Feasibility of a dose-intensive CMF regimen with granulocyte colony-stimulating factor as adjuvant therapy in premenopausal patients with node-positive breast cancer.

Our aim was to study the feasibility of an intensified intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) schedule with the aim to escalate dose intensity (DI). Twenty-three premenopausal breast cancer patients received 6 cycles of adjuvant CMF intravenously on days 1 and 8 every 3 weeks and granulocyte colony-stimulating factor days 9-18. Endpoints were DI and toxicity. Twenty-one out of 23 patients (91%) received the projected total dose and reached > or =85% of the projected DI. Compared to 'classical' CMF, all patients reached > or = 111% DI. Nine patients received the planned schedule without delay. Thirteen patients (57%) were treated for infection and four patients (17%) were hospitalized for febrile neutropenia. Twelve patients received red blood cell transfusions (52%). Radiation therapy (n = 6) had no adverse impact on dose intensity or haematological toxicity. This dose-intensified CMF schedule was accompanied by enhanced haematological toxicity with clinical sequelae, namely fever, intravenous antibiotics and red blood cell transfusions, but allows a high dose intensity in a majority of patients.

Prevention of febrile leucopenia after chemotherapy in high-risk breast cancer patients: no significant difference between granulocyte-colony stimulating growth factor or ciprofloxacin plus amphotericin B.

In a prospective randomized trial, 40 stage IV breast cancer patients undergoing intermediate high-dose chemotherapy (cyclophosphamide, 5-fluorouracil plus epirubicin or methotrexate), received either recombinant human G-CSF (rhG-CSF, group I) or ciprofloxacin and amphotericin B (CAB, group II) for prevention of febrile leucopenia (FL). In group I, seven of 18 patients developed FL (after 10/108 courses); in group II, seven of 22 patients (7/98 courses) (P = NS). Median hospitalization duration and costs were not different. RhG-CSF was 6.6 times more expensive per course than CAB. In conclusion, prophylactic CAB has similar efficacy to rhG-CSF in this setting, and is more cost-effective.

Dose intensity of standard adjuvant CMF with granulocyte colony-stimulating factor for premenopausal patients with node-positive breast cancer.

The effects of granulocyte colony-stimulating factor (G-CSF) on total dose and dose intensity of standard oral adjuvant CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) chemotherapy were studied in premenopausal patients with node-positive breast cancer. Treatment consisted of standard CMF and locoregional radiotherapy (on indication). G-CSF was administered if the leukocyte count recovery was insufficient. Fifty-one patients required no G-CSF ("no cytopenia'), and 50 patients received G-CSF ("G-CSF). Twenty-two patients, however, received no G-CSF support despite insufficient leukocyte recovery ("control'). Following G-CSF, leukocyte recovery was adequate in 83% of the chemotherapy cycles. The proportion of the patients who had a dose intensity > or = 85% was 90% in the "no cytopenia' group, 74% in the "G-CSF' group, and 45% in "control' group (p < 0.05). Leukocyte recovery was adequate in 87% of the chemotherapy cycles in the patients who received radiotherapy as compared with 92% of those in the patients without radiotherapy (p < 0.05). In conclusion an adequate leukocyte recovery after G-CSF was found in 83% of all chemotherapy cycles. The dose intensity of the G-CSF group was higher as compared with controls. The impact of radiotherapy on hematological recovery was significant, but not dependent on G-CSF.

The additive effect of peripheral blood stem cells, harvested with low-dose cyclophosphamide, to autologous bone marrow reinfusion on hematopoietic reconstitution after ablative chemotherapy in breast cancer patients with localized disease.

The additive effect of peripheral blood stem cells (PBSCs) to autologous bone marrow transplantation (ABMT) on haematopoietic reconstitution, after ablative chemotherapy in patients with locally advanced breast cancer, was evaluated. Patients were treated with induction chemotherapy, followed by ablative chemotherapy consisting of mitoxantrone and thiotepa. Group I (n = 14) received ABMT and granulocyte macrophage-colony stimulating factor (GM-CSF), group II (n = 11) received ABMT, PBSCs and granulocyte-colony stimulating factor (G- CSF). PBSCs were harvested after a low-dose cyclophosphamide (750 mg/m2), followed by G-CSF. Stem cell harvest was routinely started 12 days after cyclophosphamide. Compared to group I, group II showed a significant reduction in the median number of days for leukocytes < 0.5 x 10(9)/L 4.5 days, leukocytes < 1.0 x 10(9) / l 5.5 days, platelets < 20 x 10(9)/ l 9 days and platelets < 40 x 10(9) / l 12.5 days. The median number of transfusions of platelets fell from 11.5 to 7 and of red blood cells from 8.5 to 6. The median hospitalisation duration declined from 40.5 to 30 days, fever above 38 degrees C with 7.5 days, fever above 38.5 degrees C with 4 days and antibiotic treatment with 8.5 days in group I versus group II. Improvement of haematological recovery, duration of fever and hospitalisation was observed by the addition of PBSCs, obtained after a relatively low-dose cyclophosphamide and G-CSF and stem cell pheresis on fixed days, to autologous bone marrow and growth factor in the period after ablative chemotherapy.

High-dose methotrexate, vincristine and cisplatin as salvage treatment for relapsed non-seminomatous germ-cell cancer.

Eight patients with non-seminomatous testicular cancer relapsing after primary chemotherapy were treated with salvage chemotherapy consisting of high-dose methotrexate (12 g/m2), vincristine (1.2 mg/m2) weekly for four weeks, followed after an interval of four weeks by 3 times 100 mg/m2 cisplatin (50 mg/m2 on day 1 and 2) every 10 days. This regimen resulted in 2 partial (PR) and 2 complete responses (CR). The two patients achieving CR remain disease-free for 43+ and 53+ months. Toxicity was mainly methotrexate-related and could be ameliorated to a large extent by leucovorin rescue. This small study shows that methotrexate, vincristine, followed by cisplatin is effective in the treatment of relapsed non-seminomatous testicular cancer at the cost of manageable toxicity.

Intensive chemotherapy with autologous bone marrow transfusion as primary treatment in women with breast cancer and more than five involved axillary lymph nodes.

Patients with breast cancer and a high number of involved axillary lymph nodes have a poor prognosis, despite adjuvant chemotherapy. The 5-year disease-free survival (DFS) in this group amounts to 30-40% and the 10-year DFS is only 15-20%. Therefore, new treatment modalities are being sought for this group of patients. The aim of the present study was the evaluation of the efficacy of high-dose chemotherapy combined with autologous bone marrow support. 24 patients with a primary breast cancer with more than five involved axillary lymph nodes received, after surgery, six courses of induction chemotherapy followed by ablative chemotherapy and reinfusion of autologous bone marrow. All patients were premenopausal or less than 2 years postmenopausal. Induction chemotherapy consisted of methotrexate (MTX) 1.5 g/m2 intravenous (i.v.) and 5-fluorouracil (5-FU) 1.5 g/m2 i.v. on day 1, prednisone 40 mg/m2 orally on days 2-14, doxorubicin 50 mg/m2 i.v. and vincristine 1 mg/m2 i.v. on day 14. Courses were repeated six times every 4 weeks. 10 patients received cyclophosphamide 7 g/m2 i.v. and etoposide 1.5 g/m2 i.v. as intensive regimen, in 14 patients this comprised mitoxantrone 50 mg/m2 i.v. and thiotepa 800 mg/m2 i.v. Reinfusion of autologous marrow followed on day 7. Finally, patients received locoregional radiotherapy for extranodal disease and tamoxifen 40 mg daily orally over a period of 2 years. The median age of patients was 42 years, range 29-54. The median number of involved nodes was 10. During induction therapy, fever requiring i.v. antibiotics occurred in 4% of 144 courses, 14% of patients suffered from mucositis WHO grade 2-3, and the other patients had mucositis grade 1. During the ablative chemotherapy, 1 patient died, 6 developed septicaemia, 5 showed mucositis grade 3-4 and the other patients had mucositis grade 1 or 2. In the follow-up, 1 patient died from acute cardiac failure. Reversible radiation-induced pneumonitis occurred in 7 out of 14 irradiated patients; symptoms started directly following radiotherapy and lasted for several weeks, but disappeared in due course. During follow-up, 2 patients with six and > 10 positive nodes, respectively, have relapsed after 18 and 36 months, both in the cyclophosphamide/etoposide regimen. Median observation is 3 years, disease-free survival at 5 years is predicted to be 84%. Intensive treatment in these patients with high numbers of involved axillary lymph nodes is a toxic regimen, but may improve the chance of surviving free of disease.

Modification of 5-fluorouracil activity by high-dose methotrexate or leucovorin in advanced colorectal carcinoma.

21 patients with advanced colorectal carcinoma were entered into a phase II study to evaluate efficacy and toxicity of methotrexate (MTX), 1500 mg/m2 rapid infusion on day 1, combined with continuous infusion of 5-fluorouracil (5-FU), 600 mg/m2 per 24 h on days 1-4. 12 patients who had progressive disease during this regimen subsequently received high-dose leucovorin, 200 mg/m2 bolus injection on days 1-4, combined with 4 days' continuous infusion of 5-FU. In the MTX/5-FU group 1 pathologically proven complete remission and 3 partial remissions were seen (response rate 20%). The median progression-free interval was 30 weeks. In 12 patients with progressive disease leucovorin/5-FU stabilized disease in 2 (17%). Toxicity in both regimens was tolerable, gastro-intestinal side-effects being most frequent. There were no treatment-related deaths. Median survival time was 10 months. Serum levels of carcinoembryonic antigen before treatment or doubling-time during progression did not correlate with survival.

Bleeding prophylaxis in autologous bone marrow transplantation for solid tumors. Comparison of cryopreserved autologous and fresh allogeneic single-donor platelets.

Bleeding prophylaxis with cryopreserved autologous thrombocytes was evaluated in 43 patients treated with high-dose chemotherapy and autologous bone marrow transplantation. Platelet transfusions were given prophylactically. Nineteen patients received only autologous, 10 only fresh allogeneic single-donor, and 14 both types of transfusions. The effects of 104 autologous versus 93 allogeneic thrombocyte transfusions were compared. The increment at 1 h was for allogeneic platelets twice that for autologous platelets (30.6 versus 15.2 x 10(9)/l), but the interval between transfusions in days (2.3) was the same. Twelve patients received alternating autologous platelet transfusion after washing out the cryoprotectant dimethyl sulfoxide (18 transfusions) and non-washed autologous platelets (24 transfusions). Platelet increments, corrected increments, and predicted recovery were not influenced by omitting the washing procedure, and no side effects of dimethyl sulfoxide occurred.

Clinical and endocrine effects of cyproterone acetate in postmenopausal patients with advanced breast cancer.

A phase II study with cyproterone acetate (CPA) was done as the primary treatment in female breast cancer patients. Twenty-three patients, mean age 64 years, range 52-75 years, were entered and treated with CPA 400 mg daily. Twenty patients were evaluable and responses were sparse. There was one partial and one complete remission, 17 patients were stable and one patient progressed within 3 months. Side-effects were frequent: five patients complained of nausea, three had severe weight loss, one suffered from depression and seven showed disturbed liver function tests. Six patients had to stop treatment for side-effects, while two other patients were taken off treatment because they developed an acute necrotizing hepatitis. The hepatitis recovered after drug withdrawal in both patients. The serum levels of CPA, cortisol, androstenedione, DHAS, LH, FSH and prolactin were measured during CPA treatment. The levels of cortisol and androstenedione did not change, while LH, FSH and DHAS were suppressed. The DHAS showed an inverse relation to serum CPA concentrations. The prolactin levels rose uniformly. The therapeutic effect of CPA in postmenopausal patients with advanced breast cancer is disappointing, and inferior to that of other progestins. Side-effects are frequent, possibly as a result of the high dosage used in this study. The hormonal changes are different from those of other progestins, which may explain the different efficacies.

Mechanism of adrenal suppression by high-dose medroxyprogesterone acetate in breast cancer patients.

To investigate the mechanism of adrenal suppression by high-dose MPA, we performed direct and indirect stimulation tests in postmenopausal women with disseminated breast cancer who were receiving MPA and in a postmenopausal breast cancer control group. A partial adrenal insufficiency was found during Synacthen stimulation, confirmed by a slight increase of 11-desoxycortisol after metyrapone, despite a sufficient rise in ACTH levels. Peak levels of androstenedione and 17-OH progesterone after Synacthen correlated with those after metyrapone. Peak cortisol levels after Synacthen also correlated with the sum of cortisol and 11-desoxycortisol values after metyrapone, indicating the presence of a maximum adrenal response and a sufficient rise of endogenous ACTH after metyrapone. As the peak levels of cortisol and androstenedione were highly correlated with baseline values, a short Synacthen stimulation test may give a good indication as to whether adrenal suppression by MPA is adequate. The adrenal androgen androstenedione is the precursor of the main postmenopausal oestrogen, oestrone. In this way, adrenal suppression may constitute an important therapeutic effect of high-dose MPA.

Adrenal suppression by oral high-dose medroxyprogesterone acetate in breast cancer patients.

The effects of oral MPA, 300 mg t.i.d., on adrenal function in postmenopausal patients with disseminated breast cancer were evaluated. The levels of serum cortisol, ACTH, androstenedione, DHEA-S, LH, FSH, GH, and prolactin in 22 patients receiving MPA were compared with those in another group of 28 postmenopausal patients in whom levels were measured before treatment. The median morning cortisol level was 70, 10-465 nmol/l (controls 395, range 155-785 nmol/l), median androstenedione 1.09, range 0.55-3.10 nmol/l (controls 3.75, range 1.23-9.81 nmol/l), and median DHEA-S 555, range 55-1,300 nmol/l (controls 2,440, range 1,015-6,340 nmol/l). No appreciable change in ACTH levels was found. Gonadotropins were also markedly suppressed. The median LH level was 4.3 (range 0.8-18) U/l, as against 83 (range 19-116) U/l in controls. The median FSH level was 7.2 (range 0.5-27) U/l, as against 71 (range 12-262) U/l in controls. Prolactin and GH levels remained largely unchanged. The suppression of androstenedione synthesis, the main precursor of postmenopausal estrogens, may represent the major therapeutic effect of high-dose MPA in postmenopausal patients with breast cancer.