Impact of tumor angiogenic profile on the outcome of patients with metastatic breast carcinoma treated with weekly docetaxel. A Hellenic Cooperative Oncology Group (HeCOG) study.

BACKGROUND: Metronomic taxane administration has putative antiangiogenic properties. Herein, we examined the baseline tumor angiogenic profile of patients with metastatic breast carcinoma (MBC) in a prospective-retrospective translational research study. The interplay between the angiogenic factors expressed in the tumors and their prognostic value in MBC were investigated. PATIENTS AND METHODS: Tumor tissues from patients with MBC treated with weekly docetaxel (n=159) were examined by immunohistochemistry for VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, VEGFR-3 and osteopontin (OPN) and by mRNA analysis for expression of VEGF-A, VEGFxxxa, VEGFxxxb, VEGF-C, thrombospondin-1 (THBS-1), hypoxia-inducible factor-1α (HIF-1α) and von Hippel-Lindau (VHL) genes. Associations between these parameters and outcome were statistically analyzed. RESULTS: Statistically significant correlations were identified between almost all biomarkers examined in continuous form, particularly at the mRNA level: VEGF-A with VEGFxxxa (rho=0.70); VEGF-C with VEGFxxxa, VEGFxxxb and VHL (rho=0.51, 0.60 and 0.44 respectively); HIF-1α with VEGF-C and THBS1 (rho= 0.48 and 0.45). High VEGF-A mRNA was associated with worse survival (p=0.0279) and marginally with progression free survival (PFS). Intratumoral co-expression of VEGFR-1 and VEGFR-2 proteins was associated with more favorable survival (p=0.0337). In multivariate analysis, only high VEGF-A mRNA levels retained their prognostic role for worse PFS and survival (PFS: HR=2.34, 95% CI=1.25-4.40, p=0.0080; survival: HR=3.15, 95% CI=1.48-6.72, p=0.0029). CONCLUSIONS: In MBC, this study confirms the adverse prognostic effect of high intratumoral VEGF-A mRNA and reveals the combined VEGFR-1/VEGFR-2 protein expression as a potentially favorable prognosticator, which merits further evaluation in larger studies.

Comparison of filgrastim and pegfilgrastim to prevent neutropenia and maintain dose intensity of adjuvant chemotherapy in patients with breast cancer.

PURPOSE: The aim of this study was to compare the effectiveness of prophylactic single fixed dose of pegfilgrastim and daily administration of filgrastim on febrile neutropenia (FN), severe neutropenia, treatment delay, and dose reduction in patients with breast cancer receiving dose-dense adjuvant chemotherapy. METHODS: A retrospective cohort study with 1058 breast cancer patients matched by age and chemotherapy was conducted. The primary endpoints were FN, severe (grade 3, 4) neutropenia, dose reduction (>10 % reduction of the dose planned), and treatment delay (dose given more than 2 days later). RESULTS: Eighteen episodes of FN (3.4%) in the filgrastim group and 23 (4.3%) in the pegfilgrastim group (p = 0.500) were recorded. More than half of the total episodes (27/41) occurred during the first 4 cycles of treatment. Patients who received filgrastim were almost three times more likely to experience a severe neutropenia episode and were significantly more likely to experience a dose reduction (18.5%) compared to those who received pegfilgrastim (10.8%) (p < 0.001). The percentage of patients, who received their planned dose on time, was significantly lower in patients receiving filgrastim (58%) compared to those receiving pegfilgrastim (72.4%, p < 0.001). CONCLUSIONS: No significant difference was detected on FN rate between daily administration of filgrastim and single administration of pegfilgrastim. However, patients receiving pegfilgrastim had a significantly lower rate of severe neutropenia, as well as dose reduction and treatment delay, thus, achieving a higher dose density.

alphaB-crystallin is a marker of aggressive breast cancer behavior but does not independently predict for patient outcome: a combined analysis of two randomized studies.

BACKGROUND: alphaB-crystallin is a small heat shock protein that has recently been characterized as an oncoprotein correlating with the basal core phenotype and with negative prognostic factors in breast carcinomas. The purpose of this study was to evaluate alphaB-crystallin with respect to clinicopathological parameters and the outcome of patients with operable high-risk breast cancer. METHODS: A total of 940 tumors were examined, derived from an equal number of patients who had participated in two randomized clinical trials (paclitaxel-containing regimen in 793 cases). Immunohistochemistry for ER, PgR, HER2, Ki67, CK5, CK14, CK17, EGFR, alphaB-crystallin, BRCA1 and p53 was performed. BRCA1 mutation data were available in 89 cases. RESULTS: alphaß-crystallin was expressed in 170 cases (18.1%) and more frequently in triple-negative breast carcinomas (TNBC) (45% vs. 14.5% non-TNBC, p < 0.001). alphaB-crystallin protein expression was significantly associated with high Ki67 (Pearson chi-square test, p < 0.001), p53 (p = 0.002) and basal cytokeratin protein expression (p < 0.001), BRCA1 mutations (p = 0.045) and negative ER (p < 0.001) and PgR (p < 0.001). Its overexpression, defined as >30% positive neoplastic cells, was associated with adverse overall survival (Wald's p = 0.046). However, alphaB-crystallin was not an independent prognostic factor upon multivariate analysis. No interaction between taxane-based therapy and aß-crystallin expression was observed. CONCLUSIONS: In operable high-risk breast cancer, alphaB-crystallin protein expression is associated with poor prognostic features indicating aggressive tumor behavior, but it does not seem to have an independent impact on patient survival or to interfere with taxane-based therapy. TRIAL REGISTRATIONS: ACTRN12611000506998 (HE10/97 trial) and ACTRN12609001036202 (HE10/00 trial).

In situ quantitative measurement of HER2mRNA predicts benefit from trastuzumab-containing chemotherapy in a cohort of metastatic breast cancer patients.

BACKGROUND: We sought to determine the predictive value of in situ mRNA measurement compared to traditional methods on a cohort of trastuzumab-treated metastatic breast cancer patients. METHODS: A tissue microarray composed of 149, classified as HER2-positive, metastatic breast cancers treated with various trastuzumab-containing chemotherapy regimens was constructed. HER2 intracellular domain(ICD), HER2 extracellular domain(ECD) and HER2 mRNA were assessed using AQUA. For HER2 protein evaluation, CB11 was used to measure ICD and SP3 to measure ECD of the HER2 receptor. In addition, HER2 mRNA status was assessed using RNAscope assay ERRB2 probe. Kaplan - Meier estimates were used for depicting time-to-event endpoints. Multivariate Cox regression models with backward elimination were used to assess the performance of markers as predictors of TTP and OS, after adjusting for important covariates. RESULTS: HER2 mRNA was correlated with ICD HER2, as measured by CB11 HER2, with ECD HER2 as measured by SP3 (Pearson's Correlation Coefficient, r = 0.66 and 0.51 respectively) and with FISH HER2 (Spearman's Correlation Coefficient, r = 0.75). All markers, HER2 mRNA, ICD HER2 and ECD HER2, along with FISH HER2, were found prognostic for OS (Log-rank p = 0.007, 0.005, 0.009 and 0.043 respectively), and except for FISH HER2, they were also prognostic for TTP Log-rank p = 0.036, 0.068 and 0.066 respectively) in this trastuzumab- treated cohort. Multivariate analysis showed that in the presence of pre-specified set of prognostic factors, among all biomarkers only ECD HER2, as measured by SP3, is strong prognostic factor for both TTP (HR = 0.54, 95% CI: 0.31-0.93, p = 0.027) and OS (HR = 0.39, 95%CI: 0.22-0.70, p = 0.002). CONCLUSIONS: The expression of HER2 ICD and ECD as well as HER2 mRNA levels was significantly associated with TTP and OS in this trastuzumab-treated metastatic cohort. In situ assessment of HER2 mRNA has the potential to identify breast cancer patients who derive benefit from Trastuzumab treatment.

Ixabepilone administered weekly or every three weeks in HER2-negative metastatic breast cancer patients; a randomized non-comparative phase II trial.

UNLABELLED: To explore the activity and safety of two schedules of ixabepilone, as first line chemotherapy, in patients with metastatic breast cancer previously treated with adjuvant chemotherapy, a randomized non-comparative phase II study was conducted. From November 2008 until December 2010, 64 patients were treated with either ixabepilone 40 mg/m(2) every 3 weeks (Group A, 32 patients) or ixabepilone 20 mg/m(2) on days 1, 8 and 15 every 4 weeks (Group B, 32 patients). Overall response rate (the primary end point) was 47% in Group A and 50% in Group B. The most frequent severe adverse events were neutropenia (32% vs. 23%), metabolic disturbances (29% vs. 27%) and sensory neuropathy (12% vs. 27%). Two patients in Group A and 3 in Group B developed febrile neutropenia. After a median follow-up of 22.7 months, median progression-free survival (PFS) was 9 months in Group A and 12 months in Group B. Median survival was 26 months in Group A, whereas it was not reached in Group B. Multiple genetic and molecular markers were examined in tumor and peripheral blood DNA, but none of them was associated with ORR or drug toxicity. Favorable prognostic markers included: the T-variants of ABCB1 SNPs c.2677G/A/T, c.1236C/T and c.3435C/T, as well as high MAPT mRNA and Tau protein expression, which were all associated with the ER/PgR-positive phenotype; absence of TopoIIa; and, an interaction between low TUBB3 mRNA expression and Group B. Upon multivariate analysis, tumor ER-positivity was a favorable (p = 0.0092) and TopoIIa an unfavorable (p = 0.002) prognostic factor for PFS; PgR-positivity was favorable (p = 0.028) for survival. In conclusion, ixabepilone had a manageable safety profile in both the 3-weekly and weekly schedules. A number of markers identified in the present trial appear to deserve further evaluation for their prognostic and/or predictive value in larger multi-arm studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00790894.

Topoisomerase II alpha gene amplification is a favorable prognostic factor in patients with HER2-positive metastatic breast cancer treated with trastuzumab.

BACKGROUND: The vast majority of patients with HER2-positive metastatic breast cancer (MBC) treated with trastuzumab eventually develop resistance to this agent. There is an unmet need therefore, for identifying biological markers with possible prognostic/predictive value in such patients. The aim of this study was to investigate the prognostic role of topoisomerase II alpha gene (TOP2A) amplification and protein (TopoIIa) expression in patients treated with trastuzumab-containing regimens. METHODS: Formalin-fixed paraffin-embedded tumor tissue samples were retrospectively collected from 225 eligible patients treated with trastuzumab. Protein expression of ER, PgR, Ki67, PTEN, HER2 and TopoIIa were centrally assessed by immunohistochemistry. HER2 and TOP2A gene amplification was evaluated by fluorescence in situ hybridization. PIK3CA mutations were identified by single nucleotide polymorphism genotyping. Survival was evaluated from the initiation of trastuzumab as 1st line treatment to the date of last follow-up or death. RESULTS: Among the 225 samples analyzed, only 137 (61%) were found to be HER2-positive. TOP2A was amplified in 41% and deleted in 16% of such tumors. TOP2A gene amplification was more frequent in ER-negative tumors. TopoIIa protein expression was observed in the majority (65%) of the samples and was associated with ER-positive status, high Ki67 expression, presence of PTEN protein and PIK3CA mutations. Median follow-up for patients treated in the 1st line was 51 months. Survival was more prolonged with trastuzumab-containing treatment in HER2-positive patients (50 months, log-rank, p=0.007). TOP2A non-amplified or deleted tumors were associated with increased risk for death compared to TOP2A amplified tumors (HR=2.16, Wald's p=0.010 and HR=2.67, p=0.009, respectively). In multivariate analysis, a significant interaction of TOP2A with anthracycline treatment (either in the adjuvant or the 1st line setting) was observed for survival (Wald's p=0.015). Among the TOP2A amplified subgroup, anthracycline-treated patients were associated with decreased risk for death. CONCLUSIONS: TOP2A gene amplification was shown to be a favorable prognostic marker in HER2-positive MBC patients treated with trastuzumab, such an effect however, appears to rather be related to treatment with anthracyclines (predictive marker for benefit from anthracyclines). The results of the present retrospective study warrant validation in larger cohorts of patients treated in the context of randomized trials.

Differential response of immunohistochemically defined breast cancer subtypes to anthracycline-based adjuvant chemotherapy with or without paclitaxel.

BACKGROUND: The aim of the present study was to investigate the efficacy of adjuvant dose-dense sequential chemotherapy with epirubicin, paclitaxel, and CMF in subgroups of patients with high-risk operable breast cancer, according to tumor subtypes defined by immunohistochemistry (IHC). MATERIALS AND METHODS: Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 1,039 patients participating in two adjuvant dose-dense sequential chemotherapy phase III trials were centrally assessed in tissue micro-arrays by IHC for 6 biological markers, that is, estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki67, cytokeratin 5 (CK5), and EGFR. The majority of the cases were further evaluated for HER2 amplification by FISH. Patients were classified as: luminal A (ER/PgR-positive, HER2-negative, Ki67(low)); luminal B (ER/PgR-positive, HER2-negative, Ki67(high)); luminal-HER2 (ER/PgR-positive, HER2-positive); HER2-enriched (ER-negative, PgR-negative, HER2-positive); triple-negative (TNBC) (ER-negative, PgR-negative, HER2-negative); and basal core phenotype (BCP) (TNBC, CK5-positive and/or EGFR-positive). RESULTS: After a median follow-up time of 105.4 months the 5-year disease-free survival (DFS) and overall survival (OS) rates were 73.1% and 86.1%, respectively. Among patients with HER2-enriched tumors there was a significant benefit in both DFS and OS (log-rank test; p = 0.021 and p = 0.006, respectively) for those treated with paclitaxel. The subtype classification was found to be of both predictive and prognostic value. Setting luminal A as the referent category, the adjusted for prognostic factors HR for relapse for patients with TNBC was 1.91 (95% CI: 1.31-2.80, Wald's p = 0.001) and for death 2.53 (95% CI: 1.62-3.60, p<0.001). Site of and time to first relapse differed according to subtype. Locoregional relapses and brain metastases were more frequent in patients with TNBC, while liver metastases were more often seen in patients with HER2-enriched tumors. CONCLUSIONS: Triple-negative phenotype is of adverse prognostic value for DFS and OS in patients treated with adjuvant dose-dense sequential chemotherapy. In the pre-trastuzumab era, the HER2-enriched subtype predicts favorable outcome following paclitaxel-containing treatment.

Pegfilgrastim administered on the same day with dose-dense adjuvant chemotherapy for breast cancer is associated with a higher incidence of febrile neutropenia as compared to conventional growth factor support: matched case-control study of the Hellenic Cooperative Oncology Group.

OBJECTIVE: Recombinant human granulocyte-colony-stimulating factors such as filgrastim and pegfilgrastim have been employed as primary and secondary prophylaxis against neutropenia in cancer patients receiving chemotherapy. This study was conducted to evaluate the rate of febrile neutropenia in patients with high-risk early breast cancer receiving dose-dense chemotherapy and, as primary prophylaxis, either pegfilgrastim 6 mg fixed dose on the same day as chemotherapy or filgrastim on days 2-10 of each cycle. Secondary objectives included the rate of severe neutropenia, treatment delays and dose reductions. METHODS: This was a nonrandomized matched case-control study with 214 patients receiving dose-dense chemotherapy. Each group receiving supportive therapy included 107 patients (pegfilgrastim and filgrastim groups). RESULTS: Fourteen patients (13%) in the pegfilgrastim group developed febrile neutropenia as compared to 1 patient (1%) in the filgrastim group (p = 0.001). No statistically significant differences regarding the rate of severe neutropenia, treatment delays and dose reductions were observed. CONCLUSION: The results demonstrate that pegfilgrastim administered as primary prophylaxis on the same day as dose-dense chemotherapy is less efficacious than filgrastim administered on days 2-10 of each chemotherapy cycle. For the particular regimens given in this retrospective matched case-control study, the current recommendation for administering pegfilgrastim at least 24 h after chemotherapy completion seems justified. However, further randomized controlled trials are needed to clarify this finding.

Trastuzumab combined with pegylated liposomal doxorubicin in patients with metastatic breast cancer. phase II Study of the Hellenic Cooperative Oncology Group (HeCOG) with biomarker evaluation.

OBJECTIVE: Combination of trastuzumab and anthracyclines in metastatic breast cancer (MBC) is precluded due to cardiotoxicity. Pegylated liposomal doxorubicin (PLD) is the least cardiotoxic among the anthracyclines. We performed a phase II study of trastuzumab and PLD with biomarker evaluation. METHODS: Patients with MBC and HER2 overexpression, assessed as 3+ at local laboratories, received trastuzumab 8 mg/kg as loading dose followed by 6 mg/kg in combination with PLD 30 mg/m(2), both given every 3 weeks. To be eligible, patients should have received first-line chemotherapy for MBC or should have relapsed within a year of adjuvant taxane. Tumor tissue blocks were collected for central review and exploratory biomarker evaluation. Left-ventricular ejection fraction (LVEF) was closely monitored by cardiac ultrasound. RESULTS: Among 37 patients, an overall response rate of 22% was observed with a progression-free survival (PFS) of 6.5 months (0.8-31.1, 95% CI 2.7-10.3) and a survival of 18.7 months (1.6-40.8, 95% CI 3.7-33.7). No decline in LVEF was noticed. Overexpression of mTOR and TOP2A gene alterations were associated with better PFS. PTEN gene deletion was associated with resistance to treatment. CONCLUSION: Trastuzumab combined with PLD every 3 weeks is feasible, effective and safe in HER2-positive patients.

Potential value of PTEN in predicting cetuximab response in colorectal cancer: an exploratory study.

BACKGROUND: The epidermal growth factor receptor (EGFR) is over-expressed in 70-75% of colorectal adenocarcinomas (CRC). The anti-EGFR monoclonal antibody cetuximab has been approved for the treatment of metastatic CRC, however tumor response to cetuximab has not been found to be associated with EGFR over-expression by immunohistochemistry (IHC). The aim of this study was to explore EGFR and the downstream effector phosphatase and tensin homologue deleted on chromosome 10 (PTEN) as potential predictors of response to cetuximab. METHODS: CRC patients treated with cetuximab by the Hellenic Cooperative Oncology group, whose formalin-fixed paraffin-embedded tumor tissue was available, were included. Tissue was tested for EGFR and PTEN by IHC and fluorescence in situ hybridization (FISH). RESULTS: Eighty-eight patients were identified and 72 were included based on the availability of tissue blocks with adequate material for analysis on them. All patients, except one, received cetuximab in combination with chemotherapy. Median follow-up was 53 months from diagnosis and 17 months from cetuximab initiation. At the time of the analysis 53% of the patients had died. Best response was complete response in one and partial response in 23 patients. In 16 patients disease stabilized. Lack of PTEN gene amplification was associated with more responses to cetuximab and longer time to progression (p = 0.042). CONCLUSION: PTEN could be one of the molecular determinants of cetuximab response. Due to the heterogeneity of the population and the retrospective nature of the study, our results are hypothesis generating and should be approached with caution. Further prospective studies are needed to validate this finding.

Carboplatin and paclitaxel versus cisplatin, paclitaxel and doxorubicin for first-line chemotherapy of advanced ovarian cancer: a Hellenic Cooperative Oncology Group (HeCOG) study.

INTRODUCTION: The combination of Carboplatin and Paclitaxel is considered the standard of care as initial chemotherapy for Advanced Ovarian Cancer (AOC). We compared this regimen with the combination of Cisplatin, Paclitaxel and Doxorubicin. PATIENTS AND METHODS: Patients with AOC were randomised to either six courses of Paclitaxel 175mg/m(2) plus Carboplatin 7AUC or Paclitaxel at the same dose plus Cisplatin 75mg/m(2) plus Doxorubicin 40mg/m(2). RESULTS: Analysis was performed on 451 patients. The treatment groups were well balanced with regard to patient and disease characteristics. Performance status (PS) was better in the anthracycline arm. In terms of severe toxicity, the only significant difference between the two groups was the development of febrile neutropaenia in the anthracycline arm. Overall response rate was similar in both groups. With a median follow-up of 57.5 months, a marginal significance towards improved Progression-Free Survival (PFS) was noted in favour of the anthracycline arm, whilst there was no difference in overall survival. In multivariate analysis the hazard of disease progression at any time was significantly decreased by 25.5% for patients of the anthracycline arm. CONCLUSION: The combination of Cisplatin, Paclitaxel and Doxorubicin demonstrates a marginal PFS improvement, but no additional survival benefit when compared with the standard Carboplatin/Paclitaxel regimen.

Expression of a molecular marker panel as a prognostic tool in gastric cancer patients treated postoperatively with docetaxel and irinotecan. A study of the Hellenic Cooperative Oncology Group.

INTRODUCTION: This study evaluated the prognostic role of vascular epidermal growth factor (VEGF), thymidylate synthase (TS), topoisomerase I (Topo-I), topoisomerase IIalpha (Topo-IIalpha) and E-cadherin (E-cadh) tumor expression, in patients with resectable gastric cancer, who were treated postoperatively with the docetaxel/irinotecan combination. PATIENTS AND METHODS: Forty-five patients with resectable gastric cancer were treated with 6 cycles of docetaxel 30 mg/m2 and irinotecan 110 m/m2 on day 1 and d8 every 21 days. All specimens were examined by using immunohistochemistry (IHC) for the expression of VEGF, TS, Topo-I, Topo-IIalpha and E-cadh. RESULTS: Positivity for TS was significantly correlated with age and for VEGF with diffuse histological type and good PS. No significant correlation was observed among Topo-I, Topo-IIalpha and E-cadh positivity with any of the clinicopathological parameters studied. Median overall survival (OS) was 31.7, and disease-free survival (DFS) 26 months, respectively. None of the above-investigated molecular markers were significantly associated with OS and DFS. Finally, according to the univariate analysis for survival, only advanced stages (III, IV) of the disease implied risk of death, mainly due to lymph node involvement and, to a lesser extent, tumor size. None of the studied molecular markers were found to be independent prognostic markers. CONCLUSION: These results should be interpreted very cautiously, due to the limited number of patients studied, as well as the limitations of the IHC technique.

Combination of topotecan and cisplatin in relapsed patients with small cell lung cancer: a phase II study of the hellenic cooperative oncology group (HeCOG).

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.

Gemcitabine plus pegylated liposomal doxorubicin in patients with advanced epithelial ovarian cancer resistant/refractory to platinum and/or taxanes. A HeCOG phase II study.

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.

Treatment of small cell lung cancer.

Small cell lung cancer (SCLC) is a very chemo- and radiosensitive systemic disease. Combination chemotherapy produces a survival advantage resulting in median survival of 9 to 12 months in extensive disease. Platinum and etoposide in combination with concurrent, early, hyperfractionated chest radiotherapy, in patients with limited disease, produces median survival of 20 months. Prophylactic cranial radiotherapy, in patients with complete response following induction chemotherapy, reduces the incidence of brain metastases and improves survival. Triplet combinations, dose intensification, and maintenance therapy have not demonstrated meaningful survival improvements. Recurrent disease can be treated with the same chemotherapy, as in the first line treatment if the progression-free interval exceeds 3 months; otherwise, monotherapy with a novel compound is suggested. Camptothesins (topotecan, irinotecan) appear the most promising new compounds and may become first-line agents for SCLC in the near future. Molecular advances have provided many new targets for SCLC therapy. Many studies, ongoing or planned, evaluate the effectiveness of new agents developed to attack these targets.

Weekly administration of topotecan and paclitaxel in pretreated advanced cancer patients: a phase I/II study.

PURPOSE: This study was a phase I/II, cohort, dose-escalation trial of topotecan and paclitaxel. Its aim was to determine the dose-limiting toxicity (DLT) of the combination and to define the maximum tolerated dose (MTD), as a recommended dose for phase II, as well as to get preliminary data on the efficacy (activity) of the drug in pretreated patients with ovarian cancer, small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). METHODS: Included in the study were 52 pretreated patients, 19 with ovarian cancer, 20 with SCLC and 13 with NSCLC. The doses of topotecan were escalated from 1.25 to 2 mg/m2 and of paclitaxel from 60 to 80 mg/m2. A minimum of four patients were included at each of the six levels of dose escalation. RESULTS: We found that DLT due to grade 3 and 4 myelotoxicity was at levels 5 and 6 at doses of 1.75 and 80 mg/m2 (level 5) and 2 and 80 mg/m2 (level 6) for topotecan and paclitaxel, respectively. The MTD and recommended accepted doses are 1.75 mg/m2 for topotecan and 70 mg/m2 for paclitaxel. Of the 52 patients, 17 (33%) showed a response: 1 complete response (1.92%) and 16 partial responses (30.77%). CONCLUSIONS: Topotecan combined with paclitaxel administered once weekly for three consecutive weeks repeated for every 28 days resulted in well-tolerated toxicity at doses of 1.75 and 70 mg/m2, respectively, and a response rate of 33% in pretreated cancer patients.

Prognostic significance of the deleted in colorectal cancer gene protein expression in high-risk resected gastric carcinoma.

The deleted in colorectal cancer (DCC) gene is a candidate tumor suppressor gene that may be associated with differentiation and proliferation of normal cells. Loss of heterozygosity (LOH) of 18q, where the gene is located, and absence of DCC protein expression have been associated with worse prognosis in certain subgroups of patients with colorectal adenocarcinoma. We studied the prognostic significance of loss-of-protein expression in 66 patients with resected gastric cancer with a high probability of relapse (T3, T4, N+). The DCC protein was detected with immunohistochemistry using an anti-DCC monoclonal antibody on paraffin-embedded sections. The DCC protein expression was present in 51 cases (77.3%) and absent in 15 cases (22.7%). Poorly differentiated and signet ring carcinomas had significantly lower expression than more differentiated tumors (p < 0.05) as did diffuse-type tumors compared to intestinal and mixed (p < 0.01). There was no correlation with proliferation rate, estimated immunohistochemically using an anti-proliferating cell nuclear antigen (PCNA) monoclonal antibody. Absence of DCC protein was an independent favorable prognostic factor (median survival 57 months vs. 18 months, p = 0.0176). The DCC protein expression was correlated with relapse site: all patients with distant metastases were positive for DCC staining, while one-third of patients with local/peritoneal relapse were negative (p < 0.01). In conclusion, DCC protein expression seems to be a significant prognostic factor in high-risk resected gastric cancer. Our results support previous data associating the DCC gene with differentiation and indicate that this gene may play a role in the metastatic potential of these tumors. These findings need to be confirmed by future larger studies.