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The aim of this retrospective study was to illustrate the clinicopathologic data and the treatment results in patients with primary gastrointestinal tract non-Hodgkin's lymphoma (GI NHL). Among 810 patients with NHL, 128 cases (15.8%) were diagnosed as primary GI tract NHL. There were 79 males and 49 females with median age of 62 years. The most common primary site was the stomach (68%). Overall, 67.2% of the patients were in stages I - II, and 32.8% in stages III - IV. Simultaneous involvement of the GI tract and other extranodal sites was observed in 26 patients (20%). Extranodal marginal zone B-cell lymphoma (MZBL) (i.e., low-grade lymphoma of mucosa-associated lymphoid tissue type) accounted for 48.4% of lymphomas. Aggressive lymphomas (diffuse large B-cell lymphoma [DLBL]) accounted for 44.5%. Eighty-three patients (67.5%) achieved complete response (CR), either by surgery (43/43 patients, 17 with DLBL and 25 with MZBL) or by primary chemotherapy (40/64 patients, 22 with DLBL and 17 with MZBL). Sixty-two patients remain in CR; 33/43 after surgical resection (13/17 with DLBL and 20/25 patients with MZBL), and 29/40 after only chemotherapy (18/22 with DLBL and 10/17 with MZBL). The major prognostic factor for outcome in the present study was the stage of the disease. Patients with localized lymphoma (stage I and II) had significantly longer DFS and OS (DFS and OS at 3-year: 83% and 87%, respectively) than patients with extended disease (stage III and IV) (DFS and OS at 3-year: 46% and 60%, respectively) (P < 0.0001). The International Prognostic Index (IPI) for patients with aggressive lymphomas was prognostic only for DFS (79% for low-risk patients [IPI score 0 - 1] vs 49% for higher risk groups [IPI score >1] at 3-year, P = 0.0131). Leuk Lymphoma

Background: The ubiquitin-proteasome system (UPS) plays a pivotal role in tumorigenesis. Components of the UPS have recently been implicated in breast cancer progression. In the present study, we sought to explore the prognostic and/or predictive significance of UBE2C messenger RNA (mRNA) expression on disease-free survival (DFS) and overall survival (OS) in high-risk operable breast cancer patients. Methods: Five hundred and ninety-five high-risk breast cancer patients were treated in a two-arm trial evaluating postoperative, dose-dense sequential chemotherapy with epirubicin followed by CMF (cyclophosphamide, methotrexate and 5-fluorouracil) with or without paclitaxel (Taxol). RNA was extracted from 313 formalin-fixed primary tumor tissue samples followed by one-step quantitative RT-PCR for assessment of mRNA expression of UBE2C. Results: High UBE2C mRNA expression was associated with poor DFS (Wald's P = 0.003) and OS (Wald's P = 0.005). High tumor grade, as well as high Ki67 protein expression, was more frequent in the high-expression group of UBE2C. Results of the Cox multivariate regression analysis revealed that high UBE2C mRNA expression remained an independent adverse prognostic factor for relapse (P = 0.037) and death (P = 0.05). Conclusions: High UBE2C mRNA expression was found to be of adverse prognostic significance in high-risk breast cancer patients. These findings need to be validated in larger cohorts. 23 6 1422 1427

Background: The aim of this retrospective study was to present the epidemiological, pathological and clinical characteristics and treatment results of Greek women with epithelial ovarian cancer (EOC). Patients and Methods: From February 1976 to December 2006, 1,791 patients had been diagnosed, treated and followed up in the participating centers of the Hellenic Cooperative Oncology Group (HeCOG). Cox-regression analysis was carried out in order to identify possible prognostic factors. Results: The median age at diagnosis was 60 years. Seventy-five percent had a performance status (PS) of 0-1, 58.5% had a serous carcinoma, 36% had poorly differentiated tumors and 57% had International Federation of Gynecology and Obstetrics (FIGO) stage III disease. Approximately half of the patients had been subjected to a total abdominal hysterectomy, bilateral oophorectomy and omentectomy, and 80% of them had undergone optimal debulking surgery. Among 1,462 patients with advanced disease, 96% had received platinum-based chemotherapy, while platinum plus paclitaxel had been administered to two-thirds of them. Among 609 patients with known data for response, 34% had achieved a complete objective response (CR) and 30% a partial response (PR), resulting in an overall response rate (RR) of 64%. Performance status, FIGO stage and residual disease (RD) after cytoreductive surgery were the strongest prognostic factors for time-to-tumor progression (TTP) and for overall survival (OS), while age was found to be significant only for OS. The median TTP was 107 months (95% confidence interval (CI), 92-121 months) for patients with stages I-II, 17 months (95% CI, 15-18 months) for those with stages III-IV, 96 months (95% CI, 58-133 months) for patients without RD and 17 months (95% CI, 15-18 months) for those with RD. Median OS had not been reached for the patients with stages I-II, while it was 40 months (95% CI, 37-43 months) for those with stages III-IV, 141 months (95% CI, 103-179 months) for patients without RD and 42 months (95% CI, 39-45 months) for those with RD. Conclusion: There were no significant differences in patient characteristics or types of treatments administered in Greek women with EOC in comparison with those reported in the English literature. 29 2 745 751

Introduction. Taxane/platinum combinations exhibit synergistic cytotoxicity and activity against a broad range of solid tumours. We sought to optimise the regimen as a suitable outpatient palliative treatment for cancer of unknown primary (CUP). Patients and methods. Eligible CUP patients with adenocarcinoma or poorly differentiated carcinoma, performance status of 0-2, adequate organ function and assessable disease were treated with docetaxel 75 mg/m2 and carboplatin at an area under the concentration time-curve (AUC) of 5, both as 30-minute intravenous infusions, every three weeks. Patients with isolated axillary adenopathy, squamous cell cervical or inguinal adenopathy and PSA or germ-cell serum tumour markers were excluded. Results. Forty-seven patients entered the trial, 24 with predominantly nodal disease or non-mucinous peritoneal carcinomatosis (favourable risk) and 23 with visceral metastases (unfavourable risk). A median of 6 cycles of chemotherapy were administered, with relative dose intensities of both drugs >90%. Response rates were 32% (46% in favourable risk, 17% in unfavourable), comparable to the activity of paclitaxel/platinum regimes, though complete remissions were seen only in favourable risk patients. Granulocyte-colony stimulating factor support was used in a third of treatment cycles. Toxicity was mild and manageable, with grade 3-4 neutropenia in 26% of patients, febrile neutropenia in 7% and severe non-hematologic side-effects in less than 8% of patients. No toxic deaths or severe neurotoxicity were seen. Median time to progression (TTP) and overall survival (OS) were 5.5 and 16.2 months respectively. Survival was driven mainly by favourable-risk patients (22.6 months), as those with visceral metastases had a poor median survival of only 5.3 months. Good performance status and low-volume disease predicted for superior outcome, while docetaxel relative dose-intensity was a positive prognosticator only in favourable-risk patients. Conclusions. One-hour docetaxel/carboplatin is a convenient, safe and effective outpatient palliative treatment for CUP patients, providing meaningful survival prolongation only in favourable-risk patients. Insights in the molecular biology of CUP are needed for the development of targeted therapeutic manipulations of malignant resistance and progression. © 2008 Taylor & Francis. 47 6 1148 1155

Background: The aim was to examine characteristics and treatment results of patients with mucosa-associated lymphoid tissue (MALT) non-Hodgkin's lymphomas. Patients and methods: Epidemiological and clinical features of 97 patients with MALT lymphoma from the Hellenic Cooperative Oncology Group registry were analysed retrospectively for their prognostic significance in progression-free survival (PFS) and overall survival (OS). Comparisons were made between patients with gastric and nongastric sites of primary lymphoma and between different therapeutic modalities. Results: Sixty-five patients presented with gastric and 32 with nongastric lymphomas. The most frequent locations of nongastric lymphomas were the bowel, lung and parotid. Gastric lymphomas occurred more frequently in males and younger patients compared with nongastric lymphomas. Seventy-four per cent of patients had early (Ann Arbor stages I-II) and 26% had advanced (stages III-IV) disease. The median PFS for the entire population was 44 months. At 5 years, 47% of patients were progression free and the OS rate was 80%. The most reliable prognostic factor for PFS and OS was the Ann Arbor stage; 5-year PFS was 67% versus 13% and 5-year OS 91% versus 51% for patients with early versus advanced disease, respectively (P < 0.001). Of the patients treated with chemotherapy only, 87% achieved an objective response and 71% complete response. Surgery did not offer survival benefit compared with chemotherapy in localised gastric lymphoma. Conclusion: MALT lymphomas represent a distinct disease entity with widespread extranodal origin, indolent clinical course and high chemosensitivity. Ann Arbor stage was the most reliable prognostic and predictive factor. © The Author 2007. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. 19 4 780 786

Introduction: Cancer in the elderly is a common health issue in developed societies. We sought to present epidemiology, management and outcome data on fit elderly patients with common metastatic cancers and to identify predictors of clinical benefit from palliative chemotherapy. Methods: All patients aged >65 years who were diagnosed with metastatic breast, colorectal or non-small cell lung carcinomas and managed with palliative chemotherapy in the context of Hellenic Cooperative Oncology Group (HeCOG) clinical trials or protocols were eligible for electronic data retrieval and analysis. Common eligibility criteria included adequate performance status (ECOG 0-3), organ function and absence of severe co-morbidity forbidding cytotoxic chemotherapy. Results: One thousand three hundred and seventy-two fit patients (PS 0-1 in 73%) with a median age of 70 years diagnosed with metastatic breast (n = 250), colorectal (n = 621) or lung cancer (n = 501) received chemotherapy from 1991 until 2006. Most patients received modern full-dose chemotherapy regimens including platinum, taxanes, anthracyclines, fluoropyrimidines, oxaliplatin or irinotecan. Mild to moderate co-morbidity was present in 35%. At a median follow-up of 3 years, objective responses were seen in 41% of patients with breast cancer, 25% with colorectal cancer and 31% with lung cancer, while median survival was 21, 16 and 9.4 months, respectively. Grade 3 or 4 toxicity was seen in a quarter of patients, the most common being neutropenia (14%), diarrhoea (6%), neurotoxicity (4%), fatigue, nausea and febrile neutropenia (each 2%). In multivariate analysis, diagnosis of colorectal or lung cancer, metastases in multiple organ sites, presence of liver/brain/peritoneal deposits, impaired PS and low baseline serum albumin levels were prognostic factors for adverse outcome. The same factors excluding metastatic sites and with the addition of anemia predicted for resistance to chemotherapy. Toxicity was more likely in females with low serum albumin and renal dysfunction. A six-variable geriatric assessment for palliation (GAP) score that included tumour type, sites of metastatic dissemination, impaired PS, low serum albumin and anemia classified elderly patients to groups with low, intermediate and high risk for disease progression and death (relative risks of 1.59 and 2.50 for resistance to therapy and 1.87 and 3.12 for death in the intermediate and high-risk groups). Conclusions: Our data indicate that relatively fit elderly patients with advanced cancer safely tolerate modern chemotherapy and enjoy disease control in a manner comparable to younger patients. Our GAP score, if further validated, offers promise for geriatric application in combination to comprehensive geriatric assessment tools for the optimisation of palliative therapy on an individualised basis. © 2007 Elsevier Ireland Ltd. All rights reserved. 66 3 237 247

Background: In this study we investigated whether administering CEOP (cyclophosphamide, epirubicin, vincristine [Oncovin], and prednisone) every 2 weeks (CEOP-14) instead of every 3 weeks (the standard CEOP-21 regimen) improves outcomes in patients with previously untreated aggressive lymphomas. In a secondary analysis we evaluated the impact of adding rituximab to CEOP-14/CEOP-21 chemotherapy. Study Design: The trial opened in March 1999, and patients were randomly assigned to either CEOP-14 or CEOP-21. All patients enrolled from May 2002 onward received rituximab with each chemotherapy cycle, and those attaining a complete response received rituximab consolidation. Results: Complete and overall response rates in the CEOP-21 ± rituximab (N ≤ 114) and CEOP-14 ± rituximab (N ≤ 103) arms were similar, as were the overall survival (P ≤ 0.769) and time to progression distributions (P ≤ 0.969). Rituximab was shown to have a beneficial effect both on the overall survival and on the time to progression. Conclusions: Thus far, no significant improvement in outcome has been demonstrated with CEOP-14 ± rituximab versus CEOP-21 ± rituximab. However, with addition of rituximab to CEOP-21/CEOP-14, significant improvements in time to progression and overall survival were achieved. © 2007 by Lippincott Williams & Wilkins. 13 5 327 334

Background: The prognosis of patients with recurrent and/or metastatic head and neck cancer (HNC) is poor. Median survival of these patients following chemotherapy is in the range of 6 to 9 months. In the present randomized phase III trial we compared two new combinations containing new drugs with proven activity in phase II studies with patients with HNC. Patients and methods: From November 1999 until November 2004, 166 eligible patients with HNC were enrolled in the study. They were treated with paclitaxel 175 mg/m2 on day 1 and gemcitabine 1000 mg/ m2 on days 1 and 8 every 3 weeks (group A, 85 patients) or with paclitaxel, as in group A, and pegylated liposomal doxorubicin 40 mg/m2 on day 1 every 4 weeks (group B, 81 patients). Results: There was no significant difference in response rate (20% versus 29%, P = 0.21), time to disease progression (median; 4.4 months versus 6.0 months, P = 0.09) and survival (median; 8.6 months versus 11.05 months, P = 0.25). Both regimens were generally well tolerated. The most frequently reported side effect, apart from alopecia, was neutropenia. Overall, there was no significant difference in severe toxicity between the two treatment arms. Conclusions: The present study could not demonstrate a survival benefit with either regimen. Both treatments were well tolerated. Randomized studies comparing each of the two regimens with standard chemotherapy are warranted. © 2006 Oxford University Press. 17 10 1560 1567

Introduction: Glycodelin and survivin are key polypeptide regulators of cellular proliferation, apoptosis and angiogenesis. In view of contradictory reports on their functional role in tumors, we studied their transcriptional levels in localized breast cancer. Patients and methods: Glycodelin and survivin messenger ribonucleic acid (mRNA) was isolated and amplified by quantitative reverse-trancription PCR from paraffin-embedded breast carcinomas of 275 women. A normalized score was calculated by the use of GAPDH, RPL37A reference genes and was correlated with clinicopathologic/molecular parameters and patient outcome. Results: A total of 272 patients were eligible, most harbored stage III node-positive breast carcinomas larger than 2 cm. Glycodelin mRNA was expressed in 68 patients (25%), more frequently in premenopausal women (P = 0.01) and those with HER2 mRNA-positive tumors (P = 0.02). Survivin mRNA was present in 263 tumors (97%) and its levels correlated significantly with high nuclear grade, VEGF mRNA and p53 mRNA presence (P < 0.05). At a median follow-up of 64 months, neither glycodelin nor survivin mRNA expression demonstrated prognostic utility for overall or disease-free survival at univariate and multivariate analysis. Conclusions: Glycodelin and survivin transcriptional activity are associated with adverse clinicopathologic and molecular characteristics of node-positive primary breast cancer but do not predict patient outcome. Further study is needed for illumination of their functional roles in tumorigenesis. © 2006 Springer Science+Business Media, LLC. 100 2 161 167

Purpose.: Ovarian clear-cell carcinomas (OCCC) are known to be possibly resistant to platinum-based chemotherapy and to have a poorer prognosis with respect to other subtypes of epithelial ovarian cancer (EOC). This study was undertaken to compare response and survival to platinum-based chemotherapy between patients with advanced stage III and IV OCCC and serous EOC (sEOC). Patients and methods.: A retrospective analysis was performed in patients with advanced stage of OCCC treated with first-line platinum-based chemotherapy in the context of several study protocols of the Hellenic Cooperative Oncology Group (HeCOG) between 1/2/1987 and 31/10/2003. The outcome was compared to that of patients with sEOC treated according to the same protocols during the same study period. Results.: One hundred and five patients (35 stage III and IV OCCC, 70 stage III and IV sEOC) treated with platinum-based chemotherapy were analyzed. The overall response rate for OCCC was 45% (complete response 25%) (95% CI, 23.1% to 68.5%) and 81% (complete response 46%) (95% CI, 67.4% to 91.1%) for sEOC. The overall response rate was significantly higher for sEOC (P = 0.008). In the subgroup of stage III patients, the rate of complete responders was higher among sEOC patients (P = 0.023). After a median follow-up of 61.1 months, median survival and time to tumor progression were not significantly different between the two groups (25.1 months [95% CI 11.7 to 38.5 months] versus 49.1 months [95% CI 36.5 to 61.6 months], P = 0.141, 12.0 months [95% CI 6.5 to 17.3 months] versus 18.0 months [95% CI 14.7 to 21.6 months], P = 0.384, respectively). Conclusion.: Patients with OCCC have significantly lower response to platinum-based first-line chemotherapy compared to patients with sEOC. This low response to platinum-based chemotherapy was not translated in significantly shorter survival. The current study outcomes are provocative and suggest that a new strategy for chemotherapy in OCCC should be adopted, possibly one that focuses on new agents without cross-resistance to platinum agents. © 2006 Elsevier Inc. All rights reserved. 102 2 285 291

The purpose of this retrospective study, the largest unselected series in our country, was to illustrate the clinicopathological features of non-Hodgkin's lymphoma (NHL) classified according to the World Health Organization (WHO) classification of lymphoid neoplasms. A retrospective analysis was conducted and clinical features of histological subtypes were established in 810 patients (age ≥ 15 years) with NHL who were treated at 8 major centers representative of Greece. There were 435 males and 375 females 95% of them aged >30 years. B symptoms were present in 34% of the patients, while 45.3% had stages I-II and 54.6% had stages III-IV. LDH was increased in 37% of the patients. B cell lymphomas formed 88% of the cases whereas T cell lymphomas formed 12% of the total. Indolent lymphomas accounted for 31.1%, aggressive ones for 66.7% and very aggressive ones for 2.4% of all NHLs. Among indolent lymphomas extranodal ones (MALT B cell lymphoma) were the most common subset while follicular lymphoma grade I and II and small lymphocytic ones presented with equal frequency. Among the aggressive lymphomas diffuse large cell lymphoma (DLCL) was the most common subtype; this entity along with large-cell immunoblastic lymphomas accounted for 45.2% of all B cell lymphomas. Among the T cell lymphomas, peripheral T cell lymphomas and anaplastic large cell lymphomas of the T/null-cell type were the most common subtypes. The most common extranodal presentation was the gastrointestinal tract (GI). Next in frequency were primary extranodal NHL of the head and neck region. MALT B cell lymphomas were found in almost half of the patients with GI tract NHL, whereas in all other extranodal places DLCL was the predominant histological subtype. The median survival for indolent and aggressive NHL was 123.5 and 55.5 months, respectively. This is the first report of a large series of malignant lymphomas in Greece using the WHO classification. It appears that there are no significant differences between NHL in Greece and other large series as far as clinical and extranodal presentation is concerned. The frequency of follicular lymphoma in the current study is comparable to that reported from Asian countries and mainland Europe, but lower than that of US and Northern European series. There were no important differences in the incidence of the remaining histological subtypes between Greece and other European countries. Copyright © 2005 S. Karger AG. 113 2 97 103

Background: A phase II study was conducted to evaluate the efficacy and toxicity of the combination of gemcitabine (GEM) and pegylated liposomal doxorubicin (PLD) in patients with platinum- and/or taxane-resistant/refractory advanced epithelial ovarian cancer (AEOC). Patients and Methods: Patients (pts), who had been treated with platinum or paclitaxel and met the criteria of resistant/refractory AEOC, received GEM 650 mg/m2 days 1 and 8 and PLD 25 mg/m2 day 1 every 4 weeks up to a total of 6 cycles, unless disease progression or adverse effects prohibited further therapy. Results: Thirty-seven patients entered the study. There was 1 complete (3%) and 7 partial responses (19%) for an overall response rate of 22%. Two patients had stable disease (5.5%). After a median follow-up of 16.2 months, the median survival was 8.4 months and time to treatment failure 2.7 months. The most frequent severe toxicity was myelosuppression recorded in 13 (35%) patients. Severe stomatitis was recorded in only 2 (5%) cases and severe palmar-plantar erythrodysesthesia in 1 patient. One severe allergic reaction (grade 4) to PLD was recorded following the third cycle of treatment. Conclusion: The combination of GEM and PLD in patients with AEOC, who are resistant/refractory to platinum and/or Taxanes, did not show any superiority over monotherapy. However, in view of the acceptable toxicity profile, the above combination may deserve further investigation in a randomised setting. 25 4 3103 3108

Background: Brain metastases from epithelial ovarian cancer (EOC) are rare. A retrospective study of all patients diagnosed with brain metastases from EOC over the last 20 years, according to the Hellenic Cooperative Oncology Group (HeCOG) tumor registry, was conducted. Patients and Methods: A total of 1450 patients with EOC were treated within various HeCOG protocols from 1983 to 2004. Seventeen (1.17%) of them developed brain metastases. Results: The median age at diagnosis of brain metastases was 58 years (range, 24 to 77). At initial diagnosis, 2 patients had stage II, 12 had stage III and 3 had stage IV disease. Serous papillary adenocarcinoma was the most common histological subtype [12 patients (71%)]. All patients had received initial cisplatin-based chemotherapy. The median time from initial diagnosis to central nervous system (CNS) relapse was 15.9 months (range, 1.4 to 70.8). The CNS was the only site of disease in 13 (76.5%) patients, whereas 4 (23.5%) patients had additional extracranial disease. Two (12%) patients with isolated single brain lesions underwent surgical excision of the metastases, followed by whole brain radiation therapy (WBRT) and chemotherapy. Four (24%) patients were treated with WBRT alone, 6 (35%) patients with WBRT plus chemotherapy and 2 (12%) had only supportive care, while 3 (18%) patients decided not to have any further treatment after the diagnosis of brain metastases. The median survival time from diagnosis of CNS relapse was 5.7 months (range, 0.2 to 22.6) and the median survival time from diagnosis of EOC was 27.4 months (range, 3.0 to 71.4). In patients with CNS recurrence as the only site of disease, the median survival time from diagnosis of CNS relapse was 5.3 months (range, 0.6 to 22.6) and in those with both CNS and extracranial disease, the median survival time was 3.9 months (range, 0.2 to 11.9) (p=0.5597). There was a statistically significant difference in survival for those treated with WBRT plus chemotherapy (10.0 months) versus those treated with WBRT alone (1.5 months) and those who had only supportive care (0.2 months) (p=0.0003). Conclusion: The incidence of cerebral metastases in our patients with EOC was 1.17%, which is consistent with the mean value of all series reported in the literature. The prognosis of patients with brain metastases from EOC is poor. Patients who had WBRT and chemotherapy fared better than those who received WBRT alone. 25 5 3553 3558

The purpose of this retrospective study was to illustrate the clinicopathological features of patients presenting with multifocal extranodal non-Hodgkin lymphoma (NHL). Among 810 patients with NHL, 37 cases (4.2%) were found to have multiple extranodal involvement (two or more sites). There were 24 men and 13 women, with a median age of 63 years. The majority of these cases (n = 26) had gastric or intestinal (GI) involvement with or without other extranodal sites. Lung along with another extranodal site was relatively common in the present series. Stratification of the 37 cases according to the International Prognostic Index (IPI) showed that 89% of the patients belonged to the high-risk groups. Diffuse large-B-cell lymphoma (DLBCL) accounted for 62%, and mucosa-associated lymphoma tissue (MALT) lymphoma accounted for 27% of all cases. After induction treatment with anthracycline-based regimens, complete remission was achieved in 21 patients (57%), partial remission was achieved in six patients (16%), and seven patients (19%) had no response, while three patients (8%) were nonevaluable. In conclusion, multifocal extranodal NHL is a heterogeneous group of diseases. The majority of them arise at various sites in the GI tract. DLBCL was the most frequent histological subtype followed by MALT lymphoma. Risk group, as defined by the IPI, was predictive of survival.

To investigate the efficacy and toxicity of the combination of gemcitabine and vinorelbine in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBL), 22 patients with relapsed or refractory DLBL were treated with gemcitabine 1000 mg/m2 and vinorelbine 30 mg/m2 on days 1 and 8 every 3 wk for a maximum of six cycles. Fourteen patients were considered chemosensitive while eight patients were considered chemoresistant to the last treatment regimen. All 22 patients were assessed for response to treatment. Three patients (14%) achieved complete remission and eight patients (36%) had partial remission of their disease, with an overall response rate of 50%. With a median follow up of 44 months, the median time to progression (TTP) for all patients was 8.1 months while the median overall survival (OS) was 12.9 months. Toxicity was minimal and all patients were treated on an outpatient basis. The combination of gemcitabine and vinorelbine is an effective and well-tolerated regimen for patients with relapsed of refractory DLBL. © Blackwell Munksgaard 2005. 75 2 124 129

SUMMARY: The present randomized phase III trial was designed to detect a 15% benefit in relapse-free survival (RFS) or overall survival (OS) from the incorporation of adjuvant tamoxifen to the combination of CNF [cyclophosphamide, 500 mg/m2; mitoxantrone (Novantrone), 10 mg/m2; fluorouracil, 500 mg/m2 chemotherapy and ovarian ablation in premenopausal patients with node-positive breast cancer and conversely from the incorporation of CNF chemotherapy to adjuvant tamoxifen in node-positive postmenopausal patients. From April 1992 until March 1998, 456 patients with operable breast cancer and one to nine infiltrated axillary nodes entered the study. Premenopausal patients were treated with six cycles of CNF chemotherapy followed by ovarian ablation with monthly injections of triptoreline 3.75 mg for 1 year (Group A, 84 patients) or the same treatment followed by 5 years of tamoxifen (Group B, 92 patients). Postmenopausal patients received 5 years of tamoxifen (Group C, 145 patients) or 6 cycles of CNF followed by 5 years of tamoxifen (Group D, 135 patients). Adjuvant radiation was administered to all patients with partial mastectomy. After a median follow-up period of 5 years, 125 patients (27%) relapsed and 79 (17%) died. The 5-year actuarial RFS for premenopausal patients was 65% in Group A and 68% in Group B (p = 0.86) and for postmenopausal patients 70% in Group C and 67% in Group D (p = 0.36). Also, the respective OS rates were 77% and 80% (p = 0.68) for premenopausal and 84% and 78% (p = 0.10) for postmenopausal patients. Severe toxicities were infrequently seen, with the exception of leukopenia (18%), among the 311 patients treated with CNF. In conclusion, the present study failed to demonstrate a 15% difference in RFS in favor of node-positive premenopausal patients treated with an additional 5 years of tamoxifen after CNF adjuvant chemotherapy and ovarian ablation. Similarly, six cycles of CNF preceding 5 years of tamoxifen did not translate to a 15% RFS benefit in node-positive postmenopausal patients. Am J Clin Oncol

Rituximab, a chimeric monoclonal antibody, produces response rates of up to 73% in patients with previously untreated indolent non-Hodgkin's lymphoma (NHL), and has high activity when combined with chemotherapy. The purpose of this phase II study was to determine the efficacy and safety of rituximab plus cyclophosphamide, mitoxantrone, vincristine and prednisone (CNOP) chemotherapy in patients with indolent NHL. In all, 42 patients (median age 67 years) with previously untreated follicular, marginal zone or small lymphocytic/lymphoplasmacytic NHL received six infusions of rituximab (375 mg/m2) in combination with six cycles of CNOP. The overall response rate was 90% comprising 30 complete (71%) and eight partial (19%) responses. Although patients with marginal zone lymphoma or International Prognostic Index (IPI) score 3 had lower complete response rates, no significant difference in overall response rate was observed between the histological groups (P = 0.24) or between patients stratified according to IPI score (P>0.05). Median overall survival, time-to-progression and response duration had not been reached after a median 19.5-month follow-up. In all, 31 patients (74%) are currently free from progression and 38 (90%) remain alive. Treatment was well tolerated. One patient (2% experienced grade 3/4 infusion-related toxicity; 13 (31%) grade 3/4 leukopenia and 18 (43%) grade 3/4 neutropenia. Infection was observed in nine patients: eight (19%) grade 1/2 and one (2.4%) grade 3. This study demonstrates that combining rituximab with CNOP achieves high remission rates without significant additional toxicity in patients with previously untreated indolent NHL. Further follow-up will determine response duration and survival. 4 2 110 115

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. 68 3 135 143

Dose-dense sequential chemotherapy appears to be a promising approach in the management of patients with operable breast cancer. We evaluated the tolerability of such a novel chemotherapeutic regimen in high-risk patients. From February 1995 until September 1997, 49 women with histologically confirmed breast cancer and ≧10 involved axillary nodes were treated postoperatively with three cycles of epirubicin (110 mg/m2) followed by three cycles of paclitaxel (250 mg/m2 in a 3-hour infusion) followed by three cycles of ‘intensified’ CMF (cyclophosphamide 840 mg/m2, methotrexate 57 mg/m2, fluorouracil 840 mg/m2; E-T-CMF). All cycles were repeated every 2 weeks with G-CSF support. Ovarian ablation with monthly injections of triptorelin for 1 year was performed in premenopausal patients and tamoxifen was prescribed for 5 years to all women with positive receptor status after the completion of chemotherapy. A total of 456 cycles of chemotherapy were administered, 363 (80%) of them at full dose. Forty-seven (96%) patients received all 9 cycles of chemotherapy. Relative dose intensity of epirubicin was 0.98, of paclitaxel 0.97, of cyclophosphamide 0.99, of methotrexate 0.98 and of fluorouracil 0.99. Grade 3–4 toxicities included anemia (8%), leukopenia (8%), peripheral neuropathy (6%), neutropenia (4%), thrombocytopenia (4%), stomatitis (2%), diarrhea (2%), fatigue (2%) and hypersensitivity reaction (2%). Febrile neutropenia occurred in 2 patients. Alopecia was universal. After a median follow-up of 3 years, 11 women (22%) relapsed and 4 (8%) died. The 3-year actuarial disease-free survival rate was 72% and the 3-year overall survival rate 90%. The E-T-CMF regimen is well tolerated, as adjuvant treatment, in patients with operable breast cancer with promising activity and deserves further evaluation in phase III studies.

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Primary extranodal NHL of the head and neck (HN-NHL) accounts for 10-20% of all cases of NHL. Despite their frequency, the natural history and biological behaviour of these lymphomas is poorly understood. In this study we analysed the data 116 cases of HN-NHL. There were 65 males and 51 females with a median age of 56 years. The distribution among different anatomical sites was: tonsils 56 cases (48.3%), nasopharynx 15 (12.9%), mandible/gingiva 9 (7.8%), hard palate 7 (6%), parotis 6 (5.2%), thyroid 5 (4.3%), ocular adnexa 4 (3.5%), paranasal sinuses 2 (1.7%). The patients were treated with radiotherapy alone (14 cases), combined chemotherapy (52 cases) and combined modality (50 cases). According to the WF historical classification 73 cases (62.9%) had intermediate, 32 (27.6%) high and 11 (9.5%) low grade. Patients were separated in two groups: Tonsillar NHL (56 cases) and NHL of all other sites (non-tonsillar group - 60 cases). A comparison between the two groups showed that there was no statistically significant difference with respect to age, sex, and histological subtypes. Also treatment reponse was similar (82.1% for the tonsillar vs 83.3% for the non-tonsillar). The two groups differed in stage distribution, survival and pattern of relapse. Stage I was more frequent in the non-tonsillar NHL (60%) in contrast to tonsillar NHL where stage II was more prominent (51.8%). Median survival was 86 months for the tonsillar while it has not been reached yet for the non-tonsillar group had better survival compared to stages I and II of the tonsillar patients. Finally GI tract was a common site of relapse in the tonsillar group while a considerable number in CNS relapses were observed in the non-tonsillar group. We concluded that HN-NHL constitutes a heterogeneous group of patients. Tonsillar lymphomas represent a distinct group with some special clinicopathological findings. 18 6 B 4655 4660

The independent effects of several patient, tumor and treatment-related prognostic factors on relapse-free survival (RFS) and overall survival (OS) were assessed by Cox multivariate regression analysis in 988 Greek patients with stage II breast cancer. At a median follow-up time of 83 (range 3.3-131+) months and after the evaluation of all patients together, the number of positive axillary nodes (p < 0.0001), tumor size (p = 0.0024) and tumor grade (p = 0.0008) were identified as significant prognostic factors for RFS. Also, the number of positive nodes (p < 0.0001), tumor size (p = 0.0002) and ER status (p = 0.0001) were found to be significant for OS. These short-term prognostic variables are similar to those reported for this group of patients in other European countries and in the USA. 17 6 D 4681 4689

The risk and the type of second malignancies (SM) developing in 217 treated Hodgkin's disease (HD) patients were studied. The median age of the patients was 35 years (range 14-83) and the M/F ratio 1.8. Treatment consisted of radiotherapy alone (24 patients, 11%), chemotherapy alone (96 patients, 44.3%), or a combination of both modalities (43 patients, 19.8%), while 54 patients (24.9%) received salvage treatment. The median follow-up time was 67 months (range 12-224). Ten patients developed a SM with a 5-year and 10-year actuarial risk of 3.3% and 5.4%, respectively. There were 3 cases of ANLL and MDS (actuarial risk of 2.4% at 6 years), 1 case of non-Hodgkin's lymphoma and 6 cases of solid tumors (actuarial risk of 3.2% at 10 years). The risk of developing SM was higher in males and older patients (>40 years). SM represent a serious late side effect of successful treatment for HD. The possibility of developing a SM must be taken into consideration in the initial treatment of the disease. 79 3 273 276