Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 26
Filter
1.
PLoS One ; 13(12): e0207707, 2018.
Article in English | MEDLINE | ID: mdl-30521571

ABSTRACT

In the current study, we performed a complete analysis, with four different methods, of all four HER family receptors, in a series of patients with metastatic breast cancer treated with trastuzumab-based regimens and evaluated their prognostic value. Formalin-fixed paraffin-embedded tumor tissue samples were collected from 227 patients, considered to be HER2-positive when assessed at the local laboratories. We evaluated gene amplification, copy number variations (CNVs), mRNA and protein expression of all four HER family members. In addition, our analysis included the evaluation of several other factors by immunohistochemistry (IHC), such as pHER2Tyr1221/1222, pHER2Tyr877 and PTEN. Central review of HER2 status by IHC and fluorescence in situ hybridization revealed that of the 227 patients, only 139 (61.2%) were truly HER2-positive. Regarding the 191 patients treated with trastuzumab as first-line therapy, median time to progression (TTP) was 15.3 and 10.4 months for HER2-positive and HER2-negative participants, respectively, whereas median survival was 50.4 and 38.1 months, respectively. In HER2-positive patients, high HER3 mRNA expression was of favorable prognostic significance for TTP and survival (HR = 0.43, 95% CI 0.21-0.88, Wald's p = 0.022 and HR = 0.43, 95% CI 0.21-0.88, p = 0.021, respectively), while EGFR copy gain and EGFR protein expression were associated with higher risk for disease progression in HER2-negative patients (HR = 3.53, 95% CI 1.19-10.50, p = 0.023 and HR = 3.37, 95% CI 1.12-10.17, p = 0.031, respectively). Positive HER3 protein expression was a favorable factor for TTP in HER2-negative patients (HR = 0.43, 95% CI 0.22-0.84, p = 0.014). In the multivariate analysis, only EGFR copy gain retained its prognostic significance for TTP in the HER2-negative population (HR = 3.96, 95% CI 1.29-12.16, p = 0.016), while high HER3 mRNA expression retained its favorable prognostic significance for TTP in the HER2-positive subgroup (HR = 0.47, 95% CI 0.23-0.99, p = 0.048). The present study suggests that EGFR copy gain represents a negative prognostic factor for TTP in HER2-negative patients with metastatic breast cancer treated with trastuzumab. In addition, high HER3 mRNA expression appears to be of favorable prognostic significance for TTP in HER2-positive patients. Given the small number of patients included in the current analysis and the retrospective nature of the study, our findings should be validated in larger cohorts.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , ErbB Receptors/metabolism , Trastuzumab/therapeutic use , Adult , Aged , Aged, 80 and over , Breast Neoplasms/pathology , Class I Phosphatidylinositol 3-Kinases/genetics , DNA Copy Number Variations , ErbB Receptors/genetics , Female , Gene Amplification , Gene Expression , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Middle Aged , Neoplasm Metastasis/drug therapy , Neoplasm Metastasis/genetics , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Prognosis , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Receptor, ErbB-3/genetics , Receptor, ErbB-3/metabolism , Receptor, ErbB-4/genetics , Receptor, ErbB-4/metabolism , Retrospective Studies
2.
Cancer Genomics Proteomics ; 15(6): 461-471, 2018.
Article in English | MEDLINE | ID: mdl-30343280

ABSTRACT

BACKGROUND: Trastuzumab is a monoclonal antibody against HER2-positive breast cancer. Despite improving the natural history of the disease, there is a number of patients who are resistant to it, whereas all patients will eventually develop resistance and disease will progress. Inconsistent preclinical data show that the IGF-R pathway may contribute to either de novo or acquired resistance to trastuzumab. MATERIALS AND METHODS: In total, 227 trastuzumab-treated metastatic breast cancer patients were evaluated for IGF-1, IGF-1R, GLP-1R, Akt1, Akt2 Akt3 mRNA expression, and IGF-1Rα, IGF-1Rß, IGF-2R protein expression. RESULTS: Only 139 patients were truly HER2-positive by central assessment. Among HER2-positive patients, high Akt2 and GLP-1R mRNA expression showed a trend towards higher and lower risk of progression, respectively (HR=1.83, 95%CI=0.90-3.72, p=0.094 and HR=0.62, 95%CI=0.36-1.06, p=0.079), while high Akt1 and GLP-1R mRNA expression presented a trend towards unfavorable survival (HR=1.67, 95%CI=0.93-2.99, p=0.086 and HR=1.67, 95%CI=0.94-2.96, p=0.080). Among HER2-negative patients, high GLP-1R mRNA expression and negative stromal IGF-1Rß protein expression showed a trend towards worse survival (HR=2.31, 95%CI=0.87-6.13, p=0.094 and HR=2.03, 95%CI=0.94-4.35, p=0.071, respectively). In the multivariate analyses, HER2-positive patients with high Akt1 and GLP-1R mRNA expression had a worse survival (HR=1.86, 95%CI=1.01-3.43, p=0.045 and HR=1.83, 95%CI=0.99-3.41, p=0.055, respectively). CONCLUSION: This study revealed a crosstalk between the IGF-R pathway and HER2. There was evidence that high Akt1 and GLP-1R mRNA expression might affect survival among HER2-positive metastatic breast cancer patients treated with trastuzumab.


Subject(s)
Breast Neoplasms , Gene Expression Regulation/drug effects , Neoplasm Proteins/biosynthesis , Receptor, IGF Type 1/biosynthesis , Signal Transduction/drug effects , Trastuzumab/administration & dosage , Adult , Aged , Aged, 80 and over , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Disease-Free Survival , Female , Humans , Middle Aged , Neoplasm Metastasis , Retrospective Studies , Survival Rate
3.
Anticancer Res ; 37(6): 2947-2957, 2017 06.
Article in English | MEDLINE | ID: mdl-28551632

ABSTRACT

BACKGROUND: The retinoblastoma (RB) gene is a tumor-suppressor gene that plays a central role in regulating the cell cycle. Inactivation of this gene is involved in breast cancer. PATIENTS AND METHODS: A total of 827 patients with breast cancer treated with taxane-based adjuvant chemotherapy were included in the study. Protein expression of RB, phosphorylated RB (pRB), p16, cyclin D1 and p53 was evaluated by immunohistochemistry. RESULTS: Neither of the retinoblastoma markers (RB and pRB) reached statistical significance in terms of their association with disease-free or overall survival. Nevertheless, when clustering analysis was performed, patients with tumors featuring low levels of p16, cyclin D1 and p53 with concomitantly high levels of pRB had reduced risk for relapse (Wald's p=0.015). CONCLUSION: The p53-mediated sensitivity of breast cancer cells to chemotherapeutic agents appears to be driven mostly by pRB. Using agents that enhance RB phosphorylation might possibly increase the chemosensitivity of breast cancer cells.


Subject(s)
Breast Neoplasms/metabolism , Cyclin D1/metabolism , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Retinoblastoma Protein/metabolism , Tumor Suppressor Protein p53/metabolism , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Phytogenic/therapeutic use , Breast Neoplasms/drug therapy , Chemotherapy, Adjuvant , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Middle Aged , Paclitaxel/therapeutic use , Phosphorylation , Prognosis , Young Adult
4.
Mol Clin Oncol ; 4(2): 211-220, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26893865

ABSTRACT

Prophylactic erythropoiesis-stimulating agent (ESA) administration for chemotherapy-induced anemia (CIA) is not supported by current guidelines. Long-term follow-up of patients WHO had been treated with ESA for CIA in the past may provide useful information. In 2002, we undertook a prospective, randomized phase III trial of prophylactic vs. hemoglobin (Hb)-based (threshold: 11 mg/dl) ESA administration in patients with solid tumors and CIA. ESA administration FOR CIA was permanently suspended in 2007 in view of published data at that time, while patient surveillance continued. Among 630 evaluable patients, 38.6% were male, 50.9% had advanced cancer at diagnosis, 40.6% had Hb levels <12 mg/dl at baseline and 47.9% received ESA prophylactically (1:1 randomization). The major tumor types included colorectal (36.0%), breast (20.6%), non-prostate genitourinary (11.0%) and lung CANCER (8.4%). After a median follow-up of 85.4 months, 358 patients had relapsed and 380 had succumbed to the disease. Patients in the prophylactic ESA group (GROUP A; experimental arm), as compared with those in the Hb-based group (GROUP B; iron supplementation alone), exhibited A significantly more prominent increase in median Hb levels, particularly in the subset of patients with non-metastatic disease (two-sided P<0.01) among patients receiving chemotherapy for advanced cancer, those who received ESAs prophylactically exhibited a lower incidence of CIA (all grades: P=0.014, grades 3-4: P=0.034) and fatigue (all grades: P<0.001, grades 3-4: P=0.055), but a higher rate of a composite outcome encompassing all thrombosis-related events (all grades: P=0.043, grades 3-4: P=0.099). These differences were less prominent in the group of patients who received adjuvant treatment. There were no significant differences in overall mortality and relapse/progression rates between the two groups. therefore, prophylactic, compared with Hb-based, administration of ESAs for CIA in patients with solid tumors, was found to be associated with a significantly lower incidence of anemia and fatigue, but with a marginally higher rate of thrombosis-related adverse events, particularly in patients receiving first-line chemotherapy for advanced cancer.

5.
BMC Cancer ; 15: 384, 2015 May 10.
Article in English | MEDLINE | ID: mdl-25956750

ABSTRACT

BACKGROUND: The aim of the trial was to compare two active adjuvant chemotherapy regimens in patients with early stage colorectal cancer (CRC). METHODS: Patients were assigned to oxaliplatin, leucovorin and 5-FU for 12 cycles (group A, FOLFOX6) or oxaliplatin and capecitabine for eight cycles (group B, CAPOX). Primary endpoint was disease-free survival (DFS). Tumors were classified as mismatch repair proficient (pMMR) or deficient (dMMR) according to MLH1, PMS2, MSH2 and MSH6 protein expression. KRAS exon two and BRAF V600E mutational status were also assessed. RESULTS: Between 2005 and 2008, 441 patients were enrolled, with 408 patients being eligible. After a median follow-up of 74.7 months, 3-year DFS was 79.8 % (95 % CI 76.5-83.4) in the FOLFOX group and 79.5 % (95 % CI 75.9-83.1) in the CAPOX group (p = 0.78). Three-year OS was 87.2 % (95 % CI 84.1-91.1) in the FOLFOX and 86.9 % (95 % CI 83.4-89.9) in the CAPOX group (p = 0.84). Among 306 available tumors, 11.0 % were dMMR, 34.0 % KRAS mutant and 4.9 % BRAF mutant. Multivariate analysis showed that primary site in the left colon, earlier TNM stage and the presence of anemia at diagnosis were associated with better DFS and overall survival (OS), while grade one-two tumors were associated with better OS. Finally, a statistically significant interaction was detected between the primary site and MMR status (p = 0.010), while KRAS mutated tumors were associated with shorter DFS. However, the sample was too small for safe conclusions. CONCLUSIONS: No significant differences were observed in the efficacy of FOLFOX versus CAPOX as adjuvant treatment in high-risk stage II or stage III CRC patients, but definitive conclusions cannot be drawn because of the small sample size. TRIAL REGISTRATION: ANZCTR 12610000509066 . Date of Registration: June 21, 2010.


Subject(s)
Capecitabine/administration & dosage , Colorectal Neoplasms/drug therapy , Fluorouracil/administration & dosage , Leucovorin/administration & dosage , Organoplatinum Compounds/administration & dosage , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms/surgery , Female , Humans , Male , Microsatellite Instability/drug effects , Middle Aged , Neoplasm Staging , Oxaliplatin , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras) , ras Proteins/genetics
6.
J Transl Med ; 13: 171, 2015 May 29.
Article in English | MEDLINE | ID: mdl-26021752

ABSTRACT

BACKGROUND: The aim of the study was to evaluate the prognostic ability of the transcriptional profiling of the HER family genes in early breast cancer, as a validation analysis of another previously published HeCOG study. METHODS: RNA was extracted from 663 formalin-fixed paraffin-embedded (FFPE) tumor tissue samples of high-risk early breast cancer patients enrolled in the randomized HE10/00 trial. Relative mRNA expression of all four HER family members was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS: In compliance with our previous study, the overall agreement between qRT-PCR and IHC/FISH for HER2 status determination was good (69%). Likewise, the overall concordance between qRT-PCR and IHC for EGFR status was high (81%). In line with our previously reported data, we demonstrated a positive association between HER2 and HER3 mRNA expression. Similarly, mRNA expression of HER3 and HER4 was positively associated with each other and negatively associated with EGFR. Regarding relationships with clinico-pathological parameters, our findings are also in agreement with our previous results. Generally, increased EGFR and HER2 mRNA expression was related to unfavorable, whereas high HER3 and HER4 mRNA expression was associated with favorable clinico-pathological parameters. In univariate analysis, no significant association between EGFR, HER2 and HER3 mRNA expression and overall survival (OS) or disease-free survival (DFS) was demonstrated. However, high EGFR protein expression was associated with significantly shorter OS (log-rank, p = 0.015). In compliance with our previously published data, increased HER4 mRNA expression had a significantly favorable prognostic value in terms of OS (p = 0.044) and DFS (p = 0.047). In multivariate analysis, among all HER receptors, only EGFR protein expression was found to affect OS (Wald's p = 0.028) and DFS (p = 0.015) independently. Concerning the combined expression of all four HER family receptors, the combination of high EGFR, high HER2, low HER3 and low HER4 mRNA expression was associated with a trend for shorter OS (log-rank, p = 0.065) and significantly worse DFS (p = 0.033), compared with all other co-expression profiles. CONCLUSIONS: These data indicate that qRT-PCR may represent a valid alternative method for evaluating the expression of HER family members in FFPE breast carcinoma tissue samples. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12609001036202.


Subject(s)
Breast Neoplasms/genetics , ErbB Receptors/metabolism , Gene Expression Regulation, Neoplastic , Adult , Aged , Disease-Free Survival , ErbB Receptors/genetics , Female , Greece , Humans , Immunohistochemistry , Middle Aged , Prognosis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Receptor, ErbB-3/genetics , Receptor, ErbB-3/metabolism , Receptor, ErbB-4/genetics , Receptor, ErbB-4/metabolism , Reproducibility of Results , Risk Factors , Young Adult
7.
PLoS One ; 8(10): e78157, 2013.
Article in English | MEDLINE | ID: mdl-24205138

ABSTRACT

Serglycin is a proteoglycan expressed by some malignant cells. It promotes metastasis and protects some tumor cells from complement system attack. In the present study, we show for the first time the in situ expression of serglycin by breast cancer cells by immunohistochemistry in patients' material. Moreover, we demonstrate high expression and constitutive secretion of serglycin in the aggressive MDA-MB-231 breast cancer cell line. Serglycin exhibited a strong cytoplasmic staining in these cells, observable at the cell periphery in a thread of filaments near the cell membrane, but also in filopodia-like structures. Serglycin was purified from conditioned medium of MDA-MB-231 cells, and represented the major proteoglycan secreted by these cells, having a molecular size of ~ 250 kDa and carrying chondroitin sulfate side chains, mainly composed of 4-sulfated (~ 87%), 6-sulfated (~ 10%) and non-sulfated (~ 3%) disaccharides. Purified serglycin inhibited early steps of both the classical and the lectin pathways of complement by binding to C1q and mannose-binding lectin. Stable expression of serglycin in less aggressive MCF-7 breast cancer cells induced their proliferation, anchorage-independent growth, migration and invasion. Interestingly, over-expression of serglycin lacking the glycosaminoglycan attachment sites failed to promote these cellular functions, suggesting that glycanation of serglycin is a pre-requisite for its oncogenic properties. Our findings suggest that serglycin promotes a more aggressive cancer cell phenotype and may protect breast cancer cells from complement attack supporting their survival and expansion.


Subject(s)
Breast Neoplasms/metabolism , Proteoglycans/metabolism , Vesicular Transport Proteins/metabolism , Cell Line, Tumor , Cell Movement/genetics , Cell Movement/physiology , Cell Proliferation , Female , Humans , MCF-7 Cells , Mannose-Binding Lectin/metabolism , Protein Binding
8.
Urol Oncol ; 29(2): 189-93, 2011.
Article in English | MEDLINE | ID: mdl-19362863

ABSTRACT

OBJECTIVES: Stage I testicular nonseminomatous germ-cell tumors (NSGCT) are highly curable. Following orchidectomy surveillance, adjuvant chemotherapy and retroperitoneal lymph node dissection can be applied. Certain factors are used to select patients in high-risk for relapse. We report the outcome and safety of a risk-adapted strategy by the Hellenic Cooperative Oncology Group. METHODS: Between 1994 and 2004, 142 patients with stage I NSGCT and 1 of the following risk factors: lymphovascular invasion (LVI), invasion of tunica vaginalis, spermatic cord, rete testis or scrotal wall, embryonal component >50% of the total tumor, were prospectively included in a protocol of adjuvant chemotherapy consisting of two 3-week courses of bleomycin 15 IU, etoposide 120 mg/m(2), and cisplatin 40 mg/m(2) for 3 consecutive days with G-CSF support. RESULTS: Median follow-up was 79 months and 138 patients have been followed for at least 2 years. Seventy-seven patients (54%) had LVI and 74 (52%) had >50% embryonal component. There was 1 relapse, which was cured with chemotherapy and surgery. Another patient died due to disease-unrelated causes and 1 patient developed a new primary of the remaining testicle, which was cured with surgery. CONCLUSION: Two cycles of bleomycin/etoposide/cisplatin is an effective and safe form of adjuvant therapy in high-risk stage I NSGCT.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Testicular Neoplasms/drug therapy , Adolescent , Adult , Alopecia/chemically induced , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bleomycin/administration & dosage , Bleomycin/adverse effects , Chemotherapy, Adjuvant , Cisplatin/administration & dosage , Cisplatin/adverse effects , Drug Administration Schedule , Etoposide/administration & dosage , Etoposide/adverse effects , Follow-Up Studies , Humans , Male , Middle Aged , Nausea/chemically induced , Neoplasm Staging , Neoplasms, Germ Cell and Embryonal/drug therapy , Neoplasms, Germ Cell and Embryonal/pathology , Neutropenia/chemically induced , Retrospective Studies , Testicular Neoplasms/pathology , Time Factors , Treatment Outcome , Vomiting/chemically induced , Young Adult
9.
Acta Oncol ; 47(6): 1148-55, 2008.
Article in English | MEDLINE | ID: mdl-18607872

ABSTRACT

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/m(2) 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.


Subject(s)
Adenocarcinoma/drug therapy , Ambulatory Care , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma/drug therapy , Neoplasms, Unknown Primary/drug therapy , Outpatients , Palliative Care/methods , Adult , Aged , Ambulatory Care/methods , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Area Under Curve , Carboplatin/administration & dosage , Disease Progression , Disease-Free Survival , Docetaxel , Drug Administration Schedule , Female , Greece , Humans , Infusions, Intravenous , Kaplan-Meier Estimate , Lymphatic Metastasis , Male , Middle Aged , Neoplasms, Unknown Primary/pathology , Peritoneal Neoplasms/drug therapy , Peritoneal Neoplasms/secondary , Predictive Value of Tests , Prognosis , Risk Factors , Taxoids/administration & dosage , Treatment Outcome
10.
Cancer Chemother Pharmacol ; 59(1): 51-9, 2007 Jan.
Article in English | MEDLINE | ID: mdl-16622691

ABSTRACT

PURPOSE: Treatment options in patients with recurrent non-small cell lung cancer (NSCLC) remain limited as a result of poor activity of most agents after failure of platinum-based therapy. In the present phase I-II study, we evaluated the feasibility and efficacy of bi-weekly gemcitabine (GEM) + irinotecan (CPT-11) in patients with relapsed NSCLC. PATIENTS AND METHODS: Patients with advanced NSCLC, WHO-performance status (PS)

Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Adult , Aged , Antibiotics, Antineoplastic/administration & dosage , Antineoplastic Agents/administration & dosage , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Blood Cell Count , Bridged-Ring Compounds/administration & dosage , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/psychology , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Diarrhea/chemically induced , Diarrhea/epidemiology , Dose-Response Relationship, Drug , Female , Humans , Irinotecan , Lung Neoplasms/pathology , Lung Neoplasms/psychology , Male , Middle Aged , Neutropenia/chemically induced , Neutropenia/epidemiology , Organoplatinum Compounds/administration & dosage , Patient Compliance , Quality of Life , Survival Analysis , Taxoids/administration & dosage , Gemcitabine
11.
Curr Top Med Chem ; 6(16): 1687-705, 2006.
Article in English | MEDLINE | ID: mdl-17017951

ABSTRACT

Thorough understanding of the complex interactions between components of immunological response has led to the arousal of the concept of immune-mediated anti-cancer therapy. Although, the use of monoclonal antibodies (MAbs) in hematological malignancies met with success, therapy of solid tumors has been impeded by many obstacles. Some MAbs have increased the efficacy of treatment of certain tumors with acceptable adverse events. Trastuzumab, cetuximab and bevacizumab have become FDA approved for the treatment of breast and colorectal cancer, respectively. The dosing strategies, timing and schedule of antibody administration, duration of treatment are yet to be determined under specific circumstances. Combinations with other biologic agents, such as small-molecule inhibitors of the same pathway would be really useful. Multimodality approaches are based on synergistic effects observed with the combination of antibodies with chemotherapeutic drugs and/or radiotherapy. Immune-mediated effects may be further exploited with the use of bivalent (bispecific) molecules, while radioimmunotherapy via radiolabelling of the antibody is feasible. Modified recombinant antibodies could be applied for toxin delivery to tumor cells, while molecules fused with drug-activating enzymes can mediate prodrug therapy. Increased penetrability into tumors can also be achieved with novel antibody fragments. In the future, better selection of patient subpopulations with tumors overexpressing disease-related clinical biomarkers could result in an increase in both efficacy and specificity of antibody-based treatment.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Immunization, Passive , Neoplasms/immunology , Neoplasms/therapy , Animals , Antibodies, Monoclonal/genetics , Humans , Immunization, Passive/methods , Immunization, Passive/trends , Neoplasms/genetics
12.
Anticancer Res ; 26(2B): 1657-68, 2006.
Article in English | MEDLINE | ID: mdl-16619588

ABSTRACT

The expressions ofp27Kip1 (p27) and p21waf1 (p21) cyclin-dependent kinase inhibitors and p53 were examined in a series of 170 node-negative breast carcinomas (NNBCs) to evaluate their prognostic significance. Low nuclear (p27TN) and cytoplasmic (p27TC) p27 expressions were noted in 66% and 81% of NNBCs, respectively. p21 and p53 overexpressions were detected in 56% and 26%, respectively. Low p27TN was significantly associated with high grade (p=0.001), age < or = 50 years (p=0.01), negative hormone receptors (p<0.001), low p27TC (p<0.001) and p53 overexpression (p=0.02). Low p27TC was associated with negative hormone receptors (p<0.001). p53 overexpression was associated with high grade (p<0.001) and negative hormone receptors (p<0.001). p21 overexpression, although not correlated with the examined parameters, was associated with increased disease-free survival in univariate analysis. In multivariate analysis, p27TN, p27TC, p21 and p53 were not associated with disease-free survival or overall survival. These findings argue against the prognostic value of p27, p21 and p53 in NNBC.


Subject(s)
Breast Neoplasms/metabolism , Carcinoma, Ductal, Breast/metabolism , Cyclin-Dependent Kinase Inhibitor p21/biosynthesis , Cyclin-Dependent Kinase Inhibitor p27/biosynthesis , Tumor Suppressor Protein p53/biosynthesis , Adult , Aged , Aged, 80 and over , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/pathology , Cell Nucleus/metabolism , Female , Humans , Middle Aged , Prognosis , Retrospective Studies
13.
Cancer Chemother Pharmacol ; 57(2): 207-12, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16028103

ABSTRACT

PURPOSE: To assess the safety and efficacy of a 3-day schedule of cisplatin and topotecan in patients with recurrent small-cell lung cancer (SCLC). METHODS: Thirty-four relapsed patients were treated with cisplatin 20 mg/m2 and topotecan 0.9 mg/m2, both given on days 1-3 every 3 weeks, in a phase II study. RESULTS: Complete response (CR) was achieved in two patients (6%), partial response (PR) in 4 (12%), stable disease in 6 (18%) and progressive disease in 14 (41%). Eight patients (23%) were non-evaluable for response. Among 21 sensitive patients, 2 (9.5%) achieved CR and 3 (14%) PR. Among 13 refractory patients, none achieved CR and only 1 (8%) PR. Median survival was 6.5 months for all patients, 7.8 for sensitive and 6.2 for refractory. Median time to progression (TTP) was 4.4 months for all patients, 5.9 for sensitive and 3.2 for refractory. Grade 3-4 toxicities included anemia (15%), thrombocytopenia (15%), neutropenia (42%), nausea/vomiting (3%), and alopecia (6%). No toxic death occurred. CONCLUSIONS: This 3-day schedule was well tolerated, produced modest response rates but good survival and TTP both in sensitive and refractory patients with relapsed SCLC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Small Cell/drug therapy , Lung Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/administration & dosage , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Survival Analysis , Topotecan/administration & dosage , Treatment Outcome
14.
Cancer ; 106(2): 297-303, 2006 Jan 15.
Article in English | MEDLINE | ID: mdl-16342065

ABSTRACT

BACKGROUND: The toxicity of platinum-based combinations represents a common problem for patients with advanced urothelial carcinoma. The authors previously reported encouraging efficacy for the combination of carboplatin and gemcitabine in patients considered to be unfit for cisplatin-based treatment. The objective of the current multicenter Phase II study was to evaluate the safety and efficacy of the combination of gemcitabine and carboplatin as first-line treatment in unselected patients with advanced urothelial carcinoma. METHODS: Patients with previously untreated, bidimensionally measurable, inoperable or metastatic urothelial carcinoma were treated with carboplatin, area under the concentration curve of 5 (Day 1) and gemcitabine at a dose of 1000 mg/m(2) (Days 1 and 8), every 21 days for a total of 6 cycles. RESULTS: Sixty patients (49 men and 11 women, with a median age of 69 yrs) were enrolled in the current study. Intent-to-treat analysis demonstrated an objective response rate (ORR) of 38.4% (95% confidence interval [95% CI], 26-51.8%) (11.7% complete responses and 26.7% partial responses). The median time to disease progression was 7.6 months (95% CI, 4.5-10.7 mos) and the median overall survival was 16.3 months (95% CI, 12-20.6 mos). The median survival was comparable to that reported for the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) according to the Memorial Sloan-Kettering Cancer Center prognostic model for patients with similar baseline prognostic features. Grade 3 or 4 toxicity (according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) included anemia (18%), thrombocytopenia (23%), and neutropenia (52%), with 7 episodes of febrile neutropenia (11%) reported. Nonhematologic toxicity was rare. One toxic death occurred during the study. CONCLUSIONS: The combination of gemcitabine and carboplatin appears to have considerable activity as the first-line treatment of unselected patients with advanced urothelial carcinoma with manageable toxicity, and deserves further evaluation in this setting.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/therapeutic use , Carcinoma/drug therapy , Deoxycytidine/analogs & derivatives , Urinary Bladder Neoplasms/drug therapy , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/adverse effects , Deoxycytidine/adverse effects , Deoxycytidine/therapeutic use , Female , Humans , Male , Middle Aged , Treatment Outcome , Urothelium/pathology , Gemcitabine
15.
Oncology ; 69(4): 333-41, 2005.
Article in English | MEDLINE | ID: mdl-16282711

ABSTRACT

PURPOSE: In the present phase II study we evaluated the docetaxel-ifosfamide-carboplatin (DICb) combination in the outpatient setting in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced NSCLC (stages IIIB/IV), WHO performance status (PS) <2, and no prior chemotherapy were eligible. Chemotherapy drug doses were: docetaxel: 80 mg/m2, ifosfamide: 3.5 g/m2, and carboplatin at a target area under the curve of 5 (based on Calvert's formula), all on day 1, followed by prophylactic G-CSF. RESULTS: Fourty patients were entered and all are evaluable for response and toxicity: median age: 64 (48-72); PS: 1 (0-1); gender: 29 males/11 females; stages: IIIB: 13 (33%), IV: 27 (67%). Metastatic sites at diagnosis included: lymph nodes: 25; bone: 7; liver: 4; brain: 5; lung nodules: 13; adrenals: 6. Responses were as follows: 22/40 [55%; 95% confidence interval (CI), 54-81%] evaluable patients responded: 4 complete responses, 18 partial responses, 11 had stable disease, and 7 had progressive disease. The median response duration was 7 months (range 2-14 months), median time to progression 9 months (range 2-18 months) and median overall survival 11 months (range 3-46+ months). 1-year survival was 47.5%. Grade 3/4 toxicities included: neutropenia 28/40, with 12 developing grade 4 and 12% febrile neutropenia, thrombocytopenia grade 3: 3/40 and grade 4: 1/40, no grade 3 neuropathy, grade 1 CNS toxicity in 3, no renal toxicity, 8 grade 2 diarrhea and 4 grade 3 vomiting. CONCLUSION: In the present phase II study the DICb combination yielded important activity and good tolerability in advanced NSCLC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Actuarial Analysis , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/secondary , Docetaxel , Drug Administration Schedule , Female , Humans , Ifosfamide/administration & dosage , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Quality of Life , Survival Analysis , Taxoids/administration & dosage , Treatment Outcome
16.
Breast Cancer Res Treat ; 92(1): 1-9, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15980985

ABSTRACT

Paclitaxel (Taxol) and carboplatin are an effective combination regimen for treating advanced breast cancer. Gefitinib (IRESSA) is the first epidermal growth factor receptor tyrosine kinase inhibitor to be approved for cancer treatment. This multicenter phase II trial treated 68 patients with advanced breast cancer with paclitaxel (175 mg/m(2) over 3 h) and 3-weekly carboplatin (area under the curve of 6) for six cycles, and 250 mg/day gefitinib orally. Median age was 57 (range 35-77) years, patients had performance status 0 (69.1%), 1 (27.9%) 2 (2.9%), 82.4% of patients had visceral metastases and 63.2% had received adjuvant chemotherapy. Forty-eight (70.6%) patients completed six cycles of chemotherapy and 20 (29.4%) patients discontinued treatment (seven [10.3%] due to disease progression, seven [10.3%] due to toxicity, five [7.4%] withdrew consent and one [1.5%] died after the first cycle). Sixty-three (92.7%) patients were evaluable for response; nine (13.2%) had complete responses, 30 (44.1%) had partial responses, 21 (30.9%) had stable disease and three (4.4%) had disease progression. Grade 3/4 adverse events in > or =5% of patients except of alopecia, included neutropenia (17.7%), anemia (10.3%), diarrhea (7.4%), thrombocytopenia (5.9%) and peripheral neuropathy (5.9%). Of those tumor biopsies available for immunohistochemical analysis (n=60), 5.0% were positive and 35.0% negative for expression of all HER-family receptors. Comparable numbers of tumor biopsies were nuclear p27(kipl) positive and negative (39.7 and 42.7%, respectively), with the majority (72.1%) negative for cytoplasmic p27(kipl). The observed efficacy data in this study were similar to those reported for the combination of paclitaxel and carboplatin alone.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/drug therapy , Adult , Aged , Breast Neoplasms/pathology , Carboplatin/administration & dosage , Female , Gefitinib , Humans , Middle Aged , Neoplasm Staging , Paclitaxel/administration & dosage , Quinazolines/administration & dosage , Treatment Outcome
17.
Cancer Invest ; 22(5): 655-62, 2004.
Article in English | MEDLINE | ID: mdl-15581045

ABSTRACT

PURPOSE: Advanced breast cancer (ABC) is an incurable disease. Standard first-line treatment for patients with HER-2/neu overexpressing tumors includes the combination of the humanized monoclonal antibody trastuzumab with chemotherapy, mainly paclitaxel. This combination is the first to demonstrate a survival advantage in this group of patients. To improve on these results, we investigated a triplet, paclitaxel-gemcitabine-trastuzumab (TGH), in a phase II study. PATIENTS AND METHODS: Patients with ABC were accrued to the study. Treatment consisted of paclitaxel 80 mg/m2/week, gemcitabine 1000 mg/m2 every 2 weeks, and trastuzumab 4 mg/kg loading dose and then 2 mg/kg/week. Patients were treated on study for a total of 12 weeks. Response evaluation was performed at the end of the 12 weeks. Continuation of treatment beyond the 12 weeks was left to the discretion of the investigator. Primary study endpoint was response. Toxicity assessment and survival were secondary endpoints. RESULTS: Between November 2000 and May 2002, 40 patients were accrued and 32 patients completed all 12 weeks of therapy. One patient died of septic shock during therapy. Grade III and IV neutropenia was seen in 12.5% of cases each. Grade III anemia was seen in two patients, and grade III and IV thrombocytopenia in three and two patients, respectively. Both paclitaxel and gemcitabine were delivered at 86% of the planned dose intensity. Six patients achieved a complete response (CR) and 15 a partial response for an overall response rate of 52.5%. An additional 25% demonstrated stable disease and 20% progressive disease. Median duration of response was 14 months. All six patients who achieved CR are still in CR for 6 to 19 months. After a median follow up of 12.2 months, 19 patients have progressed and 7 have died. Median time to progression is 13.7 months, whereas median survival has not been reached. CONCLUSION: TGH is a well-tolerated and effective regimen for the first-line treatment of ABC. Randomized comparison between paclitaxel, trastuzumab, and triplets are warranted.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Deoxycytidine/analogs & derivatives , Adult , Aged , Anemia/chemically induced , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Breast Neoplasms/mortality , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Female , Greece , Humans , Middle Aged , Neutropenia/chemically induced , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Trastuzumab , Treatment Outcome , Gemcitabine
18.
Melanoma Res ; 14(4): 289-94, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15305160

ABSTRACT

Cerebral metastases from melanoma are correlated with a poor prognosis. Temozolomide is an oral alkylating agent that can cross the blood-brain barrier and in phase II and III trials, patients with advanced metastatic melanoma achieved overall response rates of 13 to 21%. The present study evaluated the efficacy and toxicity of temozolomide-based chemotherapy in patients with cerebral metastases from melanoma. Twenty-five patients (median age 48 years) with histologically confirmed stage IV melanoma and cerebral metastases treated with temozolomide-based chemotherapy. 10 patients received temozolomide plus docetaxel, nine patients temozolomide plus cisplatin and six patients temozolomide as single agent. Six patients achieved an objective response (24%). All responses were partial. The disease was stable in five patients (20%) and 13 patients progressed (52%). The median response duration was 6.9 months (range 1.8 to 16 months). The median time to progression (TTP) for all patients was 2 months, compared with a median TTP of 3.9 months, among responders and a median TTP of 1.8 months, for patients who remained stable or progressed (P<0.0001). The median survival time for the entire patient population was 4.7 months. The median survival for responders was 5.5 months and for non-responders was 3.6 months. The difference was statistically significant (P<0.05). The toxicity was mild. The most frequently reported adverse event were myelotoxicity and nausea and vomiting. Four patients developed grade 3/4 leukopenia, two grade 4 neutropenia, and one patient developed grade 3 thrombocytopenia. There was no treatment discontinuation caused by toxicity. Temozolomide-based chemotherapy may have a role in patients with cerebral metastases from melanoma. Further exploration is required. Toxicity was manageable.


Subject(s)
Brain Neoplasms/drug therapy , Brain Neoplasms/secondary , Dacarbazine/analogs & derivatives , Dacarbazine/therapeutic use , Melanoma/drug therapy , Melanoma/pathology , Adult , Aged , Brain Neoplasms/pathology , Dacarbazine/administration & dosage , Dacarbazine/adverse effects , Disease Progression , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Neoplasm Staging , Prognosis , Survival Rate , Temozolomide , Time Factors
19.
Anticancer Res ; 24(3b): 1947-52, 2004.
Article in English | MEDLINE | ID: mdl-15274382

ABSTRACT

BACKGROUND: High-dose interferon alfa-2b (IFN-alpha2b) as adjuvant therapy for melanoma is associated with substantial dose-limiting toxicity. It has been suggested that the 1-month intravenous (i.v.) induction regimen may be sufficient to reduce the risk of relapse and death. PATIENTS AND METHODS: The Hellenic Cooperative Oncology Group is conducting a multicenter, randomized trial of 1-month i.v. induction versus 1 year of adjuvant IFN-alpha2b therapy in patients with stage IIB/III melanoma. Adverse events reported by the first 200 patients to complete therapy are described. RESULTS: Both induction and maintenance regimens were well tolerated. The most common toxicities were flu-like and gastrointestinal symptoms, neutropenia, liver toxicity, and neurologic toxicity. The incidence of grade 3/4 toxicity was low and occurred mainly during the induction phase in both arms. Dose was reduced in 31% of patients during induction. Only 2% of patients discontinued. Dose was reduced in 8% of patients during maintenance and only 5% of patients discontinued. CONCLUSION: Intravenous induction with 15 MIU/m2/day IFN-alpha2b is well tolerated. Efficacy results from this trial are eagerly anticipated.


Subject(s)
Antineoplastic Agents/administration & dosage , Interferon-alpha/administration & dosage , Melanoma/drug therapy , Skin Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Chemotherapy, Adjuvant , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Interferon alpha-2 , Interferon-alpha/adverse effects , Male , Melanoma/pathology , Middle Aged , Neoplasm Staging , Recombinant Proteins , Remission Induction , Skin Neoplasms/pathology
20.
Anticancer Drugs ; 15(5): 479-87, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15166622

ABSTRACT

A phase I pharmacokinetics and dose-finding study and a phase II study of the combination of pegylated liposomal doxorubicin HCl (PLD) and paclitaxel were conducted in patients with recurrent or metastatic head and neck cancer (HNC). Sixty patients with recurrent or metastatic disease were enrolled in the study: 11 patients in the phase I study and 49 patients in the phase II study. In the phase I study, the initial dose level of PLD was 35 mg/m as a 1-h infusion with escalating increments of 5 mg/m until the maximum tolerated dose (MTD) was reached. A fixed dose of paclitaxel (175 mg/m) was administered as a 3-h infusion. The combination was administered every 28 days. Pharmacokinetic studies performed on 10 patients indicated that the sequence of drug administration did not cause clinically significant modifications in the pharmacokinetics of either drug. The MTD for PLD was 45 mg/m (dose level 3) and the dose-limiting toxicity was febrile neutropenia, occurring in three of five patients. The phase II dose of PLD was 40 mg/m (dose level 2) and a total of 214 cycles were delivered. Grade 3 or 4 neutropenia was observed in 26% patients and febrile neutropenia occurred in 16% of patients. Grade 3 palmar-plantar erythrodysesthesia (PPE) was recorded in only one patient. The overall response rate was 28% for patients with non-nasopharyngeal tumors [95% confidence interval (CI) 15-45%] and 28.6% for the study population (95% CI 17-43%). The median survival for the study population was 9.7 months; 1-year survival was 38%. We conclude that the recommended dose for the combination of PLD and paclitaxel is 40 and 175 mg/m every 28 days, without granulocyte colony stimulating factor support. The combination of paclitaxel with PLD demonstrated activity in recurrent or metastatic HNC, a favorable toxicity profile and relative ease of administration.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Head and Neck Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Doxorubicin/administration & dosage , Doxorubicin/pharmacokinetics , Drug Administration Schedule , Female , Head and Neck Neoplasms/mortality , Humans , Infusions, Intravenous , Liposomes , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Metastasis , Neutropenia/chemically induced , Paclitaxel/administration & dosage , Paclitaxel/pharmacokinetics , Survival Rate , Treatment Outcome
SELECTION OF CITATIONS
SEARCH DETAIL
...