Expression of the microRNA regulators Drosha, Dicer and Ago2 in non-small cell lung carcinomas.

PURPOSE: MicroRNAs are evolutionarily conserved non-coding components of the transcriptome that can post-transcriptionally control gene expression. Altered microRNA expression has been found to be a common feature of several cancers, including lung carcinomas. The biogenesis and maturation of microRNAs is known to be mediated by the ribonucleases Drosha, Dicer and Ago2. The purpose of the present study was to investigate the expression and distribution of Drosha, Dicer and Ago2 in human non-small cell lung carcinomas (NSCLC) and to relate the respective expression patterns to clinocopatholical features. METHODS: We used five human NSCLC-derived cell lines and primary formalin-fixed paraffin-embedded tissue samples from 83 NSCLC patients. Drosha, Dicer and Ago2 mRNA and protein expression levels, and their sub-cellular distributions, were assessed using RT-PCR, Western blotting, immunofluorescence and immunohistochemistry, respectively. RESULTS: We found that Drosha, Dicer and Ago2 were expressed in all the cell lines and primary neoplastic and non-neoplastic tissue samples tested. The intensity of the immunohistochemical staining was found to be significantly lower in stage I tumors compared to normal lung tissues. Dicer expression was found to be significantly higher in stage II compared to stage I tumors, and in stage III compared to stage II and stage I tumors. CONCLUSIONS: Our results point at a role of Drosha, Dicer and Ago2 in the development of NSCLC and suggest that Dicer may be implicated in the progression of these tumors to advanced stages.

The inhibition of aromatase alters the mechanical and rheological properties of non-small-cell lung cancer cell lines affecting cell migration.

Tumor invasion and metastasis are key aspects of non-small cell lung cancer (NSCLC). During migration, cells undergo mechanical alterations. The mechanical phenotype of breast cancer cells is correlated with aromatase gene expression. We have previously shown that targeting aromatase is a promising strategy for NSCLC. The aim of this study was to examine morphological and mechanical changes of NSCLC cells, upon treatment with aromatase inhibitor and correlate their ability to migrate and invade. In vitro experiments were performed using H23 and A549 NSCLC cell lines and exemestane was used for aromatase inhibition. We demonstrated that exemestane reduced H23 cell migration and invasion and caused changes in cell morphology including increased vacuolar structures and greater pleomorphism. In addition, exemestane changed the distribution of α-tubulin in H23 and A549 cells in a way that might destabilize microtubules polymerization. These effects were associated with increased cell viscosity and decreased elastic shear modulus. Although exemestane caused similar effects in A549 cells regarding viscosity and elastic shear modulus, it did not affect A549 cell migration and caused an increase in invasion. The increased invasion was in line with vimentin perinuclear localization. Our data show that the treatment of NSCLC cells with an aromatase inhibitor not only affects cell migration and invasion but also alters the mechanical properties of the cells. It suggests that the different origin of cancer cells is associated with different morphological characteristics and mechanical behavior.

Vascular endothelial growth factor polymorphisms and clinical outcome in patients with metastatic breast cancer treated with weekly docetaxel.

The aim of the study was to evaluate the association of vascular endothelial growth factor (VEGF) genotypes with treatment efficacy in a phase II trial. This study evaluated weekly docetaxel, as first-line treatment for metastatic breast cancer. Existing data from in vitro and animal model experiments suggest that docetaxel at low doses has anti-angiogenic activity. DNA was extracted from blood samples of 86 patients participating in the trial. Genotyping was performed for selected single-nucleotide polymorphisms (SNPs; VEGF-2578, -1498, -1154, and +936). Moreover, due to the highly polymorphic nature of the studied areas, we were able to analyze additional registered SNPs. All candidate genotypes were evaluated for associations with overall survival (OS), progression-free survival (PFS) and response rate. The VEGF-1154 GG genotype was more frequent in patients not responding to treatment compared with responders (42.9% vs 0.0%, P=0.048). Moreover, the VEGF-2578 AA genotype was associated with longer PFS compared with CC (hazard ratio (HR)=0.40; 95% confidence interval (CI) 0.17-0.98; pairwise P=0.0457). Patients with the VEGF-1190 GG genotype demonstrated shorter PFS compared with those with the alternative genotypes (GA and AA) combined (HR=3.85; 95% CI: 1.20-12.50; P=0.0224). In addition, the VEGF-2551/-2534 homozygous del18bp and VEGF-2430/-2425 homozygous ins1bp genotypes were associated with worse PFS compared with no deletion and no insertion, respectively (HR=2.49; 95% CI: 1.02-6.07; pairwise P=0.0442 and HR=2.57; 95% CI: 1.05-6.27; pairwise P=0.0385, respectively). Furthermore, patients with the VEGF-1498 CC genotype exhibited longer median OS compared with those with the alternatives genotypes (CT and TT) combined (HR=0.27; 95% CI: 0.08-0.89; P=0.0311). In multivariate analysis, the VEGF-2578 AA genotype retained its significance (P=0.0220) for PFS. Our results support the association of specific VEGF genotypes with clinical outcome in patients with metastatic breast cancer treated with a potentially anti-angiogenic regimen, such as weekly docetaxel. However, current results should be validated prospectively in larger cohorts.

Physician-assessed and patient-reported outcome measures in chemotherapy-induced sensory peripheral neurotoxicity: two sides of the same coin.

BACKGROUND: The different perception and assessment of chemotherapy-induced peripheral neurotoxicity (CIPN) between healthcare providers and patients has not yet been fully addressed, although these two approaches might eventually lead to inconsistent, possibly conflicting interpretation, especially regarding sensory impairment. PATIENTS AND METHODS: A cohort of 281 subjects with stable CIPN was evaluated with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC v. 2.0) sensory scale, the clinical Total Neuropathy Score (TNSc©), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sumscore (mISS) and the European Organization for Research and Treatment of Cancer CIPN specific self-report questionnaire (EORTC QOL-CIPN20). RESULTS: Patients' probability estimates showed that the EORTC QLQ-CIPN20 sensory score was overall more highly related to the NCI-CTC sensory score. However, the vibration perception item of the TNSc had a higher probability to be scored 0 for EORTC QLQ-CIPN20 scores lower than 35, as vibration score 2 for EORTC QLQ-CIPN20 scores between 35 and 50 and as grade 3 or 4 for EORTC QLQ-CIPN20 scores higher than 50. The linear models showed a significant trend between each mISS item and increasing EORTC QLQ-CIPN20 sensory scores. CONCLUSION: None of the clinical items had a perfect relationship with patients' perception, and most of the discrepancies stood in the intermediate levels of CIPN severity. Our data indicate that to achieve a comprehensive knowledge of CIPN including a reliable assessment of both the severity and the quality of CIPN-related sensory impairment, clinical and PRO measures should be always combined.

Rasch-built Overall Disability Scale for patients with chemotherapy-induced peripheral neuropathy (CIPN-R-ODS).

Chemotherapy-induced peripheral neuropathy (CIPN) is a common neurological side-effect of cancer treatment and may lead to declines in patients' daily functioning and quality of life. To date, there are no modern clinimetrically well-evaluated outcome measures available to assess disability in CIPN patients. The objective of the study was to develop an interval-weighted scale to capture activity limitations and participation restrictions in CIPN patients using the Rasch methodology and to determine its validity and reliability properties. A preliminary Rasch-built Overall Disability Scale (pre-R-ODS) comprising 146 items was assessed twice (interval: 2-3 weeks; test-retest reliability) in 281 CIPN patients with a stable clinical condition. The obtained data were subjected to Rasch analyses to determine whether model expectations would be met, and if necessarily, adaptations were made to obtain proper model fit (internal validity). External validity was obtained by correlating the CIPN-R-ODS with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) neuropathy scales and the Pain-Intensity Numeric-Rating-Scale (PI-NRS). The preliminary R-ODS did not meet Rasch model's expectations. Items displaying misfit statistics, disordered thresholds, item bias or local dependency were systematically removed. The final CIPN-R-ODS consisting of 28 items fulfilled all the model's expectations with proper validity and reliability, and was unidimensional. The final CIPN-R-ODS is a Rasch-built disease-specific, interval measure suitable to detect disability in CIPN patients and bypasses the shortcomings of classical test theory ordinal-based measures. Its use is recommended in future clinical trials in CIPN.

The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting complication of cancer treatment. Thus far, the impact of CIPN has not been studied in a systematic clinimetric manner. The objective of the study was to select outcome measures for CIPN evaluation and to establish their validity and reproducibility in a cross-sectional multicenter study. PATIENTS AND METHODS: After literature review and a consensus meeting among experts, face/content validity were obtained for the following selected scales: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), the Total Neuropathy Score clinical version (TNSc), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory sumscore (mISS), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and CIPN20 quality-of-life measures. A total of 281 patients with stable CIPN were examined. Validity (correlation) and reliability studies were carried out. RESULTS: Good inter-/intra-observer scores were obtained for the TNSc, mISS, and NCI-CTC sensory/motor subscales. Test-retest values were also good for the EORTC QLQ-C30 and CIPN20. Acceptable validity scores were obtained through the correlation among the measures. CONCLUSION: Good validity and reliability scores were demonstrated for the set of selected impairment and quality-of-life outcome measures in CIPN. Future studies are planned to investigate the responsiveness aspects of these measures.

Advanced age and liability to oxaliplatin-induced peripheral neuropathy: post hoc analysis of a prospective study.

BACKGROUND AND PURPOSE: The aim of this post hoc analysis of data extracted from a prospective, multicenter study is to test in a large homogenous population of chemotherapy-naïve patients with colorectal cancer (CRC) treated with oxaliplatin (OXA)-based chemotherapy whether advanced age increases the risk of developing OXA-induced peripheral neuropathy (OXAIPN). METHODS: One-hundred and forty-five patients with CRC, without other significant co-morbidities predisposing to peripheral neuropathy, were divided according to their age into two groups: patients aged between 50 and 68 years (group I, n = 75); and patients aged ≥ 69 years (group II, n = 70). Patients were prospectively monitored at baseline and followed-up during chemotherapy using the motor and neurosensory National Cancer Institute Common Toxicity criteria, the clinical version of the Total Neuropathy Score and neurophysiology. The incidence and severity of both the acute and cumulative OXAIPN was thoroughly determined and then compared between age groups. RESULTS: No statistically significant difference was observed in the incidence of both the acute (n = 64/75 vs. 56/70; P = 0.510) and cumulative OXAIPN (n = 51/75 vs. 49/70; P = 0.858) between age groups. The severity of OXAIPN was also similar between age groups. In line with the clinical data, the neurophysiological results between age groups were also comparable. CONCLUSION: The results of this study indicate that advanced age does not seem to represent a significant risk factor of OXAIPN in patients with CRC without any other significant co-morbidities.

Peripheral neurotoxicity of oxaliplatin in combination with 5-fluorouracil (FOLFOX) or capecitabine (XELOX): a prospective evaluation of 150 colorectal cancer patients.

BACKGROUND: To report our prospective experience on the incidence and pattern of oxaliplatin (OXA)-induced peripheral neuropathy (OXA-IPN) in patients with colorectal cancer (CRC) treated with either FOLFOX-4 or XELoda + OXaliplatin (XELOX). PATIENTS AND METHODS: One hundred and fifty patients scheduled to be treated with either FOLFOX or XELOX for CRC were prospectively monitored at baseline and followed-up during chemotherapy. The incidence and severity of symptoms secondary to OXA-IPN were recorded using three different types of assessment, i.e. the motor and neurosensory National Cancer Institute common toxicity criteria, version 3.0 (NCI-CTCv3), the clinical version of the total neuropathy score (TNSc) and electrophysiological scores. RESULTS: Patients treated with either FOLFOX-4 or XELOX manifested similar incidence rates and severities of acute OXA-IPN. However, FOLFOX-4 was associated with increased incidence of chronic neurotoxicity, compared with XELOX-treated patients (n = 64/77 versus 44/73; P = 0.002), at a very similar OXA median cumulative dose during both regimens. Both the NCI-CTCv3 and TNSc demonstrated that the severity of cumulative OXA-IPN in FOLFOX-4-treated patients is higher than in those treated with XELOX. CONCLUSION: The incidence of acute neurotoxicity during FOLFOX-4 therapy is similar to XELOX. However, it seems that FOLFOX-4 is more neurotoxic than XELOX in terms of cumulative OXA-IPN, despite comparable OXA cumulative dose.

Vascular endothelial growth factor polymorphisms and clinical outcome in colorectal cancer patients treated with irinotecan-based chemotherapy and bevacizumab.

The aim of the study was to evaluate the association of vascular endothelial growth factor (VEGF) genotypes with treatment efficacy in a randomized trial. This study compared two chemotherapy regimens (FOLFIRI versus XELIRI) combined with bevacizumab, as first-line treatment for metastatic colorectal cancer. DNA was extracted from blood samples of 173 patients participating in the trial. Genotyping was performed for selected SNPs (VEGF-1154, +936, -634, -2578 and -1498). All candidate genotypes were evaluated for associations with overall survival (OS), progression-free survival (PFS) and response rate (RR). There were no significant differences with respect to the distribution of genotypes in the treatment groups. The VEGF-1154 GG genotype was more frequent in patients not responding to treatment compared with responders (65.5 versus 39.8%, P = 0.032). Furthermore, the VEGF-1154 GG genotype was associated with inferior median OS compared with GA (hazards ratio = 1.68; 95% confidence interval: 1.10-2.57; P = 0.016) or with the alternative genotypes (GA and AA) combined (hazards ratio = 1.62; 95% confidence interval: 1.09-2.40; P = 0.017). In multivariate analysis, the VEGF-1154 GG genotype remained a significant adverse factor for OS. Our results support the potential predictive ability of VEGF genotypes in patients with metastatic colorectal cancer receiving irinotecan-based chemotherapy plus bevacizumab, in terms of RR and OS. However, current results should be validated prospectively, in larger cohorts.

Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer.

Trastuzumab (T) is effective in metastatic breast cancer (MBC) with HER2 overexpression and/or amplification, but resistance to T develops in a significant number of HER2-positive patients. Understanding the mechanisms of resistance is critical to the care of these patients. Formalin-fixed paraffin-embedded tumor tissue samples were collected from 256 patients with T-treated MBC. Clinical information was collected retrospectively from the patients' medical records. Central review of HER2 status by fluorescent in situ hybridization (FISH) and/or immunohistochemistry (IHC) revealed that of the 227 eligible patients only 139 (61%) were truly HER2-positive. PTEN, ER, PgR, and Ki67 were evaluated by IHC, while PTEN status was evaluated by FISH as well. PIK3CA mutations were identified with single nucleotide polymorphism (SNP) genotyping. Median time to progression (TTP) was 14.4 months for the HER2-positive and 10.3 for the HER2-negative patients (log-rank, P = 0.22). Survival from the initiation of T (survivalT) was 50.4 months for the HER2-positive and 35.3 for the HER2-negative subgroups (P = 0.006). Higher risk of progression was associated with HER2-positive status and the presence of PIK3CA mutations (P = 0.014). PTEN loss, as determined by IHC, was associated with lower survivalT in the whole population (P = 0.029) and in the HER2-positive population (P = 0.017). PIK3CA mutations and/or PTEN loss status were evaluated together as a single parameter, to estimate the impact of activation of the PI3K/AKT molecular pathway, and it was significantly associated with both decreased TTP (P = 0.003 in the total population, P = 0.004 in HER2-positive patients) and survival (survivalT, P = 0.011 in total, P = 0.006 in HER2-positive). In this trastuzumab-treated breast cancer population, PIK3CA activating mutations were associated with shorter TTP and PTEN loss with decreased survival. The activation of the PI3K/AKT pathway from either defect was associated with both TTP and survival, indicating the adverse effect of this pathway's status on trastuzumab efficacy.

Targeted therapy in colorectal cancer: current status and future challenges.

Treatment of metastatic colorectal cancer (mCRC) has progressed significantly over the last years, particularly with the introduction of targeted therapies. Two groups of agents targeting either the epidermal growth factor receptor (EGFR) or the vascular endothelial growth factor (VEGF) have been integrated into clinical practice. Currently available agents with established role include the anti-EGFR monoclonal antibodies (mAbs) cetuximab / panitumumab and the anti-VEGF mAb bevacizumab. This review presents an update on the clinical studies evaluating the role of anti-EGFR and anti-VEGF agents in mCRC. Moreover, we provide current data regarding the mechanism of action and pathways mediating resistance to these agents. In addition, we present recent data with respect to biomarkers and we discuss future therapeutic strategies.

Pathophysiology and pharmacological targeting of tumor-induced bone disease: current status and emerging therapeutic interventions.

Bone disease is a common complication of metastatic solid tumors but also of primary hematological malignancies such as multiple myeloma. Our understanding of the molecular mechanisms underlying the development of bone disease by solid tumors and multiple myeloma has been significantly improved. A complex inter-dependence exists between bone disease and malignant cell growth, creating a vicious cycle of extensive bone destruction and tumor progression. Although myeloma and solid tumors share a number of common molecular pathogenetic mechanisms, they involve distinct pathophysiological pathways, resulting in osteoclastic bone resorption and inhibition of bone formation. In this review, we analyze the molecular mechanisms, involved in tumor-induced bone disease and discuss the current therapeutic approaches and the most recent clinical developments of emerging targeted therapies.

Paclitaxel and gemcitabine versus paclitaxel and vinorelbine in patients with advanced non-small-cell lung cancer. A phase III study of the Hellenic Cooperative Oncology Group (HeCOG).

BACKGROUND: Paclitaxel (Taxol) and vinorelbine have shown synergism of cytotoxic effects in vitro and clinical activity in phase I and II studies. This combination was compared prospectively with the paclitaxel/gemcitabine regimen in non-operable non-small-cell lung cancer. PATIENTS AND METHODS: Chemotherapy-naive patients, stage IIIbwet and IV with performance status (0-1), were randomized to receive paclitaxel 200 mg/m(2) on day 1 plus gemcitabine 1 gm/m(2) (group A) on days 1 and 8 every 3 weeks or paclitaxel 80 mg/m(2) plus vinorelbine 22.5 mg/m(2) (group B) on days 1, 8 and 15 every 4 weeks. RESULTS: A total of 398 out of 415 patients were eligible for analysis on intent-to-treat basis (group A: 196, group B: 202). Progression-free survival (PFS) was 5.0 months [95% confidence interval (CI) 4.3-5.6] and 4.4 months (95% CI 3.7-5.2) for groups A and B respectively (P=0.365). Median survival was 11.1 months (95% CI 9.2-13.0) and 8.6 months (95% CI 7.0-10.2) for groups A and B respectively (P = 0.147). Grade 3/4 neutropenia and leukopenia were worse in group B (P<0.001, in both cases). Febrile neutropenia and severe infections were more prominent (P<0.001, P=0.029 respectively) in group B. CONCLUSION: Although response rate, PFS and survival were non-different in both groups, toxicity was significantly worse in group B and therefore further investigation of P-Vin is of no value.

Toxic peripheral neuropathy associated with commonly used chemotherapeutic agents.

Peripheral neuropathy ranks among the most common non-haematological adverse effects of a number of effective chemotherapeutic agents, including platinum compounds, taxanes and vinca alkaloids. Newer agents, such as bortezomib, thalidomide and lenalidomide, frequently exert similar neurotoxic effects on peripheral nerves. Chemotherapy-induced peripheral neuropathy (CIPN) may result from a variety of mechanisms and may be related to causal factors, such as single dose per course, cumulative dose and risk factors including treatment schedule, prior or concomitant administration of other neurotoxic agents, age and pre-existing peripheral neuropathy of other causes. The symptoms usually begin during chemotherapy and they may even worsen after cessation of treatment. In most of the cases, patients experience positive (pain, paresthesias) or negative (numbness) sensory symptoms in distal extremities in a stocking-and-glove distribution with less prominent motor and autonomic involvement. To date, several neuroprotective agents including thiols, neurotrophic factors, anticonvulsants and antioxidants have been tested in preclinical models and clinical open label or randomized controlled trials for their ability to prevent or treat symptoms of CIPN. Although several of these agents hold promise as possible neuroprotective factors, clinical data are still controversial and none have as yet robustly been proven effective against CIPN. This review critically looks at the pathogenesis, incidence, risk factors, diagnosis, characteristics and management of peripheral neuropathy associated with commonly used chemotherapeutic agents. We also highlight areas of future research to pursue.

Integrin beta-3 L33P: a new insight into the pathogenesis of chronic oxaliplatin-induced peripheral neuropathy?

AIM: To assess the significance of the ITGB3 polymorphism at residue 33 (ITGB3 L33P) in the development of chronic oxaliplatin-induced peripheral neuropathy (OXLIPN). METHODS: Fifty-five patients with advanced colorectal cancer were genotyped, using allele-specific primers and sybr green in real-time PCR. Patients had received adjuvant oxaliplatin-based chemotherapy. The severity of the OXLIPN was defined by means of the clinical total neuropathy score (TNSc). Following the discontinuation of treatment, 34/55 patients (61.8%) developed OXLIPN. Grade I neurotoxicity was revealed in 13 (38.2%) patients and grade II neurotoxicity in 21 (61.8%) patients. RESULTS: Patients without OXLIPN (n = 21) were 19% homozygous for C, 33.3% were heterozygous, and 47.7% were homozygous for T. The corresponding percentages for patients developing any grade of OXLIPN (n = 34) were similar. About half of patients (46.1%) with grade I OXLIPN were heterozygotes (CT), 23.1% were CC, and 30.8% were TT. The majority of patients with grade II OXLIPN were TT (66.7%) with the remaining 33.3% being CT. The TT genotype was associated with increased severity of OXLIPN compared to the genotypes containing the C allele (P = 0.044). CONCLUSION: The ITGB3 L33P seems to be unrelated to the development of OXLIPN, but it appears to be related to its severity.

Targeting epidermal growth factor receptor in solid tumors: critical evaluation of the biological importance of therapeutic monoclonal antibodies.

Numerous cellular pathways have a significant impact in the growth and metastatic potential of tumors. Essential element of such pathways is the epidermal growth factor receptor (EGFR), a member of the HER family of receptor tyrosine kinases. One of the most important issues in cancer, which attracted the attention of clinical oncologists, is the potential use of targeted therapies. EGFR signaling pathway is implicated in the control of cell survival, proliferation, metastasis and angiogenesis. EGFR is, therefore, an appealing target for molecular-targeted cancer therapy as it is expressed in a variety of solid tumors (colorectal, breast, head and neck, etc.). Receptor antagonists that target EGFR have already been of high interest for a number of years. Multiple therapeutic strategies have been developed to target EGFR, including monoclonal antibodies (mAbs), tyrosine kinase inhibitors (TKIs), ligand-toxin conjugates, and antisense oligonucleotides. In particular, mAbs block ligand from binding to the extracellular domain of the receptor. Two mAbs that block EGFR (erbB1), cetuximab and panitumumab, have been approved by FDA. Cetuximab is a chimeric IgG1 anti-EGFR monoclonal antibody, whereas panitumumab is a fully human IgG2 anti-EGFR monoclonal antibody. This review highlights the cellular effects of EGFR blockade by mAbs and their relationship to therapeutic efficacy and biological significance.

Effects of epoetin-alpha on quality of life of cancer patients with solid tumors receiving chemotherapy.

BACKGROUND: Erythropoietin corrects and prevents anemia and decreases the need for red blood cell (RBC) transfusions; its impact on quality of life (QOL) of cancer patients receiving chemotherapy is not clear. PATIENTS AND METHODS: 399 patients with solid tumors and Hb level of < or = 12 g/dl receiving chemotherapy were randomized to receive or not 10,000 IU epoetin-alpha thrice weekly. QOL was measured by the Functional Assessment of Cancer Therapy-Anemia (FACT-An) scale and various subscales at baseline, at two months and at the end of the study. RESULTS: Changes in the average QOL scores were similar in the two groups. The improvement in Hb levels was significantly higher for the epoetin-alpha group, with a decrease in transfusion requirements compared to the control group. CONCLUSION: Epoetin-alpha does not improve QOL of patients with solid tumors receiving chemotherapy as assessed using FACT-An scale and various subscales, despite improving Hb levels and reducing transfusion requirements.

Epithelial ovarian cancer in Greece: a retrospective study of 1,791 patients by the Hellenic Cooperative Oncology Group (HeCOG).

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.

A randomized phase III study comparing three anthracycline-free taxane-based regimens, as first line chemotherapy, in metastatic breast cancer: a Hellenic Cooperative Oncology Group study.

BACKGROUND: Effective anthracycline-free combinations need to be evaluated in metastatic breast cancer (MBC), due to the increased number of patients treated with anthracycline-based adjuvant chemotherapy. PATIENTS AND METHODS: Patients with MBC were randomized to paclitaxel and carboplatin (PCb) every 3 weeks or docetaxel and gemcitabine (GDoc) every 3 weeks or weekly paclitaxel (Pw). Trastuzumab was given to patients with HER-2 over-expressing tumors. The primary endpoint of the study was survival. Quality of life (QoL) and cost were assessed. RESULTS: Totally, 416 eligible patients entered the study. Median survival times were 29.9 months for PCb, 26.9 for GDoc and 41.0 for Pw (P = 0.037). According to multivariate analysis, adjuvant chemotherapy, >1 metastatic sites, lack of maintenance hormonal therapy, and worse performance status (PS) were significant adverse prognostic factors for survival, while Pw when compared to GDoc improved survival (P = 0.03), as well as when compared to PCb in the subgroup of patients with PS = 1 (P = 0.01, treatment by PS interaction P = 0.03). No significant differences in terms of time to progression were found. Severe myelotoxicity and mucositis were more frequent with GDoc, while severe neuropathy with PCb and Pw. QoL changes did not differ significantly between treatment groups, while cost analysis favored Pw. CONCLUSIONS: Pw appears to be the most preferable choice among the 3 anthracycline-free taxanes-based regimens tested in the present study.