Introduction: During the last few years epirubicin (E) and mitoxantrone (M) (Novantrone) have been used in the treatment of non-Hodgkin's lymphoma (NHL), because of their favorable principal profile. In particular, M has less severe non-hematological toxicity. Patients and methods: A randomized multicenter phase III study was conducted in order to compare the efficacy and toxicity of CEOP and CNOP in intermediate- and high-grade NHL. CEOP (arm A) consisted of cyclophosphamide 1000 mg m-2, vincristine 2 mg, E 70 mg m-2 on day 1 and prednisone 60 mg on days 1-7. The CNOP regimen (arm B) was identical to CEOP except for replacement of E by M at a dose of 12 mg m-2. Randomization was stratified according to stages I-IV. From September 1993 to March 1999, 249 patients registered for the trial. Patient characteristics were equally distributed in the two arms, except for age and International Prognostic Index (IPI) groups. Results: There were no significant differences between the two groups in the rates of complete (CR) and partial response (PR). The overall response rate was 78% in arm A (57% CR, 21% PR) and 82% in arm B (60% CR, 22% PR). With a median follow-up time of 47.3 months, the median survival was not reached in arm A, while it was 39.5 months in arm B (P=0.09). Three-year survival rates were 62.5% for CEOP and 51.5% for CNOP. There was no significant difference regarding the time to progression between the two groups (29.7 vs. 18.5 months); furthermore the median duration of CRs was 71.6 and 49 months for CEOP and CNOP, respectively (P=0.07). The therapeutic efficacies of both regimens were equivalent among the four IPI groups. More alopecia was observed in arm A. WHO grade >2 neutropenia was more frequent in arm B. Supportive treatment with G-CSF was given to 22 and 24 patients, respectively. Conclusion: There were no significant differences in terms of overall response rates, overall survival and time to progression between CEOP and CNOP in the treatment of intermediate- and high-grade NHL. Patients with low or low intermediate IPI risk treated with either CEOP or CNOP showed significantly better survival, response rates and time to progression than those with high intermediate or high IPI risk. Therefore, new improved therapeutic approaches should be developed for the treatment of high IPI risk patients.

Solitary bone and extramedullary plasmacytomas are rare plasma cell proliferative disorders. Their diagnosis is based on histologic confirmation of monoclonal plasma cell infiltration of a single disease site and on the exclusion of systemic myeloma. For both entities, the treatment of choice is localized radiotherapy. With modern radiotherapy and with a total dose of at least 4000 cGy, the risk for local recurrence is less than 5%. There is no role for systemic chemotherapy in the management of these disorders. Approximately 30% of patients with solitary bone plasmacytoma (SBP) remain disease-free for several years; some of these patients may be cured. Patients with the best prognosis are those in whom the monoclonal protein disappears by 1 year after radiotherapy. The prognosis of patients with solitary extramedullary plasmacytoma (SEP) appears to be better than for patients with SBP because approximately 70% of patients with SEP remain disease-free at 10 years. With more sensitive staging procedures, the diagnosis of SBP and SEP may become less common, but the number of patients with prolonged stability and cure may increase.

CD40 ligand (CD40L, CD154) is overexpressed on T and B cells in systemic lupus erythematosus (SLE). Monocytes have been shown to contribute to immune-mediated pathology in SLE and to express CD40L under certain conditions. Therefore, we studied CD40L expression on lupus monocytes ex vivo, as well as after activation in vitro. A highly significant sevenfold increase in the frequency of CD40L-expressing peripheral monocytes from 23 SLE patients, compared to 16 healthy individuals (mean percentage of CD40L+CD14+ among CD14+ cells, 11.7 versus 1.6), was found by flow cytometry. Increased CD40L expression on monocytes correlated significantly with disease activity, elevated γ-globulin serum levels, as well as increased CD40L expression on T cells. CD40L expression by lupus monocytes was verified at both the mRNA and protein levels, while LPS stimulation was found to upregulate CD40L mRNA accumulation and surface protein expression. CD40L expression on activated lupus monocytes within anti-CD3-stimulated, mononuclear cell cultures was also enhanced compared to control-derived monocytes. These novel findings underscore the multiplicity of pathways through which monocytes may contribute to SLE pathology and suggest that T cell-independent CD40L-mediated cell to cell interactions may be also involved in humoral immune activation in SLE. © 2002 Elsevier Science (USA).

Purpose: Waldenström's macroglobulinemia (WM) is a low-grade lymphoplasmacytic lymphoma in which CD20 is usually expressed on tumor cells. There is evidence that patients with WM may benefit from treatment with the anti-CD20 monoclonal antibody rituximab. We performed a prospective phase II study to clearly define the activity of rituximab in patients with this disease. Patients and Methods: Twenty-seven patients with WM were treated with rituximab 375 mg/m2 intravenously (IV) for 4 weeks. Three months after completion of rituximab, patients without evidence of progressive disease received repeat 4-week courses of this agent. All patients were symptomatic, their median age was 72 years, and 15 patients were previously untreated. Results: Twelve patients (44%; 95% confidence interval, 25.5% to 64.7%) achieved a partial response after treatment with rituximab. Median time to response was 3.3 months (range, 2.2 to 7.1 months). Responses occurred in six (40%) of 15 previously untreated patients and in six (50%) of 12 pretreated patients. Patients with a serum immunoglobulin M less than 40 g/L had a significantly higher response rate. The median time to progression for all patients was 16 months, and with a median follow-up of 15.7 months, nine of 12 responding patients remain free of progression. Treatment with rituximab was well tolerated, with approximately one fourth of patients experiencing some mild form of infusion-related toxicity, usually fever and chills. Conclusion: Our prospective data indicate that rituximab is well tolerated and active in patients with WM. Previously untreated and pretreated patients seem to benefit equally. Repeat 4-week courses of rituximab may prolong the duration of response of the disease, but this observation requires confirmation in prospective, randomized trials. Furthermore, studies that will combine rituximab with chemotherapy may be relevant. © 2002 by American Society of Clinical Oncology.

The treatment of patients with recurrent low-grade lymphoma with the combination of fludarabine, mitoxantrone and dexamethasone has been associated with significant activity but has also caused frequent infectious complications. We designed a phase II study for previously untreated patients with the combination of fludarabine and mitoxantrone but without steroids. Our aim was to assess the activity of this combination as primary treatment for low-grade lymphoma and to avoid the additional immunosuppression induced by dexamethasone. Twenty seven patients with low-grade lymphoma received fludarabine 25 mg/m2/day IV on days 1-3 and mitoxantrone 10 mg/m2 IV on day 1. The treatment was repeated every 28 days for a maximum of six cycles. Twenty patients (74%) achieved an objective response including 12(44%) complete and 8(30%) partial responses. The main toxicity was grade III or IV neutropenia, which occurred in 40% of patients but there were no severe opportunistic infections. The median time to progression for all patients was 32 months. With a median follow-up of 33.4 months, six patients have died and the probability of survival at 3 years is 75%. We conclude that the fludarabine and mitoxantrone regimen is safe and effective for newly diagnosed patients with low-grade lymphoma who require treatment. Prospective randomized trials are needed in order to assess the impact of this treatment on patients' survival.

We conducted a phase III study in patients with advanced colorectal carcinoma (ACC). The total number of patients randomized from October 1993 until July 1998 was 192, whereas therapy was started on 179 and 158 (82.3%) have been evaluable. The treatment schedules consisted of weekly bolus administration for 6 weeks of 5-fluorouracil (5-FU), 600 mg/m2 (arm I) versus 5-FU (500 mg/m2) intravenous bolus and interferon-α, 5 MU subcutaneously, three times a week (arm II) versus leucovorin 200 mg/m2 in 2-hour infusion and 5-FU 500 mg/m2 intravenous bolus at the midtime of leucovorin infusion (arm III) followed by a 2-week rest period. Treatment was continued for six cycles or until progression. This study failed to show any superiority of the modulated 5-FU versus single administration of 5-FU. There were no significant differences between the three arms in the overall response rate (10.3% versus 11.3% versus 12.9%, p = 0.95), the time to tumor progression (median, 3.9 versus 3.8 versus 6.0 months, p = 0.59), or survival duration (median, 14.7 versus 12.4 versus 16.3 months, p = 0.71). The incidence of severe (grades III and IV) toxicity was significantly higher in patients in arm II and III (24.5% and 18.6%) versus arm I (6.0%) (p = 0.01). Because modulated 5-FU failed to show superiority versus 5-FU, new agents and new strategies are needed for the treatment of advanced colorectal carcinoma.

BACKGROUND. Adverse effects of paclitaxel and carboplatin have been well described; however, pulmonary toxicity after patients receive this regimen has not been investigated extensively. METHODS. To clarify this issue, 33 consecutive patients who were treated with paclitaxel and carboplatin underwent prospective evaluation of respiratory function, which included pulmonary symptoms, pulmonary function tests (PFTs), arterial blood gas levels, and radiographic studies. Assessment was performed before and after completion of chemotherapy in all patients. Patients with substantial declines in PFTs, defined as a decline ≥ 20 percent in forced expiratory volume in 1 second (FEV1), total lung capacity (TLC), or diffusion capacity for carbon monoxide (DLCO), were reassessed 5 months later. RESULTS. After chemotherapy, there were no significant changes in forced vital capacity (FVC; 111% ± 21% of the predicted value before chemotherapy vs. 111 ± 20% of the predicted value after chemotherapy), FEV1 (108% ± 24% of the predicted value before chemotherapy vs. 107% ± 22% of the predicted value after chemotherapy), FEV1/FVC ratio (79% ± 8% before chemotherapy vs. 78% ± 6% after chemotherapy), alveolar volume (VA; 95% ± 14% of the predicted value before chemotherapy vs. 96% ± 14% of the predicted value after chemotherapy), or TLC (96% ± 14% of the predicted value before chemotherapy vs. 97% ± 13% of the predicted value after chemotherapy). In contrast, there was a significant decline in DLCO (101% ± 20% of the predicted value before chemotherapy vs. 96 ± 21% of the predicted value after chemotherapy; P < 0.05). Arterial blood gas levels did not change after treatment. No patient had decreased FEV1 or TLC levels by ≥ 20%, whereas 4 of 33 patients (12%) exhibited a substantial decline (≥ 20%) in DLCO that persisted 5 months after treatment (DLCO at baseline, immediately after chemotherapy, and 5 months after the completion of chemotherapy, respectively: 99% ± 36% of the predicted value vs. 75% ± 28% of the predicted value vs. 74% ± 31% of the predicted value; P < 0.05). None of the 33 patients developed respiratory symptoms or had radiologic signs suggestive of lung toxicity. Among the various risk factors examined, baseline DLCO and FEV1 levels were associated with changes in DLCO post-treatment. CONCLUSIONS. This prospective analysis showed that the combination of paclitaxel with carboplatin induced an isolated decrease in DLCO level in the absence of clinical or radiologic evidence of toxicity. Further studies are needed to clarify whether this reduction in DLCO is predictive of subsequent pulmonary impairment. © 2002 American Cancer Society.

Objectives. Ifosfamide, paclitaxel, and cisplatin have moderate single-agent activity in patients with metastatic or recurrent cancer of the uterine cervix. We administered a combination of these three agents to a large number of patients with metastatic or recurrent cervical cancer to evaluate its activity. Methods. Sixty patients were treated on an outpatient basis with Ifosfamide (I) 1500 mg/m2 intravenously over 1 h on Days 1-3, paclitaxel (T) 175 mg/m2 as a 3-h intravenous infusion on Day 1, and cisplatin (P) 75 mg/m2 intravenously over 2 h on Day 2 with granulocyte colony-stimulating factor (G-CSF) support. The chemotherapy was repeated every 4 weeks for a maximum of six courses. Results. Fifty-seven patients received at least two courses of treatment and are evaluable for response. Twenty-six patients (46%) achieved an objective response, including 19% complete and 27% partial responses. The median duration of response was 11.5 months and the median time to progression and survival for all patients were 8.3 and 18.6 months, respectively. Patients with excellent performance status, with disease recurrence outside the radiation field, and with nonsquamous tumors had the highest response rate and best survival. Some degree of neurotoxicity occurred in 44% of patients. Grade 3 or 4 toxicity included granulocytopenia in 26% of patients, anemia in 13%, thrombocytopenia in 7%, and neurotoxicity in 3%. Conclusion. The ITP regimen is relatively well tolerated and moderately active in patients with metastatic carcinoma of the uterine cervix. Patients more likely to benefit are those with nonsquamous histology, with excellent performance status, and with disease recurrence outside the radiation field. © 2002 Elsevier Science (USA).

Monoclonal gammopathy of undetermined significance (MGUS) is a relatively common condition among individuals older than 70 years. The actuarial risk of MGUS progression to an overt plasma cell malignancy (PCM) after 20 years of follow-up has been reported to be as high as 30%. The purpose of this study was to evaluate the incidence and evolution of MGUS in a Greek population: 1564 consecutive patients older than 50 years who were admitted to the Department of Clinical Therapeutics at the University of Athens School of Medicine for various reasons over a 26-month period were evaluated with serum protein electrophoresis. In cases in which a monoclonal protein was detected, a panel of tests was performed to rule out an underlying plasma cell malignancy (PCM). Serum levels of interleukin (IL)-6, IL-6-soluble receptor (IL-6SR), IL-1 beta, and transforming growth factor beta 1 were also measured in the MGUS cases. Patients with MGUS were monitored at regular intervals for evidence of multiple myeloma or other PCMs. The incidence of MGUS was 4% and there was a positive correlation with increasing age. The median value of serum M peak was only 5.3 g/l. After a median follow-up of 71 months, only two patients developed multiple myeloma (60 and 75 months after initial diagnosis). Our data are consistent with those of other epidemiological studies regarding the incidence of MGUS, but the monoclonal protein levels and the probability of evolution to a malignant plasma cell disorder appeared to be lower in our study than in other series. Our data support the hypothesis that individuals with low M peak values require only regular annual follow-up examinations.

Waldenström's macroglobulinemia is a low-grade lymphoplasmacytoid lymphoma characterized by CD20 expression on malignant cells. Several studies have indicated that the anti-CD20 monoclonal antibody rituximab has activity against this disease. Thus, we performed a prospective study in which 17 previously untreated patients with symptomatic macroglobulinemia were treated with rituximab 375 mg/m2 intravenously for 4 weeks. Three months after completion of rituximab, patients without evidence of progressive disease received repeat 4-week courses of this agent. Six patients (35%) achieved a partial response after extended treatment with rituximab. Median time to response was 3 months. The median time to progression (TTP) for all patients was 13 months. One of 6 responding patients has progressed at 10 months, while the other 5 patients remain progression free with a follow-up range of > 22-40 months. Eight patients (47%) were rated as stable disease, and their median TTP was 9 months. Treatment with rituximab was well tolerated and was not associated with myelosuppression; one third of the patients experienced infusion-related toxicity, usually fever and chills of mild degree. Our prospective trial of extended rituximab therapy for previously untreated patients with Waldenström's macroglobulinemia indicates that this agent is active, well tolerated, and might be associated with a long period without the need for further treatment. Studies that will combine rituximab with chemotherapy or with other monoclonal antibodies might be of interest.

Background: The aim of this study is firstly to determine the response rates and toxicity of two regimens containing vinblastine (VBL) in combination with interferon-gamma (IFN-γ) in the treatment of patients with advanced renal cell carcinoma (RCC), and secondly to evaluate the additional efficacy of 13-cis retinoic acid (13-CRA) in RCC. Methods: Twenty-nine patients were included in the first trial (Trial 1) and 40 in the second one (Trial 2). The therapy given in Trial 1 consisted of VBL 0.15 mg/kg i.v. every 2 weeks and IFN-γ 100 μg s.c. 3 times weekly. In Trial 2, the therapy consisted of the same two drugs, in the same doses, plus oral 13-CRA 40 mg/day. Results: In Trial 1 there were 3 (10.3%) patients with complete response, 3 (10.3%) patients with partial response, 8 (27.6%) patients with stable disease and 15 (51.7%) patients with progressive disease. In Trial 2, there was no complete response, however, 3 (7.5%) patients had partial response. Additionally, 15 (37.5%) patients maintained stable disease and 14 (35%) patients had progressive disease. In Trial 1, the median survival was 12.56 months (95% CI, 6.8-18.3, range 0.59-42.49) and the median time to progression was 3.21 months (95% CI, 1.7-4.7, range 0.03-42.49). In Trial 2, the median survival was 9.54 months (95% CI, 5.9-13.1, range 0.43-24.1) and the median time to progression was 3.9 months (95% CI, 0.8-7, range 0.26-24.1). In Trial 1, granulocytopenia grade 3 and 4 appeared in 5 (17.2%) patients and anaemia grade 3 in 1 (3.4%) patient. In Trial 2, there were grade 3 toxicities, as granulocytopenia in 5 (12.5%) patients, anemia in 4 (10.0%) patients, stomatitis in 3 (7.5%) patients, fatigue/ malaise in 3 (7.5%) patients and 1 (2.5%) had diarrhea. No toxic deaths occurred in both studies. Conclusion: The use of IFN-γ does not enhance the low response of VBL-based chemotherapy. The additional administration of 13-CRA with the combination of VBL and IFN-γ does not add to the efficacy of this combination in patients with advanced renal cell carcinoma. New active agents are needed to treat patients with this disease. Copyright © 2002 S. Karger AG, Basel.

Determinations of the cadmium content of a wide variety of foodstuffs from the Greek market were carried out. The values detected ranged from <0.1 ng g-1 in alcoholic beverages to 1595.8 ng g-1 in large snails. The highest values were observed in molluscs and crustaceans (117.4ng g-1), followed by leafy vegetables (28.3 ng g-1), potatoes (22.3 ng g-1) and organs and offal (20.7 ng g-1), whereas the other food categories had a lower cadmium content. The results are comparable with those from the rest of Europe. Preliminary analytical data on the cadmium content of food samples of organic cultivation showed significantly lower values compared with those of samples of conventional produce.

Purpose: We conducted this randomized study comparing the activity and toxicity of paclitaxel and gemcitabine (PG) and paclitaxel and carboplatin (PC) combinations for the treatment of advanced non-small-cell lung cancer (NSCLC). Patients and Methods: Chemotherapy-naive patients were randomized to paclitaxel 200 mg/m2 on day 1 plus either carboplatin at an area under the concentration-time curve of 6 on day 1 (group A) or gemcitabine 1,000 mg/m2 on days 1 and 8 (group B) every 3 weeks. A retrospective cost analysis was conducted using Student's t test to compare independent samples between groups. Results: A total of 509 patients (group A, 252 patients; group B, 257 patients) were enrolled; all characteristics were well balanced. The median survival time was 10.4 months (95% confidence interval [CI], 8.8 to 12 months) for group A and 9.8 months (95% CI, 8.0 to 11.7 months) for group B (P = .32). Respective 1-year survival rates were 41.7% and 41.4%. The response rate for group A was 28.0% (2% complete response [CR], 26% partial response [PR] [95% CI, 22% to 34%]), and the response rate for group B was 35.0% (5% CR, 30% PR) [95% CI, 29% to 41%]) (P = .12). Toxicity was mild. Grades 3/4 neutropenia, thrombocytopenia, and anemia for groups A and B were seen in 15% and 15%, 2% and 1%, and 5% and 2%, respectively. The mean total cost (outpatient clinic visits plus chemotherapy drug fee) for group A (€ 7,612.64) versus group B (€ 7,484.77) was not statistically significant (P < .66). Conclusion: The PG combination is as equally active and well tolerated as the PC combination in patients with advanced NSCLC. © 2002 by American Society of Clinical Oncology.

Background: The usefulness of tumor volumetry in ovarian epithelial cancer has never been intensively investigated. The aim of the present study was to determine the value of quantitative analysis of tumor volume as a predictive method for response to treatment and as a prognostic method for disease outcome. Materials and Methods: Seventy-five women with advanced ovarian cancer who presented with measurable disease on CT scan prior to chemotherapy were retrospectively studied. The patients were treated with platinum-based chemotherapy. The median follow-up was 113.36 weeks. An independent radiologist identified and delineated tumor contours in each slice of sequential CT scans before and after therapy. Volumetry was measured with a three-dimensional approach by utilizing a digitizer and a specific algorithm on a software computed program. Results: Data were analyzed according to initial and to residual tumor volumes. Patients with low initial volume of <52 cm3 exhibited higher responses (p<0.01), while patients with medium (52-165 cm3) or high (> 165 CM3) initial tumor volume had a shorter time to progression (p<0.01). Patients without or with low residual volume of <35 cm3 were found to have a longer time to progression (p<0.05) and longer survival (p<0.01 and p<0.05). In addition, serum CA 125 levels followed precisely tumor volumetry for both initial and residual disease. Conclusion: Tumor volumetry in advanced ovarian cancer was found to have predictive value for response to platinum-based chemotherapy. Initial tumor volume has prognostic significance only for the time to progression, whereas residual tumor volume has for both time to progression and survival.