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MYELOSUPPRESSION AFTER METHOTREXATE, MITOZANTRONE, AND MITOMYCIN C FOR TREATMENT OF ADVANCED BREAST CANCER
915 undetectable and xylose absorption was again decreased. Although graft function was satisfactory at this time (creatinine clearance 40 ml/min), it was decided to add steroids to his therapy to improve cyclosporin absorption. However, because the patient did not cooperate, steroids were not administered and the patient failed to attend the hospital for 3 weeks. When he was finally admitted, his renal function had decreased to a creatinine clearance of 5 ml/min and xylose absorption was now unrecordable. A renal biopsy again revealed severe cellular rejection. Cyclosporin was administered intravenously (3 mg/kg) and prednisolone (30 mg per day) was added to the therapy. After a further 2 weeks, xylose absorption returned to normal and cyclosporin absorption improved from 6 to 13 % of an orally administered dose. This improvement in cyclosporin absorption was maintained for 5 months with a daily dose of 15 mg prednisolone. Despite satisfactory blood levels of cyclosporin, creatinine clearance remained less than 10 ml/min and 5 months later the patient was re-started on CAPD. Cyclosporin malabsorption in a patient with long-standing Crohn’s disease has not been reported. Malabsorption of cyclosporin has been described in patients with bowel dysfunction associated with bone marrow transplantation after radiotherapy, infective diarrhoea, or graft-versus-host disease.’ Isolated case reports24 have claimed a beneficial effect of cyclosporin in Crohn’s disease and, in one of these reports, cyclosporin absorption appeared satisfactory in the presence of active disease.4 Because cyclosporin is being considered for the treatment of diverse conditions, it is important to note that this patient relapsed despite adequate whole blood levels of cyclosporin.4 The ensuing malabsorption further reduced the level of immunosuppression, which was improved by prednisolone. The adequate whole blood levels of cyclosporin suggest either that Crohn’s disease is not controlled with this compound or that the levels required for suppression of inflammatory bowel disease are greater than the levels required to prevent allograft rejection.
Departments of Renal Medicine, Transplantation and Pathology, University of Wales College of Medicine, Royal Infirmary, Cardiff CF2 1SZ
J. D. WILLIAMS J. R. SALAMAN P. J. A. GRIFFIN A. N. HILLIS W. Ross G. T. WILLIAMS
1. Atkinson K, Bntton R, Paull P, et al. Detrimental effect of intestinal disease on absorption of orally administered cyclosporin. Transplant Proc 1983; 15: 2446. 2. Allison MC, Pounder RE. Cyclosporin for Crohn’s disease. Lancet 1984; i: 902-03. 3. Bianchi PA, Mondelli M, Quarto di Palo F, Ranzi T. Cyclosporin for Crohn’s disease. Lancet 1984; i: 1242. 4. Allison MC, Pounder RE. Ciclosporin for Crohn’s disease. In: Schindler R, ed. Ciclosporin in autoimmune diseases. Berlin: Springer-Verlag, 1985: 185-87.
MYELOSUPPRESSION AFTER METHOTREXATE, MITOZANTRONE, AND MITOMYCIN C FOR TREATMENT OF ADVANCED BREAST CANCER
Sip,—The combination of methotrexate, mitozantrone, and mitomycin C (MMM) has been reported as safe and effective in advanced breast cancer. 1. We began using the combination in the recommended doses (methotrexate 35 mg/m2, every three weeks; mitozantrone 8 mg/m2, every three weeks; and mitomycin C 8 mg/m2, every six weeks). Whilst the regimen was well tolerated subjectively, myelosuppression has been notable. Case 1.-A 41-year-old woman had rapidly progressing bony metastases and hypercalcaemia 9 months after primary treatment with lumpectomy and radiotherapy. 8 days after the first course of MMM, haemoglobin (Hb), white blood cells (WBC), and platelets decreased (table). The nadir WBC was on day 10 and had recovered by day 14. The nadir platelet count was on day 12. She required intravenous broad-spectrum antibiotics for septicaemia, but there were no haemorrhagic complications or stomatitis. Full haematological and clinical recovery followed, but the patient is now receiving 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) because of disease progression. Case 2.-A 56-year-old woman with progressive bony metastases had previously been treated with hormone therapy. She had also been extensively irradiated for painful bony metastases. The first
MYELOSUPPRESSION AFTER MMM
I
I
I
J
*Normal liver function except for allzalme phosphatase, increased at 139 30-120). Urea was 10 mmol/I (normal 2-5-6 5). talkahne phosphatase 934 VII (nonnal 80-280); alanine aminottansferase 5 < 40); and bilirubin 6 pmol/I (nonnal < 17). tNonnalliver function and urea.
U/) (normal VII (normal
of MMM was tolerated without significant myelosuppression. Because of our experience with MMM we reduced the dose of her day 22 methotrexate and mitozantrone (phase 2) and this too was well tolerated. 10 days after her second course of full-dose MMM, V.7BC, and platelets decreased (table). There was partial recovery at 21 days and further therapy was deferred at that time. Case 3.-A 75-year-old woman with advanced local disease had been previously treated with chest wall irradiation and hormone therapy. She had also received oral cyclophosphamide in an intermittent regimen from July, 1982, to January, 1985. The first course of MMM (phase 1 and 2) was given at full dose and was well tolerated except for mouth ulceration. We reduced the dose of both mitozantrone and mitomycin C to 6 mg/mz, with folinic acid rescue for the second course. After 10 days, WBC and platelets decreased (table) and further decreases on day 28 caused us to delay phase 2. By day 42 WBC and platelets had recovered somewhat. Methotrexate, 35 mg/m2 (with folinic acid rescue), and mitozantrone and mitomycin C, 5 rng each, were then given. 21 days after this dose Hb, WBC, and platelets were all decreased compared with pretreatment values. Full recovery has still not occurred and further chemotherapy has been deferred. We have also treated a further 2 cases with the full-dose regimen. In all 5 patients, WBC has decreased to or below 2-0 x 109/1 and, in 3, the platelet count has decreased below 100 x 109/1. This contrasts with the reported incidence of 34% leucopenia (less than 30 x 109/1) and 9% thrombocytopenia (less than 100 x 109/1).1 We note that although case 1 had an increased urea level, stomatitis did not develop, which suggests that the myelosuppression was not the result of methotrexate toxicity. Case 2 had been heavily irradiated and case 3 had received continuous low-dose cyclophosphamide. As a result both had compromised bone-marrow function, despite appropriate dose reduction toxicity was still seen. MMM is more myelotoxic than the combinations FAC or 5-fluorouracil, mitozantrone, and cyclophosphamide (unpublished data). Chemotherapy in advanced breast cancer is palliative, and should be as safe as possible. Although we saw only one infection as a result of myelosuppression, we still feel that full-dose MMM placed the patients at an unjustifiably increased risk. We therefore no longer recommend MMM for patients with bone marrows that are course
compromised by previous chemotherapy or extensive radiotherapy. For other patients, we have reduced the dose of both mitozantrone and mitomycin C to 6 mg/m2. We also do nadir counts at 10 days. We should like to hear from other groups with experience of this regimen. Regional Centre for Radiotherapy and Mount Vemon Hospital, Northwood, Middlesex HA6 2RN 1. Powles
Oncology,
ANNABELLA MARKS ANDREW GOODMAN SHONA DOUGHERTY RICHARD ASHFORD
T, et al. 14th International Cancer Congress (Budapest) Vol II:
514
(abstr).
Departments of Renal Medicine, Transplantation and Pathology, University of Wales College of Medicine, Royal Infirmary, Cardiff CF2 1SZ
J. D. WILLIAMS J. R. SALAMAN P. J. A. GRIFFIN A. N. HILLIS W. Ross G. T. WILLIAMS
1. Atkinson K, Bntton R, Paull P, et al. Detrimental effect of intestinal disease on absorption of orally administered cyclosporin. Transplant Proc 1983; 15: 2446. 2. Allison MC, Pounder RE. Cyclosporin for Crohn’s disease. Lancet 1984; i: 902-03. 3. Bianchi PA, Mondelli M, Quarto di Palo F, Ranzi T. Cyclosporin for Crohn’s disease. Lancet 1984; i: 1242. 4. Allison MC, Pounder RE. Ciclosporin for Crohn’s disease. In: Schindler R, ed. Ciclosporin in autoimmune diseases. Berlin: Springer-Verlag, 1985: 185-87.
MYELOSUPPRESSION AFTER METHOTREXATE, MITOZANTRONE, AND MITOMYCIN C FOR TREATMENT OF ADVANCED BREAST CANCER
Sip,—The combination of methotrexate, mitozantrone, and mitomycin C (MMM) has been reported as safe and effective in advanced breast cancer. 1. We began using the combination in the recommended doses (methotrexate 35 mg/m2, every three weeks; mitozantrone 8 mg/m2, every three weeks; and mitomycin C 8 mg/m2, every six weeks). Whilst the regimen was well tolerated subjectively, myelosuppression has been notable. Case 1.-A 41-year-old woman had rapidly progressing bony metastases and hypercalcaemia 9 months after primary treatment with lumpectomy and radiotherapy. 8 days after the first course of MMM, haemoglobin (Hb), white blood cells (WBC), and platelets decreased (table). The nadir WBC was on day 10 and had recovered by day 14. The nadir platelet count was on day 12. She required intravenous broad-spectrum antibiotics for septicaemia, but there were no haemorrhagic complications or stomatitis. Full haematological and clinical recovery followed, but the patient is now receiving 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) because of disease progression. Case 2.-A 56-year-old woman with progressive bony metastases had previously been treated with hormone therapy. She had also been extensively irradiated for painful bony metastases. The first
MYELOSUPPRESSION AFTER MMM
I
I
I
J
*Normal liver function except for allzalme phosphatase, increased at 139 30-120). Urea was 10 mmol/I (normal 2-5-6 5). talkahne phosphatase 934 VII (nonnal 80-280); alanine aminottansferase 5 < 40); and bilirubin 6 pmol/I (nonnal < 17). tNonnalliver function and urea.
U/) (normal VII (normal
of MMM was tolerated without significant myelosuppression. Because of our experience with MMM we reduced the dose of her day 22 methotrexate and mitozantrone (phase 2) and this too was well tolerated. 10 days after her second course of full-dose MMM, V.7BC, and platelets decreased (table). There was partial recovery at 21 days and further therapy was deferred at that time. Case 3.-A 75-year-old woman with advanced local disease had been previously treated with chest wall irradiation and hormone therapy. She had also received oral cyclophosphamide in an intermittent regimen from July, 1982, to January, 1985. The first course of MMM (phase 1 and 2) was given at full dose and was well tolerated except for mouth ulceration. We reduced the dose of both mitozantrone and mitomycin C to 6 mg/mz, with folinic acid rescue for the second course. After 10 days, WBC and platelets decreased (table) and further decreases on day 28 caused us to delay phase 2. By day 42 WBC and platelets had recovered somewhat. Methotrexate, 35 mg/m2 (with folinic acid rescue), and mitozantrone and mitomycin C, 5 rng each, were then given. 21 days after this dose Hb, WBC, and platelets were all decreased compared with pretreatment values. Full recovery has still not occurred and further chemotherapy has been deferred. We have also treated a further 2 cases with the full-dose regimen. In all 5 patients, WBC has decreased to or below 2-0 x 109/1 and, in 3, the platelet count has decreased below 100 x 109/1. This contrasts with the reported incidence of 34% leucopenia (less than 30 x 109/1) and 9% thrombocytopenia (less than 100 x 109/1).1 We note that although case 1 had an increased urea level, stomatitis did not develop, which suggests that the myelosuppression was not the result of methotrexate toxicity. Case 2 had been heavily irradiated and case 3 had received continuous low-dose cyclophosphamide. As a result both had compromised bone-marrow function, despite appropriate dose reduction toxicity was still seen. MMM is more myelotoxic than the combinations FAC or 5-fluorouracil, mitozantrone, and cyclophosphamide (unpublished data). Chemotherapy in advanced breast cancer is palliative, and should be as safe as possible. Although we saw only one infection as a result of myelosuppression, we still feel that full-dose MMM placed the patients at an unjustifiably increased risk. We therefore no longer recommend MMM for patients with bone marrows that are course
compromised by previous chemotherapy or extensive radiotherapy. For other patients, we have reduced the dose of both mitozantrone and mitomycin C to 6 mg/m2. We also do nadir counts at 10 days. We should like to hear from other groups with experience of this regimen. Regional Centre for Radiotherapy and Mount Vemon Hospital, Northwood, Middlesex HA6 2RN 1. Powles
Oncology,
ANNABELLA MARKS ANDREW GOODMAN SHONA DOUGHERTY RICHARD ASHFORD
T, et al. 14th International Cancer Congress (Budapest) Vol II:
514
(abstr).