Weekly-dose doxorubicin (WDA) in advanced breast cancer

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

13 3

RTO 00257

Weekly-dose doxorubicin (WDA) in advanced breast cancer Helgi Sigurdsson 1, Ingrid J o h a n s s o n - T e r j e 1, K n u t A s p e g r e n 2, T o r s t e n L a n d b e r g 3, T o r s t e n A n d e r s s o n 1, Stig B o r g s t r 6 m 3 a n d A n n - M a r i e Thelin 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-dosedoxorubicin (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 combination 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 effective 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 chemotherapy regimens [19,23,31], but the response duration tends to be shorter [6,23,27,31]. Dose-response relationships have been demonstrated 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 SciencePublishers B.V. (BiomedicalDivision)

134 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 combination chemotherapy in breast cancer [39]. The standard dose schedule of doxorubicin (SDA) is 60-75 mg/m 2 every 3 weeks, but the optimal dosage has not yet been determined, and other schedules have been reported with lower dosage but shorter dose intervals [7,11,13,44]. Weekly-dose doxorubicin has been used in the treatment of breast cancer and various other malignancies and the treatment has a favourable profile with a low frequency of side effects [1114,19,32,36,41,42].

gressive disease when starting WDA. Two had previously responded to doxorubicin treatment. All patients treated with WDA in both hospitals are included and none received any other systemic therapy, at the same time, during the study period. The WDA treatment consisted of 20 mg doxorubicin as fixed dose given i.v. with concomitant saline infusion over 3-10 min at weekly intervals. Hereafter, when stating the total amount of doxorubicin 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.

Material and methods

Results

The present phase II report is based on a retrospective study of 48 patients with advanced, progressive 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 chemotherapy and 12 adjuvant endocrine therapy and this is included in previous systemic therapy. When starting 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 chemotherapy in 21 [44%] patients, and as 2nd to 4th line in 27 [56%]. Nineteen of the 27 patients previously treated with systemic chemotherapy had been treated with either mitoxantrone [7], intermittent doses of doxorubicin in combination chemotherapy [11] or with both [1]. All patients had pro-

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 responders, 2 had soft tissue as dominant site, 3 had bone and 4 had viscera as dominant site. The interval to remission was 1-19 months (median = 3 and mean = 7 months). Three of the nine respondTABLE I WDA treatment in advanced breast cancer. Patients characteristics. Number of patients Median age (range) Menopausal status PrePostMedian Karnofsky index (range) Median disease-free interval (mean) Dominant site of metastases (%) Soft tissue Bone Visceral Previous endocrine therapy (%) Previous chemotherapy (%) VAC Mitoxantrone Other No previous systemic therapy (%)

48 58 (33-82) 8 40 80 (20-100) 23 (41) 12 (25) 19 (40) 17 (35) 35 (73) 27 (56) 12 8 18 6 (13)

135 TABLE II Results of WDA treatment. CR + PR 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

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 respective 9 months. Three stopped treatment in remission 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

9 80 16 6 6 3

SD

(19)

16 (33) 80 28 (44) 14 (40) 9 (33) 6 (32)

(84) (17) (22) (16)

1

PD 23 (48) 70 13 (22) 15 (43) 12 (45) 10 (52)

1

3 (1-19) 10 (7-27+) 13 (7-27+) 600

11 (4-28+) 18 (6-29+) 510

4

7 (1-12+) 240

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 platelets counts more than 100 x 109/1. During treatment 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 lengthening due to toxicity was unusual and minor adjustments 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

Nausea and vomiting GI side effects (stomatitis, gastritis, diarrhoea) Myelosuppression (WBC < 2 • 109/1, Platelets < 75 x 109/1) Alopecia Cardiotoxicity Allergy

WDA (%)

SDA (%)

8 17 17

20-50 I0 23-67

40 13 4

70-100 2 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].

136 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 Hoogstraten [231 Nemoto [31] Gottlieb [18] Fredriksen [17] Ingle [25] Knight [28]

no no no yes yes yes yes

60/3-4 60/3 75/3 60-75/3 70/3 60/4 70/3-5

20 79 32 40 30 19 36

50 39 38 38 30 21 44

Panutti [33] Legha [29] Creech [14] Cort6s Funes [12] Gundersen [19]

yes yes yes yes 18/62

80/3 60/3a 20/b 10-12/1-2 20/1r

20 27 60 17 62

50 48 27 47 31

Present study

27/48

20/1~

48

19

8 4 7 7 3 8 5

5 7 7 6 11 (CR) 5 (PR) 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, gated cardiac scintigraphy or phonography were usually carried out only when clinically indicated, but some patients had also such examinations at fixed intervals, after the accumulated dose of doxorubicin had reached 550 mg/m 2. There were six instances of doxorubicin-induced cardiotoxicity, thereof one fatal. Five of the 6 were previously treated with either mitoxantrone (3) or combination chemotherapy containing doxorubicin (2). Five of these 6 had their breast cancer on the left side, and 4 had received radiotherapy towards the internal mammary 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 W D A in breast cancer (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 W D A was given as 1st line chemotherapy, 15 of these had previously received endocrine systemic treatment. Surprisingly 19 patients, who had previously received either mitoxantrone 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 explanation. Nineteen had bone metastases as dominant metastatic site, and some of these had a long duration of response (mean -- 14+ months) and SD (mean -- 11 + months). Some of the patients had a slowly growing tumour, reflected by a long D F I and often long interval to remission. These patients tended to respond better than patients with D F I 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 o f

137 the cycle are vulnerable, too, and even cells in G1 phase [2]. Doxorubicin is thus potentially active against slowly growing tumours, which may contain 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 doxorubicin [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 probably due to previous therapy and hair loss thus seems also to be related to peak drug concentration. Gastrointestinal side effects such as stomatitis, gastritis and diarrhoea were more frequent than previously reported for SDA but this has also been noticed previously for W D A and continuous infusion 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 W D A 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 previously received irradiation to the ventral parts of the myocardium (20-30 Gy). Radiation to the mediastinum increases the risk of developing doxorubicin cardiomyopathy [5,10,30,41], and 30 Gy is estimated 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 chemotherapy 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 kinetics 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-

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 treatment 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 doxorubicin is as effective as some combination chemotherapy 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. W D A is one such an alternative and patients with slowly growing tumours can probably benefit from this only moderately toxic 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 previously treated with mitoxantrone or combination chemotherapy containing doxorubicin and these are at high risk of developing cardiomyopathy. W D A should not be considered to be a low dose treatment. Dose modifications are c o m m o n with SDA and in one series the patients could only receive 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 W D A approximates that of SDA.

References

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