Cyclophosphamide, methotrexate, and chronic oral tegafur modulated by folinic acid in the treatment of patients with advanced breast carcinoma.

BACKGROUND: Chronic oral tegafur (a 5-fluorouracil prodrug) modulated by folinic acid has antitumor activity in patients with metastatic breast carcinoma resistant to 5-fluorouracil or doxorubicin-based regimens. In this study, bolus 5-fluorouracil was substituted with chronic oral tegafur and folinic acid in a cyclophosphamide, methotrexate, and 5-fluorouracil-based regimen to study the activity of this novel regimen in patients with advanced breast carcinoma. METHODS: This study was comprised of patients with advanced breast carcinoma and measurable or evaluable disease. Patients with prior chemotherapy were eligible. The regimen was comprised of cyclophosphamide, 600 mg/m2, and methotrexate, 40 mg/m2, both given intravenously on Day 1, and tegafur, 750 mg/m2, with folinic acid, 45 mg/day, both given orally in 3 daily fractions on Days 2-14, every 3 weeks. RESULTS: Forty-seven patients were included, 44 of whom were fully assessable. Three patients (7%) achieved a complete remission and 17 (38.6%) achieved a partial remission, for an objective response rate of 45.5% (95% confidence interval, 29-59%). The median duration of response was 11 months. In previously untreated patients the response rate was 54.5%. In patients previously treated with anthracycline or 5-fluorouracil-based regimens the response rates were 41% and 39%, respectively. Sixteen patients (36.4%) had disease stabilization. The median overall time to progression was 10 months. Toxicities usually were mild and were comprised of leukocytopenia, mucositis, emesis, and diarrhea. CONCLUSIONS: Chronic oral tegafur and folinic acid combined with intravenous cyclophosphamide and methotrexate at the dose and schedule used in the current study has significant antitumor activity both as first-line chemotherapy as well as in other patients with advanced breast carcinoma who had prior chemotherapy. This regimen is well tolerated, with gastrointestinal toxicity being the most frequent and dose-limiting toxicity.

Frequent dose delays and growth factor requirements with the sequential doxorubicin-CMF schedule.

Doxorubicin for four cycles plus cyclophosphamide, methotrexate and 5-fluorouracil (CMF) for eight cycles is an effective adjuvant regimen for breast cancer patients with more than three involved axillary lymph nodes. We reviewed the incidence of dose delays and growth factor requirements when this regimen is administered to patients receiving concurrent irradiation. Thirty-six patients with more than three involved axillary lymph nodes were treated with the sequential regimen doxorubicin-CMF and irradiation. Patients with two or more dose delays received G-CSF treatment. Seventy-five percent of the patients required dose delays for day-22 neutropenia, and growth factors were needed for half of the patients in order to maintain a received dose intensity of 0.940. The first delayed cycle occurred in 74% of the patients while receiving concomitant chemoradiotherapy. Frequent dose delays were required when the sequential regimen doxorubicin-CMF was administered along with radiotherapy. Growth factors are needed to maintain dose intensity similar to that achieved in the original trial.

Early results of the value of p53 in predicting survival in a homogeneous cohort of patients with invasive bladder cancer treated with a neoadjuvant carboplatin-based regimen (M-CAVI).

AIMS AND BACKGROUND: Several reports on prognostic factors for infiltrating-bladder cancer have given controversial results. We assessed the prognostic value of p53 nuclear overexpression together with known prognostic factors for survival in patients with invasive T2-4 N0 M0 bladder cancer treated with neoadjuvant chemotherapy. STUDY DESIGN: Thirty-five paraffinized tumor samples from initial transurethral resection of patients with bladder cancer were analyzed immunohistochemically to detect overexpression of p53 protein. Patients were treated with 3 to 4 cycles of neoadjuvant methotrexate, carboplatin, and vinblastine (M-CAVI) and then underwent radical cystectomy. Prechemotherapy, treatment, and postchemotherapy factors were analyzed for correlation with survival by univariate and multivariate analysis. Fifty-seven percent of tumors were positive for p53 protein, 71.5% had grade III-IV tumors, and 72% had organ-confined disease. The median follow-up was 20 months (range 5-71+). RESULTS: By univariate analysis, the significant pretreatment factors were initial tumor (T) stage (P < 0.0001) and the male sex (P = 0.03). Five postchemotherapy variables were found significant: surgery performed according to protocol (P = 0.003), overall clinical (P = 0.004), and overall pathologic (P = 0.02) response to therapy, postchemotherapy pathologic stage (P = 0.0002), and tumor status after surgery (P = 0.0006). By multivariate analysis, the initial prechemotherapy T stage was the only factor that demonstrated independent significance. CONCLUSIONS: Although the median follow-up of the study is still too short, in this group of patients treated with a neoadjuvant carboplatin-based regimen, a classical variable (prechemotherapy T stage) rather than p53 nuclear overexpression was an independent prognostic factor for survival. Further follow-up will be required to assess the value of p53 overexpression as a prognostic factor in invasive bladder cancer patients treated with neoadjuvant carboplatin-based chemotherapy.

[Preliminary results of a phase II randomized controlled trial comparing M-VAC and M-CAVI in patients with bladder cancer (T2-4 N0-1 M0)]. / Resultados preliminares de un ensayo randomizado en fase II comparando M-VAC y M-CAVI en pacientes con cáncer de vejiga (T2-4 N0-1 M0).

OBJECTIVES: The combination of carboplatin, methotrexate and vinblastine (M-CAVI) is an active and well-tolerated regimen for patients with bladder cancer who are ineligible for cisplatin-based regimens. We have prospectively randomized patients with locally advanced (T2-4 N0 M0) or locoregional (Tx N1 M0) bladder cancer suitable for subsequent surgical treatment to M-VAC or M-CAVI chemotherapy. METHODS: M-CAVI consisted of carboplatin (300 mg/m2 on day 1 and later adjusted to 4.5 mg/dl/min according to Calvert's formula), methotrexate (30 mg/m2 on days 1, 15 and 22) and vinblastine (3 mg/m2 on days 1, 15 and 22). After 3-4 cycles, the patients were assessed for surgical resection. RESULTS: To date, 60 patients have been included. There were 58 completely evaluable patients, 27 were randomized to M-VAC and 31 to M-CAVI. The overall response rates were similar for M-VAC (48%; confidence interval 95%, 26%-67%) and M-CAVI (45%; confidence interval 95%, 28%-62%). The pathological complete responses were similar for the M-VAC and M-CAVI regimens for both the group with locally advanced (27% vs 39%, p = NS) and locoregional (14% vs 14%, p = NS) bladder cancer. The median actuarial survival for the M-VAC treated group was 23 months and 18 months for the M-CAVI. M-VAC therapy was statistically significantly associated with more events of granulocytopenic fever, grade 2-3 nausea and vomiting, grade 2 alopecia and grade 3-4 mucositis. CONCLUSIONS: The results achieved in the 60 patients included in the study indicate that M-CAVI is better tolerated than M-VAC, although both treatment regimens have similar overall response rates, pathological response rates and survival in patients with locally advanced and locoregional bladder cancer.

Five-day course of granulocyte colony-stimulating factor in patients with prolonged neutropenia after adjuvant chemotherapy for breast cancer is a safe and cost-effective schedule to maintain dose-intensity.

PURPOSE: To analyze the safety and efficacy of a short course of granulocyte colony-stimulating factor (G-CSF) to maintain dose-intensity of subsequent cycles of chemotherapy after a prior episode of prolonged neutropenia, without febrile complications, in patients receiving adjuvant treatment for breast cancer. PATIENTS AND METHODS: Thirty-two patients undergoing adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) or doxorubicin-CMF for stages I to II breast cancer were included after having chemotherapy delays due to neutropenia (absolute neutrophil count [ANC] < 1.5 x 10(9)/L) on day 22. G-CSF was administered subcutaneously on days 15 to 19 of each subsequent cycle. RESULTS: None of the patients included in this study had to be admitted to the hospital for fever and neutropenia. The median percentage of the projected dose-intensity for CMF or doxorubicin-CMF on an intent-to-treat basis was 0.994, which was significantly higher than the delivered dose-intensity before the start of G-CSF treatment (P < .0001). Patients who received concomitant G-CSF and radiotherapy achieved a similar dose-intensity as patients who did not undergo radiotherapy. Seven patients discontinued G-CSF treatment due to musculoskeletal pain. These patients had more subsequent cycle delays because of day 22 neutropenia than the 25 patients who followed the G-CSF schedule (P = .0028). CONCLUSION: A 5-day course of G-CSF in patients with prior chemotherapy delays due to prolonged neutropenia seems to be a safe and cost-effective schedule to maintain CMF or doxorubicin-CMF dose-intensity in the adjuvant treatment of breast cancer.

Node-negative breast cancers with p53(-)/HER2-neu(-) status may identify women with very good prognosis.

BACKGROUND: The contribution of p53 and HER-2/neu to the management of node-negative breast cancer (NNBC) could be improved by combining their results. MATERIAL AND METHODS: We studied paraffin-embedded primary tumors for p53 (BP-53-12-1) (n=57) and HER2/neu (pAB1) (n=63) from NNBC patients. The results were grouped in a negative (p53(-)/neu(-)) versus a positive group (one or both overexpressed). The association between both groups (negative and positive) and clinicopathologic parameters, S-phase fraction and DNA ploidy, and patients' outcome, was analyzed. RESULTS: In 28% of the tumors p53 was overexpressed, and HER2/neu in 11%. Sixty-five percent (37 out of 57) were p53(-)/neu(-), and 35% overexpressed one (31.5%) or both (3.5%) oncoproteins. Significant correlations were found between p53(-)/neu(-) tumors and age greater than 50 (p=0.003), S-phase fraction lower than 7 (p=0.03), and positive estrogen receptor contents (p=0.049). Actuarial 5-year disease-free and overall survival for p53(-)/neu(-) tumors were 88% and 97%, respectively, versus 50% and 66%, for tumors overexpressing one or both oncoproteins (p=0.004).

[Treatment with interferon of systemic Langerhans-cell histiocytosis in an adult]. / Tratamiento con interferón de la histiocitosis de células de Langerhans sistémica en un adulto.

We report an adult patient with systemic Langerhans' cell histiocytosis (LHX), who was refractory to multiple chemotherapy courses and in whom a partial clinical and biological 3-month remission was achieved with alpha-2-interferon. The patient's response was associated with an increase in the rate of natural killer cells and to a return to normal of the H/S T-lymphocyte ratio. Immunological abnormalities have been reported in this condition, and it is now accepted that the most important one is a decrease in suppressor lymphocytes. However, it is not known whether these abnormalities are endogenous or exogenous. The experience with modifiers of the biological response for the treatment of LHX is scanty, but the probable immunological pathogenesis of the condition justifies a therapeutic trial of those agents in patients not responding to conventional therapy.