and calcium, chest film, and radionuclide bone scan. Patients with abnormal bone scans had conventional radiologic examinations of areas of increased uptake. A CT scan of the head was required for patients with neurologic symptoms. The complete blood count was repeated before each course of therapy; the biochemical tests were repeated if abnormal values requiring dose modification were found before any treatment or for evaluation of new or worsening symptoms. History taking, physical examination, and performance-status assessment were performed every six weeks. Chest films were also repeated every six weeks if there was radiologic evidence of metastatic disease. Before randomization, all metastatic sites were reevaluated with appropriate scanning and x-ray films. Such studies then were repeated every three months for two follow-up periods and every six months thereafter. Patients who had evidence of lytic metastases on the bone survey were not required to have follow-up bone scanning unless complete healing of the lesions was apparent on radiologic examination. In addition, patients who had stabilization of the disease at any site were not required to have other sites of metastatic disease followed up, unless such follow-up was clinically indicated to document progression. This strategy was used to minimize the costs of scanning and x-ray procedures. Patients with partial or complete response were required to have all metastatic sites reevaluated as specified above.
Assessment of Response
Strict criteria proposed by the International Union against Cancer were used to assess response.13 A complete response was defined as the disappearance of all known metastases. A partial response was defined as a decrease of 50 percent or more in the product of the longest perpendicular diameters of measurable lesions and improvement in nonmeasurable lesions. Patients with more than a 50 percent decrease in the size of soft-tissue metastases, pulmonary metastases, or measurable disease on CT scanning, but who had no improvement of bone lesions, were considered to have stable disease unless disease progressed at other sites. Those who had more than a 25 percent increase in the size of any measurable lesion or in whom a new lesion developed were considered to have disease progression. Patients who did not have appropriate follow-up of all previously documented metastatic sites were considered unassessable with regard to response even if disease at some sites had regressed partially or completely. For the patients who were randomized, the time to progression was defined as the time from randomization until disease progression or the last day of follow-up; the time to treatment failure was defined as the time from randomization to removal from the study for any cause including disease progression, drug toxicity, or refusal of further therapy; and survival was calculated as the time from study entry until death or the last day of follow-up.
Statistical Analysis
The study was designed to detect a 50 percent increase in the time to disease progression for patients randomly assigned to receive maintenance therapy as compared with patients assigned to the observation group (for example, nine months vs. six months), with 80 percent power at the 5 percent one-sided level of significance. A one-sided design was used since it was thought unlikely that maintenance would be associated with a shorter time to progression. It was estimated that 250 patients would be necessary. This number would provide approximately 150 events, assuming an induction-failure rate of 33 percent and a 10 percent patient loss during the induction period for other reasons. Patients were stratified according to response level (complete response, partial response, or stable disease) and dominant site of metastases (soft tissue, bone, or viscera). Simple random sampling within strata was used to allocate patients to treatment, and intention-to-treat analyses were used.
The median follow-up was estimated according to the method of Korn.14 Logistic-regression analysis was used to determine which variables predicted a response to induction therapy. Differences between treatment groups were analyzed with chi-square tests for categorical variables and Wilcoxon rank-sum tests for continuous variables.
The survival and time-to-progression curves were estimated with the Kaplan–Meier method. Unadjusted differences in these estimates between treatment groups were assessed with log-rank tests. Proportional-hazards regression analysis was used to determine which variables were significantly associated with survival and the time to progression and to assess the effect of treatment after adjustment for other factors. All P values presented in this report are two-tailed.
Results
Between February 1984 and May 1989, we treated 250 women who met all the eligibility criteria for this study. The pretreatment characteristics of these patients are shown in Table 1Table 1
Pretreatment Characteristics of 250 Women with Metastatic Breast Cancer., and the distribution of their metastatic sites is shown in Table 2Table 2
Distribution of Metastases in 250 Women with Metastatic Breast Cancer.. The duration of follow-up ranged from 0.1 to 65.1 months, with a median of 36.1 months.Response to Induction Therapy
The response to the CAF induction regimen is summarized in Table 3Table 3
Response to Induction Chemotherapy in 233 Women with Metastatic Breast Cancer.*. The response in 17 patients could not be evaluated: 7 refused further treatment before the site of metastatic disease could be reassessed, 4 received concurrent endocrine therapy while receiving CAF, 2 died of chemotherapy-related sepsis during CAF induction before randomization, and 4 could not be evaluated for other reasons. Of the remaining 233 patients, 14 (6 percent) had a complete response and 57 (24 percent) had a partial response; the overall rate of response was therefore 30 percent (95 percent confidence interval, 25 percent to 37 percent). Logistic-regression analysis was used to determine which factors were jointly predictive of a complete or partial response. Age, race, performance status, previous hormonal therapy, status of estrogen and progesterone receptors, previous radiation therapy, location of treatment center (university medical center or the office of a community physician), number of metastatic sites, dominant metastatic site, and disease-free interval were all included in the analysis. Only two factors — progesterone-receptor-negative tumor status (P = 0.01) and the presence of one disease site (P = 0.002) — were significantly associated with a complete or partial response to induction therapy.Disease Status during Maintenance Therapy or Observation
Of the 250 patients who entered the study, only 145 (58 percent) were randomly assigned: 74 to the observation group and 71 to the maintenance-therapy group. The reasons why the remaining 105 patients were not randomized are given in Table 4Table 4
Reasons for Exclusion from Randomization of 105 Women with Metastatic Breast Cancer.. Before randomization the patients were stratified according to their response during the induction period and the dominant site of disease; the disease characteristics of the patients in the two groups were similar. Five additional patients had a complete or partial response after randomization; three were in the maintenance-therapy group and two in the observation group. Two patients had a change in the level of response from partial to complete while they were receiving maintenance therapy.The estimates of the time to disease progression are shown in Figure 1Figure 1
Progression-free Survival of Patients in the Maintenance-Therapy and Observation Groups.A. The median time to progression was 3.2 months for the patients in the observation group and 9.4 months for those in the maintenance-therapy group (P<0.001). Among the factors predictive of the time to progression in the regression analysis, maintenance therapy was the most favorable factor (P<0.0001). The patients in the observation group had an approximately 3.8-fold risk of progression per unit of time as compared with the patients in the maintenance-therapy group (95 percent confidence interval, 2.3 to 6.3). Other factors associated with a longer time to progression included a positive estrogen-receptor status (P = 0.0002), treatment outside the medical center (P = 0.033), and fewer metastatic sites (P = 0.02). A similar analysis of the time to treatment failure revealed that maintenance therapy significantly prolonged the time to treatment failure as compared with observation, with median times to failure of 8.1 months (95 percent confidence interval, 6.1 to 9.4) and 3.0 months (95 percent confidence interval, 2.2 to 3.9), respectively.The time to progression according to the treatment regimen is shown in Figure 1B. In this analysis, the definition of time to progression in the maintenance-therapy group did not change. For the observation group, however, the time to progression was defined as the interval from randomization to removal from the study because of disease progression during or after the completion of reinduction therapy. When the groups were analyzed in this manner, the patients in the observation group had a median time to progression of 6.7 months, as compared with 9.4 months for those in the maintenance-therapy group (P = 0.41), indicating that reinduction may have been somewhat successful in prolonging disease control. Regression analysis of these data revealed that younger age, positive estrogen-receptor status, and fewer disease sites were predictive of longer progression-free survival, but the treatment regimen was not. In this analysis of disease progression, the estimated relative risk of progression for patients in the observation group relative to those in the maintenance-therapy group was 1.2 (95 percent confidence interval, 0.8 to 1.9).
The overall survival data for the two groups are shown in Figure 2Figure 2
Survival of Patients in the Maintenance-Therapy Group and Patients in the Observation Group, Including All Patients in the Observation Group in Whom Chemotherapy Was Reinstituted (Reinduction).. Deaths from any cause were considered treatment failures; at the time of the most recent follow-up, 188 of the 250 patients (75 percent) had died. The median length of survival from study entry was 14.8 months for all patients; for the patients in the observation group the median was 19.6 months, as compared with a median of 21.1 months for the patients in the maintenance-therapy group (P = 0.68). A positive estrogen-receptor status (P = 0.002), treatment outside the medical center (P = 0.01), and nonvisceral metastases (P = 0.005) were the factors significantly associated with improved survival, whereas treatment adjusted for these factors had no significant effect (P = 0.77). The risk of death per unit of time in the observation group was 0.9 times that in the maintenance-therapy group (95 percent confidence interval, 0.6 to 1.5).Drug-related toxicity during induction and reinduction treatment was moderate. During induction 8 percent of patients had granulocyte counts of less than 1.0 × 109 per liter and 2 percent had platelet counts of less than 20×109 per liter. Fever developed in six of the patients with granulocytopenia, and two died. Twenty-five percent had mild nausea and vomiting, whereas 32 percent had moderate and 21 percent had severe nausea and vomiting; 27 percent had stomatitis.
Data on changes in performance status were available for 57 patients in the maintenance-therapy group and 49 in the observation group. As compared with the performance status at the time of randomization, on average performance status improved during 17 percent and worsened during 14 percent of the four-week periods in the maintenance-therapy group as compared with 11 percent and 20 percent, respectively, of the four-week periods in the observation group (P>0.1). These changes were observed over a median of eight months for patients in the maintenance-therapy group and four months for patients in the observation group. Nausea or vomiting and mucositis occurred in 61 percent and 38 percent of the patients in the maintenance-therapy group but in almost none of the patients in the observation group (P<0.01). Life-threatening granulocytopenia (granulocyte count, <0.5×109 per liter) or thrombocytopenia (platelet count, <20×109 per liter) occurred in 8 percent and 3 percent of the patients in the maintenance-therapy group and in none of the patients in the observation group (P = 0.01 and 0.24, respectively).
Discussion
The 30 percent rate of complete and partial response in this study after six courses of CAF induction chemotherapy (33 percent when the five patients who had responses after the completion of induction were included) is generally lower than the rates of 25 to 82 percent reported by others.4 , 6 , 7 , 15 16 17 18 19 20 21 22 23 The reasons for these differences in response may be related to patient selection, response criteria, frequency of assessment, or other factors. In spite of the low rate of response, the time to disease progression and overall survival were similar to those reported in other studies, including those reporting much higher rates of response to CAF chemotherapy.6 , 17 , 19 , 20 , 22 , 23 The reported differences in the response rates therefore may be due to differences in patient assessment during treatment rather than to major differences in the effectiveness of treatment.
Continuous chemotherapy in this trial resulted in a significantly longer median time to progression than a six-course induction regimen followed by observation: 9.4 months as compared with 3.2 months. The efficacy of chemotherapy of limited duration in metastatic breast cancer has been examined in four studies. Tormey and colleagues24 treated 23 patients with a multiagent regimen for three to six 28-day cycles; the rate of response was 91 percent, the median time to treatment failure was 12.3 months, and the median length of survival was 19.4 months. Ahmann and Pugh25 studied 63 patients who were treated with three sequential, non—cross-resistant regimens that were repeated once during a 4.5-month period. The rate of response was 35 percent, and patients who responded did not receive chemotherapy for a median of five months before disease progression. The overall median length of survival was 14 months from the initiation of therapy. Smalley et al.6 treated 362 patients with a regimen containing methotrexate or doxorubicin for 24 to 30 weeks; the overall length of survival for patients treated with the doxorubicin regimen was approximately 15 months, and 25 percent of them remained in remission for more than 12 months. In the fourth study, Harris and coworkers26 randomly assigned 43 patients to receive no further treatment or continuous chemotherapy (mitoxantrone every three weeks) after an initial four-course induction period. The median time to progression was 6.0 months and 5.1 months, respectively, in the observation group and the continuous-treatment group, and the overall survival was 12 months and 11.3 months, respectively. These results as well as our own suggest that shorter trials of chemotherapy are not associated with poorer survival in women with metastatic breast cancer.
Quality-of-life issues have become an important factor in the design and assessment of treatment programs for patients with breast cancer.27 28 29 Coates et al.30 compared continuous chemotherapy with intermittent therapy in 307 women with advanced breast cancer. The rate of response and time to progression were better for patients treated with continuous therapy than for those treated with intermittent therapy (49 percent vs. 32 percent, and 6.0 months vs. 4.0 months); however, survival was not significantly different in the two groups. The quality of life was significantly better for the patients in the continuous-therapy group, and the quality-of-life measures could be used as independent prognostic factors for the likelihood of survival. In our trial a change in performance status and the level of drug toxicity were used as surrogate measures of quality of life. There was no difference between treatment groups with respect to performance status, but nausea, vomiting, and mucositis were significantly more frequent and more severe in those receiving maintenance therapy. Although there is no ideal way to measure quality of life, drug-induced side effects undoubtedly diminish a patient's functional status during treatment. In this trial quality of life was not formally measured; however, many patients requested a temporary cessation of chemotherapy, especially if they had a major improvement in performance status or symptoms while receiving therapy. In contrast, and as the results of Coates et al. suggest, many patients receiving treatment, irrespective of whether they are responding, may feel more secure if therapy is continued, even if it is causing substantial side effects.
The selection of palliative treatment for advanced breast cancer depends on the symptomatic status of the patient and most of all on the patient's desires. Since survival appears to be little influenced by the use of short-term rather than continuous treatment, patients who wish to delay therapy after several courses because of drug-induced side effects can be reassured that such a decision will not ultimately affect their survival. For those who have had an objective response and marked improvement in symptoms, continuous chemotherapy might be preferable to prolong the time to disease progression.
Supported by grants (CA-12197, CA-37378, and CA-45808) from the National Cancer Institute, National Institutes of Health.
We are indebted to Ms. Barbara Miller for her assistance in the preparation of the manuscript and to Ms. Sally Reed for her help in data management.
The following members of the Piedmont Oncology Association participated in this trial: James N. Atkins, M.D.,* Goldsboro, N.C.; James D. Bearden, III, M.D., Spartanburg, S.C.; William R. Berry, M.D.,* Raleigh, N.C.; William F. Bobzien, III, M.D., Rocky Mount, N.C.; James E. Bradof, M.D., Spartanburg, S.C.; Richard A. Brodkin, M.D.,* Winston-Salem, N.C.; Robert Brown, M.D., Oklahoma City; Richard D. Callahan, M.D., Asheville, N.C.; Richard M. Christian, M.D., Greenwood, S.C.; Leonard Farber, M.D., New Haven, Conn.; Brian V. Geister, M.D., Oklahoma City; Gerald Goldklang, M.D., Atlanta; Frank W. Green, M.D., Albemarle, N.C.; Ruby A. Grimm, M.D., Statesville, N.C.; James Hampton, M.D., Oklahoma City; Robert Harding, M.D., Rutherfordton, N.C.; Ervin A. Hire, Jr., M.D.,* Kingsport, Tenn.; Jack B. Hobson, M.D.,* Charlotte, N.C.; John D. Hunter, M.D., Wilmington, N.C.; Jack R. Hutcheson, M.D., Roanoke, Va.; Don V. Jackson, M.D.,* Asheville, N.C.; Stephen S. Kennedy, M.D., Roanoke, Va.; William R. Kincaid, M.D., Johnson City, Tenn.; Mary Louise Kistner, M.D., Bluefield, W.V.; Harvey C. Lebos, M.D.,* Savannah, Ga.; Lance Loomer, M.D.,* Goldsboro, N.C.; John A. Lusk, III, M.D.,*
*Member of the Southeastern Gancer Control Consortium.
Greensboro, N.C.; John H. McCulloch, M.D., Spartanburg, S.C.; James A. McFarland, M.D.,* Columbia, S.C.; Nalin C. Mehta, M.D., Albemarle, N.C.; T. Mark Meyer, M.D., Aiken, S.C.; Eric C. Nelson, M.D., Spartanburg, S.C.; Eric S. Niejstrom, M.D.,* Greensboro, N.C.; Barton R. Paschal, M.D.,* Asheville, N.C.; Michael D. Pavy, M.D.,* Florence, S.C.; James B. Puckett, M.D.,* Asheville, N.C.; Mary Raab, M.D., Greenville, N.C.; Spencer Raab, M.D., Greenville, N.C.; William L. Ramseur, M.D., Greenwood, S.C.; Richard J. Rosen, M.D.,* Greensboro, N.C.; Frederick M. Schnell, M.D.,* Macon, Ga.; David W. Sillmon, M.D.,* Greensboro, N.C.; Marc L. Slatkoff, M.D.,* Winston-Salem, N.C.; James E. Smith, M.D.,* Macon, Ga.; Robert Stuart, M.D., Charleston, S.C.; Mark Yoffe, M.D.,* Raleigh, N.C.; Ruth T. Young, M.D., Kingsport, Tenn.; and Patricia J. Zekan, M.D.,* Winston-Salem, N.C.
Source Information
From the Comprehensive Cancer Center of Wake Forest University, Bowman Gray School of Medicine, Winston-Salem, N.C. Address reprint requests to Dr. Muss at the Comprehensive Cancer Center of Wake Forest University, 300 S. Hawthorne Rd., Winston-Salem, NC 27103.
- References
References
1
Petru
Web of Science | Medline2
Garber
Web of Science | Medline3
Buckner
CrossRef | Web of Science | Medline4
Bull
CrossRef | Web of Science | Medline5
Muss
CrossRef | Web of Science | Medline6
Smalley
CrossRef | Web of Science | Medline7
Aisner
Web of Science | Medline8
Hayes
Web of Science | Medline9
Frei
Web of Science | Medline10
Henderson IC, Gelman RS, Harris JR, Canellos GP. Duration of therapy in adjuvant chemotherapy trials. In: NCI monographs. No. 1. Washington, D.C.: Government Printing Office, 1986:95–8. (NIH publication no. 86–2860.)
11
Bonadonna G, Valagussa P, Tancini G, et al. Current status of Milan adjuvant chemotherapy trials for node-positive and node-negative breast cancer. In: NCI monographs. No. 1. Washington, D.C.: Government Printing Office, 1986:45–9. (NIH publication no. 86–2860.)
12
Fisher
Web of Science | Medline13
Hayward
CrossRef | Web of Science | Medline14
Korn
CrossRef | Web of Science | Medline15
Tranum
CrossRef | Web of Science | Medline16
Nemoto
CrossRef | Web of Science | Medline17
Tranum
CrossRef | Web of Science | Medline18
Vogel
Web of Science | Medline19
Falkson
CrossRef | Web of Science | Medline20
Hortobagyi
Web of Science | Medline21
Bennett
Web of Science | Medline22
Italian Multicentre Breast Study with Epirubicin
Web of Science | Medline23
French Epirubicin Study Group
Web of Science | Medline24
Tormey
CrossRef | Web of Science | Medline25
Ahmann
CrossRef | Web of Science | Medline26
Harris
CrossRef | Web of Science | Medline27
Donovan
Web of Science | Medline28
Moinpour
CrossRef | Web of Science | Medline29
Schipper
Web of Science | Medline30
Coates
Full Text | Web of Science | Medline
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Surabhi Amar, Vivek Roy, Edith A. Perez. (2009) Treatment of metastatic breast cancer: looking towards the future. Breast Cancer Research and Treatment 114:3, 413-422
CrossRef17
A Sánchez-Muñoz, E Pérez-Ruiz, N Ribelles, A Márquez, Emilio Alba. (2008) Maintenance treatment in metastatic breast cancer. Expert Review of Anticancer Therapy 8:12, 1907-1912
CrossRef18
Joaquim Bellmunt, Santiago Albiol, Joan Albanell. (2007) INTERMITTENT CHEMOTHERAPY IN METASTATIC ANDROGEN-INDEPENDENT PROSTATE CANCER. BJU International 100:3, 490-492
CrossRef19
Erica L. Mayer, Harold J. Burstein. (2007) Chemotherapy for Metastatic Breast Cancer. Hematology/Oncology Clinics of North America 21:2, 257-272
CrossRef20
Amy M. Lin, Charles J. Ryan, Eric J. Small. (2007) Intermittent chemotherapy for metastatic hormone refractory prostate cancer. Critical Reviews in Oncology/Hematology 61:3, 243-254
CrossRef21
V. Heinemann. (2006) Systemische Chemotherapie beim metastasierten Mammakarzinom. Der Onkologe 12:7, 683-698
CrossRef22
Nicholas J. Robert, Charles L. Vogel, I. Craig Henderson, Joseph A. Sparano, Melvin R. Moore, Paula Silverman, Beth A. Overmoyer, Charles L. Shapiro, John W. Park, Gail T. Colbern, Eric P. Winer, Alberto A. Gabizon. (2004) The role of the liposomal anthracyclines and other systemic therapies in the management of advanced breast cancer. Seminars in Oncology 31, 106-146
CrossRef23
Francesco Recchia. (2003) Intermittent chemotherapy may be as effective as indefinite palliative chemotherapy in advanced colorectal cancer. Cancer Treatment Reviews 29:4, 337-340
CrossRef24
Giovanni Mantovani, Clelia Madeddu, Giulia Gramignano, Maria Rita Lusso, Miria Mocci, Elena Massa, Luca Ferreli, Giorgio Astara, Antonio Maccio, Roberto Serpe. (2003) Subcutaneous interleukin-2 in combination with medroxyprogesterone acetate and antioxidants in advanced cancer responders to previous chemotherapy: phase II study evaluating clinical, quality of life, and laboratory parameters. Journal of Experimental Therapeutics and Oncology 3:4, 205-219
CrossRef25
Volker Heinemann. (2003) Definition of An Optimal First-line Chemotherapy in Metastatic Breast Cancer. Breast Cancer Research and Treatment 81:S1, 43-48
CrossRef26
Semir Beslija. (2003) The Role of Anthracyclines/Anthraquinones in Metastatic Breast Cancer. Breast Cancer Research and Treatment 81:S1, 25-32
CrossRef27
Richard Bell. (2001) Duration of therapy in metastatic breast cancer: management using Herceptin®. Anti-Cancer Drugs 12:7, 561-568
CrossRef28
William F. Anderson, James E. Reeves, Abdalla Elias, Hans (J) Berkel. (2000) Outcome of patients with metastatic breast carcinoma treated at a private medical oncology clinic. Cancer 88:1, 95-107
CrossRef29
Giorgio Cocconi, Giancarlo Bisagni, Mariangela Bella, Luigi Acito, Paola Anastasi, Amalia Carpi, Francesco Di Costanzo, Antonio Frassoldati, Annamaria Mosconi, Adriano Borrini, Paola Buzzi. (1999) Comparison of CMF (Cyclophosphamide, Methotrexate, and 5-Fluorouracil) With a Rotational Crossing and a Sequential Intensification Regimen in Advanced Breast Cancer. American Journal of Clinical Oncology: Cancer Clinical Trials 22:6, 593
CrossRef30
O. Kloke, U. Klaassen, C. Oberhoff, G. Hartwich, J. Szanto, E. Wolf, M. Heckmann, R. Huhn, L. Stephan, U. Schnepper, G.‐M. Donsbach, C. Bechtel, R. Rudolph, A. Berke, D. Borquez, I.rtwich Hawig, H. Hirche, A.E. Schindler, S. Seeber, R. Becher. (1999) Maintenance treatment with medroxyprogesterone acetate in patients with advanced breast cancer responding to chemotherapy: results of a randomized trial. Breast Cancer Research and Treatment 55:1, 51-59
CrossRef31
Kathy D. Miller, George W. Sledge. (1999) THE ROLE OF CHEMOTHERAPY FOR METASTATIC BREAST CANCER. Hematology/Oncology Clinics of North America 13:2, 415-434
CrossRef32
Gamal H. Eltabbakh, M.Steven Piver, Ronald E. Hempling, Fernando O. Recio, Leslie E. Blumenson. (1998) Prolonged Disease-Free Survival by Maintenance Chemotherapy among Patients with Recurrent Platinum-Sensitive Ovarian Cancer. Gynecologic Oncology 71:2, 190-195
CrossRef33
R Gregory. (1997) A randomised trial of six versus twelve courses of chemotherapy in metastatic carcinoma of the breast. European Journal of Cancer 33:13, 2194-2197
CrossRef34
Richard P. McQuellon, Gretchen Kimmick, Gail J. Hurt. (1997) Quality-of-Life Measurement in Women with Breast Cancer. The Breast Journal 3:4, 178-186
CrossRef35
Bernard Brun, Mohamed Benchalal, Christelle Lebas, Pascal Piedbois, Ma Lin, Jean-Paul Lebourgeois. (1997) Response to second-line chemotherapy in patients with metastatic breast carcinoma previously responsive to first-line treatment. Cancer 79:11, 2137-2146
CrossRef36
Robert Dreicer, Mark W. Karwal, Gerardo Midence, Charles S. Davis, Mary Nettleman. (1997) The Role of Radionuclide Angiocardiography in the Treatment of Patients Receiving Doxorubicin-Based Chemotherapy. American Journal of Clinical Oncology 20:2, 132-137
CrossRef37
KAREN K. FIELDS, GERALD J. ELFENBEIN, JANELLE B. PERKINS, LYNN C. MOSCINSKI. (1995) High Dose versus Standard Dose Chemotherapy for the Treatment of Breast Cancer.. Annals of the New York Academy of Sciences 770:1 Bone Marrow T, 288-304
CrossRef38
M. D. GREEN. (1995) Improving treatment for breast cancer. Australian and New Zealand Journal of Medicine 25:5, 461-462
CrossRef39
Robert B. Livingston. (1994) Dose intensity and high dose therapy. Two different concepts. Cancer 74:S3, 1177-1183
CrossRef40
Brendan D. Curti. (1993) Physical barriers to drug delivery in tumors. Critical Reviews in Oncology/Hematology 14:1, 29-39
CrossRef41
David M. Gershenson, Michele F. Mitchell, Neely Atkinson, Elvio G. Silva, John J. Kavanagh, Mitchell Morris, Thomas W. Burke, Donna Warner, J.Taylor Wharton. (1992) The effect of prolonged cisplatin-based chemotherapy on progression-free survival in patients with optimal epithelial ovarian cancer: “Maintenance” therapy reconsidered. Gynecologic Oncology 47:1, 7-13
CrossRef42
Stephen D Williams. (1992) Chemotherapy of ovarian cancer: Is longer better?. Gynecologic Oncology 47:1, 5-6
CrossRef43
Norton, Larry, . (1991) Metastatic Breast Cancer. New England Journal of Medicine 325:19, 1370-1371
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