The Djerba statement: just another declaration, or a new beginning?
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Developing Countries↗
Biomedical subjects
F Cavalli
Publications and source records attributed to F Cavalli.
Granulocyte growth factors: achieving a consensus.
A consensus meeting held under the auspices of the European School of Oncology concluded that the use of granulocyte growth factors is definitely indicated, or acceptable given existing evidence, in the following circumstances: to alleviate congenital neutropenia; in the mobilisation of peripheral blood progenitor cells for autotransfusion; to encourage engraftment following bone marrow transplantation and in cases of failed engraftment; to support continuation of ganciclovir anti-CMV therapy in certain patients with AIDS, where the switch to foscarnet is contraindicated or where toxicity to foscarnet develops. It was also agreed that there is an overwhelming need for carefully controlled clinical trials in a wide range of indications in which growth factor use may improve outcome. In the majority of tumours, the possible benefit of dose optimisation and intensification, and therefore the role of growth factors in support of such measures has still to be defined. Extramedullary toxicities may in these instances become dose limiting.
AIDS-Related Opportunistic Infections↗
Patterns of survival in mantle cell lymphoma.
BACKGROUND: The term mantle cell lymphoma (MCL) describes a subtype of non-Hodgkin's lymphoma that includes those lymphomas previously defined as centrocytic lymphoma, intermediate lymphocytic lymphoma, and mantle zone lymphoma. Since MCL has only recently been recognised as a distinct entity, the clinical literature is sparse and very little information is available about its treatment. PATIENTS AND METHODS: We retrospectively attempted to analyse the clinical features and outcome of 65 patients with mantle cell lymphoma (MCL) treated from 1979 to 1993 at two institutions in the same geographic area. Univariate (Log-rank test) and multivariate (Cox regression) analyses of the major prognostic factors were performed. RESULTS: At the time of analysis the median follow-up was 49 months. Median age was 64 years with a range of 27-85 years. The male to female ratio was 2:1. Forty-seven patients (72%) had stage IV at presentation and 20 (31%) had B-symptoms at presentation. The patients usually presented with generalised adenopathy (78% of cases) and bone marrow involvement (58%). Serum LDH were analysed at diagnosis in 61 patients and found to be elevated in 30%. beta 2-Microglobulin was determined at presentation in 42 patients and was higher than normal in 54% of them. In comparison with the other subtypes of NHLs in our series, MCL appears to have a very poor survival pattern. The median overall survival was 42 months. The CR rate was 51% with a median DFS of 44 months. Good performance status, normal LDH, normal beta 2-microglobulin, younger age (< 65 years), and a low prognostic risk according to the International Index were significantly associated (p < 0.05) with a better outcome. CONCLUSIONS: The characteristics of the patients in this study appear to be in general agreement with those in most of the previously reported series except for the somewhat lower rate of bone marrow infiltration observed in this series. Despite the limitations of a retrospective analysis and the lack of randomization between the treatment options, this study seems to suggest a survival advantage with anthracycline-containing regimens in some patients with MCL. However, this benefit was evident only for the patients with favourable International Index prognostic scores (i.e., low- and to low-intermediate-risk disease) who may already have a better prognosis. Patients with intermediate-high and high-risk disease according to the International Index have a poor prognosis regardless of the type of therapy given.
Adult↗
Informed consent for phase I studies: evaluation of quantity and quality of information provided to patients.
BACKGROUND: The process by which patients are informed and their consent is obtained in phase I trials has thus far been only marginally studied. Since 1986 we have followed an oral procedure, consisting of three consecutive conversations in which the investigator responsible for phase I studies, the research nurse and the patients' relatives and/or friends also participate, followed by the patients signing of a written consent form. It is required that six items of information considered essential by our staff be conveyed to patients by the responsible investigator. Meerwein's model, which defines three main dimensions of the informing process (the information itself, the emotional and interactive aspects), has been studied to ascertain whether it can be applied to evaluate the quality of the information proffered. METHODS: Thirty-two conversations were taped, transcribed and evaluated by one psychiatrist and one psychologist. A quantitative analysis of information was performed by calculating the number of patients to whom the essential items of information had been conveyed. The qualitative analysis was performed by rating on a five-point scoring system, from 1 (very bad) to 5 (excellent), the three dimensions of the informing process for each patient and by calculating for each dimension the mean score of the constituent items. RESULTS: Complete information about the characteristics of the phase I drug and the modalities of the treatment and follow up was given to almost 80% of the patients. All but one of the items of the information dimension scored 3.5 or higher, with the one related to the assessment by the doctor of the patient's understanding at the end of the consultation scoring less than 3 in 53% of the patients. All items of the emotional dimension scored higher than 3.5. Greater difficulty was encountered by the physician with the interactive dimension, the lowest mean scores being reported on the items related to the doctor's awareness of the indirectly expressed anxieties of the patients. In 71% of the consultations the three dimensions of information scored more than 3 and balanced one another, indicating a successful consultation by the Meerwein model. CONCLUSIONS: The informed consent procedure applied was satisfactory from a quantitative point of view, and the main items of information were acceptable to the patients. Meerweins's model proved to be applicable and useful for identifying pitfalls in communication. Greater attention should be paid to the indirect messages and implied criticisms of the patients to improve their participation in decision making. Physicians should become more skillful in providing adequate information and improve their methods of communication.
Adolescent↗
High incidence of other neoplasms in patients with low-grade gastric MALT lymphoma.
BACKGROUND: Low-grade gastric MALT lymphoma is an uncommon tumour for which a close association with chronic Helicobacter pylori infection has been suggested. However, given the rarity of MALT lymphoma of the stomach despite the high prevalence of H. pylori infection, it seems plausible that genetic host factors might play a fundamental role in gastric lymphomagenesis. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 83 patients with low-grade gastric MALT, all of whom resided in a geographic area (southern Switzerland and northern Italy) where the incidence of gastric tumours appears to be uncommonly high. RESULTS: One or more additional cancers were observed in 17 of 83 patients (20%, 95% CI 12% to 31%) for a total of 23 tumours. Of these, 5 were diagnosed prior to, 12 concomitantly with, and 7 after the gastric MALT lymphoma. Eleven patients had a single additional solid tumour (13%, 95% CI 7% to 22%); 3 patients had non-Hodgkin's lymphoma and one had Hodgkin's disease. Multiple additional cancers were present in 3 cases. Nine of 83 patients have died and 8 of them of a second cancer. CONCLUSIONS: Unexpectedly an extraordinarily large number of patients with other malignancies was observed in this series. The reasons for this finding are still unknown, but genetic alterations are speculated to play an important role.
Female↗
Detection of chromosome 11 alterations in blood and bone marrow by interphase cytogenetics in mantle cell lymphoma.
The t(11;14)(q13;q32) translocation is a consistent chromosome change in mantle cell lymphomas. This study investigates the application of fluorescent in situ hybridization (FISH) with chromosome painting probes for interphase cytogenetic analysis in patients with mantle cell lymphomas. Chromosome 11 paints have been able to show splitting of the chromosome signal consistent with the t(11;14) translocation in interphase cells from bone marrow and blood of patients with mantle cell lymphomas. These include some in clinical remission. The chromosome probes conjugated with fluorescent molecules are hybridized with patient's DNA allowing the easy detection of chromosome 11 abnormalities with fluorescent-light microscopes. Interphase FISH has a higher sensitivity and is quicker than standard metaphase cytogenetics. This may be beneficial in rapid detection of chromosome 11 abnormalities, assisting in the diagnosis of mantle cell lymphomas. In addition, detection of a clonal population of cells is possible.
Bone Marrow↗
Phase I clinical and pharmacokinetic study of oral etoposide phosphate.
PURPOSE: To determine the bioavailability (F) and the pharmacokinetic profile of both etoposide and its prodrug, etoposide phosphate, after oral and intravenous administration of etoposide phosphate, and to determine the maximum-tolerable dose (MTD) of oral etoposide phosphate administered daily for 5 consecutive days every 3 weeks. In addition, we sought to develop and validate two limited-sampling models (LSMs) to predict the etoposide area under the curve (AUC) 24 hours after administration of oral and intravenous etoposide phosphate. PATIENTS AND METHODS: In the F part of the study, patients were assessed for pharmacokinetic studies after one oral and one intravenous administration of the same dose of etoposide phosphate. Etoposide phosphate and etoposide plasma concentrations were assayed by high-performance liquid chromatography (HPLC). To develop LSMs after oral and intravenous administration, patients were randomized between the training and validation data sets. In the phase I part of the study, which followed the F part, the dose of etoposide phosphate was escalated from 50 mg/m2/d for etoposide equivalents for 5 days to 220 mg/m2/d for 5 days. RESULTS: Forty adult patients with solid tumors or lymphoma entered the study and 35 were assessable for toxicity. The MTDs were defined as 175 mg/m2 and 220 mg/m2 in previously treated and untreated patients, respectively. Neutropenia was dose-limiting, with high interpatient variability. Within 15 minutes after intravenous administration, etoposide phosphate was no longer detectable in plasma, and it was never detectable after oral administration. Plasma concentrations and pharmacokinetic parameters of etoposide following etoposide phosphate were comparable to those reported for etoposide. The relative F (mean +/- SD) of etoposide after oral etoposide phosphate was 76 +/- 27%, with a range of 37% to 144%. CONCLUSION: The clinical and pharmacokinetic results of this study confirm the prodrug hypothesis of etoposide phosphate. Although firm conclusions cannot be drawn, the F of oral etoposide phosphate seems to be comparable to or only slightly better than that of oral etoposide.
Administration, Oral↗
Dose-finding study of paclitaxel and cyclophosphamide in patients with advanced breast cancer.
Escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (administered as a 3-hour infusion) and cyclophosphamide have been given to patients with advanced breast cancer every 3 weeks to determine the maximum tolerated dose of the two drugs in combination without granulocyte colony-stimulating factor (G-CSF) support. The maximum tolerated dose of the same regimen with G-CSF support will then be determined in a subsequent group of patients. Patients who had received no more than one prior chemotherapy regimen for advanced disease were eligible for this study. The need for G-CSF support was established by an absolute neutrophil count (ANC) less than 0.5 x 10(9)/L for more than 7 days, an ANC count less than 0.1 x 10(9)/L for more than 3 days, febrile neutropenia requiring intravenous antibiotics, World Health Organization grade 3 or greater mucositis for more than 7 days, or the failure of the ANC to recover by day 28. The maximum tolerated dose was defined as the dose level at which more than two of six patients treated needed G-CSF support during the second treatment cycle. To date, 20 patients have been entered at the following dose levels: paclitaxel 135 mg/m2 and cyclophosphamide 750 mg/m2 (level 1), paclitaxel 155 mg/m2 and cyclophosphamide 750 mg/m2 (level 2), paclitaxel 175 mg/m2 and cyclophosphamide 600 mg/m2 (level 3), and paclitaxel 175 mg/m2 and cyclophosphamide 750 mg/m2 (level 4). Only one patient at level 2 needed G-CSF support because of an ANC below 0.1 x 10(9)/L for more than 3 days after the first cycle. Neither febrile neutropenia nor treatment delay for more than 1 week was reported. Antitumor activity has been observed from level 3. The evaluation of the toxicity of paclitaxel 200 mg/m2 and cyclophosphamide 175 mg/m2 without G-CSF support is ongoing.
Adult↗
Platinum dose-intensity in solid tumors: pharmacological and clinical perspectives.
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Antineoplastic Combined Chemotherapy Protocols↗
[Adriamycin/cyclophosphamide: current standard in the adjuvant therapy of breast carcinoma? Or: how should one really put this question?].
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Adult↗
Phase I study of the novel distamycin derivative tallimustine (FCE 24517).
BACKGROUND: Tallimustine, a benzoyl nitrogen mustard derivative of the antiviral agent distamycin A, is a new alkylating agent which binds to A-T rich regions of DNA in the minor groove producing highly sequence-specific alkylations. Its main preclinical features are a significant antitumor activity in animal models and a lack of cross-resistance in vitro and in vivo with L-PAM. Myelotoxicity was dose-limiting in animals, with a more than 100-fold difference in bone marrow sensitivity between mice and dogs. PATIENTS AND METHODS: Forty adult patients (pts) with solid malignancies were entered in the study. The drug was administered as an IV bolus every 4 weeks. CBC was repeated twice a week and serial assessments of renal function were performed in the week following the first cycle. From the starting dose of 50 micrograms/m2, corresponding to 1/3 of the highest non-toxic dose (HNTD) in dogs, there were increases through 10 dose levels, with reliance only on the features of the myelotoxicity observed. RESULTS: The main toxic effect was neutropenia which was dose-limiting, selective and short-lasting. Only previously-untreated pts received doses of 750 micrograms/m2 or more, with grade 4 neutropenia occurring in > or = 75% of the cycles. The maximally tolerable dose (MTD) was defined as 1250 micrograms/m2, with 3 of 3 pts developing febrile neutropenia requiring IV antibiotics. A platelet count of < 100 x 10(3)/microliters was observed in only one pt. Bone marrow aspiration performed in selected pts on days 8 and 15 confirmed a highly selective impairment by tallimustine of the myeloid lineage, with rapid recovery of the proliferative compartment. Pharmacokinetic studies performed at 1000 micrograms/m2 and 1250 micrograms/m2 showed a rapid fall of the plasma levels within the first 2 hours with drug concentrations between 100 ng/ml and 400 ng/ml within the first hour. A partial response of 4 months' duration was reported in one previously-untreated pt with cutaneous recurrences of malignant mesothelioma. CONCLUSIONS: The report of some antitumour efficacy, the high selectivity of neutropenia, the lack of significant non-hematological toxic effects and the occurrence of detectable but still low plasma drug concentrations suggest that further clinical evaluation of higher doses of tallimustine in combination with colony-stimulating factors would be justified.
Adult↗
Recent progress in B- and T-cell lymphomas.
The data we review indicate substantial progress in understanding of the biology of T- and B-cell lymphomas in humans. They indicate how processes central to normal development of B- and T-cells are corrupted in lymphomas and how these abnormalities may be approached or reversed in the context of therapy. Recent progress in treating lymphomas is less striking. The key issues here are whether more intensive therapy is better, whether some persons can be cured with less intensive therapies and whether immune therapies will prove useful. We hope to address these at the next B and T-cell lymphoma meeting scheduled for 1996.
Genes, Tumor Suppressor↗
First isolated locoregional recurrence following mastectomy for breast cancer: results of a phase III multicenter study comparing systemic treatment with observation after excision and radiation. Swiss Group for Clinical Cancer Research.
PURPOSE: We performed a randomized phase III multicenter study to compare systemic treatment versus no treatment after complete excision and radiotherapy for isolated first locoregional recurrence in patients with breast cancer. PATIENTS AND METHODS: One hundred sixty-seven good-risk patients with an estrogen receptor (ER+) positive recurrence or, in case of unknown receptor status, a disease-free interval (DFI) of greater than 12 months and < or = three recurrent tumor nodules each < or = 3 cm in diameter were entered onto the study. They were randomized to observation subsequent to local treatment or to receive tamoxifen (TAM) until disease progression. Seventy-nine percent of the patients were postmenopausal. RESULTS: The median observation period for the entire study population was 6.3 years. The median disease-free survival (DFS) duration was 26 months for observation and 82 months for TAM patients (P = .007). This was mainly due to the reduction of further local recurrences, whereas the occurrence of early distant metastases was delayed. A multivariate analysis identified DFI and treatment with TAM as significant prognostic factors for DFS. The 5-year overall survival (OS) rates were 76% and 74%, respectively (P = .77). DFI was also a prognostic factor for OS. CONCLUSION: Systemic therapy with TAM after isolated locoregional recurrence of breast cancer significantly increased 5-year DFS rates from 36% to 59% compared with observation alone and prolonged median DFS by more than 4.5 years in patients with ER+ tumors or in the case of unknown ER status with a DFI of greater than 12 months and minimal tumor burden. Treatment with TAM currently has no significant impact on OS, but the median survival duration of the study population has not yet been reached.
Adult↗
Treatment and prognosis of centrocytic (mantle cell) lymphoma: a retrospective analysis of twenty-six patients treated in one institution.
We retrospectively attempted to analyse prognostic factors in a group of 26 patients with centrocytic lymphomas (CCL) treated from 1979 to 1991 (representing 7% of all cases of NHL diagnosed in our institution during that period). Ten of the patients were females and 16 males, and their median age at diagnosis was 69 years (range 38-85). The majority of patients (77%) had advanced disease (Ann Arbor stage III-IV) at presentation. Twenty-two patients (85%) had good performance status (0-1 ECOG). B-symptoms were present in 10 cases. Most patients (87%) presented with generalized adenopathies. Bone marrow involvement was observed in 12 patients (46%) and Waldeyer's ring involvement in 5 (4 of them with stage I-II). In 5 cases the liver was involved and 3 pts had gastrointestinal localizations; 15 patients had more than 2 sites of disease: LDH elevation was observed in 8/24 pts. Fourteen patients (54%) received single-agent chlorambucil (3 pts) or CVP (11 pts). Eleven patients were treated with ADM-containing regimens (7 with CHOP or M-ACOD and 4 with 3rd generation regimens). One patient had radiotherapy alone. The complete response (CR) rate was 50% (13/26); 8 patients relapsed with a median time to progression of 19 months, and only 3 responded to salvage treatment. The median overall survival was 33 months, with fewer than 40% of patients surviving longer than 3 years. At univariate analysis the use of ADM-containing regimens seems significantly correlated with the CR rate (p = 0.047), the failure-free survival (p = 0.023), and the overall survival (p = 0.004).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Mass spectrometric identification and analysis of some aphidicolin metabolites in cancer patients.
We used gas chromatography/mass spectrometry to identify and quantitate some aphidicolin metabolites in plasma and urine of patients receiving aphidicolin-17-glycinate. The major metabolite found in plasma was 3-ketoaphidicolin, present at about one thent the concentrations of aphidicolin. 3-Ketoaphidicolin undergoes dehydroxymethylation to give 18-nor-3-ketoaphidicolin. This metabolite was also found in plasma and its concentration reached a maximum of 1% of aphidicolin. Small amounts of aphidicolin and 3-ketoaphidicolin were found free in urine but almost all of the drug was conjugated to glucuronic acid, as shown by mass spectrometric analysis of urine extracts and by enzymatic digestion with beta-glucoronidase followed by gas chromatographic/mass spectrometric analysis.
Animals↗
"Fatigue and malaise" as a quality-of-life indicator in small-cell lung cancer patients. The Swiss Group for Clinical Cancer Research (SAKK)
"Fatigue and malaise" (FM) is a frequent, non-specific symptom of cancer patients caused by the disease, its treatment and psychological distress. Since comprehensive quality of life assessment is often not feasible in multicentre clinical trials, short, but clinically relevant, quality of life indicators have to be defined. In a representative subsample of 127 patients in a phase-III randomized small-cell lung cancer trial comparing two different regimens of combination chemotherapy, quality of life was assessed at the beginning of each of the six treatment cycles with a self-rating questionnaire including an early version of the EORTC questionnaire, a mood adjective check list (Bf-S) and a single linear-analogue self-assessment scale (LASA) measuring general well-being. FM, measured with a five-item Likert subscale of the EORTC questionnaire, showed moderate to high intercorrelations with other EORTC subscales assessing disease symptoms, toxicity of treatment, role functioning, personal functioning, restriction of social activity, psychological distress, emotional (Bf-S) and general well-being (LASA). At baseline, FM was one of the most pronounced symptoms. Over the six cycles 43%-31% of the patients complained of moderate to severe fatigue. Over the first two cycles FM tended to decrease, slightly increasing during cycles 3 and 4 and decreasing again before cycle 6. In a multiple regression analysis over the six cycles, 53% of the variance of FM was explained by patient-rated symptoms of disease and toxicity (disease alone: 43%; toxicity alone: 35%). Initial performance status, previous weight loss, treatment arm, cycle number and age predicted the scores of FM over the six cycles.(ABSTRACT TRUNCATED AT 250 WORDS)
Affect↗
A limited sampling model for the pharmacokinetics of etoposide given orally.
A limited sampling model of etoposide after oral administration to estimate the area under the plasma concentration-time curve from 0 to 24 h (AUC) by determination of the drug plasma levels at only two time points was developed by a multiple regression analysis on a training data set of 15 patients receiving oral doses ranging from 54 to 90 mg/m2. The equation describing the model is AUC (micrograms ml-1 h) = 5.183 (micrograms ml-1 h) + 1.193 (h) x C1h (micrograms/ml) + 8.439 (h) x C4h (micrograms/ml) (R2 = 0.93, P = 0.0001), where C1h and C4h represent the plasma etoposide concentrations at 1 and 4 h, respectively. The model was validated prospectively on a test data set of 13 patients receiving oral doses ranging from 52 to 87 mg/m2 and, additionally, on a data set of 7 patients receiving oral doses ranging between 176 and 200 mg/m2, investigated in a previous study. Validation on both test data sets gave a relative mean predictive error of 0.1% and a relative root mean square error of 15.8% and 16.7%, respectively. The present study shows that it is possible to obtain a good estimate of the plasma AUC after oral administration of etoposide using a two-time-point sampling model. The model can be used to monitor the etoposide AUC in patients receiving chronic oral treatment.
Administration, Oral↗
Detection of bcl-2/JH rearrangement in follicular and diffuse lymphoma: concordant results of peripheral blood and bone marrow analysis at diagnosis.
The capacity to detect t(14;18) breakpoints in non-Hodgkin's lymphoma (NHL) peripheral blood and bone marrow was studied by DNA PCR. We studied 33 patients with follicular lymphoma (FL) (Working Formulation subtypes B, C, D) and 38 patients with intermediate-grade NHL (subtypes F, G). In the FL subgroup, 86% of the morphologically-positive bone marrow patients had amplifiable t(14;18) breakpoints by PCR. Remarkably, of 19 FL patients with 'negative' bone marrows, 11 (58%) were PCR-positive. In addition, half of the early clinical stage patients (I and II) had detectable breakpoints in their bone marrow DNA. Samples from NHL patients with intermediate-grade disease exhibit the same phenomena but at a considerably lower frequency. Paired peripheral blood and bone marrow samples were available at diagnosis in a subset of 56 patients. The concordance between bone marrow and peripheral blood PCR findings was high, with peripheral blood of 55/56 showing the same PCR results as the corresponding bone marrow.
Base Sequence↗