Autologous CD133+ cells augment the effect of portal embolization.

AIM: The standard to treat liver tumors is a resection. When the future liver remnant (FLRV) is below 30% (healthy livers) or 40% (cirrhotic livers or previous chemotherapy), surgery carries the risk of severe complications. Portal vein embolization (PVE) gained a worldwide diffusion as a tool to augment the FLRV. Cell therapies are recent players at the frontiers of medicine. This study presents a clinical experience to evaluate the synergistic effect of combined PVE and autologous CD133+ cells coadministration. METHODS: Sixteen patients have been enrolled in the study up today. Inclusion criteria were: primary or metastatic liver malignancy with a FLRV<30% or 40%. A baseline volumetric CT-scan was obtained. CD34+ were mobilized to the blood stream by G-CSF administration and collected by immunomagnetic separation. Simultaneously with PVE, cells were administered to the non occluded liver segments. Follow-up CT scans were taken at 30th post treatment day. RESULTS: The patients (N.=6) showed an increased volume gain (Mann-Whitney test P<0.001, two sided) compared to a set of cases whose treatment was PVE only (N.=10). DISCUSSION: The use of autologous stem cells as an augmenter of liver regeneration has a clinical potential to improve the resectability of liver tumors.

Circulating endothelial cells and endothelial progenitors as predictive markers of clinical response to bevacizumab-based first-line treatment in advanced colorectal cancer patients.

BACKGROUND: Despite the consistent clinical results demonstrated by studies on anti-angiogenic drugs targeted against the vascular endothelial growth factor in metastatic colorectal cancer (mCRC) patients, no specific direct/indirect biomarker of their efficacy has been validated. In this field, circulating endothelial cells (CECs) and endothelial progenitor cells (CEPs) have recently been proposed as noninvasive biomarkers. PATIENTS AND METHODS: The absolute numbers of CEPs, total CECs (tCECs) and their resting (rCECs) and activated subsets were evaluated by multiparameter flow cytometry in 40 mCRC patients at baseline and before the administration of the third and sixth course of a bevacizumab-based first-line treatment. Fifty healthy subjects were utilized as control. RESULTS: The overall response rate was 80%, overall clinical benefit was 90% and median progression-free survival (PFS) was 13.8 months. In our patients, tCECs and rCECs were significantly increased compared with healthy subjects. The patients who achieved a radiological response showed, at baseline, a significant decrease of rCECs and a trend in decrease of tCECs in comparison with patients not achieving response. Finally, a baseline absolute number of tCEC and rCEC <40 cells/ml was evidenced in patients with a longer PFS. No correlation was found regarding CEP. CONCLUSIONS: Our study suggests significant correlations between both tCEC and rCEC baseline levels and the antitumor efficacy of a bevacizumab-based combination therapy in mCRC patients, thus confirming that these biomarkers could be used in the clinical setting as an early predictor of tumor response.

UFT as maintenance therapy in patients with advanced colorectal cancer responsive to the FOLFOX4 regimen.

BACKGROUND: In advanced colorectal cancer (ACC), FOLFOX4 has been accepted as a standard chemotherapeutic regimen. Due to the neurotoxicity induced by oxaliplatin, which occurs in about 50% of patients during the 6-month FOLFOX4 regimen, and the frequent need for hospitalization, alternative regimens may be required. We aimed to determine whether a 'maintenance' therapy with oral UFT (uracil-tegafur) in patients responding to FOLFOX4 is able to maintain the response and improve the quality of life (QoL) as a result of the outpatient regimen and lower psychological distress. METHODS: Untreated patients with ACC who did not progress after 6 months of FOLFOX4 received oral UFT until disease progression or unacceptable toxicity. The aim of the study was to maintain the response obtained with the FOLFOX4 regimen for at least 6 months. The secondary objective was to evaluate QoL during the two different treatment regimens utilizing the 36-item Short Form Health Survey (SF-36). RESULTS: From January 2003 to August 2004, out of the enrolled 30 patients [22 males and 8 females; 2 patients with a complete response (CR), 14 patients with a partial response (PR) and 6 patients in stable disease (SD) after 6 months of FOLFOX4] 22 continued therapy with UFT until progression without significant toxicity; the remaining 8 patients (27%) had progressive disease (PD) during or at the end of FOLFOX4 and were treated with other regimen. After 6 months of UFT, 4 patients (13%) had CR, 6 patients (20%) PR and 4 patients (13%) SD; 16 patients (53%) progressed. Median follow-up was 31 months [interquartile range (IQR): 20-31 months]; 14 patients died of PD. The median time to progression was 13.9 (IQR: 7.7-20.1) months and the median survival time was 31 months (IQR: 20-31 months). Evaluation of QoL demonstrated a trend towards better QoL during UFT treatment. CONCLUSIONS: These results support the feasibility of maintaining good response and improving QoL (measured by SF-36) with an oral fluoropyrimidine after combination chemotherapy in ACC patients; moreover, since UFT can be used orally, patient compliance is increased and the duration of hospitalization can be decreased.

Cell kinetics in human malignancies studied with in vivo administration of bromodeoxyuridine and flow cytometry.

Bromodeoxyuridine (BrdUrd) is a pyrimidine analogue which is incorporated into the DNA of proliferating cells. When in vivo BrdUrd infusion is coupled with bivariate flow cytometry to measure cell BrdUrd incorporation and DNA content, both the percentage of DNA-synthesizing cells [BrdUrd-labeling index (LI)] and the DNA synthesis time (TS) can be determined on the same tissue sample. From experimentally determined LI and TS, the potential doubling time of the population and its cell production rate are calculated. To ascertain whether the BrdUrd infusion method is clinically feasible and if data are reliable, we studied patients with leukemia, refractory anemia, multiple myeloma, and brain and gastric tumors. The BrdUrd incorporation data were compared with those determined on duplicate samples with the techniques conventionally used for LI and TS values, i.e., 3H- and 14C-labeled thymidine autoradiography, respectively. The complete BrdUrd procedure takes 6-9 h, and no immediate toxicity from BrdUrd administration has been observed. In an 8-month period, 154 patients were studied. Successful LI and TS determinations were obtained in 78.9 and 59.7% of cases, respectively, more often in hematological than in solid tumors. The values for LI and TS assessed with the BrdUrd technique were very close to those found with 3H- and 14C-labeled thymidine autoradiography (r = 0.88, P less than 0.005, and r = 0.89; P less than 0.005, respectively). The potential doubling time and production rate were accordingly similar. These data indicate that in vivo BrdUrd infusion coupled with flow cytometry measurements can be performed in clinical settings and that this method is reliable. It could be used for kinetic studies in clinical trials aimed at evaluating the prognostic relevance of proliferative parameters and for planning radio- and/or chemotherapy.

Effects of desferrioxamine on normal and leukemic human hematopoietic cell growth: in vitro and in vivo studies.

The iron chelator desferrioxamine (DFO) has been previously shown to be an S-phase inhibitor of cell proliferation. To investigate its potential as an antileukemic drug, we first studied the effects of DFO on the in vitro growth of normal human hematopoietic progenitors (CFU-GM and BFU-E) and clonogenic cells from human leukemic cell lines. Then we evaluated the effects of DFO on progression of leukemia refractory to conventional therapy in two individuals. Micromolar concentrations of DFO determined a dose-dependent inhibition of normal progenitor growth, with inhibitory dose 50% (ID50) for CFU-GM and BFU-E being 6.7 and 5.5 microM/liter, respectively. Marked inhibitory effects were observed on clonogenic cells from HL-60 (ID50 = 1.4 microM/liter) and U-937 (ID50 = 3.6 microM/liter) human leukemic cell lines grown in semisolid medium. When DFO was given intravenously to a patient with lymphoid blast crisis of chronic myelogenous leukemia, a marked reduction in circulating blast count was observed. On the contrary, no in vivo effect was observed in a patient with acute nonlymphocytic leukemia having transfusional iron overload. We conclude that: (a) DFO is an inhibitor of both normal and leukemic myeloid cell proliferation in vitro; (b) our limited in vivo observations and a previous case study suggest that intravenous administration of DFO to patients with normal to low plasma iron may result in leukemic cytoreduction in vivo.

Cell kinetics with in vivo bromodeoxyuridine and flow cytometry: clinical significance in acute non-lymphoblastic leukaemia.

From 1986 to 1988, 54 consecutive previously untreated patients with acute non-lymphoblastic leukaemia (ANLL), median age 54 years, were treated for remission (CR) induction with vincristine and intravenous medium-dose cytarabine sequentially followed by daunomycin and infusion cytarabine. CR patients received intensive consolidation. Bone marrow blast kinetics was studied before therapy with in vivo bromodeoxyuridine and bivariate flow cytometry. CR rate was 70.2%, median CR was 13.2 months, responsive patient survival was 16.9 months and overall survival was 9.2 months. Besides lower median age, the 33 responsive patients also had shorter potential doubling time (Tpot) and greater cell production rate (PR) than the 14 unresponsive patients (mean values = 10.9 vs. 25.4 days, P less than 0.05, and 14.7 vs. 8.9 cells/100 cells/day, P less than 0.02, respectively), due to a higher mean labelling index (7.0 vs. 5.1%, P less than 0.05) and/or to a shorter mean DNA synthesis time (13.6 vs. 18.6 hours, P less than 0.05). Besides lower white blood cell count and bone marrow blast percentage, patients who experienced CR longer than 13.2 months had shorter Tpot (P less than 0.05) and a greater PR (P less than 0.02) than those who relapsed before this time. These data indicate that kinetic parameters have prognostic relevance in ANLL patients treated with sequential vincristine, cytarabine and daunomycin for inducing CR and with intensive consolidation after CR, a high proliferative activity being a favourable factor for both CR achievement and its duration.

Postremission chemotherapy in adult acute non-lymphoblastic leukaemia including intensive or non-intensive consolidation therapy.

From October 1983 to December 1988, 84 consecutive adult patients with acute non-lymphoblastic leukaemia (ANLL; median age = 51 yr) were uniformly treated to induce remission (CR) with intravenous vincristine and cytarabine sequentially followed by daunomycin and infusion cytarabine. From October 1983 to December 1985 consolidation was non-intensive (2 courses with the same drugs used for induction) (protocol ANLL83: 27 patients, median age = 45). From January 1986 to December 1988 consolidation was intensive (4 courses of vincristine and cytarabine sequentially followed by etoposide plus thioguanine or amsacrine) (protocol ANLL86: 57 patients, median age = 57). Excluding early deaths, the CR rate was 71.6%. Median CR, responsive patient survival and overall survival were 11.1, 15.3 and 8.5 mo, respectively. For protocol ANLL83 and ANLL86, median CR was 8.7 and 13.2 mo (P less than 0.05) and median survival was 13.1 and 16.9 mo (P less than 0.05) for responders and 8.0 and 9.2 mo (P not significant) for all patients. Intensive consolidation including drugs not previously used for induction seems to prolong CR duration and responder survival in adult ANLL.

Response to first-line chemotherapy and long-term survival in patients with multiple myeloma: results of the MM87 prospective randomised protocol.

In this study we evaluated whether a good response to conventional chemotherapy, i.e. a significant tumour reduction, is a prerequisite for improved survival in multiple myeloma (MM). Between January 1987 and March 1990, 341 consecutive previously untreated patients with MM received chemotherapy within the prospective, multicentre, randomised Protocol MM87. Of these, 258 patients were evaluable for both response and long-term survival and 244 (94.6%) have died. The median survival of all patients was 40 months (6-162 months). The median survival did not differ between patients who had complete response (CR) (50 months (9-162 months)), partial response (PR) (46 months (8-147 months)) or stable disease (SD) (41 months (7-135 months)). The median survival was shorter (13.6 months (6-135 months)) (P<0.0001) in patients whose disease progressed while they were receiving first induction chemotherapy. Causes of death were more frequently (P=0.04) related to MM in patients who had progressive disease (PD) than in patients who had a CR or PR or SD. The main clinical and laboratory characteristics were similar in the four groups. These data indicate that patients who maintain SD during first-line chemotherapy have a prognosis similar to that of patients who attain a response. Only patients whose disease progresses have a distinctly worse outcome.

Circulating progenitor cell release and functional characterization after topotecan plus G-CSF and erythropoietin in small cell lung cancer patients.

Topotecan is a new antineoplastic agent active in ovarian cancer, with promising activity in small cell lung cancer and predictable toxicity. As a part of our ongoing attempt to optimize the use of disease-specific drugs as circulating progenitor cell (CPC) priming in solid tumors, we have evaluated the effects on CPC release of single-agent Topotecan followed by granulocyte colony-stimulating factor (G-CSF) + human recombinant erythropoietin (rhEPO), together with the cell cycle status of the collected CD34+ cells. Ten pretreated patients with small cell lung cancer received Topotecan (1 mg/m2, i.v. for 5 consecutive days) followed by G-CSF (5 microg/kg/day, s.c.) + rhEPO (10,000 I.U. daily, s.c.), starting 24 h after Topotecan. The combination was well tolerated and no relevant side-effects were recorded. On day +10 (range +9 to +11) after the last dose of Topotecan, the median WBC count and the CD34+ cell peak were 8.2 x 10(3) microl (range 4.9-13.9) and 55 microl (range 28-75), respectively. Using flow cytometry, a detailed cell cycle analysis was performed on these CD34+ cells. The cell cycle distribution was determined by DNA content coupled with bromodeoxyuridine incorporation analysis. Apoptosis was evaluated by quantitating DNA strand breaks. The percentage of CD34+ cells in active S-phase was 10.2+/-5%, while early apoptotic CD34+ cells were detected in a low percentage (5.5+/-3%). Topotecan followed by G-CSF + rhEPO mobilizes CPCs effectively. This sequence exerts a stimulation on CD34+ cell cycle with a protective effect from chemotherapy-induced apoptosis. Taken together, these data could be of value for the incorporation of Topotecan, as well as of the combination of G-CSF and rhEPO, into high-dose chemotherapy programs with CPC support.

A prospective, controlled, nonrandomized study on prophylactic parenteral dichloromethylene bisphosphonate (clodronate) in multiple-myeloma.

Bone resorption by osteoclasts causes neoplastic bone disease, which is a significant cause of death in multiple myeloma (MM). Counteracting bone resorption with prophylactic bisphosphonates has delayed bane disease, and this is expected to improve survival. Between January, 1987 and March, 1990, 341 evaluable previously untreated, consecutive patients with MM entered a prospective, multicenter study in which cytostatic therapy was randomized. The first 148 patients recruited were not planned for prophylaxis and the following 193 were scheduled to receive parenteral, prophylactic clodronate. Clodronate was administered at a dose of 600-1000 mg/4-6 weeks and was started at diagnosis and continued throughout survival time. Data on clodronate prophylaxis were evaluated on both an intention-to-treat and a compliance analysis basis. The rate of response and the duration of response were independent of clodronate prophylaxis. Progression of skeletal disease occurred less often in patients who received the drug than in those who were not given prophylaxis (50.5 vs 34.8%; p<.02 by compliance analysis). Survival was longer for patients on clodronate prophylaxis than for those who were not planned for (p<.02 by intention to-treat-analysis) or for those who did not receive clodronate prophylaxis (p<.009 by compliance analysis). Local pain associated with i.m. administration was the only significant side effect of clodronate. Parenteral clodronate prophylaxis prolongs survival in MM, probably because it allows better control of bone disease and reduces deaths related to it.

Doubling of the epirubicin dosage within the 5-fluorouracil, epirubicin and cyclophosphamide regimen: a prospective, randomized, multicentric study on antitumor effect and quality of life in advanced breast cancer.

In metastatic breast cancer (MBC) doubling the epirubicin (EPI) dose intensity (DI) within the FEC (5-fluorouracil, EPI, cyclophosphamide) regimen could increase the response rate (RR) and ameliorate the quality of life (QoL) over standard FEC. From May, 1995, 74 consecutive patients with MBC were randomly treated with 6 courses of two FEC regimens containing 60 (60FEC) or 120 (120FEC, supported by primary G-CSF) mg/m2 of EPI. Drugs were administered every 21 days. The QoL was assessed over and after treatment by the EORTC QLQ-C30 (VER 2.0) and QLQ-BR23 questionnaires, compiled by the patient, and the Spitzer's QL-index, compiled by the physician. The study was prematurely closed in May, 1997, due to RR and QoL data of 4th interim analysis. The delivered EPI DI was 20.0 and 37.9 mg/m2/week in 60- and in 120FEC, respectively. Among the two regimens, there was no statistically significant difference in RR or in improvement of baseline overall QoL. With respect to 60FEC patients, the 120FEC patients had longer time to progression (19.2 vs 13.1 mos, p=0.04). Over baseline, the 120- but not the 60FEC patients had significantly greater pain decrease and lower deterioration of body image. In MBC, both 60- and 120FEC regimens furnished the same RR and improvement in overall baseline QoL. With respect to 60FEC patients, the 120FEC patients experienced longer time to progression. Over baseline, pain decrease and preservation of body image were also greater in these patients.

Advanced breast-cancer - a randomized study of different doses of epirubicin associated with fixed doses of cyclophosphamide and 5-Fluorouracil.

A moderate increase in the dose of anthracycline could be feasible and of clinical benefit in advanced breast cancer. Between April 1991 and April 1994, 69 consecutive patients with recurrent or metastatic breast cancer were randomly treated with two regimens, including different dosages of epirubicin (75 versus 100 mg/m(2)) associated with the same dosage (600 mg/m(2)) of cyclophosphamide and 5-fluoruracil (75-FEC vs 100-FEC). Patients were planned to receive 6 courses at 21 day-intervals. Thirty-six patients received the 75-FEC regimen and 33 received the 100-FEC regimen. The two groups were comparable for age, menopausal status, disease-free interval, previous therapy, performance status and sites of disease: Over the whole study, the 100-FEC regimen has allowed a 18% actual increase in the epirubicin dosage over the 75-FEC regimen. Overall response rate was 56% for the 100-FEC and 51% for the 75-FEC, with the 100-FEC inducing some more complete responses than the 75-FEC (38% vs 23%). Survival (but not time to progression) tended to be longer with the 100- than with the 75-FEC (median: 20 vs 13 mos, p<0.09). Nonhematologic side effects Were similar. Hematologic toxicity was slightly higher with 100- than with 75-FEC, with granulocyte colony stimulating factors used to recycle in the scheduled time in the 15 and 4% of courses, respectively.

Cell cycle status and apoptosis of hematopoietic progenitor cells released into the peripheral blood after taxanes and granulocyte colony-stimulating factor in breast cancer patients.

Paclitaxel and its analogue docetaxel show a significant antitumor activity, particularly evident in breast cancer. Paclitaxel has also been proved to be effective as a peripheral blood progenitor cell (CPC) mobilizing agent. To optimize the use of active, disease-specific drugs as CPC priming, we have evaluated the effects of either paclitaxel or docetaxel both at standard dosages and followed by granulocyte colony-stimulating factor (G-CSF), on circulating CPC release and function in 18 patients with advanced breast cancer who had failed previous anthracycline-based regimens. The reported differences in biological behaviour between bone marrow and blood-derived hematopoietic progenitor cells and the ability of both paclitaxel and docetaxel to induce apoptosis, prompted us to simultaneously evaluate the cell cycle perturbations induced on CD34+ cells. Median CD34+ peaks were 24 microl (range: 10-58) in the paclitaxel-treated patients and 39 microl (range: 17-91), respectively, in the patients who received docetaxel. After paclitaxel, the percentage of CD34+ cells in S-phase was low (bromodeoxyuridine, BrdU, labelling index = 3.4+/-2%) with a concomitant presence of early apoptotic cells (8.1+/-3%). On the contrary, after docetaxel, the percentage of CD34+ cells in S-phase was higher (BrdU labelling index = 14.5+/-4%, p<0.05 vs. paclitaxel), while early apoptotic cells were detected at a similar rate (8. 6+/-3%, p = n.s. vs. paclitaxel). In conclusion, when used at standard dosages, with respect to paclitaxel + G-CSF, docetaxel + G-CSF is a more satisfactory tool to mobilize CPC and to induce them into the cell cycle. These data should be taken into account when combinations of docetaxel with other agents are explored as CPC mobilizing regimens for autografting.

A short-term infusion regimen of Cisplatin, 5-Fluorouracil and L-folinic Acid in advanced head and neck-carcinoma.

Treatment of advanced head and neck cancer is still a matter of controversy. Although current chemotherapy regimens are able to induce high response rates, they have not shown improved survival. We employed a combination of cisplatin (CDDP), 5-fluorouracil (5FU) and 1-folinic acid (1-FA) in a 6-hour infusion schedule easy to administer on an outpatient basis. 49 patients have been included to date. The treatment plan consists of 5-FU (375 mg/m(2)) plus 1-FA (100 mg/m(2)) in a 4-hour i.v. infusion followed by a 2-hour i.v. administration of CDDP (20 mg/m(2)). This therapy was repeated for five consecutive days and recycled every 3-4 weeks. Out of 46 evaluable patients there were 6 complete responses (CR) and 23 partial responses (PR) for an overall response rate of 63%. Overall survival was 10.2 months (mean). Untreated patients had a higher probability of response as well as patients with naso-oropharyngeal primary tumor. Toxicity was generally mild with leukopenia, anemia and vomiting being the most frequent side effects. In conclusion, this combination appears well tolerated and active in the palliation of advanced head and neck cancer. However we think that increasing dose intensity of standard regimens and experimental new therapeutic approaches are needed to improve the clinical outcome of this disease.

Paclitaxel in anthracycline-treated breast cancer patients.

Between May 1995 and July 1997, paclitaxel (TX) (175 mg/m2 by 3 h i. v. infusion every 21 days) was administered to 70 consecutive patients (median age: 57 years) previously treated with the FEC regimen (cyclophosphamide and 5-fluorouracil, 600 mg/m2, plus epirubicin, 60 or 120 mg/m2) as an adjuvant setting or as a first-line therapy for metastatic disease. Sixty-eight patients were evaluable for response, while two died early. Patients received a median of 4.7 (3-12 course) of TX for a total of 211 courses. The overall response and stable disease rate was 54% in 11 patients, who relapsed following adjuvant FEC, and 60% in 57 patients, who received FEC as first treatment for their metastatic disease. No complete respose was obtained. In patients pretreated for metastatic disease, response and stable disease rates were similar irrespective of previous response to FEC. Main hematologic toxicity of TX was of short duration, grade II/III leukopenia (86% of patients) and non-hematologic toxicity was grade II/III peripheral neuropathy, related to the cumulative dose of TX. At this schedule, TX offers a significant rate of partial responses or disease stabilization in patients with metastatic breast cancer previously treated with FEC.

Sequential docetaxel and vinorelbine for patients with advanced breast cancer previously treated with anthracyclines: a phase II study.

With respect to their association, sequential non-cross-resistant cytostatics could be better tolerated and allow a similar antitumor effect. From January, 1998 to July, 1999, 42 consecutive patients with metastatic breast cancer (MBC) previously treated with anthracyclines as adjuvant- or first-line therapy entered a phase II multicenter study where docetaxel (TXT, 100 mg/m2/3 weeks/4 times) was followed by vinorelbine (VNR, 25 mg/m2/10 days/8 times). Median follow-up is 21 months and 22/42 patients have died. Four patients did not complete therapy due to early death, grade 3-4 gastrointestinal mucosytis (2 patients) and grade 3 neurotoxicity during TXT therapy. Overall response rate was 57%, and 5% of patients had stable disease. There were 38% of therapy failures due to non-evaluability (10%) or progressive disease (28%). Median time to progression and survival are 10.1 and 17.1 months. Sequential TXT-VNB is a suitable strategy for MBC patients previously treated with anthracyclines. It avoids haematologic toxicity and allows a good antitumor effect. Careful monitoring of intestinal mucosytis is required.

Immunocytochemical detection of proliferating cells in the rat tooth germ by monoclonal antibodies against 5-bromo-2'-deoxyuridine.

5-Bromo-2'-deoxyuridine incorporated into DNA synthesizing cells in vivo is detected by a monoclonal antibody. The results are similar to those obtained with cytoautoradiography, but show variance with data from some past autoradiographic studies. This immunocytochemical technique may be a useful tool for study of cell kinetics in the oral tissues.

Cell kinetics aspects of human malignant neuroepithelial tumors: a follow-up study.

The prognostic value of proliferative activity and DNA distribution (ploidy), determined by flow cytometry (FCM), was evaluated in 38 cases of human malignant neuroepithelial tumors. No statistically significant correlation was found between flow cytometric data and clinical outcome. In particular, there was no significant difference between mean survival in cases with percentage of cells in S-phase lower and higher than 5%, respectively. In 21 cases with unimodal DNA distribution, the mean survival was 11.7 months; in 17 cases with bimodal DNA distribution, the mean survival was 12.5 months. The difference was not statistically significant. In our experience, proliferative activity and ploidy do not correlate well with the clinical course and survival of patients with malignant neuroepithelial tumors. However, application of FCM may provide, aside from histopathologic examination, additional biologic information that may be valuable in understanding the variation observed in the course of individual patients.

Myeloprotective effect of early primary granulocyte-colony stimulating factor during six courses of intensified 5-fluorouracil, epirubicin and cyclophosphamide (120FEC) chemotherapy for advanced breast cancer. Cooperative Group of Study and Treatment of Breast Cancer.

AIMS AND BACKGROUND: The neutropenia induced by six courses of an intensified FEC regimen is expected to be checked by early primary administration of G-CSF which is stopped eight days before the next chemotherapy course. Less information is available about megakaryocytic and erythroid toxicity over six courses. METHODS AND STUDY DESIGN: Sixty-six consecutive patients with metastatic breast cancer completed six courses of a randomized treatment with two FEC regimens administered every 21 days, in which 600 mg/m2 of cyclophosphamide and 5-FUwas associated with 60 or 120 mg/m2 of epirubicin (60FEC, 35 patients, vs 120FEC, 31 patients). 120FEC was supported by early primary G-CSF (days 4 to 13). Blood counts were obtained seven times during each course. RESULTS: The non-hematologic toxicity over 364 courses was similar in 60FEC and 120FEC. No cumulative hematologic toxicity was observed for white blood cells (WBC) and platelets (PLT), while for hemoglobin (Hb) a somewhat higher cumulative toxicity was observed with 120FEC than with 60FEC. WBC, PLT and Hb grade III-IV toxicity occurred in 40.1% and 45.6% (P=ns), in 23.1% and 0.8% (P <.0001) and in 15.6% and 3.0% (P <.005) of the two regimens, respectively. There were no febrile or hemorrhagic episodes. The epirubicin relative dose intensity delivered was 1.95 in 120FEC with respect to 60FEC. CONCLUSIONS: Our G-CSF schedule permitted to deliver six courses of 120FEC without any clinically relevant side effects. Grade III-IV leukopenia was similar with 120FEC and 60FEC, while grade III-IV thrombocytopenia and anemia occurred more often with 120FEC than with 60FEC.