J Cancer Res Clin Oncol (1990) 116:13 14
C~ilcer ~esearch Clinical 9 @ Springer-Verlag 1990
Rapid communication Anthracycline-carboplatin combination in metastatic breast cancer B. Thiirlimann, H . J . Senn, and W.F. Jungi Department of Internal Medicine, Division Oncology-Haematology, Kantonsspital, CH-9007 St Gallen, Switzerland
Summary. In a pilot study a carboplatinum, 250 mg/ m 2 i.v., and 4-epidoxirubicin, 90 mg/m 2 i.v. or mitoxantrone, 10 mg/m 2 i.v., combination chemotherapy regimen was studied in a group of breast cancer patients with high-risk metastatic disease. All 11 patients had liver and/or lung metastases. Of the 11 patients, 9 had progressive disease and in 2 patients the disease had stabilised. The toxicity of both anthracycline-containing regimes was similar. Subjective toxicity was mild, but hematological toxicity was inacceptable. The tested carboplatinum-anthracycline combination regimes given in the administered doses are not useful in the treatment of metastatic breast cancer, mainly because of toxicity.
With the intention of decreasing the high rate of subjective toxicity (nausea, vomiting, alopecia, stomatitis and diarrhoea) of doxorubicin-cisplatinum based chemotherapy, we tested in potentially less toxic combination of carboplatinum and 4-epidoxorubicin or mitoxantrone in a pilot study at a single institution, mainly to determine the feasibility of the treatment regimens.
Key words: Metastatic breast cancer 4-Epidoxirubicin
Table I. Patient characteristics"
Carboplatinum
- Mitoxantrone
Introduction
Platinum-based regimens in the treatment of metastatic breast cancer have been used with partially promising results (Kolaric et al. 1984). The reported high response rate in visceral disease and the high complete response rate of the cyclophosphamidedoxorubicin-cisplatin combination is of special interest, but toxicity was considerable. Moderate to severe nausea and vomiting were almost universal and approached clinical intolerability (Creagan et al. 1984): 83%-91% of all patients developed alopecia; haematotoxicity was pronounced, particularly anaemia 39% (Kolaric et al. 1984) and there was leucopenia with a median leucocyte nadir of 1.8 x 109/1. Treatment delay and dose reduction were frequently necessary. Stomatitis and diarrhoea were less common (Creagan et al. 1984). Offprint requests to." H.J. Senn
Patients and methods A group of 11 with high-risk metastatic disease according to SAKKcriteria were entered in the protocol. All patients had multiple liver and/or lung metastases. Of the 11 patients, 9 had multiple organ in-
Characteristic
No. patients
Site of disease Liver Lung Pleura Bone Lymph node Subcutaneous/skin Pericardium
9 3 4 5 6 3 1
Prior treatment None Hormonotherapy + local radiotherapy Chemotherapy _+hormonotherapy
4 3 4
Prior chemotherapy Chlorambncil, methotrexate, 5-fluorouracil (LMF) Doxifluridin p.o. I. LMF II. Vincristine, Adriamycin, cyclophosphamide III. Mitomycin C, etoposide I. Adriamycin, cyclophosphamide II. Mitomycin C, etoposide None
1 1 1
1 7
Total number of p a t i e n t s = l l ; mean age 58 years (range 47-73 years)
14 volvement (up to five organs); their mean age was 58 years (range 47 73 years). Seven of the patients had no prior exposure to any chemotherapy and 2 patients had received only one treatment for their disease but without inclusion of anthracyclines or platinum compounds (oral doxifluridine in one case and chlorambucil-methotrexate-5-fluorouracil in one case). Patients with a SAKK-ECOG performance status of 3 and 4, an abnormal hemogram and creatinine clearance < 50 ml were not eligible. In a protocol addendum patients with severe liver disfunction (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase > 3 x normal) were also excluded from the protocol. Patient characteristics can be seen in Table 1. The treatment regimen consisted of carboplatinum, 250 mg/m 2 i.v., and 4-epidoxorubicin, 90 mg/m z i.v. (6 patients), or mitoxantrone, 10 mg/m 2 i.v. (5 patients). Medication was given in short consecutive infusions over 15 min and was repeated every 4-5 weeks, mostly on an out-patient basis. Response and toxicity were evaluated according to S A K K / W H O criteria.
Results
Of the 11 patients, 9 had progressive disease after at least two cycles of study chemotherapy. Two patients had stable disease for several months (still on treatment). Subjective and objective toxicity were similar for both anthracyclines. Dose-limiting toxicity was granulocytopenia in most patients and thrombocytopenia in one patient. All patients needed dose reduction of both drugs because of haematological toxicity. Even after a dose reduction of 30%-60% the haematological toxicity was severe. 4-Epidoxorubicin was stopped in i patient with an episode of tachycardia and palpitations after the second chemotherapy application. Carboplatinum was stopped in 1 patient after five cycles because of a continuously falling platelet nadir. Three patients needed red blood cell transfusions because of haemoglobin values below 85 g/1 and symptomatic anaemia. The mean white blood cell nadir was 1.3 x 109/1 (range 0.4x 109~.4x 109/1) and the mean platelet nadir was 85 x 109/1 (range 5 x 109-207 x 109/1). Details of haematological toxicity can be seen in Table 2. Subjective toxicity was minimal. Mild to moderate nausea and short episodes of vomiting in some paTable 2. Haematological toxicity Parameter
White blood cell count b Granulocyte count Platelet count ~ Hb
No. patients evaluable a
tients could easily be controlled with conventional doses of oral metoclopramide. Using cold caps during chemotherapy administration, prevented any of the patients developing alopecia.
Discussion
The results of this pilot study show that the haematological toxicity of the above-mentioned anthracyclinecarboplatinum regimen, using the present dosing schedule, is not acceptable. All patients needed dose reduction and several patients had to be prematurely readmitted to the hospital because of infectious complications requiring maximal supportive care. No toxic death occurred and all patients fully recovered from toxicity. In two patients, administration of one drug had to be stopped because of cardiac toxicity or thrombocytopenia respectively. Subjective toxicity was moderate. It is not possible to compare easily the efficacy of these anthracycline-carboplatinum chemotherapy regimens with the results of most other cisplatinumdoxorubicin-based combinations. In our study all patients had high-risk disease (mostly including advanced liver metastasis) with a poor chance of response and a poor survival rate. None of the 9 patients with progressive disease responded to any further treatment. Additionally, 2 patients who received radiation had progressive disease in the radiated area during continuing subsequent radiotherapy. Anthracycline-carboplatinum combination chemotherapy, using the above-mentioned regimen, is not an adequate treatment in metastatic breast cancer patients with high-risk disease, mainly because of severe haematological toxicity. The promising results in terms of response achieved by using doxorubicin-cisplatinum combinations, as reported in the literature, could not be confirmed in this pilot study and for these particular patients. Haematological toxicity might be reduced and might not become dose-limiting if such a chemotherapy regimen is combined with haematopoietic growth factors.
Grade 0
1
2
3
4
9
1
0
0
4
4
9
l
0
0
2
6
10 11
3 8
3 1
1 2
0 0
3 0
a Total no. patients = 11 b Mean white blood cell nadir = 1.3 x 109/i; range (0.4-4.4) x 109/1 c Mean platelet nadir= 85 x 109/1; range (5-297)x 109/1
References Kolaric K, Roth A, Vukas D, Cervek J (1984) CAP versus CMFVP combination chemotherapy in untreated metastatic breast cancer. Cancer Chemother Pharmacol 13:142-144 Creagan ET, Green SJ, Ahmann DL, Ingle JN, Edmonson JH, Marschke RF Jr. (1984) A phase III clinical trial comparing the combination cyclophosphamide/Adriamycin/cisplatin with cyclophosphamide/5-fluorouracil/prednisone in patients with advanced breast cancer. J Clin Oncol 11, 1260-1265 Received 12 July 1989/Accepted 16 October 1989
C~ilcer ~esearch Clinical 9 @ Springer-Verlag 1990
Rapid communication Anthracycline-carboplatin combination in metastatic breast cancer B. Thiirlimann, H . J . Senn, and W.F. Jungi Department of Internal Medicine, Division Oncology-Haematology, Kantonsspital, CH-9007 St Gallen, Switzerland
Summary. In a pilot study a carboplatinum, 250 mg/ m 2 i.v., and 4-epidoxirubicin, 90 mg/m 2 i.v. or mitoxantrone, 10 mg/m 2 i.v., combination chemotherapy regimen was studied in a group of breast cancer patients with high-risk metastatic disease. All 11 patients had liver and/or lung metastases. Of the 11 patients, 9 had progressive disease and in 2 patients the disease had stabilised. The toxicity of both anthracycline-containing regimes was similar. Subjective toxicity was mild, but hematological toxicity was inacceptable. The tested carboplatinum-anthracycline combination regimes given in the administered doses are not useful in the treatment of metastatic breast cancer, mainly because of toxicity.
With the intention of decreasing the high rate of subjective toxicity (nausea, vomiting, alopecia, stomatitis and diarrhoea) of doxorubicin-cisplatinum based chemotherapy, we tested in potentially less toxic combination of carboplatinum and 4-epidoxorubicin or mitoxantrone in a pilot study at a single institution, mainly to determine the feasibility of the treatment regimens.
Key words: Metastatic breast cancer 4-Epidoxirubicin
Table I. Patient characteristics"
Carboplatinum
- Mitoxantrone
Introduction
Platinum-based regimens in the treatment of metastatic breast cancer have been used with partially promising results (Kolaric et al. 1984). The reported high response rate in visceral disease and the high complete response rate of the cyclophosphamidedoxorubicin-cisplatin combination is of special interest, but toxicity was considerable. Moderate to severe nausea and vomiting were almost universal and approached clinical intolerability (Creagan et al. 1984): 83%-91% of all patients developed alopecia; haematotoxicity was pronounced, particularly anaemia 39% (Kolaric et al. 1984) and there was leucopenia with a median leucocyte nadir of 1.8 x 109/1. Treatment delay and dose reduction were frequently necessary. Stomatitis and diarrhoea were less common (Creagan et al. 1984). Offprint requests to." H.J. Senn
Patients and methods A group of 11 with high-risk metastatic disease according to SAKKcriteria were entered in the protocol. All patients had multiple liver and/or lung metastases. Of the 11 patients, 9 had multiple organ in-
Characteristic
No. patients
Site of disease Liver Lung Pleura Bone Lymph node Subcutaneous/skin Pericardium
9 3 4 5 6 3 1
Prior treatment None Hormonotherapy + local radiotherapy Chemotherapy _+hormonotherapy
4 3 4
Prior chemotherapy Chlorambncil, methotrexate, 5-fluorouracil (LMF) Doxifluridin p.o. I. LMF II. Vincristine, Adriamycin, cyclophosphamide III. Mitomycin C, etoposide I. Adriamycin, cyclophosphamide II. Mitomycin C, etoposide None
1 1 1
1 7
Total number of p a t i e n t s = l l ; mean age 58 years (range 47-73 years)
14 volvement (up to five organs); their mean age was 58 years (range 47 73 years). Seven of the patients had no prior exposure to any chemotherapy and 2 patients had received only one treatment for their disease but without inclusion of anthracyclines or platinum compounds (oral doxifluridine in one case and chlorambucil-methotrexate-5-fluorouracil in one case). Patients with a SAKK-ECOG performance status of 3 and 4, an abnormal hemogram and creatinine clearance < 50 ml were not eligible. In a protocol addendum patients with severe liver disfunction (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase > 3 x normal) were also excluded from the protocol. Patient characteristics can be seen in Table 1. The treatment regimen consisted of carboplatinum, 250 mg/m 2 i.v., and 4-epidoxorubicin, 90 mg/m z i.v. (6 patients), or mitoxantrone, 10 mg/m 2 i.v. (5 patients). Medication was given in short consecutive infusions over 15 min and was repeated every 4-5 weeks, mostly on an out-patient basis. Response and toxicity were evaluated according to S A K K / W H O criteria.
Results
Of the 11 patients, 9 had progressive disease after at least two cycles of study chemotherapy. Two patients had stable disease for several months (still on treatment). Subjective and objective toxicity were similar for both anthracyclines. Dose-limiting toxicity was granulocytopenia in most patients and thrombocytopenia in one patient. All patients needed dose reduction of both drugs because of haematological toxicity. Even after a dose reduction of 30%-60% the haematological toxicity was severe. 4-Epidoxorubicin was stopped in i patient with an episode of tachycardia and palpitations after the second chemotherapy application. Carboplatinum was stopped in 1 patient after five cycles because of a continuously falling platelet nadir. Three patients needed red blood cell transfusions because of haemoglobin values below 85 g/1 and symptomatic anaemia. The mean white blood cell nadir was 1.3 x 109/1 (range 0.4x 109~.4x 109/1) and the mean platelet nadir was 85 x 109/1 (range 5 x 109-207 x 109/1). Details of haematological toxicity can be seen in Table 2. Subjective toxicity was minimal. Mild to moderate nausea and short episodes of vomiting in some paTable 2. Haematological toxicity Parameter
White blood cell count b Granulocyte count Platelet count ~ Hb
No. patients evaluable a
tients could easily be controlled with conventional doses of oral metoclopramide. Using cold caps during chemotherapy administration, prevented any of the patients developing alopecia.
Discussion
The results of this pilot study show that the haematological toxicity of the above-mentioned anthracyclinecarboplatinum regimen, using the present dosing schedule, is not acceptable. All patients needed dose reduction and several patients had to be prematurely readmitted to the hospital because of infectious complications requiring maximal supportive care. No toxic death occurred and all patients fully recovered from toxicity. In two patients, administration of one drug had to be stopped because of cardiac toxicity or thrombocytopenia respectively. Subjective toxicity was moderate. It is not possible to compare easily the efficacy of these anthracycline-carboplatinum chemotherapy regimens with the results of most other cisplatinumdoxorubicin-based combinations. In our study all patients had high-risk disease (mostly including advanced liver metastasis) with a poor chance of response and a poor survival rate. None of the 9 patients with progressive disease responded to any further treatment. Additionally, 2 patients who received radiation had progressive disease in the radiated area during continuing subsequent radiotherapy. Anthracycline-carboplatinum combination chemotherapy, using the above-mentioned regimen, is not an adequate treatment in metastatic breast cancer patients with high-risk disease, mainly because of severe haematological toxicity. The promising results in terms of response achieved by using doxorubicin-cisplatinum combinations, as reported in the literature, could not be confirmed in this pilot study and for these particular patients. Haematological toxicity might be reduced and might not become dose-limiting if such a chemotherapy regimen is combined with haematopoietic growth factors.
Grade 0
1
2
3
4
9
1
0
0
4
4
9
l
0
0
2
6
10 11
3 8
3 1
1 2
0 0
3 0
a Total no. patients = 11 b Mean white blood cell nadir = 1.3 x 109/i; range (0.4-4.4) x 109/1 c Mean platelet nadir= 85 x 109/1; range (5-297)x 109/1
References Kolaric K, Roth A, Vukas D, Cervek J (1984) CAP versus CMFVP combination chemotherapy in untreated metastatic breast cancer. Cancer Chemother Pharmacol 13:142-144 Creagan ET, Green SJ, Ahmann DL, Ingle JN, Edmonson JH, Marschke RF Jr. (1984) A phase III clinical trial comparing the combination cyclophosphamide/Adriamycin/cisplatin with cyclophosphamide/5-fluorouracil/prednisone in patients with advanced breast cancer. J Clin Oncol 11, 1260-1265 Received 12 July 1989/Accepted 16 October 1989
