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Japanese Journal of Clinical Oncology Pages 316-320

Treatment of Previously Treated Metastatic Breast Cancer by Mitoxantrone and 48-hour Continuous Infusion of High-dose 5-FU and Leucovorin (MFL): Low Palliative Benefit and High Treatment-related Toxicity
Introduction
Materials and Methods
Results
Discussion
References

Treatment of Previously Treated Metastatic Breast Cancer by Mitoxantrone and 48-hour Continuous Infusion of High-dose 5-FU and Leucovorin (MFL): Low Palliative Benefit and High Treatment-related Toxicity

Treatment of Previously Treated Metastatic Breast Cancer by Mitoxantrone and 48-hour Continuous Infusion of High-dose 5-FU and Leucovorin (MFL): Low Palliative Benefit and High Treatment-related Toxicity Chueh-Chuan Yen, Shiao-Lin Tung, Ruey-Kuen Hsieh, Tzeon-Jye Chiou, Jin-Hwang Liu, Wei-Shu Wang and Po-Min Chen

Section of Medical Oncology, Department of Medicine, Veterans General Hospital-Taipei, Taipei and National Yang Ming University School of Medicine, Taipei, Taiwan, ROC

For previously treated advanced breast cancer, there is no standard second-line therapy. Combination chemotherapy with mitoxantrone, high-dose 5-fluorouracil (5-FU) and leucovorin (MFL regimen) had been reported as an effective and well tolerated regimen.From October 1993 to November 1995, we treated 13 patients with previously chemotherapy-treated metastatic breast cancer by mitoxantrone, 12 mg/m2, on day 1 and continuous infusion of 5-FU, 3000 mg/m2, together with leucovorin, 300 mg/m2, for 48 h from day 1 to 2. Each course of chemotherapy was given every 4 weeks. Most of these patients had more than two metastatic sites, with lung metastasis predominant. Seven patients had been treated with anthracycline. Seven patients had previously received radiotherapy and seven had received hormone therapy. Median number of courses of MFL regimen given was six and the median cumulative dose of mitoxantrone was 68.35 mg/m2. One patient had complete response, seven had stable disease, none had partial response and five had progressive disease. The overall objective response rate was 7.6%. The median follow-up period was 14 months. Median survival was 16 months. Median progression-free survival was 5 months. A complete responder had relapse-free survival up to 17 months. Major toxicities were cardiotoxicity and leukopenia. Eight patients were dead in the last follow-up; two of them died of treatment-related toxicity. The MFL regimen achieves little palliative benefit and induces severe toxicity at a fairly high rate. Administration of this regimen to breast cancer patients who have been treated by chemotherapy and those with impaired heart function requires careful attention.

Key words: breast neoplasm - 5-fluorouracil - leucovorin - mitoxantrone

Introduction

Metastatic breast cancer remained an incurable disease with current treatment modality. However, systemic therapy can still provide effective palliation for many patients. For previously untreated patients, combination chemotherapy can produce a response rate in the range of 50-70%, but complete response can only be obtained in 10-20% of them (1 -3 ). For most patients, remission is not durable and it is difficult to show any survival benefit by chemotherapy (4 ). When relapse occurs, second- and third-line regimens produce less response with short duration. Currently, there is no standard salvage therapy for these patients.

Mitoxantrone is an anthracenedione. It is usually considered as a member of the anthracycline family. Mitoxantrone demonstrated considerable antitumor activity for breast cancer (5 ). Its major toxicity is myelosuppression, while nausea, vomiting, mucositis, alopecia and cardiotoxicity are significantly less evident than with other anthracyclines (6 ).

5-Fluorouracil (5-FU) is another active drug. Its activity can be enhanced by leucovorin (7 ). The combination of a conventional dose of 5-FU with leucovorin had been used in the treatment of advanced breast cancer, with reported response rates ranging from 14 to 45% (8 ,9 ).


Figure 1. Overall survival after MFL treatment.

In advanced colonic cancer, intermittent continuous infusion of high-dose 5-FU showed better anti-tumor activity than bolus injection of conventional dose. It also had low toxicity and almost no myelosuppression (10 ). We therefore tried to combine mitoxantrone, high-dose 5-FU and leucovorin (MFL) in treating advanced breast cancer. The potential benefit of this combination is that both mitoxantrone and 5-FU/leucovorin are active as second-line agents for metastatic breast cancer, there is no known mechanism of cross-resistance between them and they have different toxicity profiles. Here we report the results for 13 patients receiving this regimen.

Materials and Methods

From October 1993 to December 1995, 13 histologically proven breast cancer patients were enrolled in this study. Patients were eligible if they had progressive disease after either adjuvant chemotherapy or previous chemotherapy for metastatic disease, or both. Also, they had to have performance status 0, 1 or 2, a white cell count over 3000/mm3, a platelet count over 100 000/mm3 and adequate liver and renal function. The clinical characteristics of the patients are summarized in Table 1 . The median age was 55 years. The median number of metastatic sites was two. Dominant sites of involvement included lung (twelve patients), bone (seven patients) and liver, brain and lymph nodes (three patients in each site). Seven patients had previously received adjuvant chemotherapy only, two had received chemotherapy for metastatic disease only and four had received both. Nine patients had received only one regimen of chemotherapy before MFL, one had received two and three had received three kinds of regimens. Seven patients had been treated with an anthracycline-containing regimen, either doxorubicin or epirubicin or both. Seven patients had previously received radiotherapy either for primary site or for metastatic lesions. Also, seven patients had received hormone therapy. Hormone receptor status of the tumor was available only for six patients. Four of them had either estrogen or progesterone receptor positive and two of them had neither. Pre-MFL cardiac ejection fraction (EF) was available in nine patients with a median value of 50% for the left ventricle (LV) and 45% for the right ventricle (RV).

Mitoxantrone was given at a dose of 12 mg/m2 on day 1 by bolus intravenous injection. 5-FU, 3000 mg/m2, and leucovorin, 300 mg/m2, were given by continuous intravenous infusion for 48 h from day 1 to day 2. This regimen was given every 4 weeks. Treatment was continued until disease progression or severe toxicity. Definitions of measurability, response and toxicity were assessed according to WHO criteria. Patients were evaluated for response after two or three courses of treatment. Overall survival and progression-free survival were plotted by Kaplan-Meier methods.

Results

Of the 13 patients, one had complete response, none had partial response, seven had stable disease and five had progressive disease. The overall response rate was 7.6%. Patients received a median of six courses of MFL (ranging from 2 to 15 courses). The median cumulative dose of mitoxantrone was 68.35 mg/m2 (Table 2 ). The median follow-up period was 14 months (ranging from 3 to 26 months). Eight patients were dead in the last follow-up and the overall survival rate was 38.5%. Median overall survival was 16 months (Fig. 1 ) and median progression-free survival was 5 months (Fig. 2 ). The relapse-free survival of the complete responder was 17 months.

Table 1 Patients' characteristics
Median age (years) 55
Median pre-MFL cardiac ejection fraction LV/RV = 50%/45%
Clinical/pathological characteristics No. of patients
Hormone receptor status
ER or PR positive 4
Both negative 2
Unknown 7
Median No. of metastatic sites 2
Metastatic sites
Lung 12
Bone 7
Brain 3
Liver 3
Lymph node 3
Ovary 1
Peritoneum 1
Previous treatment
Adjuvant C/T only 7
Metastatic C/T only 2
Adjuvant and metastatic C/T 4
Anthracycline treatment 7
Radiation therapy 7
Hormone therapy 7
No. of previous chemotherapy regimens
One 9
Two 1
Three 3
MFL, mitoxantrone, 5-fluorouracil and leucovorin; LV, left ventricle; RV, right ventricle; ER, estrogen receptor; PR, progesterone receptor; C/T, chemotherapy.

Table 2 . Treatment results
Median Cu. dose of mitoxantrone 68.35 mg/m2
Median MFL courses 6
Complete responders 1
Partial responders 0
Patients with stable disease 7
Patients with progressive disease 5
Alive 5
Expired 8
Toxic death 2
Cu. dose: cumulative dose.

Seven patients had previously been treated with anthracycline, with a mean equivalent cumulative dose of doxorubicin up to 260 mg/m2. The median number of courses of MFL treatment was 5 (ranging from 2 to 10 courses) for these patients. Three of them and one who had not been treated with anthracycline developed grade III-IV cardiotoxicity (31%). One of them, who had previously received an equivalent cumulative dose of doxorubicin up to 400 mg/m2, died of severe congestive heart failure after ten courses of MFL.

Six patients had grade III-IV leukopenia (46%); one of them died of septic shock. Other side effects, such as diarrhea or mucositis, were generally equal to or less than grade II (Table 3 ).

Discussion

The combination chemotherapy of 5-fluorouracil, leucovorin and mitoxantrone for advanced breast cancer has been studied in several different trials. Different dose schedules were used in each study with variable response rate (Table 4 ). Hainsworth et al. (11 ) treated 35 previously treated breast cancer patients by bolus injection of 5-FU, 350 mg/m2, and leucovorin, 300 mg/m2, from day 1 to day 3, in combination with mitoxantrone, 12 mg/m2, on day 1. The course of treatment was repeated every 3 weeks. The overall response rate was 65% and the median response duration was 6 months. Myelosuppression was the main toxicity but was mild in most patients. Jones et al. (12 ) used mitoxantrone, 10 mg/m2, on day 1 and continuous infusion of high-dose 5-FU, 1000 mg/m2, and leucovorin, 100 mg/m2, for 24 h from day 1 to day 3 for 57 patients with advanced breast cancer who had received chemotherapy before. Patients received treatment every 3 weeks; 45% of these patients responded with a median duration of 6 months. Diarrhea and mucositis accounted for the majority of dose reduction. Wils (13 ) treated 27 advanced breast cancer patients with mitoxantrone, 14 mg/m2, on day 1, leucovorin, 300 mg/m2, on day 1 and day 15 and continuous infusion of high-dose 5-FU, 2000 mg/m2/day, for 24 h from day 1 to day 2 and from day 15 to day 16. Chemotherapy was given every 4 weeks. The overall response rate was 46%. For the previously untreated patient the response rate was 100% and for patients who had received chemotherapy before, the response rate was 33%. During therapy 52% of the patients had grade 3-4 leukopenia. The median duration of response was 13 months in previously untreated and 12 months in pretreated patients. The overall response rate in these three studies was ~49% and was ~38% for previously treated patients.


Figure 2. Progression-free survival after MFL treatment.

The response rate obtained in our study (7.6%) is much lower than those in other reports. The most probable reason may be the small sample size in our study. Another reason may be that most of our cases had multiple metastases with predominant visceral diseases, especially lung involvement (92%). In the studies of Hainsworth et al. (11 ) and Wils (13 ), most of the cases had non-visceral (bone and soft tissue) diseases (54 and 59%, respectively). In the study of Jones et al. (12 ), although detailed information about the metastatic sites of all patients was not shown, about half of the responders had predominant bone and lymph node metastases.

The majority of our patients had stable disease (53.8%) with median progression-free survival of 5 months. Although higher response rates have been reported in other studies, the response duration was brief. The overall survival duration in this study was 16 months, which was not significantly different from those in other reports (Table 4 ).

Seven patients had previously received anthracycline with equivalent cumulative doses of doxorubicin up to 260 mg/m2. The median cumulative dose of mitoxantrone they received was 60 mg/m2, which is equivalent to about 215 mg/m2 of doxorubicin. Hence the total equivalent doxorubicin dose is close to the upper limit of the cumulative dose of doxorubicin (450-500 mg/m2). Three of them developed grade III-IV cardiotoxicity, with one toxic death. One patient who had not received anthracycline before suffered from grade IV cardiotoxicity after receiving mitoxantrone with a cumulative dose up to 117 mg/m2. Her pre-MFL heart function was moderately decreased (LV/RV = 40%/38%).

Also, there were six patients (46%) with grade III-IV leukopenia of whom one died of sepsis. Myelosuppression was the major toxicity in the study of Hainsworth et al. (11 ), but it was generally mild. In the study by Wils (13 ), in which the dose intensity was the highest, 52% of the patients (14/27) had grade III-IV leukopenia during the course of treatment, which was similar to our result. However, in the study by Jones et al. (12 ), myelosuppression was not frequently seen.

In conclusion, the response rate of our MFL regimen was low in comparison with other studies, although the survival duration was similar. We also found that the MFL regimen induced severe toxicity at a fairly high rate and myelosuppression and cardiac toxicity were the predominant two. One should be very careful in using this regimen with breast cancer patients who have been treated by chemotherapy, especially with anthracycline, and those whose heart function was impaired.

Table 3 . Patients' characteristics and toxicity profile in all 13 patients, with toxicity graded according to WHO criteria
Case No. Age Adjuv
-ant C/T		 Meta
-static C/T		 Meta
-static sites		 DOX
Cu. dose (mg/m2)		 Pre-MFL
EF (LV/RV)		 MITOX
Cu. dose (mg/m2)		 Heart
failure		 Leuko-
penia		 Anemia Thrombo
cytopenia		 Nausea/
vomit		 Diarrhea Mucositis
1 71 Yes No Lung, bone None NA 23.5 0 III 0 0 I 0 0
2 50 Yes Yes Lung, LN, liver, brain 60 NA 78.47 0 I I 0 I 0 0
3 61 Yes No Lung None 59/46 68.35 II II I 0 0 I II
4 54 Yes Yes Lung, bone, brain 486 44/50 70.71 IV 0 0 0 0 0 0
5 53 Yes No Lung, LN None 40/38 117.36 IV III III III II II 0
6 55 Yes No Lung, liver, bone None 58/58 130.72 I IV II II 0 0 0
7 55 Yes No Lung, bone 360 58/50 60 III IV II 0 I 0 0
8 43 No Yes Lung, bone, brain 260 42/39 35.06 II 0 II 0 0 0 0
9 57 Yes No Lung None NA 102.27 II II I 0 0 0 0
10 55 No Yes Lung 180 57/41 24 0 II 0 0 0 0 0
11 46 Yes No Lung, bone, liver None NA 24 0 IV I 0 0 0 I
12 66 Yes Yes LN, lung 220 50/45 32.18 I III II 0 I IV 0
13 42 Yes Yes Ovary, perito-neum, bone 400 50/44 113.92 IV II II III 0 0 0
C/T, chemotherapy; LN, lymph nodes; DOX, doxorubicin; Cu. dose, cumulative dose; Pre-MFL, evaluated before MFL treatment; EF, ejection fraction of heart; LV, left ventricle; RV, right ventricle; NA, not available; MITOX, mitoxantrone.

Table 4 . Comparison with other studies
Study Predominant metastatic site 5-FU (mg/m2/day) Mitoxantrone (mg/m2/day) Interval (week) RR (%) RD (month) PFS (month) OS (month)
Hainsworth et al. (11) Non-visceral 300
D1-D3, bolus		 12, D1 3 65 6 NA NA
Jones et al. (12) Non-visceral* 1000
D1-D3, CIVI		 10, D1 3 45 6 NA 13*
Wils (13) Non-visceral 2000
D1-D2, D15-D16
CIVI		 14, D1 4 33 12 NA 14
Present study Lung 1500
D1-D2, CIVI		 12, D1 4 7.6 17 5 16
D, day; CIVI, continuous intravenous infusion; RR, response rate; RD, remission duration; PFS, progression-free survival; NA, not available; OS, overall survival.* Only for the responders.

References

1. Canellos GP, DeVita VT, Gold GL, Chabner BA, Schein PS, Young RC. Combination chemotherapy for advanced breast cancer: response and effect on survival. Ann Intern Med 1976;84:389-92. MEDLINE Abstract

2. Falkson G, Gelman RS, Tormey DC, Cummings FJ, Carbone PP, Falkson HC. The Eastern Cooperative Oncology Group experience with cyclophosphamide, adriamycin and 5-fluorouracil (CAF) in patients with metastatic breast cancer. Cancer 1985;56:219-24. MEDLINE Abstract

3. Tormy DC, Gelman RS, Band PR, Sears M, Rosenthal SN, DeWys W, et al. Comparison of induction chemotherapies for metastatic breast cancer. An Eastern Cooperative Oncology Group trial. Cancer 1982;50:1235-44.

4. Powles TJ, Smith IE, Ford HT, Coombes RC, Jones JM, Gazet JC. Failure of chemotherapy to prolong survival in a group of patients with metastatic breast cancer. Lancet 1980;1:580-2. MEDLINE Abstract

5. Yap HY, Blumenschein GR, Schell FC, Buzdar AU, Valdivieso M, Bodey GP. Dihydroxyanthracenedione: a promising new drug in the treatment of metastatic breast cancer. Ann Intern Med 1981;95:964-7.

6. Henderson IC, Allegra JC, Woodcock T, Wolff S, Bryan S, Cartwright K, et al. Randomized clinical trial comparing mitoxantrone and doxorubicin in previous treated patients with metastatic breast cancer. J Clin Oncol 1989;5:560-71.

7. Zaniboni A. The emerging role of 5-fluorouracil and leucovorin in the treatment of advanced breast cancer. J Chemother 1989;1:330-7. MEDLINE Abstract

8. Margolin KA, Doroshow JH, Akman SA, Leong LA, Morgan RT, Raschko JW. Effective initial therapy of advanced breast cancer with fluorouracil and high dose, continuous infusion calcium leucovorin. J Clin Oncol 1992;10:1278-83. MEDLINE Abstract

9. Swain SM, Lippman ME, Egan EF, Drake JC, Steinberg SM, Allegra CJ. Fluorouracil and high dose leuocovorin in previously treated patients with metastatic breast cancer. J Clin Oncol 1989;7:890-9. MEDLINE Abstract

10. Wils JA. High dose fluorouracil: a new perspective in the treatment of colorectal cancer. Sem Oncol 1992;19(Suppl. 3):126-30. MEDLINE Abstract

11. Hainsworth JD, Andrews MB, Johnson DH, Greco FA. Mitoxantrone, fluorouracil and high dose leucovorin: an effective, well tolerated regimen for metastatic breast cancer. J Clin Oncol 1991;9:1731-5. MEDLINE Abstract

12. Jones SE, Mennel RG, Brooks B, Westrick MA, Allison MA, Paulson RS, et al. Phase II study of mitoxantrone, leucovorin and infusional fluorouracil for treatment of metastatic breast cancer. J Clin Oncol 1991;10:1736-9.

13. Wils JA. Mitoxantrone, leucovorin and high dose infusional 5-fluorouracil: an effective and well tolerated regimen for the treatment of advanced breast cancer. Eur J Cancer 1993;29A:2106-8. MEDLINE Abstract

Received April 14, 1997; accepted June 20, 1997
For reprints and all correspondence: Ruey-Kuen Hsieh, Section of Medical Oncology, Department of Medicine, Veterans General Hospital-Taipei, No. 201, Section 2, Shih-Pai Road, Taipei, Taiwan
Abbreviations: MFL, mitoxantrone, 5-fluorouracil and leucovorin; 5-FU, 5-fluorouracil; EF, ejection fraction of heart; LV, left ventricle; RV, right ventricle

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