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Background: The usefulness of chemotherapy to treat gastric diffuse large B-cell lymphomas (DLBCL) is well known. Whether or not chemotherapy should be performed as the only treatment or after surgical resection is debated. The aim of this study was to compare two strategies: surgical resection plus chemotherapy versus chemotherapy alone., Patients and Methods: Between January 1988 and December 1996, 58 patients included in the trials promoted by the Groupe d'Etude des Lymphomes de l'Adulte (GELA) (LNH-87 and LNH-93) received chemotherapy and 48 included in the protocol of the Groupe d'Etude des Lymphomes Digestifs (GELD) underwent surgical resection followed by chemotherapy. They all presented with localized DLBCL (stage IE and IIE according to the Ann Arbor classification). From the GELA group, seven patients received additional radiotherapy. Gastrectomy was total in 27 of the 48 patients in the GELD group. In both groups chemotherapy included anthracyclin and alkylating agents. Chemotherapy was more intensive in the GELA group than in the GELD group., Results: In the GELA and the GELD groups, distribution according to sex ratio, age (>60 or < or = 60 years), ECOG performance status (> or = 2 or <2) and staging (IE or IIE) was similar. Univariate analysis comparing prognostic factors in both groups showed significant differences: serum lactate dehydrogenase level above normal (28.6% versus 2.4%, P = 0.001), tumor size >10 cm (28.6% versus 12.5%, P = 0.04), patients with International Prognostic Index (IPI) >1 (21.4% versus 11.1%, P = 0.168) and 5-year survival (79% versus 90%, P = 0.03). Multivariate analysis of prognostic factors with a Cox model showed that IPI was the only independent prognostic factor (odds ratio 3, P = 0.03). Consequently, patients with IPI 0-1 were selected for comparison between the GELA group (44 patients) and the GELD group (40 patients). There was no significant difference between the two groups. Median follow-up was 59 months (range 3-128). Estimates of 5-year survival rates and event-free survival rates were 90.5% versus 91.1% (P = 0.303) and 85.9% versus 91.6% (P = 0.187), respectively. In the GELA group, seven of 44 patients died: five from a lymphoma-unrelated cause and two from tumor progression. In the GELD group, four of 40 patients died: two of unrelated causes and two from tumor progression., Conclusions: This study shows that in localized gastric DLBCL with IPI 0-1, a similar 5-year survival rate (>90%) is to be expected with either surgery plus chemotherapy or chemotherapy alone.

Background: p53 alterations have been associated with a poor prognosis in aggressive B-cell lymphoma. We investigated the clinical relevance of p53 status in diffuse large B-cell lymphoma (DLBCL), focusing on patients who belong to lower risk groups of the international prognostic index and were uniformly treated. We aimed to determine whether this biological marker could identify among such patients those with a pejorative outcome who could benefit from a distinct therapeutic approach., Patients and Methods: We studied 69 patients presenting with no, one (low-risk, n = 40) or two (low-intermediate risk, n = 29) risk factors treated with an anthracyclin-containing induction regimen. p53 exons 5-8 mutations were screened for using denaturing gradient gel electrophoresis and confirmed by direct sequencing. Immunohistochemical detection of p53 protein and of its downstream target p21 were also evaluated in 60 of 69 cases., Results: p53 mutations were detected in 16 of 69 (23%) lymphoma samples. The presence of a p53 gene mutation affected survival (P = 0.01), with a 6-year survival rate estimated to be 44% in mutated patients, compared with 79% in non-mutated ones. Using a stepwise Cox model, p53 mutation constituted the only parameter affecting survival (relative risk = 2.7, P = 0.03). A p53+/p21- immunohistochemical pattern (n = 15), suggestive of a disrupted p53 function, strongly correlated with p53 gene status and was associated with a lower 6-year survival rate when compared with a p53(-) or p53+/p21+ phenotype (47% versus 74%, P = 0.05)., Conclusions: p53 alterations constitute a pejorative biological indicator able to discriminate among clinically defined lower risk patients with DLBCL.

Purpose: In the previous LNH87-2 study, consolidative high-dose therapy followed by stem cell transplantation (HDT) improved disease-free survival, as well as survival for patients (pts) presenting with two or three factors of the age-adjusted international prognostic index (Aa-IPI) in first complete remission (CR). In order to improve further the outcome of such patients, we conducted a pilot study of consolidative tandem autotranplant., Patients and Methods: Thirty-six patients (pts) under 60 years of age with two or three factors of the Aa-IPI were enrolled. Their main characteristics were: diffuse large B-cell lymphoma (83%), Aa-IPI three factors (50%), and marrow involved (36)%. The procedure consisted of 1) induction with four cycles of ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) 2) in responding pts, peripheral blood stem cell (PBSC) collection after the fourth cycle of ACVBP (11 pts) or after an additional mobilization regimen (Cyclophosphamide-VP16) (17 pts) 3) a first HDT (mitoxantrone, cyclophosphamide, VP16 and carmustine) followed by PBSC infusion 4) a second HDT (busulfan, carboplatin and melphalan) followed by PBSC infusion. Among the 29 patients responding to induction, 28 received the first HDTand 24 the second., Results: The rates of three-year-event free survival and survival are 47% (95% confidence interval (95% CI: 31%-63%) and 50% (95% CI: 37%-69%), respectively. Eighteen patients remained free of evolutive disease and 18 patients have died, 15 from disease progression and three from treatment-related toxicity after tandem transplant (two veno-occlusive disease and one cerebral toxoplasmosis)., Conclusion: We conclude that tandem transplant did not improve the results of the LNH87-2 study in which patients received a single consolidative HDT.

Background: Incidence of central nervous system (CNS) recurrence in patients with aggressive non-Hodgkin's lymphoma who did not receive meningeal prophylaxis is about 5%. Controversy remains regarding risk factors associated with such an event preventing a rational approach of prophylactic strategies., Patients and Methods: We analyzed a cohort of 974 patients with aggressive lymphoma in complete remission (CR). All the patients received a CNS prophylaxis consisting of intrathecal injections and intravenous high-dose methotrexate. The risk repartition on the basis of the international prognostic index (IPI) of these 974 CR-patients was low (L): 41%, low-intermediate (LI): 27%, high-intermediate (HI): 19%, high (H): 13%., Results: The incidence of isolated CNS relapse was 1.6%. In a first multivariate logistic regression analysis an increased LDH (P = 0.05, RR = 5) and the presence of more than one extranodal site (P = 0.05, RR = 3) were identified as independent risk factors for isolated CNS relapse. Another multivariate analysis incorporating IPI as a unique parameter showed that only IPI remained significantly associated with a higher risk of CNS relapse (L-LI: 0.6% vs. HI H: 4.1%, P = 0.002; RR = 7)., Conclusion: Prophylaxis notably reduces the risk of CNS recurrence in the higher risk patients. By contrast, we propose the deletion of prophylactic intrathecal injections in the lower risk patients.

Background: Despite high-dose therapy and ASCT some patients with aggressive HD fail to achieve long-term survival., Patients and Methods: Forty-three patients with induction failure (n = 19) or very unfavorable (UF) relapse (n = 24) from HD were included in a multicentric study of tandem ASCT. They planned to receive two course of IVA75 with GCSF and blood stem cell collection. ASCT1 was conditioned with CBV + mitoxantrone (30 mg/m2) and ASCT2 (cytarabine 6 g/m2 melphalan 140 mg/m2 and total body irradiation at 12 Gy or busulfan 16 (n = 4) than 12 mg/kg). After salvage therapy, response > 50% was observed in 63% of the patients (six patients were included for refractory relapse). Four patients had no ASCT for disease progression; seven patients had only ASCT1 (disease progression, n = 3) and thirty-two patients (74%) received the two ASCT., Results: Hematologic recovery was normal after ASCT1 but delayed platelet recovery was observed after ASCT2 with busulfan in the conditioning regimen. Two VOD with one fatal occurred with busulfan at 16 mg/kg and one hemorrhagic cystic, no further grade 4 toxicity was observed with the reduced doses of busulfan (12 mg/kg). After ASCT2, 83% of these UF patients were in remission and 20% relapsed within the first year. On an intent-to-treat analysis, 22 of 43 patients are in continuous CR (including 8 patients with induction failure). For the whole population (n = 43) and for patients receiving the two ASCT (n = 32), the two-year survival from the date of progression were respectively at 65% and at 74%., Conclusion: Double ASCT is feasible in very UF relapse from HD and may lead to some prolonged remission.

Patients with aggressive non-Hodgkin's lymphoma who fail to achieve a complete remission (CR) with standard induction therapy have a poor prognosis with conventional-dose salvage therapy alone. Retrospective series have suggested that early introduction of high-dose salvage therapy with autologous stem cell transplantation (ASCT) may benefit partial-responder (PR) patients. However, two randomized studies (of 69 and 51 patients with partial clinical responses) failed to demonstrate any advantage of intensive therapy. By contrast, the GELA comparative study on 94 PR-patients (residual disease being histologically documented in 53 patients) suggested that high-dose therapy with ASCT improves survival. Interpretation of all these results is complicated by the heterogeneity of patient populations with respect to initial prognostic factors, induction regimens and, in particular, the criteria used to define partial response. Gallium CT scan and magnetic resonance imaging are now used to better explore residual masses. In the future, early restaging with these imaging techniques might be used to delineate patients who are likely to achieve CR from those who will fail to induction treatment and could be candidates for experimental treatments.

Objective: The treatment of patients with non-Hodgkin's lymphoma related to the human immunodeficiency virus (HIV-NHL) is complicated by the underlying acquired immunodeficiency syndrome (AIDS). Patients without adverse prognostic factors (no AIDS prior to lymphoma, CD4+ lymphocyte counts greater than 100 x 10(6)/l and good performance status) can be cured of lymphoma and experience long-term survival. Our previous study with the intensive chemotherapy LNH84 regimen yielded a 63% complete response (CR) rate but median survival was only nine months, half of the patients died of AIDS and the other half of their lymphoma. We report here the results of a phase II study combining the same chemotherapy with zidovudine and GM-CSF. Our goal was to improve the treatment outcome over that of our previous study; GM-CSF was expected to decrease the hematological toxicity of chemotherapy and thus permit a dose intensity increase, while zidovudine was supposed to slow down the evolution of AIDS., Design and Setting: A phase II non-randomized prospective clinical trial in 7 centres., Patients and Methods: Thirty-two consecutive adult patients presenting HIV-NHL and performance status of less than three without active opportunistic infection underwent three cycles of doxorubicin 75 mg/m2, cyclophosphamide 1,200 mg/m2, vindesine 2 mg/m2 for two days, bleomycin 10 mg for two days and prednisolone 60 mg/m2 for five days (ACVB). Chemotherapy was associated with zidovudine (5 mg/kg/d) and GM-CSF (5 mu g/kg/d). The induction phase was followed by a four-month consolidation phase., Results: CR and PR > 75% were observed in 56% of patients; 25% of the patients died during the induction phase. These results were analogous to those of the previous study (63% and 14%, respectively). Neither hematological tolerance nor dose intensity were improved. With a mean follow-up of 23.5 months, median survival was 6.7 months. The rate of non-NHL AIDS-related death during CR was not reduced (22% in our study vs. 16% in our previous one)., Conclusions: GM-CSF failed to reduce significantly the cumulative hematological toxicity of chemotherapy and zidovudine. New antiviral agents without hematological toxicity would perhaps be useful in this setting.

Background: Relapsed or refractory Hodgkin's disease (HD) patients were treated with an intensive salvage regimen (MINE) prior to high-dose therapy (HDT) with hematopoietic stem cell support., Patients and Methods: One hundred HD patients who either failed to respond to a front-line chemotherapy regimen (induction failure, n = 41) or relapsed (untreated relapse, n = 54; resistant relapse, n = 5) were treated with the MINE regimen. Each course of MINE comprised mitoguazone 500 mg/m2 on days 1 and 5, ifosfamide 1500 mg/m2/d from day 1 to day 5, vinorelbine (Navelbine) 15 mg/m2 on days 1 and 5, and etoposide 150 mg/m2/d from day 1 to day 3. At least two courses were given at 4-week intervals. Then, 72 patients received HDT followed by hematopoietic stem cell support., Results: After MINE salvage, 34 patients achieved a complete response (CR) and 39 a partial response, yielding an overall response rate of 75%. Patients with untreated relapse had a 92.5% response rate and those with resistant relapse or induction failure a 53% response rate. A total of 58 patients reached a CR at the end of all treatments; 12 of them relapsed. Sixty-six patients were alive with a median follow-up of 26 months, including 46 patients in CR. The 2-year survival rate for the entire group was 59%. By univariate analysis, patients with an interval between their last treatment and salvage longer than 12 months, untreated relapse, or good performance status at salvage are shown to have longer survivals. The main toxic effects were neutropenia, thrombocytopenia, and infectious episodes. Three patients died of MINE-related complications and three after HDT., Conclusion: Given early in the course of progressive HD, the MINE regimen reduced tumor burden in a high proportion of patients with relapsed or refractory disease. Responding patients further intensified with HDT have a better outcome than those who have not responded to salvage treatment.

Background: To evaluate the effects of chemotherapy dose intensity (DI) on outcome in patients with aggressive lymphoma, the received relative DI (received RDI) is usually calculated using Hryniuk's model. We applied this model to a selected patient subgroup included in the LNH87 protocol (LNH87-2 protocol), who had been treated with the ACVB induction regimen., Patients and Methods: Patients aged < 55 who had at least one of the following prognostic factors: performance status (PS) > or = 2, number of extranodal sites > or = 2, tumor burden > or = 10 cm, bone marrow or central nervous system involvement, and Burkitt's or lymphoblastic histologic subtype, were included in this study. Actual DI was calculated using the definition of DI as mg/m2/week previously described by Hryniuk., Results: Eighty-seven of the 311 patients included in the study (28%) presented a RDI below 70% of the theoretical DI. We demonstrated a decreased response rate (65% vs. 79%, p = 0.01) and shorter overall 2-year survival (61% vs. 72%, p = 0.02) in patients receiving a DI < 70%. This difference was still significant when the multiparametric analysis was used (p = 0.004)., Conclusion: Results obtained when this model was applied to aggressive lymphoma patients included in the LNH-87 protocol led to the demonstration of a strong relationship between received RDI and survival.

High dose therapy with or without hematopoietic stem cell rescue has been widely used in the past decade for treating aggressive Non-Hodgkin's lymphoma. Recent data in high and intermediate grade lymphoma were reviewed. Evidence that dose intensity is a critical factor for remission in poor prognosis lymphoma has been accumulated, although the impact on survival has not been clearly established through randomized studies. Intensive treatment with autologous bone marrow transplantation (ABMT) have been reported in more than 1,000 relapsing patients in non randomized trials. For those who are still sensitive to salvage chemotherapy, at 5 years a 40% probability of disease free survival has been uniformly noted. ABMT is accepted by most centers as the treatment of choice for relapsing lymphoma. Consequently, very few randomized studies testing ABMT vs. conventional chemotherapy such as the PARMA protocol are in progress. In patients achieving complete remission, ABMT has been proposed for consolidation in a group of lymphoma sharing adverse prognostic factors with a high risk of relapse. Results from pilot studies were encouraging. However, interim analysis of the large randomized trial LNH87, did not show at the present time an advantage for ABMT performed after CR when compared to conventional chemotherapy. Such a strategy should be only proposed in prospective studies. For patients who did not achieve CR after conventional treatment, but who are still sensitive to chemotherapy, ABMT may improve the results. Pilot studies as well as recent randomized study are in support of this approach.(ABSTRACT TRUNCATED AT 250 WORDS)