Prognostic factors in metastatic breast cancer patients obtaining objective response or disease stabilization after first-line chemotherapy with epirubicin. Evidence for a positive effect of maintenance hormonal therapy on overall survival.

Randomized trials suggest that the outcome of metastatic breast cancer (BC) patients is not affected by the currently available therapies. Although response rates per se may be associated with survival prolongation, patients experiencing objective response may be those patients fated to have the longest natural disease history. The separation of responders from progressing patients after first-line chemotherapy could allow the selection of a more homogeneous subgroup in which further treatment strategies might achieve a better control of the disease. This study investigated the influence of some patient characteristics, disease characteristics, and previous treatments on the outcome of non progressing patients after first-line chemotherapy with epirubicin administration. We also evaluated the effect of the maintenance endocrine therapy in improving response rate and overall survival (OS). From May 91 to May 93, 207 patients were enrolled in a randomized trial aiming to compare the activity of epirubicin (120 mg/sqm) +/- lonidamine (600 mg/daily). Among the 169 patients attaining complete (CR), partial response (PR) or disease stabilization (SD), 65 were not randomly submitted to maintenance endocrine therapy (MET). Liver involvement, previous adjuvant chemotherapy and previous hormonal therapy (administered in adjuvant setting or for advanced disease) were found to negatively influence OS both in univariate and multivariate analysis. Differences in OS stratifying patients according to DFI, estrogen receptor status and PS did not attain statistical significance. Patients receiving MET survived significantly longer than those submitted to observation and this difference maintained the statistical significance also within patient subsets homogeneous for specific prognostic features. In conclusion, most prognostic factors for advanced BC have been confirmed in our series of patients obtaining CR, PR or SD to full dose epirubicin. The positive prognostic impact of MET is impressive and deserves confirmation in randomized studies.

[Hepatitis C virus and mixed cryoglobulinemia in dialysis]. / Virus dell'epatite C e crioglobulinemia mista in dialisi.

Prevalence of hepatitis C virus (HCV) varies in the dialytic population according to the geographic area (5-85%); the European average is 19%, with marked differences between dialysis units. The means of virus transmission is still not clear and represents one of the major management problems faced by dialysis units. US authors and European study groups have recently demonstrated a high level od HCV infection in patients with essential mixed cryoglobulinemia (EMC), suggesting that the virus plays an etiological role. The authors examined the correlation between mixed cryoglobulinemia and HCV and the possible etiological role of the virus in the pool of patients undergoing dialysis at the Centre. In September 1994 28/63 (44.4%) patients were found to be Ab anti-HCV positive (second and third generation ELISA); circulating cryoglobulins identified as Type II following immunofixation were found in 2/28 patients (7%) using centrifugation and cold incubation techniques. In the absence of the pathologies classically associated with cryoglobulinemia, the patients were diagnoses as suffering EMC. The HCV/EMC correlation in the dialysed population has been analysed in a limited number of studies, with discrepant results (0-47%). This paper highlights the association between HCV and EMC in 7% of chronic dialysed patients and given that the finding of anti-HCV Ab in serum solely documents previous exposure to the virus, we can only indirectly attribute an etiological role to HCV. The search for viral RNA in the serum, cryocrit and surnatant of patients found affected by EMC may provide additional etiopathogenetic information.

Chemotherapy with or without estrogenic recruitment in metastatic breast cancer. A randomized trial of the Gruppo Oncologico Nord Ovest (GONO).

BACKGROUND: This phase III study was carried out to verify whether a kinetic recruitment induced with low doses of diethylstilbestrol (DES) could increase the antitumor activity of chemotherapy in patients with advanced breast cancer. PATIENTS AND METHODS: Two hundred fifty-eight women with metastatic breast cancer were randomized to receive chemotherapy consisting of cyclophosphamide 600 mg/sqm i.v., epidoxorubicin 60 mg/sqm i.v. and fluorouracil 600 mg/ sqm i.v. (CEF) on day 1 or DES-CEF (diethylstilbestrol 1 mg orally days 1-3 CEF on day 4) every 21 days. Patients were treated until progression or, if responsive, for a maximum of 10 courses. RESULTS: There were no significant differences between the two treatment arms in response rates (51.3% to CEF and 49.6% for DES-CEF); median progression-free survival (9.4 months for CEF and 11 months for DES-CEF group) or median overall survival (17.3 and 20 months for CEF and DES-CEF arms, respectively). Non-hematological toxicities were superimposable in the two arms, while DES-chemotherapy was more myelotoxic. CONCLUSIONS: This trial confirms that chemotherapy preceded by estrogenic recruitment is still in an experimental phase and that, at present, it has no role in clinical practice. Further research is needed to test the possibility of combining different mitogens in the light of new information about breast cancer cell growth.

Lonidamine significantly increases the activity of epirubicin in patients with advanced breast cancer: results from a multicenter prospective randomized trial.

PURPOSE: Some evidence in vitro and in vivo shows that lonidamine (LND) can positively modulate the activity of doxorubicin and epirubicin (EPI). On this basis, a multicenter prospective randomized trial was performed in patients with advanced breast cancer (BC) to determine if the addition of LND to EPI could increase the response rate of EPI alone. PATIENTS AND METHODS: From May 1991 to May 1993, 207 patients were enrolled onto this study and randomized to receive intravenous (IV) EPI (60 mg/m2 on days 1 and 2) alone or with LND (600 mg orally daily). EPI administration was repeated every 21 days until tumor progression or for a maximum of eight cycles. LND was administered continuously until chemotherapy withdrawal. RESULTS: Response rate was significantly superior for the EPI plus LND scheme compared with the single-agent EPI either considering assessable patients (60.0% v 39.8%; P < .01) or including all registered patients according to an intention-to-treat analysis (55.3% v 37.5%; P < .02). The distribution of the response rate according to the site of disease did not show any significant difference between the treatment arms, except for the patient subgroup with liver metastases in which the combination EPI plus LND resulted in a significant improvement of responses than EPI alone. Toxicity was moderate, and except for myalgia, no adjunctive side effects were observed in the EPI plus LND arm. Overall survival and time to progression were similar in both groups. CONCLUSION: This study confirms in vivo that the administration of EPI is enhanced by the concomitant LND administration.

Second-line hormonotherapy for breast cancer. Uselessness of first-line continuation.

The hypothesis that the results of second line hormonotherapy for breast cancer may be ameliorated with continuation of the first line has been explored in a randomized trial. Patients progressing under tamoxifen were randomly allocated to aminoglutethimide and hydrocortisone acetate with or without tamoxifen continuation. No difference has been observed between the two arms in terms of response rate and progression-free overall survival.

Short-term administration of granulocyte-macrophage colony stimulating factor decreases hematopoietic toxicity of cytostatic drugs.

BACKGROUND: Administration of granulocyte-macrophage colony stimulating factor (GM-CSF) is followed by a rapid increase in the proliferative activity of the hematopoietic precursors. Within 72 hours after its suspension, however, establishment of a negative feedback results in a reduction of the proliferative activity of the hyperplastic marrow to values below the baseline, suggesting refractoriness of hematopoietic progenitors to the action of cell-cycle-specific cytostatic agents. METHODS: The hypothesis that short treatment with GM-CSF before chemotherapy could reduce the hematopoietic toxicity of cytostatics was investigated by administering GM-CSF glycosylate (Sandoz, Basel, Switzerland/Schering-Plough, Kenilworth, NJ) subcutaneously with a 5.5 micrograms/kg protein dosage per day from day-6-day-4 before each course of adjuvant chemotherapy (cyclophosphamide, epirubicin, 5-fluorouracil/cyclophosphamide, methotrexate, 5-fluorouracil alternate) in patients with node-positive breast cancer. Twelve patients were randomized to receive GM-CSF before chemotherapy or only at chemotherapy. The hematologic picture and dose intensity of chemotherapy were compared in the two groups of patients. RESULTS: In the group of patients receiving chemotherapy only, 22% of the cycles had to be postponed because of leukopenia, with a consequent reduction of the dose intensity, whereas in the GM-CSF group, the neutrophil counts remained at significantly (P < 0.001) higher levels, and there were no delays in chemotherapy administration. No substantial systemic toxicity was associated with this brief GM-CSF schedule. Moreover, GM-CSF treatment did not result in delayed depletion of the hematopoietic pool. CONCLUSIONS: Short treatment with GM-CSF can enable the dose intensity of conventional protocols of proven efficacy to be increased.

Prevalence of hepatitis C infection in a hemodialysis unit.

To define the prevalence of NANB hepatitis, anti-HCV antibodies were determined in 51 patients on renal replacement therapy, in 7 transplanted patients and 17 staff members of the hemodialysis unit. Anti-HCV antibodies were evaluated using immunoenzymatic methods (Ortho HCV ELISA Test System, 1st and 2nd generation). Among hemodialysis patients, seroconversion was respectively documented in 17.6% (9/51) and 52.9% (27/51); none of the transplanted patients were positive with the 1st generation test, while 3/7 were positive with the 2nd. No statistically significant difference was found in the prevalence antibodies between transfused and nontransfused patients. ALT levels were statistically greater in patients with anti-HCV antibodies (X2 2nd generation = 8.83; p less than 0.01). Our results suggest: (1) that hemodialysis represents a risk factor; (2) the validity of substitute markers and (3) more sensitivity of the 2nd than 1st generation test.

In vivo effect of human granulocyte-macrophage colony-stimulating factor on megakaryocytopoiesis.

The effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on megakaryocytopoiesis and platelet production was investigated in patients with normal hematopoiesis. Three findings indicated that GM-CSF plays a role in megakaryocytopoiesis. During treatment with GM-CSF (recombinant mammalian, glycosylated; Sandoz/Schering-Plough, 5.5 micrograms protein/kg/d, subcutaneously for 3 days) the percentage of megakaryocyte progenitors (megakaryocyte colony forming unit [CFU-Mk]) in S phase (evaluated by the suicide technique with high 3H-Tdr doses) increased from 31% +/- 16% to 88% +/- 11%; and the maturation profile of megakaryocytes was modified, with a relative increase in more immature stage I-III forms. Moreover, by autoradiography (after incubation of marrow cells with 125I-labeled GM-CSF) specific GM-CSF receptors were detectable on megakaryocytes. Nevertheless, the proliferative stimulus induced on the progenitors was not accompanied by enhanced platelet production (by contrast with the marked granulomonocytosis). It may be suggested that other cytokines are involved in the regulation of the intermediate and terminal stages of megakaryocytopoiesis in vivo and that their intervention is an essential prerequisite to turn the GM-CSF-induced proliferative stimulus into enhanced platelet production.

In vivo manipulation of human breast cancer growth by estrogens and growth hormone: kinetic and clinical results.

Since 1983, a series of experimental and clinical studies have been carried out on the possibility of enhancing the chemotherapy effectiveness in breast cancer by expanding the fraction of cycling cells. Theoretically estrogens should recruit breast cancer cells and this fact should result in a higher killing efficiency of antiproliferative drugs. Actually it has been clearly shown, by means of the thymidine labeling index and primer-dependent alpha-DNA polymerase assay, that low doses of diethylstilbesterol are able to increase the tumor proliferative activity of human breast cancer in vivo (estrogenic recruitment). Three randomized trials have been carried out (one in locally advanced and two in metastatic breast cancer) comparing conventional polychemotherapy vs chemotherapy with estrogenic recruitment. Only limited advantages have been observed in these trials. Searching for new modalities of kinetic manipulation of tumors, recombinant human growth hormone has been employed in a pilot study: the preliminary results indicate that it largely enhances tumor proliferative activity, suggesting the possibility of employing a growth factor system to increase chemosensitivity.

In vivo priming of human normal neutrophils by granulocyte-macrophage colony stimulating factor: effect on the production of platelet activating factor.

The effect of granulocyte-macrophage colony stimulating factor (GM-CSF) (recombinant, mammalian, glycosylated, Sandoz, Schering Plough; 4 micrograms/kg every 12 h for 3 d, s.c.) on platelet activating factor (PAF, 1-O-alkyl-2-acetyl-sn glycero-3 phosphorylcholine) production from neutrophils was studied in five cancer patients with normal haemopoiesis. Peripheral blood counts, PAF production and lyso-PAF: acetyl transferase (EC 2.3.1.67) (AT) activity in neutrophils were evaluated before treatment, during treatment and 3 d after treatment had been discontinued. GM-CSF induced a three-fold increase in the number of circulating neutrophils. Neutrophils obtained during treatment produced about twice as much PAF than before treatment in response to a variety of stimuli (N-formyl-methionyl-leucyl-phenylalanine, tumour necrosis factor-alpha, phagocytosis of baker's yeast spores opsonized with C3b). This increased PAF synthesis and release is concomitant with a 2-3-fold increase in AT activity. Moreover, lower concentrations of stimuli are sufficient to induce PAF synthesis from neutrophils obtained during GM-CSF treatment. Three days after treatment had been discontinued, stimulus induced PAF production had returned to baseline levels. Since GM-CSF induces a marked shift to the left in the Arneth score, the increased PAF release might have been due to the presence of younger granulocytes. This was, however, ruled out by experiments showing that normal neutrophils primed in vitro with GM-CSF produce more PAF when challenged with the same stimuli. The potential relevance of this effect of GM-CSF treatment lies on the crucial role of PAF in inflammatory reactions and its intervention in some immune reactions, including delayed hypersensitivity, and in endotoxic shock. Lastly, increased PAF production from neutrophils may explain some toxicities observed during treatment with high doses of GM-CSF.

Human GM-CSF in vivo: identification of the target cells and of their kinetics of response.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) was given for three days (8 micrograms/kg/day) to 14 subjects who had solid tumors and normal hemopoiesis. The treatment induced a rapid 3- to 5-fold increase in the number of circulating neutrophils, eosinophils and monocytes. Lymphocytes, platelets and reticulocytes were unmodified during treatment. Activation of circulating neutrophils during GM-CSF treatment was demonstrated by a significant, increased release of neutrophil-derived platelet-activating factor after stimulation with N-formyl-methionyl-leucyl-phenylalanine, tumor necrosis factor-alpha or phagocytosis. The granulomonocytosis was dependent on increased bone marrow production of mature cells. Using the thymidine suicide technique, we observed that GM-CSF more than doubled the percentage of granulocyte-macrophage and megakaryocyte colony-forming units (CFU-gm and CFU-meg) and erythroid burst-forming units (BFU-e) in the S phase of the cell cycle. However, at the level of morphologically recognizable cells with autoradiography, we observed that GM-CSF increased the labeling index of the granulo-monopoietic cells, whereas that of the erythroblasts was unchanged. These data suggest that in accordance with in vitro observations, GM-CSF exerts its activity through all granulo-monopoietic lineages, whereas other cytokines (erythropoietin, thrombopoiesis-stimulating factors) may be needed to fully exploit the proliferative stimulus of GM-CSF on BFU-e and CFU-meg. After treatment discontinuation, the proliferative activity drops to values lower than before treatment, suggesting a period of relative refractoriness of marrow progenitors to the cytocidal effect of cell cycle-specific antineoplastic agents. This hypothesis is under evaluation in a controlled clinical trial where GM-CSF is given prior to chemotherapy.

[Carcinoma of the breast: information on tumoral disease in hospitalized patients]. / Carcinoma della mammella: l'informazione sulla malattia tumorale nelle pazienti ospedalizzate.

Information on their disease, received from 100 patients hospitalized for breast cancer, is assessed. Through analysis of the replies to a questionnaire on information obtained before and after treatment, it emerges that 60% of the patients had received information about the disease and that 45% knew that the diagnosis was cancer. The study confirms the importance for physicians to use uniform language, consistent with the personality of each patient.

Chemotherapy with estrogenic recruitment and surgery in locally advanced breast cancer: clinical and cytokinetic results.

Thirty-nine patients with locally advanced breast cancer (T3b-4, N1-3 or inflammatory carcinoma) received 3 cycles of induction chemotherapy with estrogenic recruitment before surgery. The therapeutic regimen consisted of diethylstilbestrol (DES) orally on days 1-3, 5-Fluorouracil + Doxorubicin + Cyclophosphamide on day 4 q 21 days (DES-FAC). After surgery 6 additional cycles of chemotherapy (3 DES-FAC alternating with 3 DES-CMF with Methotrexate + F and C as in FAC) were administered. The objective response rate was 71.8% with 15.4% CR, and 56.4% PR; after surgery 36/39 (92.3%) patients were rendered disease-free. So far, 13 of 26 patients in stage IIIb have relapsed (9 of 13 with inflammatory carcinomas). Three-year survival and progression-free survival are 60% and 53.5%, respectively. Twenty-three of the 39 patients were subjected to serial tumor biopsies during the first DES-FAC regimen to allow for tumor-cell kinetic studies during DES and chemotherapy. A significant estrogenic recruitment occurred in 16 patients (69.6%), irrespective of estrogen-receptor status. At surgery, 3-4 weeks after induction chemotherapy, tumor proliferative activity was significantly depressed in comparison to basal values. These results indicate that breast cancer cells can be recruited in vivo with DES and that chemotherapy following estrogenic stimulation is effective and feasible with acceptable toxicity.