Since treatment efficacy of cisplatin- or carboplatin-based chemotherapy in the first-line treatment of small-cell lung cancer (SCLC) remains contentious, a meta-analysis of individual patient data ...was performed to compare the two treatments.
A systematic review identified randomized trials comparing cisplatin with carboplatin in the first-line treatment of SCLC. Individual patient data were obtained from coordinating centers of all eligible trials. The primary end point was overall survival (OS). All statistical analyses were stratified by trial. Secondary end points were progression-free survival (PFS), objective response rate (ORR), and treatment toxicity. OS and PFS curves were compared by using the log-rank test. ORR was compared by using the Mantel-Haenszel test.
Four eligible trials with 663 patients (328 assigned to cisplatin and 335 to carboplatin) were included in the analysis. Median OS was 9.6 months for cisplatin and 9.4 months for carboplatin (hazard ratio HR, 1.08; 95% CI, 0.92 to 1.27; P = .37). There was no evidence of treatment difference between the cisplatin and carboplatin arms according to sex, stage, performance status, or age. Median PFS was 5.5 and 5.3 months for cisplatin and carboplatin, respectively (HR, 1.10; 95% CI, 0.94 to 1.29; P = .25). ORR was 67.1% and 66.0%, respectively (relative risk, 0.98; 95% CI, 0.84 to 1.16; P = .83). Toxicity profile was significantly different for each of the arms: hematologic toxicity was higher with carboplatin, and nonhematologic toxicity was higher with cisplatin.
Our meta-analysis of individual patient data suggests no differences in efficacy between cisplatin and carboplatin in the first-line treatment of SCLC, but there are differences in the toxicity profile.
Trastuzumab, a humanized monoclonal antibody against the extracellular portion of human epidermal growth factor receptor type 2 (HER2), is effective in HER2-positive breast cancer. This randomized ...trial shows that lapatinib, an orally active inhibitor of HER2, combined with capecitabine is superior to capecitabine alone in women with advanced HER2-positive breast cancer who have had a relapse after receiving trastuzumab. These results should provide the impetus for trials of lapatinib as an initial treatment in HER2-positive breast cancer.
This trial shows that lapatinib, an orally active inhibitor of HER2, combined with capecitabine is superior to capecitabine alone in women with advanced HER2-positive breast cancer who have had a relapse after receiving trastuzumab.
Metastatic breast cancer is the leading cause of death from cancer among women worldwide, accounting for more than 400,000 deaths per year.
1
Women with breast cancer that overexpresses human epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu) are at greater risk for disease progression and death than women whose tumors do not overexpress HER2.
2
Therapeutic strategies have been developed to block HER2 signaling pathways in order to improve the treatment of this cancer. Trastuzumab (Herceptin, Genentech), a recombinant, humanized, monoclonal antibody that binds to the extracellular domain of the HER2 protein, is a key component in . . .
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.
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).
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).
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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).
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).
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.
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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.
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.
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.
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.
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.
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.
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).
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.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Temozolomide is a well-tolerated oral alkylating agent with activity in the CNS. A multicenter, open-label, phase II study was conducted to assess the safety and efficacy of temozolomide in patients ...with brain metastases from metastatic melanoma (MM) who did not require immediate radiotherapy.
Eligible patients had histologically confirmed MM to the brain, and no prior radiotherapy or radiosurgery for brain metastases. Previously untreated patients received temozolomide at 200 mg/m(2)/d x 5 days; previously treated patients received 150 mg/m(2)/d x 5 days every 28 days. Treatment continued for 1 year or until disease progression or unacceptable toxicity.
Of 151 patients enrolled, 117 had received no prior systemic chemotherapy, and 34 had received prior chemotherapy for MM. Among previously untreated patients, 25% had more than four brain lesions, eight (7%) achieved an objective response (one complete and seven partial), and 34 (29%) had stable disease in brain metastases. Median overall survival was 3.5 months. Among previously treated patients, 21% had more than four brain lesions, one had a partial response, and six (18%) had stable disease in brain metastases. Median overall survival was 2.2 months. Temozolomide was well tolerated, with four (3%) patients discontinuing because of adverse events. Grade 3/4 hematologic toxicities included thrombocytopenia (3%), neutropenia (2%), and leukopenia (1%). Headache (9%) and vomiting (8%) were the most common nonhematologic grade 3/4 adverse events.
Temozolomide was well tolerated and demonstrated activity in the treatment of brain metastases from MM. Further evaluation of temozolomide combination therapy is warranted.
A high-dose interferon alfa (IFN-alpha) regimen as reported in E1684 was unique for the incorporation of an induction phase of maximally tolerated dosages of intravenous (IV) therapy for the initial ...4 weeks. This is the only trial that has shown prolongation of overall survival and relapse-free survival (RFS) in comparison with observation. Analysis of the hazard curves for RFS and overall survival (OS) in E1684 revealed separation of the high-dose and observation arms, suggesting that the induction phase may represent a critical component of this regimen, although this has not been tested prospectively.
We conducted a prospective randomized study of IV induction therapy versus a full year of high-dose IFN, with primary end points of RFS and OS for patients with stage IIB, IIC, and III melanoma, within 56 days of curative surgery. Patients were randomly assigned to receive IFN-alpha-2b 15 x 10(6) U/m2 IV x 5/7 days weekly x 4 weeks (arm A) versus the same regimen followed by IFN-alpha-2b 10 x 10(6) U (flat dose) administered subcutaneously three times a week for 48 weeks (arm B).
Between 1998 and 2004, 364 patients were enrolled (353 eligible: arm A, n = 177; arm B, n = 176). At a median follow-up of 63 months (95% CI, 58.1 to 67.7), the median RFS was 24.1 months versus 27.9 months (P = .9) and the median OS was 64.4 months versus 65.3 months (P = .49). Patients in arm B had more grade 1 to 2 hepatotoxicity, nausea/vomiting, alopecia, and neurologic toxicity.
There were no significant differences in OS and RFS between the regimens of 1 month and 1 year of treatment.
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.
ClinicalTrials.gov NCT 00790894.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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