We report hereby the results of the french multicentric randomized PEGASE 04 protocol established to evaluate the impact on survival of high-dose chemotherapy over conventional chemotherapy for MBC patients.

Allogeneic peripheral blood hematopoietic stem cell transplantation is being evaluated in a randomized French study comparing the use of peripheral blood stem cells vs. bone marrow graft stem cells. In order to standardize immunohematological (IH) assessment and transfusion practices within our protocol, we made suggestions to 25 allo-transplantation French centers on the following elements: pre-inclusion IH assessment, IH exclusion criteria, transfusion rules, post-transplantation IH surveillance and treatment of hemolysis. The analysis of their responses to our suggestions led us to elaborate recommendations which were approved and implemented by the French Bone Marrow Transplantation Society (SFGM). These recommendations concern the transfusion practice in the general framework of allogeneic hematopoietic stem cell transplantation and can therefore be considered as referential.

Originally developed against the effects of ionizing radiations, amifostine is an organic thiophosphate compound shown able to selectively protect normal tissues against cytotoxic agents in cellular and animal models, without protecting tumor tissues. Amifostine is a prodrug which is dephosphorylated into its active metabolite, a free thiol derivative, by membrane alkaline phosphatase of the target issue. This unique metabolism supports its cellular selectivity and its preferential uptake by normal tissues. In phase II clinical trials, a decreased toxicity has been demonstrated in patients given alkylating agents; however, reduction of the response has not been observed. On the basis of these results, a prospective, randomized, phase III study has been conducted in patients with ovarian carcinoma receiving a combination of cisplatinum and cyclophosphamide. A significant decrease in hematologic, renal and neurologic toxicity was observed in the amifostine-treated patients compared with the control group, and response rates did not significantly differ between the two groups. Insufficient or emerging data are only available for other applications, including either in vitro manipulation of hematopoietic grafts or in vivo treatment of non-Hodgkin's lymphoma, head and neck carcinoma, non-small cell lung cancer and radioprotection. No data are yet available in regard to the potential protective effects of amifostine against mutagenicity and cancerogenicity of both chemo- and radiotherapy.

The aim of this study, carried out at the Institut Paoli-Calmettes (Marseille-France), was to compare, in terms of monetary and non monetary costs, alternate procedures for hematopoietic stem cells collection i.e. peripheral blood stem cells collection (PBSCC) and bone marrow collection (BMC) used in cancer therapies. Monetary costs have been evaluated by calculating the direct costs of the two types of procedures and non monetary costs by comparing anxiety, discomfort and pain of cancer patients submitted to PBSCC or BMC. Patients, randomized (7/1993-2/1994), in view of autologous transplantation, to receive the first procedure or the second one received three self-administered questionnaires to complete before, during and after the procedure. Pain was assessed using visual analogical scale and McGill Pain questionnaire. Anxiety was evaluated by means of State-Trait Anxiety Inventory. Results showed that, under some conditions, presently realized in the current practice, direct costs of PBSCC (10,140 to 13,780 FF) were lower than BMC ones (16,509 FF) and that anxiety and pain experienced by patients submitted to PBSCC, with or without femoral catheter, were significantly less severe than in other group patients (State anxiety, before procedure : p < 0.01 ; pain related to the procedure assessed on VAS : p < 0.001 and total McGill score : p < 0.00001). These findings justify the substitution of bone marrow transplantation by peripheral blood stem cells transplantation, provided there is a demonstration of similar medical efficacy for cancer therapy.

Eighty-four patients with locally advanced, non metastatic squamous cell carcinoma of head and neck or esophagus, were included in a multicentric double-blind randomized trial, comparing goralatide (12.5 or 62.5 micrograms/kg/day, d1-d4) to placebo, associated with carboplatin (400 mg/m2, d1) and 5-fluorouracile (1 g/m2/d continuous IV over 96 hours). Haematological toxicity was analysed on 221 cycles of chemotherapy. All but one patient were evaluable because of early death without haematological toxicity. No significant difference was observed for mean nadir of leukocytes, granulocytes, platelets counts and hemoglobin level. Duration of haematological toxicity was no significantly different for the two groups of patients. Anemia and lymphopenia were more frequent in the goralatide treated patients. Clinical and biological tolerability of goralatide was excellent.

The aim of this study was to compare anxiety, pain and discomfort of cancer patients submitted to two procedures of hematopoietic stem cells collection: peripheral blood stem cells collection (PBSCC) or bone marrow collection (BMC). Patients, randomized (July 1993-February 1994), in view of autograft, to receive the first procedure or the second one, completed self-administered questionnaires before, during and after the procedure. Anxiety was evaluated by State-Trait Anxiety Inventory. Pain was assessed using visual analogical scale (VAS) and McGill Pain questionnaire. Before the procedure, in comparison with PBSCC patients (n = 40), BMC patients (n = 25) experienced more State-anxiety due to the procedure approach (p < 0.01) and more trouble or inconvenience for having to come and stay at the hospital (p < 0.0001). During the procedure, pain related to BMC, as assessed by VAS, is significatively higher than pain induced by PBSCC, whichever the access used (p < 0.001). The McGill total score is twice as high for BMC patients than for patients submitted to PBSCC with femoral catheter (n = 19). The latter patients significatively reported more pain than patients without femoral catheter (n = 21). At the discharge from hospital, 32% of BMC patients judged the procedure quite difficult vs 5% of PBSCC patients (p < 0.05). These results explain a higher acceptability of the peripheral blood stem cells collection.

Novel therapeutic agents in the form of recombinant human hematopoïetic cytokines have been developed. Two of them granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage factor (Gm-CSF) have become widely available commercially. A wholly new technique of supportive care became available to hematologists for patients from whom myelosuppressive chemotherapy represents the optimal treatment. These agents moved directly into large-scale prospective, randomized placebo-controlled studies. The data in support of glycosylated G-CSF as an adjunct to aggressive chemotherapy (ACVB) in lymphoma were provided by a randomized study on 162 patients. Reduction of duration of neutropenia < 500/microliter from 4 day to 1 day was observed during four cycles, as well as the reduction of the duration of infection and time in hospital. The same effects have been described with Gm-CSF and less intensive regimens. Hematopoietic growth factors are accepted as accelerating hematologic recovery after bone marrow grafting. In our randomized study with G-CSF, 315 patients were included. Neutrophil recovery > 1,000/microliter for 3 days was seen earlier in G-CSF treated patients (16 vs 27 d). Time to neutrophil > 500/microliter was reduced (14 vs 20 d). The difference was significant both in autograft and allograft patients. Patients had fewer days of infection and spent less time in hospital. In all randomized studies with G or Gm-CSF no difference in survival was observed at one year. If the only benefit of cytokines is to diminish toxicity, the next goals will be to determine the most appropriate situation in which these agents are most justified and to use these agents in novel approaches. Mobilization of peripheral blood stem cell with hematopoietic factors alone or in association with chemotherapy allows a further improvement in controlling toxicity after transplantation with a median time to neutrophil and platelets recovery of 12 days. Stem cells transplantation will become more easily integrated in dose-intensive treatment.

Seraspenide, a synthetic tetrapeptide, inhibits cell cycle entry of normal hematopoietic stem cells. In mice it protects hemopoiesis against the damage caused by cytarabine, cyclophosphamide and carboplatin. Seraspenide has been given to 53 cancer patients undergoing monochemotherapy with cytarabine and ifosfamide in a double-blind cross-over randomized study. A significant protection of peripheral blood cells has been observed. Seraspenide has been devoided of toxicity.

Thirty two patients with malignant lymphoma - mainly Hodgkin's disease - were randomized for simultaneous treatment by high doses of metenolone during MOPP chemotherapy, to reduce its hematological toxicity. The results have shown surprisingly an increased hemato-toxicity in patients receiving androgens, with significantly more marked anemia and thrombocytopenia, reducing the total doses of anti-cancer drugs. This side effect could be explained by a cycling of the hematopoietic stem-cells and call to some caution when androgens are used during cancer chemotherapy.