Is the small non-cleaved-cell lymphoma histologic subtype a poor prognostic factor in adult patients? A case-controlled analysis. The Groupe d'Etude des Lymphomes de l'Adulte.

PURPOSE: To study the prognostic significance of the small non-cleaved-cell lymphoma (SNCCL) histologic subtype, we compared the outcome of adult patients with SNCCL with that of patients with aggressive lymphoma other than SNCCL by means of two case-controlled studies. PATIENTS AND METHODS: We analyzed the results of the doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) regimen used as a reference scheme in our cooperative study group (Groupe d'Etude des Lymphomes de l'Adult [GELA]) in 52 adult SNCCL patients with no bone marrow (BM) or CNS involvement. Forty-five SNCCL patients younger than 60 years could be compared with two separate case-matched groups of patients with aggressive lymphoma other than SNCCL undergoing the same therapeutic regimen. In the first case-controlled study, matching ensured identity of each risk factor of the age-adjusted International Index (ie, Ann Arbor stage, performance status, and lactate dehydrogenase [LDH] level); in the second study, matching was performed according to the number of presenting risk factors (zero, one, two, or three), regardless of their nature. RESULTS: The 5-year overall survival rates were not significantly different between SNCCL and control patients in both case-controlled studies: 48% versus 51% in the first study, and 48% versus 55% in the second study. CONCLUSION: These results support the thesis that in patients with no bone marrow or CNS involvement, the SNCCL histologic subtype does not confer a prognosis worse than that of other aggressive lymphoma.

Subcutaneous interleukin-2, interferon alfa-2a, and continuous infusion of fluorouracil in metastatic renal cell carcinoma: a multicenter phase II trial. Groupe Français d'Immunothérapie.

PURPOSE: A phase II trial was designed to determine the efficacy and the tolerance of interleukin-2 (IL-2), interferon alfa-2a (IFNalpha), and fluorouracil (5-FU) in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: One hundred eleven patients were included. Patients received subcutaneous IL-2 9 x 10(6) IU daily for 6 days and IFNalpha 6 x 10(6) IU on days 1, 3, and 5 every other week for 8 weeks. 5-FU was administered through a continuous infusion at 600 mg/m2 for 5 consecutive days for 1 week every 4 weeks. RESULTS: The response rate was 1.8% (95% confidence interval [CI], 0% to 4.3%) with only two partial responses (PRs). Toxicity was moderate with 3.6% grade 4 events and two deaths related to treatment. CONCLUSION: This regimen of IL-2, IFNalpha, and 5-FU in patients with metastatic renal cell carcinoma was ineffective. The results raise the question of the dose and schedule of subcutaneous cytokines that must be used in metastatic renal carcinoma.

Granulocyte colony-stimulating factor after intensive consolidation chemotherapy in acute myeloid leukemia: results of a randomized trial of the Groupe Ouest-Est Leucémies Aigues Myeloblastiques.

PURPOSE: Ten years after the first clinical studies, the clinical impact of myeloid growth factors in acute myeloid leukemia is still unclear. One of the objectives of the Groupe Ouest-Est Leucémies Aigues Myeloblastiques (GOELAM) 2 trial was to evaluate the benefit of granulocyte colony-stimulating factor (GCSF) given only after the two courses of intensive consolidation chemotherapy (ICC) used to maintain complete remission (CR). PATIENTS AND METHODS: One hundred ninety-four patients who were in CR after induction treatment were randomly assigned to receive G-CSF (100 patients) or no G-CSF (94 patients) after two courses of ICC (ICC 1, high-dose cytarabine plus mitoxantrone; ICC 2, amsacrine plus etoposide). G-CSF (filgrastim) was administered from the day after chemotherapy until granulocyte recovery at a daily dose of 5 microg/kg. RESULTS: In the G-CSF group, the median duration of neutropenia (< 0.5 x 10(9)/L) was dramatically reduced, both after ICC 1 (12 v 19 days, P <.001) and after ICC 2 (20 v 28 days, P <.001). The median duration of hospitalization was also significantly shorter in the G-CSF group (24 v 27 days after ICC 1, P <.001; 29 v 34 days after ICC 2, P <. 001). The median duration of intravenous antibiotics was significantly reduced after ICC 1 and ICC 2, and the median duration of antifungal therapy was significantly reduced after ICC 1. However, the incidence of microbiologically documented infections, the toxic death rate, the 2-year disease-free survival, and the 2-year overall survival were not affected by G-CSF administration. Moreover, the median interval between ICC1 and ICC2 was reduced by only 2 days, and the number of patients undergoing ICC2 was not increased in the G-CSF arm. CONCLUSION: G-CSF should be administered routinely after ICC to reduce the duration of neutropenia and hospitalization. However, G-CSF did not seem to significantly increase the feasibility of this two-course program or modify overall outcome.

A double-blind, randomised comparison of the anti-emetic efficacy of two intravenous doses of dolasetron mesilate and granisetron in patients receiving high dose cisplatin chemotherapy.

This multicentre, double-blind, double-dummy, randomised trial was designed to compare the efficacy and safety of single intravenous doses of dolasetron mesilate and granisetron in the prevention of acute emesis and nausea due to high-dose (> or = 80 mg/m2) cisplatin. Single intravenous doses of 1.8 or 2.4 mg/kg of dolasetron mesilate or 3 mg of granisetron hydrochloride were administered in a volume of 50 ml over a 5-min period, beginning 30 min prior to cisplatin (> or = 80 mg/m2) administration. The number and timing of emetic episodes, time to administration of escape anti-emetic medication, severity of nausea by visual analogue scale (VAS), and safety were monitored for 24 h after the start of cisplatin-containing chemotherapy. Investigators' evaluations of overall efficacy and patients' satisfaction with therapy were recorded at the end of the 24-h study period. Of the 474 patients evaluable for efficacy, complete responses were achieved by 54, 47 and 48% of patients given dolasetron mesilate 1.8 mg/kg, dolasetron mesilate 2.4 mg/kg and granisetron, respectively. Statistically, treatment groups had comparable complete and complete plus major responses, times to first emesis, and use of escape medication; patient maximum nausea severity and treatment satisfaction ratings; and physician nausea severity and overall efficacy assessments. For the majority of efficacy endpoints, 1.8 mg/kg dolasetron mesilate produced numerically superior responses compared with the 2.4 mg/kg dose. Gender and prior chemotherapy were significant predictors of complete response; males and chemotherapy-naive patients had higher responses. The overall incidences of adverse events were comparable among the treatment groups; headache and diarrhoea were most common. In conclusion, 1.8 and 2.4 mg/kg of dolasetron mesilate and granisetron (3 mg) were equally effective in preventing nausea and vomiting induced by highly emetogenic cisplatin-containing chemotherapy. In addition, because no additional benefit was observed with 2.4 mg/kg of dolasetron mesilate and numerically greater responses were observed with the 1.8 mg/kg dose, the lower dose of 1.8 mg/kg is optimal for further clinical development.

Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer.

Treating patients with anthracycline- and taxane-pretreated metastatic breast cancer (MBC) represents a significant challenge to oncologists. The tumour-activated oral fluoropyrimidine, capecitabine, is the only treatment approved for these patients. Our study evaluated the efficacy, safety and impact on quality of life (QOL) of capecitabine in this setting. Patients (n=126) with anthracycline- and taxane-pretreated metastatic breast cancer received capecitabine 1250 mg/m(2) twice daily, days 1-14, followed by a 7-day rest period. Median time to progression was 4.9 months (95% Confidence Interval (CI): 4.0-6.4). Thirty-five patients (28%) achieved an objective response (95% CI: 20-36%), including five (4%) complete responses. Median overall survival was 15.2 months (95% CI: 13.5-19.6 months). Capecitabine demonstrated a favourable safety profile, with a low incidence of treatment-related grade 3/4 adverse events. The most common adverse events were hand-foot syndrome and gastrointestinal effects. QOL assessment showed that capecitabine treatment was associated with an increase in mean Global Health Score. Capecitabine is active, well tolerated and improves the QOL of patients with anthracycline- and taxane-pretreated metastatic breast cancer. Based on the consistently high activity demonstrated in clinical trials, capecitabine has become the reference treatment in this setting.

Tumor necrosis factor alpha release is a major biological event associated with rituximab treatment.

INTRODUCTION: In patients with low-grade non-Hodgkin's lymphoma, rituximab (MabThera) produces infusion-related toxicity, including fever, rigors, and chills in greater than 50% of those treated. The majority of these reactions are grade 1 or 2. MATERIALS AND METHODS: In the GELA study LNH98-5, a total of 400 elderly patients with previously untreated diffuse large B-cell lymphoma were randomized to treatment with CHOP or with rituximab plus CHOP (R-CHOP). In a detailed investigation of biological events which may be associated with adverse reactions specific to rituximab infusion, a subgroup of 55 patients (26 in the CHOP group and 29 in the R-CHOP group) were selected for measurement of several biological parameters at baseline and at 1, 4 and 8 h (H1, H4 and H8, respectively) after commencing therapy. For 27 patients, measurements included cytokine and complement levels. RESULTS: Baseline demographic and disease characteristics were similar for patients in both treatment groups. Compared with the CHOP treatment group, patients in the R-CHOP group had significantly higher post-treatment changes in neutrophil, lymphocyte, and monocyte counts, LDH levels, C3a levels, and TNF-alpha levels. In the R-CHOP group, neutrophil levels increased at H4 (P<0.05), lymphocyte levels decreased at H1 (P<0.05), H4 (P<0.001) and H8 (P<0.05), monocytes levels decreased at H1 (P<0.01), LDH levels increased at H4 (P<0.05) and H8 (P<0.01), and C3a decreased at H1 (P<0.01). The most statistically significant changes were observed for TNF-alpha levels: Mean values of TNF-alpha increased more than 250% at H1 and H4 and were still increased by 170% at H8 (P<0.001 at all timepoints). Since only six of the 55 evaluated patients had severe adverse events, it was not possible to correlate severe toxicity with these biological variations. CONCLUSION: This analysis demonstrates that rituximab infusion was rapidly followed by activation of complement, B-lymphocyte cytolysis, and TNF-alpha release.

Auer rods in refractory anemia with excess of blasts: presence and significance.

Auer rods were found in the bone marrow of nine out of 56 patients having all the criteria of refractory anemia with excess of blasts (RAEB). No differences were found in Auer-positive or Auer-negative subgroups according to cytology, kinetics, type of growth in agar, or disease course. Therefore, the presence of Auer rods in the bone marrow of patients with RAEB does not imply overt leukemia.

Idarubicin and high dose cytarabine: a new salvage treatment for refractory or relapsing non-Hodgkin's lymphoma.

Twenty three patients with relapsing (n = 11) or refractory (n = 12) non-Hodgkin's lymphoma (NHL) to one or two prior anthracycline based combination chemotherapy regimens were treated as second or third line regimen with 3 induction cycles of Idarubicin (IDA) (7 mg/m2/d i.v. d1-d3) and high dose cytarabine (HD Ara-C) (1 g/m2/12 h i.v. d1-d3), each cycle was repeated every 3 weeks. Responding patients received a maintenance therapy with monthly cycles of IDA: 15 mg/m2 d1-d3, Etoposide 100 mg/m2 d1-d3, both by oral route. Twenty two patients are evaluable and we observed 13 CR and 1 PR with an overall response rate of 61% (14/23: 95% Cl = 38.5% 80.3%). The median time to progression was 32 months (6.5 - 63 + m.). The response rate to IDA-HD Ara C was not different for patients with (n = 14) or without (n = 9) objective response to the last prior therapy. The main toxicity was hematological: all patients experienced grade 4 neutropenia and 22 patients had grade 4 thrombopenia, but there were no toxic deaths. IDA and HD-Ara-C combination is highly effective in refractory or relapsed. NHL. As hematological toxicity was the limiting factor for further escalation of dose-intensity, further studies might include hematopoietic growth factors support in the therapeutic scheme.

Prognostic factors in ovarian carcinoma in complete histologic remission at second-look surgery.

Prognosis of ovarian carcinoma in complete histologic remission (CHR) at second-look surgery is still controversial. In a series of 83 patients in CHR we studied retrospectively several prognostic factors (age, stage, histologic grade, histologic type, initial residual disease after surgery, CA 125 normalization period) to determine which patients present a high risk of relapsing after CHR and could be included in therapeutic protocols for consolidation treatment. Univariate analysis showed that the combination of CA 125 normalization < 8 weeks with absence of macroscopic tumoral residue after initial surgery permits the definition of a group with a very good prognosis, while for patients with CA 125 normalization period > 8 weeks and an initial macroscopic residual tumor, the prognosis is relatively poor (progression-free survival 100% vs. 47%, at 2 years P < 0.05). Using the Cox multivariate analysis, only the initial tumoral residue is of prognostic significance for progression-free survival; there is no prognostic significance for overall survival. The therapeutic strategy for ovarian cancer may be improved for patients in CHR after second-look surgery by determining those at high risk, making it possible to confine consolidation treatment trials to such a group.

Zoladex as primary therapy in advanced prostatic cancer. A French cooperative trial.

From April 1984 to May 1986, 129 patients with prostate cancer entered a prospective trial with a new LH-RH agonist, Zoladex. Mean age was 72 years (range of 45-94 years) and, in most cases, patients had metastatic disease, not previously treated by chemotherapy or hormone therapy. Patients received a monthly injection of 3.6 mg. Serum testosterone was lowered into the range of castrate levels after 4 weeks of treatment. In 105 evaluable patients at 3 months, a 65% partial response (PR) rate was observed, with 11% stable and 24% progressive disease. Median time to progression was 37 weeks. Analysis of objective criteria revealed 30% PR for prostate volume and 51% CR-PR for prostatic acid phosphatases. Seventeen percent of lytic metastases had recalcified. One hundred twenty-nine patients were evaluable for toxicity. Endocrinological side effects were common: decrease in libido, 92%; impotence, 86%; hot flushes, 48%; and breast swelling or tenderness, 9%. Nonendocrinologic side effects were rare. The treatment is generally well accepted by patients owing to the convenient depot formulation and to the minor side effects.

Intraperitoneal mitoxantrone as consolidation treatment for stage III ovarian carcinoma: a pilot study.

In June 1986 we initiated an intra-peritoneal (IP) mitoxantrone chemotherapy trial as consolidation treatment for ovarian carcinoma in CR or PR after induction therapy (surgery + CHAP combination chemotherapy). Thirty-two patients received 25 mg IP mitoxantrone every 3 wk for 6 months. The most frequent side-effects were abdominal pains; haematological toxicity was minimal. The response was assessed by third-look surgery. In group I patients (patients in histological complete remission at second-look surgery) 12 of 14 evaluable patients remained in CR at the time of third look. Ten of the 12 patients are still alive with no evidence of disease (NED) with a median follow-up of 9.7 months after completion of treatment. In group II patients (microscopic residual disease at second-look surgery), 7 of 9 evaluable patients entered in CR at the time of third look; 6 of the 7 are still alive with NED and with a median follow-up of 14.3 months. In 7 group III patients (macroscopic residual disease at the time of second look) no response to IP therapy was observed and all patients progressed. We conclude that IP mitoxantrone is a valuable consolidation treatment for patients in CR or with minimal residual disease; further follow-up is necessary to assess the impact on duration of remission and survival.

[Carboplatin and cyclophosphamide in stage Ic-IV ovarian carcinoma: retrospective study of 101 cases]. / Carboplatine et cyclophosphamide dans les cancers de l'ovaire de stade Ic à IV: une série de 101 patients.

We report our experience of CBDCA-CPM combination chemotherapy as first line therapy in 101 ovarian cancers. The therapeutic scheme was: initial cytoreductive surgery followed by six chemotherapy cycles (CBDCA 400 mg/m2/d IV dl, CPM 600 mg/m2/d IV dl, dl = d21) and second-look laparotomy. The initial stages were four Ic, three IIa, four IIb, four IIc, 15 IIIa, 28 IIIb, 23 IIIc and 20 IV. After initial surgery, there were 39 macroscopic residual diseases superior to 2 cm, 26 macroscopic residual diseases inferior or equal to 2 cm, four microscopic diseases and no residual disease in 30 cases (unknown in two cases). The overall response rate to chemotherapy was 83% with 56% histologic complete response rate. The main toxicity was haematological with 60% of leucopenia grade III-IV, 52% of thrombopenia grade III-IV. Age at diagnosis, residual disease after first look surgery and length of CA 125 normalization were significant prognostic factors for survival in this series.

[Value of a LHRH agonist (Zoladex) in hormonotherapy of advanced cancers of the prostate. Apropos of 22 patients]. / Intérêt d'un agoniste de la LHRH (Zoladex) dans l'hormonothérapie des cancers avancés de la prostate. A propos de 22 malades.

Twenty-two patients with metastatic cancer of the prostate were treated with ZoladexR, an LHRH analogue. In all cases plasma testosterone levels decreased to post-surgical castration values. This inhibitory effect of Zoladex on testicular steroid production had a favourable influence on the course of the malignancy, since 75 p. 100 of objective responses were obtained after 3 months of treatment. The functional symptoms were distinctly improved, and the drug was well tolerated, notably by the cardiovascular system. This immediate effectiveness seemed to last for several months, one-half of the patients still being in remission after 3 to 15 months. The beneficial effects of LHRH agonists, similar to those of pulpectomy or oestrogen therapy, are limited by the susceptibility of the tumour to hormones. In view of their effectiveness and good tolerance, LHRH agonists are useful in the management of advanced prostatic cancer, either as initial therapy or to replace a poorly tolerated oestrogen therapy. Further studies are needed to clarify their indications and the possible value of their association with anti-androgens or antimitotic drugs.

[Insulin-dependent diabetes with acute onset. Remissions induced by early temporary blood glucose normalization]. / Diabètes insulino-dépendants de début aigu. Rémissions induites par normalisation glycémique transitoire précoce.

Within 6 months of the acute onset of an insulin-dependent diabetes, remission of insulin-dependence was attempted in 30 hospital patients by strict control of glycaemia obtained in a few days with intravenous infusions of insulin, using a macropump. This was followed by an oral antidiabetic treatment, and the patients were considered in remission when metabolic control was achieved. By this method remission of insulin-dependence was obtained in 90% of the patients; it lasted for more than 1 year on average, and its degree seemed to depend on the time elapsed between the clinical onset of the disease and the beginning of the intravenous treatment but also, to a lesser extent, on the residual secretory capacity of the pancreas when this treatment was instituted. Thus, an intensive metabolic control increases the effectiveness of an oral treatment as regards both number of patients improved and duration of remission. When administered alone at the onset of the disease the oral treatment is only effective in about 30% of the cases.

[Multiple keratosis induced by hydroxyurea]. / Kératoses multiples induites par l'hydroxyurée.

INTRODUCTION: Specific skin manifestations including skin atrophy and stripes of erythema on the extremities have been reported in patients with long-term treatment with hydroxyurea (HU). CASE REPORT: A 60-year-old patient who had been treated with HU since 1986 for chronic myeloid leukaemia presented in March 1992 with lesions characteristic of HU-induced skin changes. Hydroxyurea was continued for two more years and the lesions worsened. Unusually encountered multiple skin keratoses developed rapidly creating a clinical picture compatible with carcinomatous transformation until the withdrawal of hydroxyurea. DISCUSSION: The chronology and the clinical signs were in favour of implicating hydroxyurea in the development of these keratoses. The literature on the subject revealed one comparable case with actinic keratoses and multiple skin carcinomas. The interactions between hydroxyurea and the keratinocytes of the basal layer could explain different aspects of hydroxyurea-related toxidermia. The most severe manifestation could be the development of epithelial skin cancer.

[AIDS-related eosinophilic folliculitis. Efficacy of high dose topical corticotherapy]. / Folliculites à éosinophiles associées au SIDA. Efficacité d'une corticothérapie locale forte.

INTRODUCTION: A chronic pruriginous eruption of eosinophil-rich follicular papules and pustules is observed in AIDS patients. The pathogenesis of this disease, termed eosinophil folliculitis, is poorly understood and treatment is debated. CASE REPORT: A 30-year-old woman with AIDS developed highly pruriginous lesions of 5 month duration localized on the face, the trunk and upper limbs. There were papulo-pustules and excoriated papules. The elementary lesion was a follicular pustula. The eosinophil count was normal. The pathology examination revealed a rich eosinophil infiltration around the hair follicles and sebaceous glands as well as follicular spongiosis. Search for demodex, pityrosporons and a large number of infectious agents was negative. Oral minocyclin was uneffective. Local high-dose corticosteroids produced a remarkable effect and led to complete remission in 9 months. DISCUSSION: Most cases of eosinophil folliculitis associated with AIDS have been reported in men, but rarely in Europe. The remarkable efficacy of the local corticosteroid in this case was exceptional. This condition could result from inappropriate inflammatory reaction in AIDS induced by various factors including demodex and pityrosporon. Several therapeutic approaches have been proposed to eradicate the triggering factors and others to modify the immune response. The exceptional response to the short local treatment with corticosteroids would suggest that this approach could be proposed as first intention treatment in eosinophil folliculitis associated with AIDS.

A phase III adjuvant randomised trial of 6 cycles of 5-fluorouracil-epirubicine-cyclophosphamide (FEC100) versus 4 FEC 100 followed by 4 Taxol (FEC-T) in node positive breast cancer patients (Trial B2000).

BACKGROUND: Standard adjuvant chemotherapy regimens for patients with node positive (N+) breast cancer consisted of anthracycline followed by taxane. The European Association for Research in Oncology embarked in 2000 on a phase III trial comparing 6 cycles of FEC100 versus 4 FEC100 followed by 4 Taxol. Primary end-point was disease free survival. Secondary end-points were overall survival, local recurrence free interval, metastases free interval and safety. PATIENTS AND METHODS: Between March 2000 and December 2002, 837 patients were randomised between 6FEC100 for 6 cycles (417patients) or FEC100 for 4 cycles then Taxol 175mg/m(2)/3 weeks for 4 cycles (4FEC100-4T) (420 patients). One thousand patients had been planned initially but the trial was closed earlier due to slow accrual. RESULTS: Hazard ratios (HRs) were 0.99 for disease-free survival (DFS) (95%CI: 0.77-1.26; p=0.91), and 0.85 for overall survival (OS) (95%CI: 0.62-1.15; p=0.29). Nine-year DFS were 62.9% versus 62.5% for 6FEC100 and 4FEC100-4T, respectively. Nine-year OS were 73.9% versus 77% for 6FEC100 and 4FEC100-4T, respectively. Toxicity analyses based on 803 evaluable patients showed that overall grade 3-4 toxicities were similar in both arms (63% versus 58% for 6FEC100 arm and 4FEC100-4T arm, respectively; p=0.16). CONCLUSION: In this trial replacing the last 2 FEC100 cycles of 6FEC100 regimen by 4 Taxol does not lead to a discernable DFS or OS advantage. The lack of a significant difference between the randomised treatment arms may however be due to a lack of power of this trial to detect small, yet clinically worthwhile, treatment benefits.

Autologous transplantation in CLL patients with B and C Binet stages: final results of the prospective randomized GOELAMS LLC 98 trial.

The relevance of high-dose chemotherapy followed by auto-SCT in CLL remains to be defined. The aim of the prospective, randomized, GOELAMS LLC 98 trial was to compare two strategies in previously untreated CLL patients aged <60 years. Conventional chemotherapy (Arm A) consisted of six monthly courses of CHOP followed by six CHOP courses in every 3 months in those achieving a complete or PR. Arm A was compared with high-dose therapy with auto-SCT (Arm B), used as consolidation after three CHOP courses in case of CR or very good PR. A total of 86 patients were enrolled, of which 39 and 43 patients were evaluable in arm A and arm B, respectively. The primary endpoint was PFS. On an intent-to-treat basis and with a median follow-up time of 77.1 (range 1-135.5) months, the median PFS was 22 months in Arm A and 53 months in Arm B (P<0.0001). Median survival time was 104.7 months in arm A and 107.4 months in arm B. This trial demonstrates that frontline high-dose therapy with auto-SCT prolongs PFS but does not translate into a survival advantage in advanced CLL patients in the pre-rituximab era.