Acta Oncologica
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`How to Improve Cytotoxic Therapy in Advanced
`Breast Cancer
`
`L. Bastholt & H. T. Mouridsen
`
`To cite this article: L. Bastholt & H. T. Mouridsen (1990) How to Improve Cytotoxic Therapy in
`Advanced Breast Cancer, Acta Oncologica, 29:3, 349-355, DOI: 10.3109/02841869009090013
`
`To link to this article: https://doi.org/10.3109/02841869009090013
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`

`FROM THE DEPARTMENT OF ONCOLOGY R, ODENSE UNIVERSITY HOSPITAL, ODENSE, AND THE DEPARTMENT
`OF ONCOLOGY ONK, FINSEN INSTITUTE, RIGSHOSPITALET, COPENHAGEN, DENMARK.
`—_—————_—————-——_—-————-———
`
`Acta Oncologica 29 (1990) Fuse. 3
`
`HOW TO IMPROVE CYTOTOXIC THERAPY IN ADVANCED BREAST CANCER
`
`L. BASTHOLT and H. T. MOURIDSEN
`
`Abstract
`
`The optimal cytotoxic treatment of patients with advanced
`breast cancer is so far not defined. Median survival after first
`metastatic manifestation is approximately 18 months. No direct
`evidence for a survival
`improvement after the introduction of
`cytotoxic therapy has been published. Major efforts have been
`made to improve treatment efficacy through manipulations of
`doses, schedules and combinations of known cytotoxic drugs.
`Three months is probably too short a treatment period. Altemat.
`ing non-cross resistant regimens offer no advantage over sequen-
`tial therapy. A dose—response relationship clearly exists in breast
`cancer, but the higher response rates have not been transformed
`into a survival benefit. Treatment of advanced breast cancer is
`palliative, and if, furthermore, we have actually reached a plateau
`where no further improvement in survival is possible, we will have
`to evaluate every new treatment modality carefully according to
`quantity as well as quality of life.
`
`Key wants: Advanced breast cancer, cytotoxic therapy, dura-
`tion of treatment, alternating therapy. sequential therapy, dose—
`response relationship.
`
`The optimal cytotoxic treatment of patients with ad-
`vanced breast cancer has yet to be defined.
`Endocrine therapy was introduced in the late l950s,
`and this treatment gave a response rate of 30—35% and
`good palliation. Some 10 years later chemotherapy was
`introduced. Great enthusiasm concerning this
`therapy
`was mainly based on the results achieved in the treat-
`ment of hematological malignancies. However,
`through-
`out
`the 19805 this optimism has been replaced by a
`more sceptical attitude. With currently used treatment
`modalities the median survival after first metastatic mani-
`
`festation is approximately 18 months. Using historical
`controls, some authors claim to have found a survival
`prolongation with cytotoxic therapy of advanced breast
`cancer (1,2). Others (3—5) have found that
`there is
`still no proof for
`this opinion. No randomized trial
`
`with a control arm without
`
`treatment has ever been
`
`published.
`Preclinical research currently focuses on I) the possibil-
`ity of overcoming genetic and kinetic resistance, 2) devel-
`opment of new drugs with a different mechanism of action,
`and 3) development of less toxic analogues of already
`known drugs.
`Since no major new developments are just around the
`comer, clinical research has concentrated its efl'orts on
`
`improving treatment efficacy, by manipulations of doses,
`schedules and combinations of known cytotoxic drugs.
`In the following we will describe some of the major
`efforts made in order to define an optimal treatment for
`patients with metastatic breast cancer.
`
`Duration of treatment
`
`Standard therapy in Denmark prior to 1985 was to
`continue treatment for one year after a complete remission
`had been obtained, or to continue treatment pending evi—
`dence of progressive disease.
`A few studies addressing this question have been pub-
`lished and two major trials are ongoing. The basic design
`of all these trials has been the same. Patients are random-
`
`ized between a standard arm with repeated treatment
`pending evidence of progressive disease versus an arm with
`short-term chemotherapy and resumption of the same
`regimen when progression occurs during the observation
`period.
`The trial published by the Australian—New Zealand
`Breast Cancer Trials Group (6) included an evaluation of
`
`
`Presented at the 1989 Nordic Post Graduate Oncology Seminar,
`April 23—26, 1989, Riksgransen, Sweden.
`Accepted for publication 6 January 1990.
`
`349
`
`

`

`350
`
`L. BASTHOLT AND H. r. MOURXDSEN
`
`quality of life, using linear analogue self assessment scores
`(LASA). A total of 308 patients were randomized to
`treatment with two different combination schedules, either
`
`for only 3
`continuously until progressive disease or
`courses. They found a significant difference in response
`rate (49% vs 32%, p=0.02), and in median time to
`treatment failure (6.0 vs 4.0 months). Median and overall
`survival were not significantly different. Concerning the
`quality of life, they found that all endpoints favoured the
`continuous therapy.
`A British study by Cantwell (7) used the same basic
`schedule and asked whether a short course of first-line,
`
`single drug mitoxantrone is as effective as continuous
`therapy with the same drug. Patient entry is now closed,
`and data on 132 randomized patients show that the overall
`response rate was quite low. 26.5%, and no differences in
`duration of response or survival have been found.
`Two randomized trials are ongoing, one conducted by
`the EORTC (8) which compares classical CMF given
`continuously until evidence of progressive disease, with 6
`cycles of CMF, and one conducted by DBCG (9) which
`compares 18 months of CEF with 6 months of CEF. So
`far no data are available from the two studies.
`
`Alternating uon-cross-resistant regimens
`
`Based on the Goldie & Coldman hypothesis (10) the use
`of alternating, non-cross-resistant regimens should mini-
`
`mize the risk of development of tumor resistance to
`chemotherapy.
`It might be anticipated that alternation
`between a doxorubicin-containing regimen with the con-
`ventional CMF regimen would increase elficacy, since
`these drugs are efiicient in advanced breast cancer and they
`are non-cross-resistant.
`
`Several studies have raised this question. Table 1 briefly
`summarizes the results of the major, randomized trials.
`Vogel et al. (11) compared CAF with CAF alternating
`with CAMELEON, (cytosine arabinoside, methotrexate,
`with leucovorin rescue, and vincristine). They investigated
`
`187 patients and found no difl'erence in the response rate,
`time to treatment failure and median survival.
`
`investigated sequential VATH and
`CALGB (12)
`CMFVP versus alternating courses of the same regimens.
`A third arm included standard CAF. Almost 500 patients
`were randomized and no statistically significant differences
`were found in response rate, time to treatment failure, and
`survival.
`
`A British study by Spittle et al. (13) compared con-
`tinuous FAVM/ehlorambucil with AVM alternating with
`CF-vindesine. No significant differences were found in
`response rate, duration of response or survival. The same
`pattern was found by Tormey et a1. (14), who randomized
`311 patients to either CMFVP or to alternating CMFP
`and AV.
`It should be mentioned that a few smaller studies have
`
`reported a marginally significant improvement in response
`
`Alternating non-cross resistant regimens in the treatment of advanced breast cancer
`
`Table 1
`
`Regimen
`
`CAF
`
`CAF/CAM ELEON
`CAF
`VATH/CM FVP
`VATH/CMFVP
`FAVM + CHLORAMB
`
`AVM/CF-VINDE
`CMFVP
`
`CMFP/AV
`
`n
`
`RR %
`
`'ITF (months)
`
`Surv. (months)
`
`Ref.
`
`7.9
`ns
`7.0
`
`ns
`
`187
`
`497
`
`262
`
`311
`
`44
`ns
`40
`52
`58
`52
`63
`ns
`64
`59
`ns
`58
`
`14.8
`ns
`15.5
`
`ns
`
`14
`ns
`15
`19
`ns
`16
`
`(11)
`
`( 12)
`
`(13)
`
`(14)
`
`RR = Response rate
`TTF = Median time to treatment failure
`SURV = Median survival
`CAF = Cyclophosphamide + doxorubicin + S-fluorouracil
`CAMELEON = Cytosar + methotrexate with leucovorin rescue + vincristine
`VATH = Vincristine + doxorubicin + trilostane + hydrocortisone
`CM FVP = Cyclophosphamide + methotrexate + S-fluorouracil + vincristine + prednisone
`FAVM = 5-fluorouraci1 + doxorubicin + vincristine + methotrexate
`CHLORAMB = Chlorambucil
`AVM = Doxorubicin + vincristine + methotrexate
`CF—VINDE = Cyclophosphamide + S-fluorouracil + vindesine
`CMFVP = chlorphosphamide + methotrexate + 5-fluorouracil + vincristine + prednisone
`AV = doxorubicin + vincristine
`
`

`

`cvroroxtc THERAPY IN ADVANCED BREAST CANCER
`
`351
`
`rate, but this did not translate into a survival benefit in
`
`any of the studies. An ongoing EORTC study compares
`three different combination schedules given either sequen-
`tially or alternating (8). No data have yet emerged from
`this study.
`
`Dose response
`
`The principle of a relationship between dose and effect is
`fundamental in pharmacology. The efficacy and toxicity of
`most drugs, including cytotoxic drugs, increases with in-
`creasing dose. The concept of a steep dose—response rela-
`tionship underlies many ongoing clinical
`trials today,
`including those using autologous bone marrow transplan-
`tation to overcome the bone marrow toxicity of high-dose
`chemotherapy.
`The experimental support for a steep dose response is
`derived from animal model systems where even a small
`increase in administered dose results in a large increase in
`tumor cell kill (15). The clinical value of a dose—response
`relationship depends upon a different sensitivity of tumor
`cells compared to normal cells. This difference in sensitiv-
`ity again is dependent upon the tumor type, the distribu-
`tion of cells in a tumor according to the cell cycle, and the
`size of the tumor. These facts clearly demonstrate the
`complexity of the dose/response relationship, and the
`difficulties of testing this correlation in clinical trials.
`Only a few randomized, clinical trials have been able to
`find a prolonged survival in patients treated with high-dose
`chemotherapy. Survival improvement was observed in tu-
`mor types known to be very sensitive to chemotherapy
`(small cell lung cancer, acute lymphatic leukemia, testicu-
`lar cancer) (16—18). Some trials, however, have questioned
`these results (19,20). Breast cancer is known to be less
`sensitive to chemotherapy compared to these tumor types.
`Bonadonna & Valagussa (21) were among the first to
`discuss the possible relationship between the dose given
`and the effect of treatment. Their analysis was retrospec-
`tive and based on information from two adjuvant trials.
`They found that patients who were given the highest dose
`had a significantly better survival than those who received
`a lower dose. Perhaps this merely indicates that patients
`with a better prognosis tolerate chemotherapy better. Bruf-
`man et al. (22) have shown that patients who receive a
`higher dose of CMF for metastatic breast cancer actually
`have a significantly higher performance status.
`Hryniuk & Bush (23) introduced another type of retro-
`spective analysis. Their analysis was based on published
`data and they calculated a dose intensity score by relating
`the actual dose levels to the dose levels recommended in
`
`the original Cooper CMFVP regimen. They found a clear
`relationship between therapeutic outcome and dose inten-
`sity, both in the adjuvant setting (relapse-free survival) and
`in the treatment of advanced breast cancer (response rate,
`time to treatment failure). Recently, however, Henderson
`
`et al. (24) have questioned the basic assumptions underly-
`ing the conclusions of Hryniuk & Bush’s study.
`Since the anthracyclines still remain the single most
`active agents in the treatment of advanced breast cancer,
`the majority of randomized studies concerning the dose/
`response relationship have included these drugs (Tables
`2—4).
`
`O’Bryan et al. (25) randomized 103 ‘good-risk‘ patients
`to receive one of three different doxorubicin regimens, and
`68 ‘poor-risk’ patients in 2 doxorubicin regimens. They
`only report the response rate and duration of response and
`there were no significant differences in these endpoints.
`The same pattern was found by Creech et al. (26), ran-
`domizing 119 patients in a 2-arm doxorubicin single drug
`study. The study of Carmo-Pereira et al. (27) included 48
`patients randomized to either standard or low-dose dox-
`orubicin. They found significantly lower response rate,
`duration of response and survival in the low-dose group.
`However it must be mentioned that the response rate in
`the standard-dose group was very high, and the results
`were based on a small number of patients. Ebbs et al. (28)
`in UK randomized 62 patients to two different weekly
`doses of epirubicin, and found no significant difference in
`time to treatment failure, response rate and survival.
`The same trends have been observed in studies using
`combination chemotherapy. A German study by Becher
`et al. (29) used difi'erent doses and schedules of epirubicin
`in combination with cyclophosphamide 600mg/m2. The
`study is ongoing, and when last presented they had seen no
`significant difference in response rate and time to treat-
`ment failure.
`
`A study from MD Anderson Hospital (30) randomized
`63 patients to standard dose CAF against a regimen with
`escalating doses of doxorubicin and cyclophosphamide.
`The high-dose group of patients were treated in protected
`environment units, which included prophylactic treatment
`with antibiotics. They found no difference in overall re—
`sponse rate, time to treatment failure and survival.
`Studies investigating non-anthracyclinc-containing regi-
`mens include a study from Canada by Tannock et al. (31).
`They randomized 133 patients to either standard-dose
`CMF or low-dose CMF with half the dose levels. Signifi-
`cant dif’ferences in response rate and survival were found in
`favor of the standard-dose regimen. However, the signifi-
`cance disappeared when the data were corrected for a
`difference in time from first relapse to randomization, a
`parameter for which they had made no stratification.
`The Italian study by Beretta et al, (32), compared a
`standard-dose CMF with a high-dose CMF. Preliminary
`data on 45 patients revealed a significant difference in
`response rate, but time to treatment failure and survival
`were similar in the two groups.
`In Denmark we are conducting a randomized study in
`which elderly patients with advanced breast cancer receive
`either 40, 60, 90 or 135 mg/m2 epirubicin every 3 weeks.
`
`

`

`352
`
`L. BASTHOLT AND H. T. MOURIDSEN
`
`Dose—response relationship. Single drug antracyline regimens in the treatment of
`advanced breast cancer
`
`Table 2
`
`RR %
`
`Surv. (months)
`
`Ref. No.
`
`(25)
`
`(26)
`
`(27)
`
`(28)
`
`Regimen
`
`‘Good-risk’
`DOX 75 mg/m2 q 3w
`60 mg/m2 q SW
`45 mg/m’ q 3w
`‘Poor-risk’
`
`DOX 50 mg/m2 q 3w
`25 mg/m2 q 3w
`
`DOX 60 mg/m2 q 3w
`
`DOX 20 mg/mzdl + 8 q 4w
`
`n
`
`44
`27
`32
`
`34
`34
`
`119
`
`25
`37 ns
`32
`
`24
`6 ns
`
`53
`ns
`29
`
`16.8
`ns
`20.0
`
`DOX 70 mg/m2 q 3w
`
`DOX 35 mg/m2 q 3w
`
`EPI 20 mg weekly
`
`EPI 40 mg weekly
`
`DOX = Doxorubicin
`EN = Epirubicin
`
`58
`p < 0.02
`25
`
`20
`p < 0.005
`8
`
`62
`
`ns
`
`ns
`
`= Response rate
`RR
`SURV = Median survival
`
`Table 3
`
`Dose—response relationship. Anthracycline containing combination regimens in the treatment of advanced
`breast cancer
`
`
`
` Regimen 11 RR % TI'F (months) Surv. (months) Ref. No.
`
`
`
`
`
`
`
`
`
`C + EPI
`60 tug/m2 q 3w
`40 mg/m2 q SW
`20 mg/m2 weekly
`
`C 500mg/m2d 1 +8
`A
`50 mg/m2 d l + 8
`F 500 mg/m2 d l + 8
`
`C 1200—1500—1800mg/m2d l
`A
`70-85—100mg/tn2d l
`F
`SOOmg/mzd [—5
`
`C = Cyclophosphamide
`EPI = Epirubicin
`A = Doxorubicin
`F = S-fluorouracil
`
`157
`
`63
`
`42
`40 ns
`27
`
`78
`ns
`
`78
`
`10
`ns
`
`12
`
`(29)
`
`(30)
`
`ns
`
`20
`ns
`
`20
`
`= Response rate
`RR
`'ITF = Median time to treatment failure
`SURV = Median survival
`
`Table 4
`
`Dose—response relationship. Non-anthracycline containing combination regimens in
`the treatment of advanced breast cancer
`
`
`
`
`
`
`
` Regimen 11 RR % Surv. (months) Ref. No.
`
`
`
`CMF 600/40/600 mg/m2 q 3w
`
`CMF 300/20/300 rug/1112 q 3w
`
`CMF 600/40/600 mg/m’ q 3w
`
`CMF 535/30/450d l + 8 q 3w
`
`133
`
`45
`
`30
`p = 0.03
`11
`
`18
`p = 0.02
`55
`
`15.6
`p = 0,026'
`12.8
`
`ns
`
`' corrected p = 0.12
`CMF = cyclophosphamide + methotrexate + S-fiuorouracil
`
`(31)
`
`(32)
`
`

`

`CY'rorox1C THERAPY IN ADVANCED BREAST CANCER
`
`353
`
`The evaluation of clinical efficacy and toxicity has been
`supplemented with pharrnacokinetic analysis during the
`first and for some patients also during the fourth cycle of
`chemotherapy. This means that apart from gaining infor-
`mation on the relation between dose and efficacy/toxicity
`we will be able to compare the pharrnacokinetic data with
`the pharmacodynamics of epirubicin.
`
`Antologous bone marrow transplantation (ABMT)
`
`The data previously mentioned suggest that the relation,
`if any, between dose and efficacy is probably only small.
`However, with even higher doses we might get into the
`steeper part of the dose—response curve. ABMT permits
`the use of very high doses of chemotherapy, that would
`normally be accompanied by a very high mortality rate
`due to prolonged bone marrow aplasia. The success of
`ABMT is, however, dependent on several factors, besides
`the existence of a steep dose—response relationship: I) The
`tumor status in the individual patient must give a reason-
`able hope of cure. This means that only patients receiving
`first-line therapy and obtaining a CR are candidates for
`ABMT. 2) Dose escalation must not produce unacceptable
`toxicity to organs other than the bone marrow. 3) The
`patient must be able to pass the difficult period of pan-
`cytopenia with relevant supportive care. 4) The reinfused
`bone marrow must not be contaminated with tumor cells
`
`capable of reestablishing tumor growth.
`More than 25 studies involving 250 patients with
`metastatic breast cancer have now been reported (24). At
`least 10% of the patients entered have died as a result of
`toxicity related to therapy. This mortality has nothing to
`do with the state of the disease since it remains 10% even
`
`if ABMT is applied as first—line therapy.
`None of the studies have been designed as comparative
`studies, and the number of patients in the individual
`studies have been small. Apparently there is a tendency to
`obtain somewhat higher response rates, but the effect of
`ABMT on patient survival is still uncertain. One study by
`Vincent et al. (33) compared the survival using melphalan
`and ABMT with that of patients treated with conventional
`chemotherapy. This was a non-randomized study, but
`survival in the two groups was identical.
`
`Discussion
`
`No major new trends in the use of chemotherapy in the
`treatment of advanced breast cancer have been presented
`for the last 5 or 10 years, and the question of whether or
`not chemotherapy actually adds to patient survival still
`remains unanswered. The only way of demonstrating a real
`survival benefit of chemotherapy would be to conduct
`a randomized trial with a no-treatment control arm. A
`
`multicenter phase III study of this type has just been
`activated in Denmark. Postmenopausal women, older
`
`than 65 years, with progressive disease upon endocrine
`treatment modalities are randomized to receive either
`
`idarubicin orally in a weekly schedule or maximum symp-
`tomatic treatment alone.
`
`The data presented in this review show, that so far no
`
`study has been able to identify a survival improvement by
`altering schedule or dose of currently used cytotoxic drugs.
`Concerning the duration of treatment,
`it seems that
`three months is probably too short a treatment period. The
`use of alternating non-cross-resistant regimens offers no
`advantage over sequential therapy. Even though a relation
`between dose and response clearly exists in breast cancer,
`the higher response rates have not been transformed into a
`survival benefit for the patients. Likewise the therapeutic
`benefit of ABMT still has to be shown in a comparative,
`randomized trial.
`
`The fact that advanced breast cancer is an incurable
`
`disease makes all treatment palliative. If, furthermore, we
`have actually reached a plateau where no further improve-
`ment
`in survival
`is possible, we will have to carefully
`evaluate every new treatment modality according to quan-
`tity as well as quality of life. The endpoints to use in future
`trials are therefore very essential. Using survival as end-
`point is time-consuming in breast cancer, and most papers
`only present median survival figures.
`It is, however, not difficult to imagine a situation in
`advanced breast cancer where two treatment modalities
`
`give similar median survival, but later on an actual differ-
`ence appears in long-term survival. This possibility makes
`long-term follow-up of these patients essential before
`drawing final conclusions from comparative clinical trials.
`Response rates and duration of response are other ob-
`jective measures used in comparative trials. However, re-
`sponse and response rates are difficult to define exactly and
`often very irreproducible (34).
`Time to treatment failure seems to be the best objective
`early measure of treatment efficacy. In a well-defined pa-
`tient material, Davis et al. (35) reported a wide range of
`response rates when using response definitions of different
`cooperative groups. However,
`time to treatment failure
`was very similar whatever definition used.
`Brunner has stated it in this way (36): ‘The real com-
`parative value of two or more palliative treatments in
`a randomized clinical trial is poorly defined by a global
`indicator of average tumor shrinkage without consider-
`ation of time, symptomatic relief and toxic side efl‘ects’.
`Brunner has actually suggested a scoring system for the
`evaluation of treatment in advanced breast cancer, using
`the same basic ideas as the TWIST analysis in the adjuvant
`setting (37). The Brunner score (36)
`includes time to
`treatment failure, symptomatic relief and toxic side effects,
`and it will enable us to make a comparison of treatment
`benefit during palliative therapy. Based on these facts, we
`recommend that overall survival, time to treatment failure
`and quality of life (Brunner score/LASA) be taken as
`
`

`

`354
`
`L. BASTHOLT AND H. T. MOURIDSEN
`
`major endpoints in future trials evaluating cytotoxic ther-
`3131’ in advanced breast cancer. In patients with evaluable
`lesions we will include WHO evaluation of response. This
`will enable the clinicians also to include patients with
`non-evaluable disease lesions in clinical trials.
`
`REFERENCES
`
`. Brincker H. Distant recurrence in breast cancer. Survival
`
`expectations and first choice of chemotherapy regimen. Acta
`Oncol 1988; 27: 729—32.
`Ross MB, Buzdar AU, Smith TL, et a1. Improved survival of
`patients with metastic breast cancer receiving combination
`chemotherapy. Cancer 1985; 55: 341-6.
`. Powles TJ, Coombes RC, Smith IE, Jones JM, Ford HT,
`Gazet J-C. Failure of chemotherapy to prolong survival in a
`group of patients with metastatic breast cancer. Lancet 1980;
`1: 580—2.
`Patel JK, Nemoto T, Vezeridis M, Petrelli N, Suh 0, Dan TL.
`Does more intense palliative treatment improve overall sur-
`vival
`in metastatic breast cancer patients? Cancer 1986; 57:
`567-70.
`
`. Todd M. Shofag M, Cadman E. Survival of women with
`metastatic breast cancer at Yale from 1920 to 1980. J Clin
`Oncol 1983; 1: 406—8.
`Coates A, Gebski V, Bishop JF, et al. Improving the quality
`of life during chemotherapy for advanced breast cancer. New
`Engl J Med 1987; 317: 1490—5.
`. Cantwell B. Short course mitoxantrone versus continuous
`chemotherapy in advanced breast cancer. Proc 2nd Nordic
`Novantrone Symposium, Oslo, November, 1988.
`. 4th EORTC Breast Cancer Working Conference. June 1987,
`London.
`
`Danish Breast Cancer Cooperative Group, DBCG 85 R2.
`Goldie JH, Coldman AJ. A mathematical model for relating
`the drug sensitivity of tumors to their spontaneous mutation
`rate. Cancer Treat Rep 1979; 63: 1727—33.
`Vogel CL, Smalley RV, Raney M, et al. Randomized trial of
`cyclophosphamide, doxorubicin, and fluorouracil alone or
`alternating with a ‘cycle active‘ non-cross-resistant combina-
`tion in women with visceral metastatic breast cancer: a South-
`
`eastern Cancer Study Group Project. J Clin Oncol 1984; 2:
`643—51.
`
`Aisner J, Korzun A, Perloff M, et a]. A randomized compari-
`son of CAF, VATH and VATH alternating with CMFVP for
`advanced breast cancer, a CALGB study. (Abstr 27) Proc
`ASCO 1988.
`
`Spittle MF, Hill BF, Ostrowski MJ, et al. A randomized,
`prospective, comparative, multicenter trial of a single combi-
`nation versus alternating combinations of antitumor drugs in
`advanced breast cancer. Eur J Cancer Clin Oncol 1987; 23:
`1155—62.
`
`Tormey D, Gelman R, Falkson G. Prospective evaluation of
`rotating chemotherapy in advanced breast cancer. Am J Clin
`Oncol 1983; 6: 1—18.
`Bruce WR, Meeker BE, Valeriote FA. Comparison of
`the sensitivity of normal hematopoietic and transplanted
`lymphoma colony—forming cells to chemotherapeutic agents
`administered in vivo. JNCI 1966; 37: 233—45.
`Pinkel D, Hernandez D, Borella L, et a1. Drug dosage and
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`l7.
`
`l8.
`
`19.
`
`20.
`
`21.
`
`22.
`
`23.
`
`24.
`
`25.
`
`26.
`
`27.
`
`28.
`
`29.
`
`30.
`
`31.
`
`32.
`
`33.
`
`remission duration in childhood lymphatic leukemia. Cancer
`1971; 39: 34—40.
`Samson MK, Rivkin SE, Jones SE, et a1. Dose-response and
`dose—survival advantages for high- versus low-dose cisplatin
`combined with vinblastin and bleomycin in disseminated tes-
`ticular cancer. Cancer 1984; 53: 1029—35.
`Intensive
`Cohen MH, Creaven PJ, Fossieck BE Jr, et al.
`chemotherapy in small-cell bronchogenic carcinoma. Cancer
`Treat Rep 1977; 61: 349—54.
`Hande KR, Oldham RKK, Fer MF, et al. Randomized study
`of high-dose versus low-dose methotrexate in the treatment
`of extensive small-cell
`lung cancer. Am J Med 1982; 73:
`413—9.
`
`Figuerado AT, Hryniuk WM, Strautmanis I, et al. Cotrimox—
`azole prophylaxis during high-dose chemotherapy of small-
`cell lung cancer. J Clin Oncol 1985; 3: 54—64.
`Bonadonna G, Valagussa P. Dose-response effect of adjuvant
`chemotherapy in breast cancer. New Engl J Med 1981; 304:
`10‘5.
`Brufman G, Sulkes A, Fuks Z, Biran S. Cytoxan, methotrex—
`ate and S-fluorouracil (CMF) chemotherapy in metastatic
`breast cancer:
`the influence of dose levels and performance
`status upon response rates and survival. Proc ASCO, 1983;
`0402, p 103.
`Hryniuk W. Bush H. The importance of dose intensity in
`chemotherapy of metastatic breast cancer. .1 Clin Oncol 1984;
`2: 1281—8.
`
`Henderson IC, Hayes DF, Gelman R. Dose-response in the
`treatment of breast cancer: a critical review. J Clin Oncol
`1988; 6: 1501—15.
`O’Bryan RM, Baker LH, Gottlieb JE, et al. Dose response
`evaluation of adriamycin in human neoplasia. Cancer 1977;
`39: 1940—8.
`
`Creech RH, Catalano RB, Hopson RC. A comparison of
`standard-dose adriamycin and low—dose adriamycin as pri-
`mary chemotherapy for metastatic breast cancer. Proc AACR,
`1980; 566, p 142.
`Canno~Pereira J, Oliveira Costa F, Henriques E, et al. A
`comparison of two doses of adriamycin in the primary
`chemotherapy of disseminated breast carcinoma. Br J Cancer
`1987; 56: 471-3.
`Ebbs SR, Graham H, A'Hern RP, Bates T, Baum M. A
`prospective randomized trial comparing low and high dose
`epirubicin given as either bolus injection or prolonged infu-
`sion for advanced breast cancer. Proc. 3rd Scandinavian
`Breast Cancer Symposium, Orenas, 1988: 13.
`Becher R, Kurschel E, Kleke O, et a1. Randomized study of
`epirubicin and cyclophosphamide in advanced breast cancer.
`Proc ASCO, 1988; 125, p 32.
`Hortobagyi G, Bodey GP, Buzdar AU, et al. Evaluation of
`highdose versus standard FAC chemotherapy for advanced
`breast cancer in protected environment units: a prospective
`randomized study. J Clin Oncol 1987; 5: 354—64.
`Tannock IF, Boyd NF, DeBoer G, et al. A randomized trial
`of two dose levels of cyclophosphamide, methotrexate, and
`fluorouracil chemotherapy for patients with metastatic breast
`cancer. J Clin Oncol 1988; 6: 1377—87.
`Beretta G, Tabiadon D, Tedeschi L, Gambrosier P, Beretta
`GD, Luporini G. Front-line treatment with CMF variations
`for advanced breast carcinoma. A randomizedstudy. Proc
`ASCO, 1986; 300, p 77.
`Vincent MD, Powles TJ, Coombes RC, et al. Late intensi-
`fication with high-dose melphalan and autologous bone
`marrow support in breast cancer responding to conventional
`chemotherapy. Cancer Chemother Pharmacol
`1988;
`21:
`255—60.
`
`

`

`cvroroxm THERAPY IN ADVANCED BREAST CANCER
`
`355
`
`34.
`
`35.
`
`Mouridsen HT, Rose C. Values and limitations of current
`criteria for objective response in advanced breast cancer, In:
`Cavalli F, ed. ESO monography. Endocrine therapy of breast
`cancer II. Berlin: Springer Verlag, 1987.
`Davis HL, Multhauf P, Klotz I. Comparison of cooperative
`group evaluation criteria for multiple drug therapy for breast
`cancer. Cancer Treat Rep 1980, 64: 507—17.
`
`36.
`
`37.
`
`Brunner KW. Evaluation criteria in comparative clinical trials
`in advanced breast cancer: a proposal for improvement. In:
`Cavalli F, ed. ESO Monography. Endocrine therapy of breast
`cancer 11. Berlin: Springer Verlag, 1987.
`Gelber RD, Goldhirsch A. A new endpoint for the assessment
`of adjuvant therapy in postmenopausal women with operable
`breast cancer. J Clin Oncol 1986; 4: 1772—9.
`
`