Radiotherapy and Oncology, 7 (1986) 133-139 Elsevier 13 3

RTO 00257

Weekly-dose doxorubicin (WDA) in advanced breast cancer

Helgi Sigurdsson 1, Ingrid Johansson-Ter je 1, K n u t Aspegren 2, Tors ten L a n d b e r g 3, Tors ten Ander s son 1, Stig Borgs t r6m 3 and A n n - M a r i e Thel in 3

Departments of l Ontology/Radiotherapy, University Hospital, Lund, S-22185 Lund, and Departments of 2Surgery and 30neology~Radiotherapy, University Hospital, Malm6, Sweden

(Received 26 August 1985, revision received 20 May 1986, accepted 26 May 1986)

Key words: Breast cancer; Doxorubicin (adriamycin); Weekly-dose doxorubicin (adriamycin) (WDA)

Summary

Doxorubicin in a weekly fixed dose of 20 mg as i.v. bolus (WDA) was given to 48 patients with mostly pretreated progressing breast cancer. The response rate ( C R + PR) was 9/48 (19%), and a further 16 (33%) of the patients achieved stable disease. Myelosuppression was mild and without clinical significance. Other side effects, particularly nausea, vomiting and hair loss were also relatively mild. Cardiac toxicity, however, was seen in six patients. Five of these six patients were previously treated with mitoxantrone [3] or combi- nation chemotherapy containing doxorubicin [2]. Median response duration was 10 + months for responders and 11 + months in patients who had stable disease. It is concluded that weekly-dose doxorubicin has a favourable profile with a low frequency of side effects and that this treatment is an alternative to other cancer chemotherapy in breast cancer, especially when not only CR and PR but even stabilization of disease is considered of benefit to the patient.

Introduction

Doxorubicin (adriamycin) is one of the most effec- tive cytotoxic drugs available in the treatment of metastatic breast cancer [21,26,34]. Doxorubicin is equally effective in achieving an objective response (CR-PR), compared with many combination chem- otherapy regimens [19,23,31], but the response dur- ation tends to be shorter [6,23,27,31].

Dose-response relationships have been demon- strated in malignant cells exposed to doxorubicin in tissue cultures. Cell death was related to both the drug concentration and the time of exposure

[15,20]. It has also been shown that this relationship existed to a threshold limit [3]. A dose-response relationship for doxorubicin was demonstrated in breast cancer patients with an initial dose of 25-30 mg/m z, 3 times a month, and then escalating the dose by 5 mg/m 2 every month [26]. Surprisingly this was not true, according to the study of O'Bryan, comparing 75 mg/m 2, 60 mg/m 2 and 45 mg/m 2, given every 3 weeks in good risk patients but on the other hand, a dose-response relationship existed in poor risk patients comparing 50 mg/m z with 25 mg/m 2 given every 3 weeks [9]. An upper saturation limit in dose relationship, 45 mg/m 2, was shown to

0167-8140/86/$03.50 �9 1986 Elsevier Science Publishers B.V. (Biomedical Division)

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exist in both patients with solid tumours as well as leukaemia [8]. Both the dose and the dose interval is of importance when doxorubicin is used in com- bination chemotherapy in breast cancer [39].

The standard dose schedule of doxorubicin (SDA) is 60-75 mg/m 2 every 3 weeks, but the op- timal dosage has not yet been determined, and other schedules have been reported with lower dos- age but shorter dose intervals [7,11,13,44].

Weekly-dose doxorubicin has been used in the treatment of breast cancer and various other malig- nancies and the treatment has a favourable profile with a low frequency of side effects [11- 14,19,32,36,41,42].

Material and methods

The present phase II report is based on a retro- spective study of 48 patients with advanced, pro- gressive breast cancer treated at the Departments of Oncology/Radiotherapy, University Hospitals in Lund and Maim6 1982-1984 with a weekly fixed dose of 20 mg doxorubicin.

The characteristics of the 48 patients are given in Table I. Seventeen patients were younger than 55 years at the start of present therapy and eight of these were still premenopausal. Four patients had an unusually long disease-free interval (DFI) and that explains the difference in mean and median DFI. Although many patients had bone metastases as dominant site and a few had pleural metastases, all patients had measurable disease at some site. Eleven patients had received adjuvant chemother- apy and 12 adjuvant endocrine therapy and this is included in previous systemic therapy. When start- ing WDA, 42 of the 48 patients had been treated before with either systemic endocrine therapy only (n = 15) or chemotherapy only (n = 7) or both (n = 20). WDA was given as 1st line systemic chem- otherapy in 21 [44%] patients, and as 2nd to 4th line in 27 [56%]. Nineteen of the 27 patients pre- viously treated with systemic chemotherapy had been treated with either mitoxantrone [7], intermit- tent doses of doxorubicin in combination chemoth- erapy [11] or with both [1]. All patients had pro-

gressive disease when starting WDA. Two had pre- viously responded to doxorubicin treatment. All patients treated with WDA in both hospitals are included and none received any other systemic ther- apy, at the same time, during the study period.

The WDA treatment consisted of 20 mg doxo- rubicin as fixed dose given i.v. with concomitant saline infusion over 3-10 min at weekly intervals. Hereafter, when stating the total amount of doxo- rubicin given, any previously given doxorubicin is included. Previous treatment with mitoxantrone is disregarded. Criteria of response are those defined by WHO [45]. Duration of response and of stable disease are calculated in months from start of WDA treatment.

Results

The results and side effects are summarized in Tables II, III and IV. There were nine responders (CR = 4 and PR = 5, 9/48 = 19%, 95% exact confidence interval being 8.95-32.63%). Of the re- sponders, 2 had soft tissue as dominant site, 3 had bone and 4 had viscera as dominant site. The in- terval to remission was 1-19 months (median = 3 and mean = 7 months). Three of the nine respond-

TABLE I

WDA treatment in advanced breast cancer. Patients character- istics.

Number of patients 48 Median age (range) 58 (33-82) Menopausal status

Pre- 8 Post- 40

Median Karnofsky index (range) 80 (20-100) Median disease-free interval (mean) 23 (41) Dominant site of metastases (%)

Soft tissue 12 (25) Bone 19 (40) Visceral 17 (35)

Previous endocrine therapy (%) 35 (73) Previous chemotherapy (%) 27 (56)

VAC 12 Mitoxantrone 8 Other 18

No previous systemic therapy (%) 6 (13)

TABLE II

Results of WDA treatment.

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CR + PR SD PD

Number of patients (%) Median Karnofsky index Median disease-free interval (mean) Previous endocrine therapy (%) Previous chemotherapy (%)

VAC or mitoxantrone (%) No previous systemic therapy Median interval (months) to remission (range) Median duration (months) of response (range) Median survival in months (range) Mean accumulated dose (mg/m z) of doxorubicin

9 (19) 16 (33) 23 (48) 80 80 70 16 (84) 28 (44) 13 (22) 6 (17) 14 (40) 15 (43) 6 (22) 9 (33) 12 (45) 3 (16) 6 (32) 10 (52) 1 1 4 3 (1-19)

10 (7-27+) 11 (4-28+) 13 (7-27+) 18 (6-29+) 7 (1-12+)

600 510 240

ing patients had a long DFI between initial surgery and first relapse (111,220 and 348 months) and in these cases the time to response was long (19, 6 and 18 months). Four patients are still in remission, 2 have progressed after being in remission for 8 res- pective 9 months. Three stopped treatment in re- mission because of side effects (cardiomyopathy 2 and photo-allergy 1).

SD was seen in 16 patients (16/48 = 33%, 95% exact confidence interval: 20.40-48.41%). Three of the patients still have SD after 9-28 months, whereas 9 have progressed after 5-19 months. Four patients stopped treatment due to cardiomyopathy. A continuous progression of disease (PD) was seen

in 23 of the 48 patients (48, 95% exact confidence interval = 33.29-62.81%).

Before start of WDA treatment, 43 of the patients had WBC more than 3 x 109/1 and pla- telets counts more than 100 x 109/1. During treat- ment the values usually decreased, with the lowest (mean) nadir values of 68% of the initial ones and this occurred after (mean) 12 cycles for WBC and (mean) 19 cycles for platelets. Interruption of the treatment, dose reduction or cycle interval length- ening due to toxicity was unusual and minor ad- justments were required in only 6 of the 48 patients. The patients received totally, during treatment period, (mean) more than 95% of planned dosage.

TABLE III

Side effects of WDA and comparison with pooled reports on standard dose doxorubicin (SDA). a

WDA (%) SDA (%)

Nausea and vomiting 8 20-50 GI side effects (stomatitis, gastritis, diarrhoea) 17 I0 Myelosuppression 17 23-67 (WBC < 2 • 109/1, Platelets < 75 x 109/1) Alopecia 40 70-100 Cardiotoxicity 13 2 Allergy 4 4

a Benjamin et al. [4], Blum et al. [6], Gottlieb et al. [18], Hoogstraten et al. [23], O'Bryan et al. [9], Fredriksen et al. [17].

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TABLE IV

Doxorubicin in progressing breast cancer as single drug chemotherapy.

Author Prior Dose mg/m2/ No. of Response Response chemotherapy interval (wks) patients rate (CR+ PR) % duration (mths)

Ahmann [ll no 60/3-4 20 50 8 Hoogstraten [231 no 60/3 79 39 4 Nemoto [31] no 75/3 32 38 7 Gottlieb [18] yes 60-75/3 40 38 7 Fredriksen [17] yes 70/3 30 30 3 Ingle [25] yes 60/4 19 21 8 Knight [28] yes 70/3-5 36 44 5 Panutti [33] yes 80/3 20 50 5 Legha [29] yes 60/3 a 27 48 7 Creech [14] yes 20/b 60 27 7 Cort6s Funes [12] yes 10-12/1-2 17 47 6 Gundersen [19] 18/62 20/1 r 62 31 11 (CR)

5 (PR) Present study 27/48 20/1 ~ 48 19 10

a Continuous infusion over 48-96 h. b Treatment days 1 and 8 every 4 weeks. c Fixed dose.

Special cardiac investigations such as ECG, gat- ed cardiac scintigraphy or phonography were usu- ally carried out only when clinically indicated, but some patients had also such examinations at fixed intervals, after the accumulated dose of doxorubi- cin had reached 550 mg/m 2. There were six instan- ces of doxorubicin-induced cardiotoxicity, thereof one fatal. Five of the 6 were previously treated with either mitoxantrone (3) or combination chemoth- erapy containing doxorubicin (2). Five of these 6 had their breast cancer on the left side, and 4 had received radiotherapy towards the internal mam- mary nodes (20-30 Gy to the anterior parts of the myocardium [24]).

Discussion

The response in the present series is only 19% (9/48), which is low compared to previous reports on single SDA treatment and WDA in breast can- cer (Table IV). It is usually stated that doxorubicin has less effect in patients who are previously treated

with chemotherapy [27]. In the present series there were no obvious such differences and only 14% (3/21) responded when WDA was given as 1st line chemotherapy, 15 of these had previously received endocrine systemic treatment. Surprisingly 19 patients, who had previously received either mitox- antrone or combination chemotherapy containing doxorubicin, had approximately the same response rate 16% (3/19) as compared to other patients.

The response duration tends to be short for SDA (Table IV), and it is of interest that the response duration in the present series is much longer, though of course patient selection may be an expla- nation. Nineteen had bone metastases as dominant metastatic site, and some of these had a long dur- ation of response (mean -- 14+ months) and SD (mean -- 11 + months). Some of the patients had a slowly growing tumour, reflected by a long DFI and often long interval to remission. These patients tended to respond better than patients with DFI shorter than one year. The same has been stated before [40]. Although doxorubicin is most active in the S-phase of the cell cycle, cells in other parts of

the cycle are vulnerable, too, and even cells in G1 phase [2]. Doxorubicin is thus potentially active against slowly growing tumours, which may con- tain a large fraction of non-dividing cells [3,35].

Many of the side effects such as nausea, vomiting, myelosuppression and cardiotoxicity are directly related to the peak plasma concentration of doxo- rubicin [4,29,32,41]. Peak plasma concentration can be lowered by repeated dose schedules [16] and also by continuous infusion chemotherapy [16,28,46]. The side effects, in the present series, were usually less compared to SDA (Table III). Only 19 patients (40%) needed a wig and in 12 of these it was prob- ably due to previous therapy and hair loss thus seems also to be related to peak drug concentration. Gastrointestinal side effects such as stomatitis, gas- tritis and diarrhoea were more frequent than pre- viously reported for SDA but this has also been noticed previously for WDA and continuous infu- sion chemotherapy [11,29]. Cardiac toxicity seems not only related to accumulated dose [22,41] but also to peak drug concentration [22,29,32,41]. When WDA of 20 mg/m 2 were compared to SDA, about 150-200 mg/m z more of doxorubicin could be given before the same endomyocardial damage was seen [22,41]. In the present series, six patients developed cardiotoxicity. Four of them had pre- viously received irradiation to the ventral parts of the myocardium (20-30 Gy). Radiation to the me- diastinum increases the risk of developing doxorub- icin cardiomyopathy [5,10,30,41], and 30 Gy is es- timated to correspond in this respect to 80 mg/m z of doxorubicin [41]. Five of the 6 were previously treated with either mitoxantrone (3 patients, 55-, 100- and 175 mg/m z) or combination chemothera- py containing doxorubicin (2 patients, 190- and 395 mg/m2). The accumulated dose of doxorubicin was more than 750 mg/m z in 5 patients and the sixth had received 200 mg/m z doxorubicin and 100 mg/m 2 mitoxantrone.

The experiments by Skipper et al. showing that the effect of cytotoxic drugs follows first order ki- netics was based on the rodent leukaemia 1210 model, where cell cycle is short, and 100% of the cells are in the active phase of the cell cycle [37]. These experiments have been considered a corner-

137

stone of combination chemotherapy, and the aim was to impart a maximal anti-tumour effect with tolerable toxicity. Combination chemotherapy has later on be found to be of great value in the treat- ment of various malignancies that usually have in common a high percentage of cells in the active phase of the cell cycle, but advanced breast cancer rarely fulfills these criteria [21,38]. Single drug dox- orubicin is as effective as some combination chem- otherapy regimens in inducing response [23,31] and toxicity is similar, but the duration tends to be less.

An alternative to more aggressive treatment of metastatic breast cancer is to focus on less toxic regimens and new 'less toxic dose schedules aiming at maintaining the patient with as small tumour burden as possible as long as possible and to treat with as little toxicity as possible, without hampering the therapeutic ratio. WDA is one such an alter- native and patients with slowly growing tumours can probably benefit from this only moderately tox- ic treatment. Treatment response can be reflected in tumour stabilization and interval to remission can be some months. Cardiomyopathy is a risk at doses over 750 mg/m 2, at least in patients pre- viously treated with mitoxantrone or combination chemotherapy containing doxorubicin and these are at high risk of developing cardiomyopathy. WDA should not be considered to be a low dose treatment. Dose modifications are common with SDA and in one series the patients could only re- ceive 62% of the planned dose [41]. In the present series, only six patients had minor dose adjustments and the patients received more than 95% of planned dose and over time the accumulated dose of WDA approximates that of SDA.

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