Is first-line single-agent mitoxantrone in the treatment of high-risk metastatic breast cancer patients as effective as combination chemotherapy? No difference in survival but higher quality of life were found in a multicenter randomized trial

E. Heidemann1,+, H. Stoeger2, R. Souchon3, W.-D. Hirschmann4, H. Bodenstein5, C. Oberhoff6, J. T. Fischer7, M. Schulze8, M. Clemens9, R. Andreesen10, M. Mahlke11, M. König12, A. Scharl13, K. Fehnle14 and M. Kaufmann On behalf of the Interdisciplinary Breast Cancer Working Group of the German Cancer Society15

1 Department of Hematology and Medical Oncology, Deaconess Hospital, Oncological Center of Stuttgart, Germany; 2 Department of Medical Oncology, University of Graz, Austria; 3 Department of Radiation Oncology, General Hospital of Hagen; 4 Department of Medical Oncology, City Hospital of Kassel; 5 Department of Medical Oncology, City Hospital of Minden; 6 Gynecological Department, University of Essen; 7 Department of Medical Oncology, City Hospital of Karlsruhe; 8 Department of Medical Oncology, City Hospital of Zittau; 9 Department of Medical Oncology, Boromaeerinnen Hospital Trier; 10 Department of Hematology and Medical Oncology, University of Regensburg; 11 Gynecological Department, University of Mainz; 12 Gynecological Department, University of Tuebingen; 13 Gynecological Department, University of Cologne; 14 Algora Munich; 15 Gynecological Department, University of Frankfurt, Germany

Received 14 January 2002; revised 13 May 2002; accepted 5 June 2002


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

To determine whether patients with high-risk metastatic breast cancer draw benefit from combination chemotherapy as first-line treatment.

Patients and methods:

A total of 260 women with measurable metastatic breast cancer fulfilling high-risk criteria, previously untreated with chemotherapy for their metastatic disease, were randomized to receive either mitoxantrone 12 mg/m2 or the combination of fluorouracil 500 mg/m2, epirubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (FEC) every 3 weeks. Treatment was continued until complete remission plus two cycles, or until disease progression. In the case of partial remission or stable disease, treatment was stopped after 12 cycles. Second-line treatment was vindesine, mitomycin and prednisolone. Gain from treatment was estimated using a modified Brunner’s score composed of time to progression, patients’ rating of the treatment benefit, alopecia, vomiting and performance status.

Results:

After recruitment from 1992 to 1997 and observation from 1997 to 1999, the final evaluation showed that single-agent treatment with mitoxantrone does not differ significantly from combination treatment with FEC in terms of response, objective remission rate, remission duration, time to response, time to best response, time to progression or overall survival. There was, however, a significant difference in gain from treatment using a modified Brunner’s score favoring the single-agent treatment arm. There was no evidence that any subgroup would fare better with combination treatment.

Conclusions:

No significant difference was detected between the treatment with mitoxantrone as a single agent and the combination of low-dose FEC in terms of response or survival; therefore, the imperative of the necessity of first-line combination chemotherapy for patients with high-risk metastatic breast cancer may be questioned. Since toxicity and quality of life score favored the single-agent mitoxantrone treatment arm, this treatment may be offered to patients preferring quality of life to a potential small prolongation of survival.

Key words: metastatic breast cancer, quality of life, single-agent treatment, survival, time to progression


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Maintenance or re-establishment of quality of life is the main goal in the treatment of patients with metastatic breast cancer as long as definitive cure is not achievable. Palliation therefore needs to be balanced against survival and toxicity. Whereas first-line single-agent treatment has been tested for patients with low-risk criteria [1], the dogma that patients fulfilling high-risk criteria have to be treated with combination chemotherapy up-front is still widely acknowledged.

In the adjuvant treatment of breast cancer patients, higher doses of anthracyclines have resulted in longer relapse-free and overall survival. The threshold dose is considered to be 60 mg/m2 for doxorubicin or 90 mg/m2 for epirubicin [24] for metastatic breast cancer patients. However, the results of several randomized trials suggest that dose intensification of one or more drugs of the CEF (cyclophosphamide, epirubicin and fluorouracil) regimen is unable to substantially ameliorate the outcome [57].

On the other hand, there are studies showing higher response rates and higher overall survival when using higher doses [812]. It has been suggested that these differences may be the result of a preponderance of lower risk groups in those treatment arms showing higher response and/or survival rates [1315].

We would like to add the results of a randomized trial comparing monochemotherapy mitoxantrone with combination chemotherapy with fluorouracil, epirubicin and cyclophosphamide to this discussion. To avoid the selection bias of high- and low-risk patients, we excluded low-risk patients using prognostic factors that had been found in an earlier study by this group [13] and which were confirmed by others [1418]. Fossati et al. [19], when comparing 189 randomized trials including 31 510 patients, found the relevance of the effectiveness of specific regimens to be limited by the modest survival benefit and the lack of evaluation of the quality of life impact of these treatments.

Since palliation and quality of life are most important in the treatment of metastatic breast cancer patients, we chose these goals as the primary endpoint. To measure palliation and quality of life, judgement of patients, that of treating physicians, and some ‘hard’ data, such as months to progression, were needed. The Brunner score [20] is an instrument based on those parameters. It was chosen in the absence of another comparable instrument. On the basis of our earlier observations [13, 21], we used a questionnaire covering functional, social, emotional and toxicity parameters. Patients’ judgement of treatment effectiveness was also assessed on that questionnaire.

Mitoxantrone was chosen as monochemotherapy, since the balance of discomfort due to the treatment on one side and effectiveness on the other side appeared to be favorable according to our earlier studies [13, 22] and several other clinical trials showing that mitoxantrone is active in metastatic breast cancer [2325].

FEC (fluorouracil, epirubicin and cyclophosphamide) was chosen as combination chemotherapy since, at the beginning of the study, this was considered standard treatment for high-risk metastatic breast cancer patients.

Since quality of life could mean less than gain of survival time to patients, we put weight on the evaluation of overall survival as the secondary endpoint so as not to overlook any disadvantage.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient selection
Women eligible for this study included those with histologically documented advanced breast cancer stage IV, age <=80 years who had measurable disease and a WHO performance status of 0, 1 or 2. Patients were ineligible if they had received prior chemotherapy for their advanced disease, were given anthracycline or anthrachinone as adjuvant treatment [previous hormonotherapy, CMF (cyclophosphamide, methotrexate and fluorouracil) or CMF-like adjuvant chemotherapy were allowed], suffered from cardiac insufficiency New York Heart Association grades II–IV, or had experienced a myocardial infarction in the last 6 months. Patients were also considered ineligible for >25% of irradiation to the bone marrow, mediastinal irradiation, concurrent hormonal treatment, cerebral metastases, bone marrow replacement, secondary malignancy (except carcinoma in situ) and an expected survival of <3 months. Patients refusing to use effective contraceptives were excluded. Randomization was only allowed after written informed consent was obtained.

The initial laboratory profile had to show adequate organ function (i.e. leucocytes >4/nl, granulocytes >2/nl, platelets >100/nl, creatinine level <2 x normal, bilirubin level <4 x normal, alkaline phosphatase <3 x normal). Only high-risk patients were eligible. To check high-risk status, a risk flow sheet was used (Figure 1), which was developed on the basis of the results of our earlier performed randomized study showing the relevance of prognostic factors and their combination [13].



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Figure 1. Advanced breast cancer risk flow sheet; developed on the basis of the results of a former randomized study [13].

 
Treatment
Mitoxantrone
An anthrachinone with similar properties as the anthracyclines [25] was chosen as the single-agent treatment because of high efficacy without causing major hair loss. The dose was 12 mg/m2 i.v. by short infusion, repeated at 21 day intervals.

FEC
The combination of fluorouracil, epirubicin and cyclophosphamide was used as a standard combination for high-risk metastatic breast cancer in those years when the study was performed. The doses of fluorouracil 500 mg/m2 i.v., epirubicin 50 mg/m2 i.v. and cyclophosphamide 500 mg/m2 i.v., each repeated at 21-day intervals, were taken from the French Epirubicine Study Group that showed no survival difference between FEC (50 mg/m2 epirubicin) and FEC (75 mg/m2 epirubicin) [6].

Second-line treatment
Since survival was one of the major endpoints of this study, second-line treatment was fixed. The combination of vindesine (3 mg/m2 i.v., day 1), mitomycin (10 mg/m2 i.v., day 1) and prednisolone (100 mg i.v. or oral, days 1–5) (VMP) repeated every 4–6 weeks was chosen, because at the time the trial was initiated, taxanes or vinorelbine were not available outside clinical trials.

Third-line treatment
Third-line treatment (chemotherapy or hormonal treatment) was left to the discretion of the treating physician, since it was accepted that third-line treatment would not contribute appreciably to the outcome.

Treatment duration
Patients were treated until they had received two treatment cycles after documented complete remission (CR). In cases of partial remission (PR) or stable disease (NC), treatment was stopped after 12 cycles. In the case of progressive disease (PD) (either primary progression or progression after NC, partial or complete response), second-line treatment with VMP was started (see above). Supportive treatment was recommended and assessed.

Dose changes
Dose reduction was outlined in the protocol according to standard accepted hematological and chemical parameters.

Patient evaluation
Pretreatment evaluation
Pretreatment evaluation consisted of the following: a complete history and physical examination including weight and blood pressure; performance status assessment; tumor measurements; chest X-ray, abdominal ultrasound, bone scan, X-ray of all positive or suspect areas in bone scan; cranial computed tomography (CT) scan had to be performed if the slightest neurological or psychiatric abnormality existed. CT scan of chest or abdomen had to be performed in case of abnormalities that could not reliably be assessed by chest X-ray or abdominal ultrasound; diagnostic pleuracentesis in the case of pleural effusion; electrocardiography; echocardiography or multigated assessment (MUGA) scan if clinically suspicious for myocardial insufficiency (classified using the authors’ own index). Laboratory tests included blood count with differential count and platelets, creatinin, bilirubin, GOT, GPT, AP, {gamma}-GT, LDH, tumor markers CEA, CA 15-3, calcium. To assess quality of life, the ‘Graduated WHO Analogue and Satisfaction Scales’ questionnaire was used [21].

On-treatment evaluation
Evaluation during treatment included history and physical examination including weight and blood pressure, WHO performance status assessment, electrocardiogram, complete blood counts, blood chemistries on day 1 of each cycle (the same as in pretreatment evaluation except differential count; tumor markers were only assessed if elevated in pretreatment evaluation). Echocardiography or MUGA scan were performed if there was clinical suspicion of myocardial insufficiency. Weekly complete blood counts were also required. Drug toxicity was evaluated on day 1 of each cycle (WHO). Tumor assessment was performed after the second, fifth, eighth and eleventh cycle, as well as 4 weeks after first documentation of any remission using the methods that had initially been diagnostic. Whenever suspicious symptoms were reported, the entire diagnostic program was performed. Quality of life questionnaires had to be completed by the patients on day 1 of each cycle.

After-treatment evaluation
One month after the last treatment cycle, history and physical examination including weight and blood pressure, WHO performance status, blood count, clinical chemistries, and quality of life questionnaires were required. Three, 6, 9 months, etc. after the last treatment cycle, chest X-ray (if initially positive), abdominal ultrasound, bone scan and bone X-ray (if initially positive or if clinical symptoms suggested PD) were required in addition. Independent from third-line or later treatment, a short documentation of the patient’s vital status had to be given every 3 months until death.

Criteria for evaluation
Patients were stratified by disease-free interval (<=18 months versus >18 months), liver involvement versus liver involvement plus other organ sites involved versus no liver involvement, lung involvement versus lung plus other sites versus without lung involvement.

CR was defined as the disappearance of all signs and symptoms of disease, without the appearance of new lesions, for a period of at least 4 weeks. Lytic lesions on radiographs had to recalcify to be scored as a CR. PR was defined as a reduction of >=50% in the sum of the products of the perpendicular diameters of all measurable lesions, without the appearance of new lesions or an increase in the size of existing lesions, for >=4 weeks. NC was defined as <50% reduction in the sum of the products of the perpendicular diameters of all measured lesions, without the appearance of new lesions, for a period of >8 weeks. PD was defined as an increase in the product of the two perpendicular diameters of any measured lesion present at entry of study by >=25% or the appearance of new lesions.

For objective responders (CR + PR) the following calculations were performed: time to response (TTR) was calculated from the date of initiation of chemotherapy to response. Time to best response (TTBR) was calculated from the date of initiation of chemotherapy until the day of best response. Duration of response (RD) was calculated from the first day of remission until the first day of progression. For all patients, time to progression (TTP) was calculated from the initiation of chemotherapy until the first day of progression or the last documented tumor assessment. If documentation ended for other reasons than PD, including deaths not due to disease progression, these events were censored, and survival was calculated from the initiation of chemotherapy until death.

Quality of life and gain from treatment
In a slight modification Brunner’s score [20] for gain from treatment, each month from the start of treatment until progression (TTP) was counted as 1 point (4 points in the original Brunner’s score). For each time interval the mean change of performance status was calculated as the mean of two assessments at beginning and at the end of the interval and subtracted from the value before start of treatment. These differences, weighted with the duration of the interval were summed up to the WHO performance status (PS/WHO) part of the score. Patient’s judgement about the utility of treatment (yes = +1; no = –1; don’t know = 0) was assessed at every visit after the start of treatment. These values multiplied with the length of the interval (months) were summed up for the SUBJ part of the score. For the contribution of toxicity, the mean of nausea/vomiting and alopecia after each treatment course was chosen as part of the study design, since they are the side-effects affecting the patients most of all. The mean values multiplied by the negative duration of the treatment were summed up (= TOX). Lengths of intervals were given in months for all parameters. The modified Brunner’s score (MBS) then was calculated as the sum of TTP, PS/WHO, SUBJ and TOX. In addition to patients with documented disease progression (real TTP), patients without progression were evaluated for MBS. In the latter group each month without progression was calculated as 1 point. In the balance of palliation and toxicity, a positive MBS means gain from treatment and a negative MBS means no gain from treatment.

Statistical analyses
Randomization
After written informed consent, the patients that qualified for high risk according to the flow sheet in Figure 1 were stratified into the following groups and randomized in the central statistical institute using a current computer program: disease-free interval <=18 months versus >18 months, liver metastases only versus liver and others versus without liver involvement, lung metastases only versus lung and others (except liver) versus without lung involvement.

Quality of data
At the Institute of Statistics, data were examined as to completeness and plausibility and after the eventual necessary correction by the treating physician, put into the database. In addition quality of data was checked for the necessity of reviewing the data on-site by the central documentation assistant who reported to the chair persons of the study. Two extramural reviews by independent researchers were performed. The reviewers were sent by the Working Group for Medical Oncology of the German Cancer Society and did not participate in the study themselves.

Sample size calculation
The sample size was calculated on the basis of overall survival and on the basis of the modified Brunner’s score. A difference of 2.5 points was considered a relevant difference in the modified Brunner’s score. Assuming a standard deviation of 6.0, {alpha} = 0.05 and power = 0.80, a minimum of 95 patients in each treatment arm was calculated to detect this difference. This patient number would be sufficient to detect a 15% difference in overall survival, which in the balance of toxicity/quality of life and survival time was considered clinically relevant in this high-risk metastatic breast cancer population.

Statistical methods
Survival time, response duration and TTP were estimated using the life-table method described by Kaplan and Meier [26]. The hypothesis of their equality in both treatment arms was tested using the log rank test. In case of equality, the modified Brunner’s score was the next primary endpoint. To judge its difference between the treatment arms, the Wilcoxon test was used; the level of significance was {alpha} = 0.05. Multivariate analysis of prognostic criteria for response was based on a logistic regression model, and for survival data Cox’s proportional hazard model was used. The variable selection method in both cases was backward elimination, and the significance level for removing a variable was set to 0.1.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Accrual
Between July 1992 and June 1997, 260 patients were randomized. Four patients never started treatment. Eighteen patients were not fully evaluable because of various protocol violations. They were, however, evaluable for toxicity and for the intention-to-treat analysis. Two hundred and thirty-eight patients were evaluated for response (Figure 2). Mean follow-up was 17.4 months (median 13.62 months, range 0.99– 73.68 months).



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Figure 2. Trial profile. Number of patients evaluated for efficacy was 119 in the FEC and 119 in the mitoxantrone treatment arm.

 
Patient characteristics
Table 1 lists patient characteristics by assigned treatment. The pretreatment characteristics were well balanced across the two arms of the study except for the estrogen receptor status, which was positive significantly more frequent in the FEC arm. If one considers the total receptor positivity (estrogen receptor + progesterone receptor, ER + PR), there was no significant difference between the two treatment groups. Nearly 50% of all patients had the prognostic category of ‘liver and other involvement’. In addition, ~20% had ‘liver involvement only’, summing up to 66.4% of liver involvement. More than 70% had more than one metastatic site involved, ~50% of the patients had a disease-free interval of <=18 months. These characteristics show that the study patients are indeed a high-risk population.


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Table 1. Patient characteristics
 
Tumor response
Table 2 shows the response rates. Although there was a trend in favor of FEC, there was no significant difference between the two treatment groups in either response rates, objective remission rates or CR rates. Median TTR, median TTBR and median RD were also not significantly different between the treatment groups (Figures 3, 4 and 5).


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Table 2. Response rates, objective remission rates, complete remission rates and confidence intervals
 


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Figure 3. TTR. Median time to response was 103 days in the FEC (thick line) and 87 days in the mitoxantrone (thin line) treatment arm (P = 0.6).

 


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Figure 4. TTBR. Median TTBR was 105 days in the FEC (thick line) and 115 days in the mitoxantrone (thin line) treatment arm (P = 0.8).

 


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Figure 5. RD. Median RD was 182 days in the FEC (thick line) and 225 days in the mitoxantrone (thin line) treatment arm (P = 0.3).

 
Time to progression
TTP by treatment arm is shown in Figure 6. There was no significant difference in median TTP between the two treatment groups.



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Figure 6. TTP. Median TTP was 6.15 months in the FEC (thick line) and 4.4 months in the mitoxantrone (thin line) treatment arm (P = 0.2).

 
Overall survival
Median survival of the patients enrolled was 15 months. The 3-year survival rate was <10%, showing that the selection for high-risk criteria using the flow sheet in Figure 1 was sucessful.

Overall survival by treatment arm is shown in Figure 7. There was no significant difference in median survival between the two treatment groups.



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Figure 7. Overall survival. Median survival was 15.8 months in the FEC (thick line) and 14.1 months in the mitoxantrone (thin line) treatment arm (P = 0.7).

 
Toxicity
Toxicity was graded according to the WHO guidelines [27]. Maximum grade of toxicity of each patient during her treatment was evaluated. Those with grade III and IV were compared between the two treatment groups (Table 3). A significant difference was seen for nausea, vomiting and for alopecia in favor of the mitoxantrone arm.


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Table 3. Patients with grade III/IV symptomsa
 
Gain from treatment
Two hundred and one patients were treated until progression or until they showed PD in the treatment-free interval. All of them returned the quality of life questionnaire. One hundred percent complete data for 110 patients were received to calculate the modified Brunner’s score. Ninety-one patients had single missing values but were nevertheless evaluable: during treatment, missing values in the WHO performance status were substituted as ‘last value carried forward’. Missing values in the patients’ subjective rating were substituted as 0 = don’t know. During the time without treatment, toxicity and subjective rating were counted as 0.

In addition, the entire population of 238 treated patients was evaluated using the time until the last documented treatment cycle, if treatment was stopped before progression occurred, or using the time until the last observation, if patients were still in remission.

Questionnaires to evaluate the single item scores were obtained from 116 patients in the FEC and from 111 patients in the mitoxantrone group.

The modified Brunner’s score by treatment group is shown in Table 4. The score for gain from treatment is positive (+1.37) using real TTP only and +1.69 using the entire population in the mitoxantrone arm, whereas the FEC arm shows no gain from treatment (–1.63 and –1.79, respectively) (P <0.001 in both populations). This significant difference is mainly a result of toxicity (significant difference for hair loss and nausea/vomiting) and due to a smaller difference in the worsening of the WHO performance status. This negative burden in the FEC group is not compensated for by the small but not significant difference in subjective rating by the patient, nor by the difference in average TTP. The higher score in the larger population (n = 238) is the result of a longer average TTP in this group (4.28 months for FEC and 4.14 months for mitoxantrone) since patients without progression were excluded from evaluation in the population using real TTP only.


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Table 4. Quality of life: modified Brunner’s score (MBS)
 
Treatment results of subgroups
The multivariate analysis of different subgroups showed prognostic relevance in relation to achieving response, objective remission, CR or longer overall survival (Table 5). Not surprisingly, age 46–50 years, hormone receptor positivity and WHO performance status 0 turned out to be favorable for overall survival. Also, the worse prognosis in patients with disease-free interval of <=18 months and with previous adjuvant treatment is well known. The extension of prognostic negativity exerted by axillary lymph node involvement (N3) or by initial grading from primary breast cancer diagnosis to the metastatic state is remarkable. Whereas in our first study [13], liver as a single site involved was not a significant prognostic factor, in this study it turned out to be unfavorable in terms of response and survival. Choice of treatment (single or combination chemotherapy) did not have an impact in this regression analysis. Treatment arm does not appear in Table 5, since in backward elimination it was eliminated very early, showing that it was neither relevant for odds ratio for response nor for hazards ratio for survival.


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Table 5. Treatment results of different patient subgroups (multivariate analysis)
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The results of this randomized phase III trial in patients with previously untreated high-risk metastatic breast cancer demonstrate that no significant difference was detected between single-agent mitoxantrone and combination chemotherapy FEC in terms of response rates, objective remission rates, CR rates, TTR, TTBR, RD, TTP and overall survival.

This is the first prospectively randomized study that compared single-agent treatment and combination chemotherapy in a selected high-risk metastatic breast cancer patients group. It is conceivable that if the trial was larger the observed differences would be statistically significant, since there was a trend in favour of FEC chemotherapy in response rates. However, one of the primary endpoints, survival, was not different. We want to point out that using a highly selected group with bad prognostic criteria (66.4% had liver involvement, 50% had liver and other involvement, >70% had more than one metastatic site involved, ~50% had a disease-free interval of <=18 months), the risk of imbalance of prognostic criteria in the treatment groups is less than in an unseletected population. Thus, one might conclude that in terms of avoiding bias the number of cases in this study would mean the same as in an unselected group that was double the size.

Current studies indicate that ‘FEC (50)’ may not be the strongest combination treatment choice for metastatic breast cancer, and that it is possible to achieve higher response rates and longer median survival time using a taxane. What we have determined now is that ‘standard FEC (50)’, as it was used in the 1990s and which is now called ‘low dose’, is not superior to single-agent mitoxantrone, whereas higher-dosed FEC or taxane combinations might be.

However, Del Mastro et al. [5] compared ‘standard CEF’ (cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2 and fluorouracil 600 mg/m2 administered every 21 days) with ‘accelerated-intensified CEF’ (cyclophosphamide 1000 mg/m2, epirubicin 80 mg/m2 and fluorouracil 600 mg/m2 administered every 14 days with the support of granulocyte colony-stimulating factor). The 80% increase in dose intensity did not improve the activity and the efficacy.

Others have shown higher response rates with combination chemotherapy [6, 19], but without prolonging the survival rate and without focusing on high-risk criteria. Older studies have in part shown benefit from combination chemotherapy for patients with liver metastases [2831]. There remain, however, questions as to trial size, treatment sequence and diagnostic facilities.

No benefit from combination chemotherapy compared with single-agent treatment was shown by a Finnish group [1]. However, by excluding patients with liver metastases they recruited lower risk patients when they compared weekly epirubicin with ‘FEC (60)’ and did not find a difference in median TTP or in median overall survival time. In Fossati et al.’s metaanalysis [19], 15 studies to compare polychemotherapy with single-agent treatment were evaluated. Response rate was higher in the polychemotherapy pooled data, but overall survival was equal. It was shown that single-agent treatment with anthracyclines gave longer overall survival than non-anthracycline single agents. Mitoxantrone, however, a substance with comparable efficacy to anthracyclines, had not been tested.

Recently, Costanza et al. [32] assessed whether the brief use of a phase II agent, regardless of its efficacy, was safe when followed by FAC standard treatment. Excluding high-risk patients, the results suggested a benefit for the FAC up front arm, but survival and response duration were not statistically different between the two study arms. The results of our study support their observation in part. At least, it can be concluded that it is safe to use a single agent in first-line treatment of high-risk metastatic breast cancer patients. This can eventually be a phase II drug, thus helping to accelerate the approval of good new drugs.

The results of this properly performed, long enough observed for survival analysis, and meticulously evaluated study indicate that in a prospectively stratified high-risk group, the influence of two quite differently acting regimens on survival, TTP, TTR, TTBR and RD is similar. In addition, the influence of the choice of treatment upon response, TTP and survival is much weaker than the influence of prognostic criteria being present before the beginning of treatment (Table 5).

Whether this will hold true also for taxane—or trastuzumab —regimens is one of the subjects of current studies.

Lück et al. [33] compared the combinations of epirubicin, paclitaxel (ET) and epirubicin/cyclophosphamide (EC) in the first-line treatment of metastatic breast cancer. The combination of ET was as active as EC, but was associated with a lower rate of primary progression.

Nabholtz et al. [34] found docetaxel significantly superior to mitomycin plus vinblastine (MV), a rather weak combination, in terms of response, TTP and survival in a heavily pretreated group. The MV group had the prognostic worse criterium of three or more sites of metastases overrepresented.

Chan et al. [35] reported a significantly higher rate of objective response in the docetaxel arm than in the doxorubicin arm in CMF-pretreated patients with similar overall survival.

Jassem et al. [36] reported that doxorubicin and paclitaxel (AT) conferred a significant advantage in response rate, TTP and overall survival compared with fluorouracil, doxorubicin and cyclophosphamide (FAC) in first-line chemotherapy for metastatic disease. They did not, however, mention how many patients had liver metastases in each group, which might obscure a selection bias. Also, the FAC group had a higher Eastern Cooperative Oncology Group (ECOG) score, meaning worse prognosis.

Initial paclitaxel 200 mg/m2 was compared with initial CMFP with epirubicin recommended as second-line therapy by Bishop et al. [37]. Patients who received paclitaxel survived significantly longer than those who received CMFP. In the paclitaxel group, however, fewer patients had received adjuvant chemotherapy, thus perhaps representing a prognostic better group.

The EORTC (Parideans et al. [38]) compared first-line paclitaxel (200 mg/m2) with first-line doxorubicin (75 mg/m2) with crossover in the case of progressive disease. First-line doxorubicin showed higher primary and secondary response rates, as well as higher TTP and higher median survival.

Whether these differences are really a result of different power of the chosen treatments or, as mentioned above, the consequence of imbalance in treatment groups, is yet to be determined. The same question will have to be investigated for the trastuzumab chemotherapy combinations (Slamon et al. [39]).

On the other hand, most studies, including the present one (although not significantly), show an increase in the rate of CR obtained with the toxicity-intensified treatment. Further efforts shoud be aimed at identifying patients who may benefit from intensified treatment by obtaining a high rate of CR. We hope to add information to this issue by gathering data from our former study, this study and the ongoing trial comparing mitoxantrone with mitoxantrone plus docetaxel.

Prognostic groups similar to these were defined by Greenberg et al. (number of organs involved, disease-free interval, performance status) [15], Zinser et al. (number of organs involved) [17], Falkson et al. (number of organs involved, age, previous adjuvant treatment) [14], Rahman et al. (number of organs involved, prior chemotherapy) [18] and Yamamoto et al. [16].

The slight imbalance of more estrogen-receptor positive patients in the FEC group is compensated partly by the distribution of the progesterone-receptor status, since the overall hormone receptor status was nearly equally distributed between the treatment groups. One might argue that it could favor the combination treatment arm at best. Therefore, it might contribute to the small but non-significant numeric differences in the various response parameters, but by no means does it favor the single treatment arm, so the results are valid in spite of this small imbalance.

The score to judge ‘gain from treatment’ was proposed by Brunner [20] as a means for the comparative evaluation of palliative treatments. Our group had applied this score in a prospectively randomized study to judge the balance between remission rates, survival and quality of life [13]. The advantage of this score is that it comprises subjective rating by the patient as to toxicity, as well as judgement of the treating physician as to performance status, and in addition a ‘hard’ criterium of benefit to be reproducibly assessed: the TTP. We modified the score by adding the patients’ rating of efficacy of treatment, which we estimate to be important in judging the benefit of treatment. In this study, all toxicity parameters recommended by the WHO [27] were assessed. A significant difference was seen only for nausea, vomiting and alopecia. Thus these parameters were taken to calculate the Brunner score that weights out toxicity from treatment (hair loss, vomiting, worsening of performance status) against benefit (months to progression, does treatment help?, ameliorating of performance status).

Using the score in this study, more gain from treatment was found in the mitoxantrone single treatment arm than in the combination treatment arm. This observation may help many patients to be saved from unnecessary toxicity. The dogma that patients with high-risk metastatic breast cancer, for example with liver metastases, have to be treated with combination chemotherapy may be questioned.

In conclusion, there is no strong evidence that patients with high-risk metastatic breast cancer draw benefit from first-line aggressive chemotherapy compared with single-agent active treatment using mitoxantrone, anthracycline or taxane. Therefore, this study is being continued to compare single-agent mitoxantrone with mitoxantrone plus docetaxel, emphasizing the assessment of quality of life and estimating gain from treatment by calculating the modified Brunner’s score. In this way, our present result, that patients with high-risk metastatic breast cancer (in the balance of palliation and toxicity) would gain more from single-agent mitoxantrone than from combination chemotherapy, might be put on an even more solid basis.


    Acknowledgements
 
The following individuals and their institutions also participated in this study: J. Albrecht (Schorndorf), H. Aydin (Giessen), R. C. Briel (Schwaebisch Gmuend), E. Friedrich (Heppenheim), K. Friese (Mannheim), M. Graubner (Schotten), W. Kaboth (Muenchen-Schwabing), E. Keller (Ingolstadt), C. Klinkenstein (Frankfurt/Oder), J. Meerheim (Goerlitz), H. Meissner (Weissenfels), U. Raeth (Heidelberg/Wiesbaden), K. Ridwelski (Magdeburg), J. Saal (Flensburg), W. Schneider (Baden/Swizerland), W. Wiest (Mainz), R. Mueck and J. Kaesberger (Stuttgart), H. Samonigg and E. Derstventschek (Graz, Austria), G. Ansorge (Hagen), B. Eggeling (Kassel), R. Waldmann (Tuebingen), and B. Hennemann (Regensburg). We thank Mrs Bernadette Frühling for excellent data monitoring and Mrs Claudia Wurster for writing the manuscript.


    Footnotes
 
+ Correspondence to: Professor E. Heidemann, Oncological Center of Stuttgart, Rosenbergstrasse 38, 70176 Stuttgart, Germany. Tel: +49-711-991-3500; Fax: +49-711-991-3590; E-mail: heidemann{at}diak-stuttgart.de Back


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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