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Background: Metastatic soft tissue sarcoma (STS) prognosis remains poor and few cytotoxic agents offer proven efficacy. This randomized open phase III study examines whether high-dose (HD) chemotherapy with peripheral blood stem cells (PBSCs) could improve overall survival (OS) of chemosensitive patients., Patients and Methods: Advanced STS patients aged 18-65 years received four courses of standard mesna, adryamycin, ifosfamide and dacarbazine (MAID) treatment. Chemotherapy-responding patients and patients with at least stable disease amenable to complete surgical resection were randomized to receive standard dose (SD) with two successive MAID cycles or HD treatments of one MAID then MICE intensification: mesna (3.6 g/m(2), day 1-5), ifosfamide (2.5 g/m(2), day 1-4), carboplatin [area under the curve (AUC) 5/day 2-4] and etoposide (300 mg/m(2), day 1-4) with PBSC reinjection at day 7., Results: From 2000 to 2008, 207 patients received four cycles of MAID and 87 assessable patients were randomly assigned to receive the following: 46 SD, 41 HD, with 45 and 38 maintained for analyses after secondary centralized histological review. Futility analyses led to study closure in November 2008. Three-year OS was 49.4% for the SD group versus 32.7% for HD arm, hazard ratio= 1.26, 95% confidence interval 0.70-2.29; progression-free survival was 32.4% and 14.0%, respectively. HD treatment led to higher grades 3-4 toxicity., Conclusion: This study failed to show an OS advantage for advanced STS patients treated with dose-intensified chemotherapy with PBSC.

Background: Neoadjuvant chemotherapy improves overall survival and renders possible breast-conserving treatment in locally advanced breast cancer. It was necessary for this method to be evaluated in operable breast tumors too large to be treated immediately by conserving surgery. Initial results of this randomized trial were published in Annals of Oncology (1991)., Patients and Methods: Women with T2 > 3 cm or T3 N0-1 M0 breast tumors were treated by either initial mastectomy followed by adjuvant chemotherapy, or neoadjuvant chemotherapy followed by adjusted locoregional treatment. Chemotherapy was the same in the two arms. The prognostic and predictive factors of response to chemotherapy were analyzed., Results: Conserving treatments were performed in 63% at the end of neoadjuvant chemotherapy and this rate had decreased to 45% at the median follow-up of 124 months. Survivals are identical in the two treatment groups. Initial clinical tumor size < 40 mm, IHC-ER < 10% and Mib1 > 40% are predictive of tumor response to chemotherapy by uni- and multivariate analyses. For outcome prediction, c-erb-B2 > 0% is the independent prognostic factor for overall and metastasis-free survivals., Conclusion: Breast-conserving therapy can be performed in more than half of all cases without alteration of survival, despite a non-negligible rate of local recurrences.

Purpose: A randomized unblinded phase III trial was designed to determine the ability of granulocyte-macrophage colony-stimulating factor (GM-CSF) to accelerate recovery from febrile neutropenia induced by chemotherapy., Patients and Methods: A total of 68 patients with febrile neutropenia following chemotherapy defined as axillary temperature greater than 38 degrees C and absolute neutrophil count (ANC) less than 1 x 10(9)/L were included. After stratification for high- and low-risk chemotherapy to induce febrile neutropenia, treatment was randomized between GM-CSF at 5 microg/kg/d or control, both being associated with antibiotics., Results: GM-CSF significantly reduced the median duration of neutropenia from 6 to 3 days for ANC less than 1 x 10(9)/L(P < .001) and from 4 to 3 days for ANC less than 0.5 x 10(9)/L (P=.024), days of hospitalization required for febrile neutropenia, and duration of antibiotics during hospitalization. The greatest benefit with GM-CSF appeared for patients who had received low-risk chemotherapy, for which the median duration of ANC less than 1 x 10(9)/L was reduced from 7 to 2.5 days (P < .001) and from 4 to 2 days for ANC less than 0.5 x 10(9)/L (P=.0011), the duration of hospitalization during the study from 7 to 4 days (P=.003), and the duration on antibiotics during hospitalization from 7 to 3.5 days (P < .001). A multivariate analysis, using Cox regression, showed that variables predictive for recovery from neutropenia were GM-CSF (P=.0010) and time interval between the first day of chemotherapy and randomization (P=.030). There was no benefit for GM-CSF when high-risk chemotherapy was considered., Conclusion: GM-CSF significantly shortened duration of neutropenia, duration of neutropenic fever-related hospitalization, and duration on antibiotics during hospitalization when febrile neutropenia occurred after low-risk chemotherapy, but not high-risk chemotherapy.

Aim of the Study: The aim of this randomised trial was to determine advantages and drawbacks of neo-adjuvant chemotherapy in patients with operable breast cancers > 3 cm., Material and Methods: Two hundred and seventy-two women (age 70) with operable breast cancers larger than 3 cm (T2-3/N0-1/M0) were included in a randomised trial from January 1, 1985 to April 30, 1989. Patients in group A (n = 138) were treated by mastectomy and axillary node dissection. Adjuvant chemotherapy was indicated for 104 patients with axillary node involvement (n = 82) or negative oestrogen and progesterone receptors (EPR-) (n = 22). Patients in group B (n = 134) were treated by initial chemotherapy (identical as in group A) followed by locoregional treatment according to the response. Before treatment, the average of clinical tumoural diameter was 43 mm., Results: The median follow-up was 124 months. In group B, 49 patients (36.5%) were resistant to chemotherapy; a conservative breast surgical treatment was performed in the other 84 patients sensitive to chemotherapy (62.6%). In this last subgroup, 19 (22.6%) needed a secondary mastectomy because of locoregional recurrence. Survival rates were not different in groups A and B, but loco-regional recurrences were frequent in group B. At 10 years, the overall survival rate was 60% and half of living patients in group B were free of cancer and with their breast., Conclusion: Neoadjuvant chemotherapy permitted in two-thirds of cases breast conservation treatment, initially considered to be impossible. Locoregional recurrences are more frequent than after mastectomy and adjuvant chemotherapy.

Primary chemotherapy in operable breast invasive carcinoma enables tumour reduction and conservative surgery. In order to search for one or more biological factors capable of predicting tumour behaviour under primary chemotherapy, and subsequent patient survival, an immunohistochemical study was performed with specific antibodies to p53, c-erbB-2 (Her-2/neu), Mib1 (antiKi-67), pS2, GST pi, oestrogen receptors (ERs) and progesterone receptors (PRs). Core biopsies, obtained before primary chemotherapy, were available from a series of 128 breast invasive carcinomas treated between January 1985 and April 1989, with a median follow-up of 93.3 months. Univariate statistical analysis showed that negative ER detection by immunohistochemistry (IHC) was highly correlated with chemosensitivity (P = 0.001). A high percentage of Mib1-positive tumour cells (> 40%), as well as initial tumour size less than 4 cm, were also correlated with tumour responsiveness to chemotherapy (P = 0.009 and P = 0.03). By multivariate analysis IHC-ER, Mib1 and initial tumour size were independent predictors, the last parameter being the most important. Concerning subsequent patient survival, c-erbB-2 overexpression, as detected by IHC, was significant with respect to overall survival (OS) (P = 0.0006), disease-free interval (DFI) (P = 0.03) and metastasis-free interval (MFI) (P = 0.008) by univariate analysis. Furthermore, c-erbB-2 was the major independent prognostic factor for OS and MFI by multivariate analysis.

Purpose: This two-arm, double-blind, randomized trial was conducted to determine the effects of lenograstim, a glycosylated recombinant human granulocyte colony-stimulating factor (rHu-G-CSF), on the hematologic tolerance of patients with sarcoma treated with mesna, doxorubicin, ifosfamide, and doxorubicin (MAID) chemotherapy., Patients and Methods: Forty-eight patients with metastatic or locally advanced soft tissue sarcoma were, following the first cycle of a combination with doxorubicin 60 mg/m2, ifosfamide 7.5 g/m2, and dacarbazine 900 mg/m2, ifosfamide 7.5 g/m2, and dacarbazine 900 mg/m2 given on days 1 to 3, randomized to receive either lenograstim 5 micrograms/kg/d by once-daily injection from day 4 to day 13, or its vehicle. For subsequent cycles, 28 patients continued on the same chemotherapy and lenograstim was systematically given as prophylactic treatment in an open manner., Results: Following the first cycle of MAID, the duration of neutropenia was reduced in patients who received lenograstim as compared with those who received placebo, with a median duration of neutropenia ( < 0.5 x 10(9)/L neutrophils) of 0 days (range, 0 to 3) and 5 days (range, 0 to 10), respectively (P < .001). All patients who received lenograstim had recovered at least 1 x 10(9)/L neutrophils (polymorphonuclear lymphocytes [PMN]) on day 14, compared with only one of 26 in the placebo group (P < .001). The median time to recover this neutrophil level was 12 days (range, 10 to 13) and 17 days (range, 14 to 21), respectively (P < .001). Neutropenic fever occurred in five (23%) and 15 (58%) patients respectively (P = .02). Twenty-eight patients received at least two cycles (median, four) of MAID at the same dose. Toxicity remained constant across all treatment cycles. A progressive increase in thrombocytopenia was noted, with median platelet nadirs of 102 x 10(9)/L at cycle 2 and 19.5 x 10(9)/L at cycle 6, but did not result in significant treatment modifications. Consequently, median relative dose-intensities remained greater than 0.95 for up to six consecutive MAID cycles., Conclusion: Lenograstim significantly improved hematologic tolerance in patients treated with the MAID chemotherapy regimen and, therefore, allowed optimal adhesion to the theoretic doses planned for up to six cycles. Whether such an optimization in relative dose-intensity will result in an improvement of treatment efficacy remains to be determined.

From January 1985 to December 1987, 228 women with breast cancer smaller than 3 cm were treated by surgery +/- radiotherapy. All of them had axillary node involvement (N+) and/or lacked estrogen and progesterone steroid receptors (EPR-). They were randomized in an adjuvant chemotherapy trial comparing 9 intravenous CMF courses (cyclophosphamide, methotrexate, 5FU)--113 patients--to a polychemotherapy consisting of 3 courses of MTV (mitomycin C, thiotepa, vindesine) plus 3 courses of EVM (epirubicin, vincristine, methotrexate)--115 patients. Prognostic factors were well balanced between the two treatment groups. With a 59-month median follow-up, local breast relapses are more frequent in the CMF group, but regional and metastatic recurrences are the same in the two groups. Overall survival is identical. Toxicity is different: alopecia and neurotoxicity are more frequent in the MTV+EVM group, but general and digestive toxicities are equivalent. Haematologic toxicity is greater in the CMF group, requiring more frequent dosage reductions.

Thymidine kinase (TK) was assayed in the cytosol of 210 primary breast cancers to assess its predictive value for response to first line chemotherapy and hormonotherapy. We performed correlations between TK and the other prognosis factors of breast cancer. TK activity is correlated with SBR grading and estrogen receptors. It has a low predictive value for response to chemotherapy and is not useful for hormonotherapy.

In order to reduce, if not completely suppress, late complications of combined chemotherapy and radiotherapy in Hodgkin's disease (HD), MOPP regimen (mechlorethamine, vincristine, procarbazine and prednisone) was replaced by ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine). Ninety-four patients with HD clinical stages I to IIIA with no staging laparotomy were treated by three courses of ABVD followed by radiotherapy. Irradiation was performed on extended fields in 41 cases and on involved fields in 53 others. Consolidation chemotherapy was planned in 67 cases with at least one unfavorable prognostic factor, but achieved only in 33 cases. Seventeen patients relapsed within 1 to 46 months after the beginning of treatment. Ten patients died, 7 of HD and 3 of intercurrent diseases or accident. Disease-free survival rate with a median follow-up of 60 months is 80%. This study showed, on the one hand, many digestive and general side-effects after ABVD and, on the other, a satisfactory hematological tolerance. Furthermore, mediastinitis or cardiovascular complications were not more frequent than with MOPP. These results point out the development and use of better tolerated regimens for initial chemotherapy in HD, without jeopardizing the good results of the treatment.

From 1966 to 1985, 103 patients with a localized (stages I and II) follicular lymphoma (Kiel classification) were treated at the Fondation Bergonié. Clinical staging was performed using, after physical examination, chest X-rays (100%), bipedal lymphangiography (98%) and unilateral bone marrow biopsy (BMB) (51.5%). The patients were then treated by radiotherapy with or without chemotherapy. Overall survival (OS) at 5 and 10 years is 69 and 56.3%, respectively. Relapse-free survival (RFS) is 53.7 and 49%. Unifactorial analysis shows three prognostic parameters to be independently significant in terms of OS: age, stage and B symptoms. In terms of RFS, only 2 factors are significant: age and B symptoms. Multivariate analysis (Cox model) shows that age is a more important prognostic factor than stage.

Sixty-eight women with metastatic breast cancer occurring less than five years positives after the treatment of the primary tumour, with estrogens and/or progesterone receptors (EPR), were randomized. Sixty-four patients were available for evaluation of efficacy and toxicity. Thirty patients received treatment A: tamoxifen 30 mg per day alternating every two weeks with medroxyprogesterone acetate (MPA) 1 000 mg per day orally. Thirty-four received treatment B: tamoxifen 30 mg per day and after relapse, high dosage of MPA alone. The distribution of the evaluable metastasis and the value of the ER are the same in the two groups. The total responses or the responses by metastatic site were as follows: complete response, one case in each treatment group, partial response, 6 and 10 cases, no change, 14 and 17 cases and progressive disease, 9 and 6 cases respectively. The duration of the response was the same in the two groups with a median of 6 months (extremes of 30 and 19 months). Among the patients under protocol B, 19 received MPA after failure of tamoxifen: eight responded (3 partial responses and 5 no change). Toxicity was slight but 2 treatments in group A were discontinued. Alternated sequential hormonal treatment is theoretically attractive for these patients with known and positive EPR but it is not more efficient than the two hormonotherapies applied successively.

From 1972 to 1976, 102 patients with stages I-IIIA Hodgkin's disease (HD) were treated by chemotherapy with cyclophosphamide, vinblastine, procarbazine and prednisone (CVPP: two courses) associated with extended field radiotherapy. Staging included neither laparotomy nor splenectomy (clinical staging). Treatment included neither splenic irradiation nor maintenance therapy. Complete remission was achieved for 98 patients and 11 of them recurred up to 94 months after treatment. Median follow-up of this controlled study is 13 years. Disease free survival (DFS) is 87% at 6 years and 84% at 10 and 15 years. Overall survival is 77% at 10 and 74% at 15 years. Disease specific survival is better (91% at 10 and 87% at 15 years) since only 38% (10/26) deaths were due to HD. The other deaths (16/26) with no evidence of HD were due to second cancer and intercurrent disease. Prognostic analysis of DFS by log-rank test gives significance to the following factors: contiguous extra-nodal involvement (P = 0.008), more than 3 involved sites (P = 0.01), signs of compression (P = 0.02), clinical stage IIIA (P = 0.03), infradiaphragmatic stages I-II (P = 0.04). The potential risk of secondary cancer is difficult to assess.

At Fondation Bergonié, a data base has been settled since ten years concerning all the patient who had been treated there for breast cancer. Collection of these data, compared with those reported in the medical literature, have allowed us to discuss orientations for clinical research, and to establish coherent treatment protocols fitting as much patients as possible. Eventually an interdisciplinary consensus was obtained on clinical trials to be performed, according to prognostic variables defined, and the foreseeable duration of patients inclusion and accrual.

From 1972 to 1976, 95 patients with clinical stages I-IIIA Hodgkin's disease were treated by chemotherapy with cyclophosphamide, vinblastine, procarbazine and prednisone (CVPP) before and after extended field radiotherapy. The CVPP schedule gave: (1) a constant drug dosage for each patient independent of body surface or weight; and (2) a total drug dosage dependent on haematological tolerance, since the treatment was given for 21 days or until the leukocyte count dropped to 2 x 10(9) l-1. The drug dosage per unit body surface (or 'dose density') significantly correlates with the drop in leukocyte count (P less than 0.001) and the tumour regression at the end of the induction course (P = 0.020). Disease-free survival is significantly related to dose density (P = 0.050) but not to dose intensity calculated on the duration of treatment (P = 0.240). However, after exclusion of three marginal recurrences due to border-line radiotherapy, the dose intensity significantly correlates with the disease-free survival (P = 0.031) and with the duration of complete remission (r = 0.870).

The purpose of a randomized trial achieved in a single centre (Fondation Bergonié, Bordeaux, France) was to compare chemotherapy alone (intravenous CMF) versus chemotherapy and hormonotherapy (CMF plus tamoxifen-30 mg per day during 2 years), for patients with stage II breast carcinoma and positive values of estrogen and/or progesterone receptor (EPR) (greater than 10 and greater than 15 fmoles mg protein-1 respectively). Three hundred and thirty four women treated by surgery +/- radiotherapy are included in this trial from 06.01.81 to 12.31.84. No patient is lost for follow-up. Eight are excluded. Three hundred and twenty six patients are evaluable with a 38 month median follow-up. For EPR assay, the dextran charcoal micromethod was used in the same centre. The two groups are identical as far as age, hormonal status, TNM, EPR values, and histological features are concerned. Analysis of results shows a significant improvement of relapse free survival (p = 0.018) and also overall survival (p = 0.04) for the CMF+ tamoxifen group.