Georges Fillet

Positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) for the staging of low-grade non-Hodgkin's lymphoma (NHL).

BACKGROUND Although PET has been shown to be highly sensitive in the primary staging of lymphoma, previous studies with small numbers of patients indicated that low-grade NHL may not always be adequately detected by PET. We undertook this study to determine factors influencing the detection of lesions by PET in low-grade NHL and to evaluate the utility of PET in this indication. PATIENTS AND METHODS Forty-two patients underwent conventional staging procedures (clinical examination, oto-rhino-laryngologic examination, computed tomography of the chest, abdomen and pelvis, gastroscopy and bone marrow biopsy as well as whole-body non-attenuation corrected 18F-FDG-PET RESULTS: PET detected 40% more abnormal lymph node areas than conventional staging in follicular lymphoma but was inappropriate for the staging of small lymphocytic lymphoma where it detected less than 58% of abnormal lymph node areas. PET showed more lesions than conventional staging for peripheral (34% more lymph node areas detected) and thoracic lymph node (39% more) areas but not for abdominal or pelvic lymph nodes (26% fewer areas detected). The sensitivity to detect bone marrow infiltration was unacceptably low for PET. In contrast, PET was as effective as standard procedures for the detection of other extranodal localizations, although a few localizations were detected only by PET and a few others only by conventional procedures. CONCLUSIONS PET may contribute to the management of patients with low-grade follicular NHL. For the other low-grade lymphoma subtypes, the role of PET is less evident. Further studies using PET to evaluate the results of treatment or to diagnose disease recurrence are warranted in low-grade follicular NHL.

Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy--the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon Group.

PURPOSE AND METHODS Optimization of remission-induction and postremission therapy in elderly individuals with acute myeloid leukemia (AML) was the subject of a randomized study in patients older than 60 years. Remission-induction chemotherapy was compared between daunomycin (DNR) 30 mg/m2 on days 1, 2, and 3 versus mitoxantrone (MTZ) 8 mg/m2 on days 1, 2, and 3, both plus cytarabine (Ara-C) 100 mg/m2 on days 1 to 7. Following complete remission (CR), patients received one additional cycle of DNR or MTZ chemotherapy and were then eligible for a second randomization between eight cycles of low-dose (LD)-Ara-C 10 mg/m2 subcutaneously every 12 hours for 1 2 days every 6 weeks or no further treatment. RESULTS A total of 242 patients was randomized to DNR and 247 to MTZ. Median age of both study groups was 68 years. Secondary AML was documented in 26% and 25% of patients in either arm. The probability of attaining CR was greater (P = .069) with MTZ (47%) than with DNR (38%). Median duration of neutropenia was 19 (DNR) and 22 days (MTZ). The greater response rate to MTZ therapy correlated with reduced occurrence of chemotherapy resistance (32% v 47%, P = .001). With a median follow-up of 6 years, 5-year disease-free survival (DFS) is 8% in each arm. Overall survival estimates are not different between the groups (6% v 9% at 5 yrs). Poor performance status at diagnosis, high WBC count, older age, secondary AML, and presence of cytogenetic abnormalities all had an adverse impact on survival. Secondary AML and abnormal cytogenetics predicted for shorter duration of CR. Among complete responders, 74 assessable patients were assigned to Ara-C and 73 to no further therapy. Actuarial DFS was significantly longer (P = .006) for Ara-C-treated (13% [SE = 4.0%] at 5 years) versus nontreated patients (7% [SE = 3%]), but overall survival was similar (P = .29): 18% (SE = 4.6%) versus 15% (SE = 4.3%). Meta-analysis on the value of Ara-C postremission therapy confirms these results. CONCLUSION In previously untreated elderly patients with AML, MTZ induction therapy produces a slightly better CR rate than does a DNR-containing regimen, but it has no significant effect on remission duration and survival. Ara-C in maintenance may prolong DFS, but it did not improve survival.

Shortened First-Line High-Dose Chemotherapy for Patients With Poor-Prognosis Aggressive Lymphoma

PURPOSE Randomized trial LNH93-3 was conducted on patients who had poor-prognosis aggressive lymphoma and were younger than 60 years with two to three factors of the age-adjusted International Prognostic Index to evaluate the benefit of early high-dose therapy (HDT) with autologous stem-cell transplantation (ASCT). PATIENTS AND METHODS Patients were randomized between doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) chemotherapy followed by sequential consolidation and an experimental shortened treatment consisting of three cycles with escalated doses of cyclophosphamide, epirubicin, vindesine, bleomycin, and prednisone and collection of peripheral-blood stem cells. On day 60, HDT was administered with 1,3-bis(2-chloroethyl)-1-nitrosourea, etoposide, cytarabine, and melphalan followed by ASCT. RESULTS Eligible patients (n = 370) with aggressive lymphoma were analyzed. For ACVBP (181 patients) and HDT (189 patients), respective complete remission rates were 64% and 63%. With a median follow-up of 60 months, 5-year overall survival and event-free survival for ACVBP and HDT were 60% +/- 8% and 46% +/- 8% (P =.007) and 52 +/- 8% and 39 +/- 8% (P =.01), respectively. Survival was independently affected by age greater than 40 years (P =.0003), T-cell phenotype (P =.009), bone marrow involvement (P =.003), and HDT treatment group (P =.04). CONCLUSION Early HDT with ASCT in high-risk patients was inferior to the ACVBP chemotherapy regimen. These results indicate that the received dose-intensity before HDT was too low when compared with ACVBP and HDT and was given too early.

CHOP Alone Compared With CHOP Plus Radiotherapy for Localized Aggressive Lymphoma in Elderly Patients: A Study by the Groupe d’Etude des Lymphomes de l’Adulte

PURPOSE Chemoradiotherapy has been considered standard treatment for patients with limited-stage aggressive lymphoma on the basis of trials conducted before the introduction of the International Prognostic Index. To evaluate this approach in elderly patients with low-risk localized lymphoma, we conducted a trial comparing chemoradiotherapy with chemotherapy alone. PATIENTS AND METHODS Previously untreated patients older than 60 years with localized stage I or II histologically aggressive lymphoma and no adverse prognostic factors of the International Prognostic Index were randomly assigned to receive either four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus involved-field radiotherapy (299 patients) or chemotherapy alone with four cycles of CHOP (277 patients). RESULTS With a median follow-up time of 7 years, event-free and overall survival did not differ between the two treatment groups (P = .6 and P = .5, respectively). The 5-year estimates of event-free survival were 61% for patients receiving chemotherapy alone and 64% for patients receiving CHOP plus radiotherapy; the 5-year estimates of overall survival were 72% and 68%, respectively. In a multivariate analysis, overall survival was affected by stage II disease (P < .001) and male sex (P = .03). CONCLUSION In this large prospective study, CHOP plus radiotherapy did not provide any advantage over CHOP alone for the treatment of low-risk localized aggressive lymphoma in elderly patients.

Cotransplantation of Mesenchymal Stem Cells Might Prevent Death from Graft-versus-Host Disease (GVHD) without Abrogating Graft-versus-Tumor Effects after HLA-Mismatched Allogeneic Transplantation following Nonmyeloablative Conditioning

Recent studies have suggested that coinfusion of mesenchymal stem cells (MSCs) the day of hematopoietic cell transplantation (HCT) might promote engraftment and prevent graft-versus-host disease (GVHD) after myeloablative allogeneic HCT. This prompted us to investigate in a pilot study whether MSC infusion before HCT could allow nonmyeloablative (NMA) HCT (a transplant strategy based nearly exclusively on graft-versus-tumor effects for tumor eradication) from HLA-mismatched donors to be performed safely. Twenty patients with hematologic malignancies were given MSCs from third party unrelated donors 30-120 minutes before peripheral blood stem cells (PBSCs) from HLA-mismatched unrelated donors, after conditioning with 2 Gy total body irradiation (TBI) and fludarabine. The primary endpoint was safety, defined as a 100-day incidence of nonrelapse mortality (NRM) <35%. One patient had primary graft rejection, whereas the remaining 19 patients had sustained engraftment. The 100-day cumulative incidence of grade II-IV acute GVHD (aGVHD) was 35%, whereas 65% of the patients experienced moderate/severe chronic GVHD (cGVHD). One-year NRM (10%), relapse (30%), overall survival (OS) (80%) and progression-free survival (PFS) (60%), and 1-year incidence of death from GVHD or infection with GVHD (10%) were encouraging. These figures compare favorably with those observed in a historic group of 16 patients given HLA-mismatched PBSCs (but no MSCs) after NMA conditioning, which had a 1-year incidence of NRM of 37% (P = .02), a 1-year incidence of relapse of 25% (NS), a 1-year OS and PFS of 44% (P = .02), and 38% (P = .1), respectively, and a 1-year rate of death from GVHD or infection with GVHD of 31% (P = .04). In conclusion, our data suggest that HLA-mismatched NMA HCT with MSC coinfusion appeared to be safe.

Whole-Body 18f-Fdg Pet for the Evaluation of Patients with Hodgkin's Disease and Non-Hodgkin's Lymphoma

Whole-body metabolic information provided by 18F-FDG PET could help in the evaluation of lymphoma patients at diagnosis and follow-up. We studied 60 patients, 42 at initial presentation and 18 for disease recurrence (23 aggressive non-Hodgkins lymphoma, 21 low-grade non-Hodgkins lymphoma and 16 Hodgkins disease). All patients underwent a clinical examination, computed tomography (CT) and a non-attenuated PET scan within 1 week. The patients received 222-296 MBq (6-8 mCi) 18F-FDG intravenously and emission scans were recorded 45-90 min later. 18F-FDG PET detected more lymph nodes than the clinical examination or CT, but this rarely resulted in upstaging (two patients). The concordance between PET and CT for the evaluation of the spleen, liver and digestive tract was quite good. Discordance was noted in 12 patients for the evaluation of bone marrow infiltration, but confirmation by MRI or focal biopsy was not always obtained. We conclude that non-attenuated 18F-FDG PET is an easy and efficient whole-body method for the evaluation of patients with lymphomas. Compared with conventional techniques, however, it does not appear to offer much improvement for staging but provides a satisfactory base for follow-up.

Clinical activity and benefit of irinotecan (CPT-11) in patients with colorectal cancer truly resistant to 5-fluorouracil (5-FU).

The aim of this prospective study was to assess the efficacy, clinical benefit and safety of CPT-11 (irinotecan) in patients with stringently-defined 5-fluorouracil-resistant metastatic colorectal cancer (CRC). 107 patients with documented progression of metastatic CRC during 5-FU were treated with CPT-11 350 mg/m2 once every 3 weeks in a multicentre phase II study. Tumour response and toxicity were assessed using WHO criteria. Changes in performance status (PS), weight and pain were also measured. The WHO response rate was 13/95 (13.7%, 95% CI 7.5% to 22.3%) eligible patients with a median duration of response of 8.5 months (37 weeks, range: 18-53+). There was also a high rate of disease stabilisation (44.2%) with a median duration of 4.8 months. The probability of being free of progression at 4 months was 50%. Median survival from first administration of CPT-11 was 10.4 months or 45 weeks (range: 3-66+ weeks). There was weight stabilisation or gain in 81% (73/90) of patients, a favourable outcome in PS in 91% (82/90) (improvement of WHO PS 2 or stabilisation of PS 0-1), and pain relief in 54% (26/48). There were no toxic deaths. Neutropenia was short-lasting and non-cumulative. Diarrhoea grade > or = 3 occurred in 7% of cycles and 28/107 (26%) of patients. CPT-11 350 mg/m2 once every 3 weeks has an encouraging degree of activity in progressive metastatic CRC truly resistant to 5-FU with a relatively high rate of tumour growth control translated into clinical benefit. The toxicity profile of CPT-11 is becoming better understood and has been considerably improved.

Erythropoiesis in multiple myeloma: defective red cell production due to inappropriate erythropoietin production

We investigated the pathophysiology of erythropoiesis in 62 patients with multiple myeloma and examined whether it would establish a rational basis for the treatment of their anaemia with recombinant human erythropoietin. Erythropoietin (Epo) production was evaluated by serum levels and erythropoiesis was quantitated by serum transferrin receptor (TfR) levels. both assessed relative to the degree of anaemia. Instead of the expected stimulation of erythropoiesis in response to anaemia. haematocrit correlated positively with marrow erythropoietic activity. indicating that the mechanism of anaemia was primarily defective red cell production. Erythropoiesis decreased and anaemia worsened significantly with advancing clinical stage. 2 5% of the patients had inadequate Epo production and this proportion increased to 50% in stage 3. Inappropriate Epo production was seen in 60% of patients with renal impairment but was also observed in a number of patients with normal renal function. Erythropoiesis correlated strongly with the adequacy of Epo production particularly in advanced disease. Ve conclude that most myeloma patients have defective red cell production even in the absence of massive marrow infiltration and that inappropriate Epo production contributes to their anaemia.

Storage Iron Kinetics. VII. A BIOLOGIC MODEL FOR RETICULOENDOTHELIAL IRON TRANSPORT

The processing of erythrocyte iron by the reticuloendothelial cell has been characterized by kinetic measurements of blood radioactivity made after the intravenous injection of heat-damaged erythrocytes labeled with (59)Fe and of transferrin-bound (55)Fe. The early reticuloendothelial release of iron, a matter of hours, was calculated from the plasma turnover rate of (55)Fe and the plasma reappearance of (59)Fe. Late release was calculated from the ratio of the cumulative incorporation of both tracers into the circulating red cell mass over a period of 2 wk. There was an initial processing period within the reticuloendothelial cell, after which radioiron either rapidly returned to circulation (t(1/2) 34 min) or was transferred to a slowly exchanging pool of storage iron within the reticuloendothelial cell (t(1/2) release to plasma of 7 days). These pathways were of equal magnitude in the normal dog. Reticuloendothelial release of iron was largely independent of the pre-existing plasma iron level or transferrin saturation. Diurnal fluctuations in the plasma iron level were shown to be the result of a variable partitioning of iron between the early and late release phases. Acute inflammation resulted in a prompt and marked increase in the fraction of iron stored (late phase), whereas depletion of iron stores resulted in a marked increase in early release.

PET scan imaging in oncology.

With the emergence of positron emission tomography (PET) from research laboratories into routine clinical use, it is important to redefine the most appropriate use of each imaging technique. The aim of this review article is to show the potential of PET in oncology. We discuss the most promising indications and the perspectives for the future. We will also point out the shortcomings and the important questions to be answered before fully considering PET as a necessary tool in the day-to-day practice of oncology. Although many studies have documented the high accuracy of 18F-FDG PET for the detection and staging of malignant tumours and for the monitoring of therapy results in these patients, it is very important to assess the impact of the technique on patient outcome and to show cost-effectiveness from the societal viewpoint.